Multiple Myeloma News

New drug: Pomalidomide Phase II results

2010-06-14T17:38:00.002-06:00

From the Celgene web site:

Press Releases

Data from Pomalidomide Study in Refractory Multiple Myeloma Patients Presented at ASCO

Jun 05, 2010 -- Celgene International Sàrl (NASDAQ: CELG) today announced results of a Phase II study of pomalidomide and dexamethasone in multiple myeloma patients who have failed both lenalidomide and bortezomib. Data were presented by Dr. Martha Lacy of the Mayo Clinic.

In this current analysis of the study, patients who were refractory to both lenalidomide and bortezomib were given 2mg daily of pomalidomide on days 1-28 of each 28-day cycle and 40mg daily of oral dexamethasone on days 1, 8, 15, 22.

The overall response rate (ORR) for these patients was 54% (19/35). Fourteen percent (5/35) of patients achieved a very good partial response (VGPR), 17% achieved a partial response (PR) (6/35) and 23% achieved a minor response (MR) (8/35). Additionally, at 6-month follow-up, the progression-free survival rate was 58% (95% CI: 42-80) and the overall survival rate was 86% (95% CI 73-100). The median progression-free survival was 8 months (95% CI: NA).

The most common grade 3 or 4 hematologic adverse events were neutropenia (34% 12/35), anemia (9% 3/35) and thrombocytopenia (9% 3/35).

These data are from an investigational study of pomalidomide, which is not approved for marketing.

About Pomalidomide
Pomalidomide is an IMiDs(R) compound, a member of a proprietary group of novel immunomodulatory agents. These immunomodulatory agents, taken orally, have unique multiple mechanisms of action that involve the microenvironment of the cancer cell, not just the malignant cell itself. The IMiDs pipeline is covered by a comprehensive intellectual property estate of issued and pending patent applications in the US, EU and other regions.

About Celgene
Celgene Corporation, headquartered in Summit, New Jersey, is an integrated global pharmaceutical company engaged primarily in the discovery, development and commercialization of innovative therapies for the treatment of cancer and inflammatory diseases through gene and protein regulation. For more information, please visit the Company's website at www.celgene.com.

This release contains certain forward-looking statements which involve known and unknown risks, delays, uncertainties and other factors not under the Company's control. The Company's actual results, performance, or achievements could be materially different from those projected by these forward-looking statements.The factors that could cause actual results, performance, or achievements to differ from the forward-looking statements are discussed in the Company's filings with the Securities and Exchange Commission, such as the Company's Form 10-K, 10-Q and 8-K reports.Given these risks and uncertainties, you are cautioned not to place undue reliance on the forward-looking statements.

Vitamin C Inhibits Velcade

2010-01-12T13:22:00.002-07:00

Vitamin C (ascorbic acid) significantly reduces the activity of Velcade (bortezomib) in treatment of multiple myeloma, according to a recent article published in Nature.

Preclinical studies suggest that vitamin C, which is one of the most common dietary supplements for cancer patients, increases the efficacy of cancer drugs and decreases treatment-related side effects. However, more recent studies show that vitamin C can counteract the activity of certain cancer chemotherapy agents, including Velcade, in the body.

Studies have shown that a hydroxyl group (-OH) in vitamin C directly binds to boronic acid in Velcade. This significantly reduces the affinity of Velcade for the proteasome, decreasing its destructive activity toward myeloma cells.

The article published in Nature examines how Vitamin C affects Velcade activity in mice. Dr. Paul Richardson, a physician at Dana Farber Cancer Institute and Associate Professor at Harvard Medical School, said that a study testing the effect of vitamin C on Velcade’s efficacy in myeloma patients is in the planning phase. As seen in previous studies, vitamin C significantly reduced the activity of Velcade, and the degree of inhibition was dose-dependent. In order to test whether vitamin C selectively inhibits Velcade by a direct binding between vitamin C and boronic acid, the authors of the article examined if vitamin C inhibited other classes of proteasome inhibitors. Vitamin C significantly blocked the activity of MG-262, which is also a boronic acid proteasome inhibitor, but it did not inhibit NPI-0052, lactacystin, or MG-132, which all belong to other classes of proteasome inhibitors. These results suggest that vitamin C selectively inhibits proteasome inhibitors containing boronic acid.

Based on these results, the authors of the article suggest that myeloma patients receiving therapy with proteasome inhibitors, particularly Velcade, should avoid taking vitamin C supplements at the same time as their proteasome inhibitor. Vitamin C should be specifically avoided at least 12 hours before and after Velcade treatment. Furthermore, the authors advise that all antioxidant supplements, which contain hydroxyl (-OH) groups that bind and inhibit Velcade, be avoided in patients receiving treatment with Velcade and other boronic acid proteasome inhibitors. In a follow-up conversation with Dr. Richardson, he specified that patients taking Velcade only need to avoid antioxidant supplements, not fruit juices that contain vitamin C. Additionally, he emphasized that supplements only need to be avoided on days when Velcade is taken.

New Drug Zolinza

2010-01-06T10:34:00.000-07:00

The 2009 American Society of Hematology (ASH) meeting showcased presentations on Zolinza (vorinostat), a histone deacetylase inhibitor developed by Merck Pharmaceuticals.

Zolinza alters the way a cancer cell’s DNA creates proteins. This can slow down cell proliferation, minimize mutations in DNA and control cell death. Zolinza is being investigated in combination with Revlimid and Velcade.

Vaccine trial for Leukemia

2010-01-04T15:46:00.003-07:00

According to today's newspaper, yet another cancer vaccine trial is in the offing.

This one is for Acute myeloid leukemia (AML), which is the most common form of Leukemia in adults. The disease returns in about half of patients following therapy ... i.e., marrow transplant and chemo.

The trial is taking place at King's College in London, England.

Cells are given two genes to identify the leukemia. This increases the immune system’s ability to attack cancer cells. The research is expected to be published in the Journal of Cancer Immunology, Immunotherapy in 2011.

Let's wish them well. If successful, this therapy will likely be investigated in other types of blood cancer.

Study leaders are Ghulam Mufti, Farzin Farzaneh and Dr. Nicola Hardwick at University College London. They have developed a virus which carries the two genes into the immune system.

New approach to Allo mismatched transplants

2009-11-30T10:42:00.000-07:00

http://www.ctv.ca/servlet/ArticleNews/story/CTVNews/20091130/stem_091130/20091130?hub=CanadaAMV2

Immune system cells treason aids growth of Multiple Myeloma

2009-10-13T09:52:00.001-06:00

Multiple myeloma cancer cells thwart many of the drugs used against them by causing nearby cells to turn traitor — to switch from defending the body against disease to shielding the myeloma cells from harm — Dana-Farber Cancer Institute scientists report in the October issue of Cancer Cell.

The researchers found that immune-system cells known as plasmacytoid dendritic cells (pDCs) essentially assume a new identity in the presence of myeloma — promoting the growth and survival of malignant myeloma cells, helping them fend off drugs, and depleting the overall strength of the immune system.

The discovery not only helps explain a little-understood aspect of myeloma biology, but also suggests a new angle of attack on the disease. Researchers found that compounds that alight on specific sites on pDCs restore the cells' original disease-fighting character and remove a trigger of myeloma cell growth.

"Our study found an unusually large number of pDCs in the bone marrow of multiple myeloma patients," says Dharminder Chauhan, JD, PhD, of Dana-Farber, who co-led the study with Ajita Singh, PhD.

"pDCs are known to be immune system 'effector' cells — the first responders of the body's attack on disease. But why are they present in such abundance in myeloma patients' marrow?"

The disease's ability to resist even the latest drugs has prompted scientists to look more closely at the basic biology of the disease, particularly the interactions between myeloma cells and their cellular neighbors.

In the current study, Chauhan and his colleagues zeroed in on those interactions in experiments involving laboratory-grown samples of myeloma cells and animals with the disease. They found that when pDCs latch onto myeloma cells, a mutual release of proteins affects both sets of cells.

In myeloma cells, these proteins cause a spurt of growth. In the pDCs, the effect is something like that of a police officer bribed to join a gang of hoodlums. The cells abandon their role as immune system sentinels and become the protectors of myeloma cells.

"This is the first time that immune system cells have been found to be converted to another function," says Chauhan, who is also a principal associate in medicine at Harvard Medical School. Investigators don't yet know how the conversion occurs, but they suspect the proteins cause a different set of genes to be activated within the pDCs.

Encouragingly, it appears possible to awaken errant pDCs to their proper duty. Researchers found that when compounds known as CpG ODNs (cytosine phosphate guanine oligodeoxynucleotides) attach to key receptors on the surface of pDCs, the cells resume their normal immune system function and stop spurring myeloma cell growth.

CpG ODNs are already in clinical trials for other forms of cancer, and Chauhan and his colleagues hope to begin trials of the compounds in myeloma patients soon.

Dr. Ken Anderson Myeloma Update

2009-10-07T21:59:00.001-06:00

Don't miss Dr. Ken Anderson's Myeloma update on October 29.

https://www.rmei.com/LLSmyeloma/event.html

Information available at the Lymphoma and Leukemia society.

MMRF new web site

2009-09-24T14:11:00.000-06:00

Check the Multiple Myeloma Reseach Foundation's new web site.

http://www.themmrf.org/

Sleep to lose weight

2009-09-19T09:09:00.002-06:00

It's possibly the world's most effortless and effective diet is simpler than author Michael Pollen's pared-down manifesto to "Eat food. Not much. Mostly plants" and far easier to swallow than the Grapefruit Diet.

Ready?

Go to bed. Sleep for eight hours.

It sounds simple, so simple that six staff members at Glamour magazine gave it a go and, in the February edition, revealed they lost an average of four kilograms each without changing anything else — how much they exercised, or how much or what they ate.

And a compelling body of research increasingly shows that, scientifically speaking, sleep as a diet aid works.

In fact, the connection between sleep, diet, stress and Canada's burgeoning weight problem — 11.3 million obese or overweight and counting, says Statistics Canada — has become a focal point for sleep researchers internationally, more so after 2004 when scientists at Stanford University in California connected lack of sleep to the alarming rise in obesity in western countries.

In their 15-year study of 1,024 volunteers with sleep disorders, they found those getting less than four hours of sleep a night were 73 per cent more likely to be obese.

While our high-fat, high-sodium, high-everything diet certainly has much to do with our national pudginess, Dr. Helen Driver, an adjunct professor of medicine at Queen's University and president of the Canadian Sleep Society, also puts the blame on sleep-killing technology.

"Edison has a lot to answer for when he invented the light bulb, because everyone started spending less time asleep," she says. "It's a technology issue; people have computers and TVs in their bedrooms, they eat or read e-mail before they go to bed. The result is they don't get a restful sleep. But I would say that if you're sleep-deprived and you follow good sleep hygiene, you will lose weight without changing much else."

How?

A lack of sleep triggers a wave of reactions in the human body that starts with the hormones leptin, ghrelin and cortisol and ends with waking up exhausted and craving fat and carbohydrates, says Dr. Joseph De Koninck, director of the University of Ottawa's Sleep Research Laboratory.

"There is no question that the hormones that control appetite are affected by the loss of sleep," De Koninck says.

And it's worse if you eat just before bed, he adds.

"People stay up late watching TV, they're on the Internet and e-mail, they get hungry and eat something high-calorie. If you eat, your sleep is more fragmented because your body is digesting."

The lack of deep, restorative rest also causes a drop in the satiety hormone leptin, which means that even after you do eat the next day, you won't feel full.

Meanwhile, the hunger hormone ghrelin rises, setting the stage for overeating.

The third hormone cortisol is strongly related to the body's daily, or circadian, rhythm, "and it's involved with metabolic regulation," explains Driver. "So stress and lack of sleep are intertwined, too."

In fact, for the busy Glamour testers — most of them are mothers — the hardest part of the Sleep Diet was going to bed at the same time every night.

The trouble is we're just not getting enough 40 winks in the first place.

Researchers at the University of Chicago also studied the sleep patterns of 669 middle-aged adult volunteers in 2006, and found that while we may bed down an average 7.5 hours a night, women actually sleep for just 6.7 of them, while men get 6.1 hours.

"The average number of hours actually spent asleep has been reduced," says Driver."

It should be up to eight hours, but it's not and it's having a negative effect."

But by learning new sleep habits — and getting any sleep disorders addressed — "You will lose weight if you get the proper amount of sleep," says De Koninck. "Your hormones will be positively affected and you will not overeat."

Sleep diet details:
- Set your bedtime. First, calculate how much sleep you need by working out when you need to get up, and counting back 7.5 hours.

Then every day, go to bed 15 minutes earlier — most people need between 7.5 and nine hours of sleep — until you notice you're waking up refreshed and without the help of an alarm clock.

At that point, you've found the optimum number of sleep hours for you.
- Keep a sleep journal. Track when you go to bed, when you awaken, any restless periods and when you ate or exercised before retiring. Also, avoid napping during the day for more 30 minutes.

"Do not be one of those people who allows bedtime and awakening time to drift," warn researchers at the University of Maryland. "The body gets used to falling asleep at a certain time, but only if this is relatively fixed."
- Other tips: Dr. Helen Driver advises getting at least a half an hour of exercise during the day — but not within a few hours of bedtime — keeping the bedroom solely for sleep or sex and developing a pre-sleep routine that could include a bath, music or reading.

"Get into a regular routine for going to bed. Cut out caffeine in the afternoon, and don't go to bed too hungry or too full. Alcohol should be in moderation and never as a sleep aid."

© Copyright (c) Canwest News Service

FDA grants orphan drug status to Keryx

2009-09-18T21:25:00.000-06:00

Keryx Biopharmaceuticals Inc. reported that the FDA gave its developing multiple myeloma drug KRX-0401, or Perifosine, orphan drug status.

The company said a late-stage study is expected to start by the end of 2009.

Health info too small to read

2009-09-14T09:30:00.001-06:00

Most pamphlets containing health facts don't meet the CNIB's legibility guidelines, study finds

By Chris Zdeb, Edmonton Journal

Health pamphlets are more about looks than legibility, it seems: Most can't be read by the people they're designed for.

A new University of Alberta study found only 23 per cent of 388 leaflets collected from pharmacies and clinics in the metro Edmonton area met the legibility recommendations of the Canadian National Institute for the Blind.

Cheryl Sadowski, an associate professor in the faculty of pharmacy and pharmaceutical sciences, who did the study, suspected as much. Working at a seniors' clinic part time, she's watched printed information on subjects such as safety, and more sensitive topics such as elder abuse and erectile dysfunction, being handed out to seniors who'd take one look and say, 'Oh, I can't even read this.' Some bring in the brochures or information sheets the pharmacy gave them with their medication and admit they've never read them because the print is too small.

"This is a generation that doesn't do a lot of advocacy for themselves, doesn't complain, so when we get them at the clinic complaining, you know the problem must be really bad," Sadowski says.

"We know that starting in your 40s, people's vision changes as they get older, yet so much of the printed material made available to older adults isn't taking that into consideration."

It's an issue that's growing in importance as the population ages, says Ellie Shuster, CNIB director of regional communications. The CNIB has been advocating for larger type for years.

"We believe 12-point is sort of the minimum type size for an aging demographic. Fourteen point is the standard at the CNIB."
( The Journal uses 10-point type.)

Sadowski's study found only 33 per cent of the brochures collected by pharmacy student Adriana Chubaty were printed in at least 12-point and most were printed in smaller than 10-point.

One leaflet providing information for patients with cataracts and age-related macular degeneration used a squint-inducing six-point type size, the size used in the Edmonton and area phone book.

"In my opinion, people shrink the type to fit the amount of space they have to print on and it's cheaper to do a three-panel brochure than a four-panel brochure," Shuster says.

Brian Steeves, one of several people waiting for a downtown medical clinic to open one day last week, says he's had to use a magnifying glass to read some of the information that comes with prescription medication.

"I think the print should be read with your naked eye, never mind glasses," he says.
Lyn Zinkiew says sometimes she's had to read prescription information to her boyfriend, who finds the print too small.

"I've had some elderly people who have stopped me in stores to help them read something on over-the-counter medication bottles," Zinkiew says.

"Why can't they make the print bigger for something as important as medication?" Zinkiew says. "They should have better leaflets to hand out or a handout with bigger print that you can get at the counter when you purchase the medication."

If people can't read information easily and quickly, they may not bother and they could miss something important, such as which medications shouldn't be taken with others. Their doctor or pharmacist may have told them, but having
something written is useful to refer to in case they forget.

With hundreds of pamphlets on pharmacy racks, it's understandable that pharmaceutical companies want an eye-catching design that will make theirs stand out, Sadowski says.

"Lots of pamphlets are stylized, almost marketing-driven rather than information-focused," she explains. "But if you want to educate people about reflux, for example, you're more likely to sell your reflux drug to people that can read about it. I think most of the producers of this information haven't really thought through that the people their literature is aimed at can't read it."

There's quite a bit of research these days on health literacy. People are concerned about people who speak English as a second language, the jargon used in medical settings, but it doesn't matter if you make something health-literate if the print is too small to read or printed on a busy background," Sadowski says.

Australia has legislation that stipulates how health literature must be written, but it hasn't worked perfectly, Sadowski says. Neither she nor Chubaty thinks similar legislation is necessary in Canada at this point, but guidelines are difficult to find, and the organizations that developed them need to make them more accessible for companies publishing leaflets, they say.

If all else fails, there's always the aging boomers who, unlike their elders, are less likely to tolerate pamphlets they can't read, and demand better, Sadowski says.

The study was published in the May online edition of Age and Aging, the journal of the British Geriatric Society.

Health Canada is developing guidelines for the labelling of pharmaceutical products. It is also looking at package design and look-alike/ sound-alike health product names to help prevent confusion over medication, a department spokesperson says.

© Copyright (c) The Edmonton Journal

Myeloma Genome Sequencing

2009-08-27T12:50:00.001-06:00

The Multiple Myeloma Research Consortium has completed the sequencing of the first multiple myeloma whole genomes, which researchers will use to identify potential targets for treatments.

The Multiple Myeloma Genomics Initiative was started by the Multiple Myeloma Research Foundation and is being conducted in collaboration with the Broad Institute of MIT and Harvard and the Translational Genomics Research Institute. The initiative is a comprehensive genomic analysis program aimed at gaining knowledge about the disease's biology in an effort to speed up the progress for treatments.

The MMRC, which has a total of 15 member institutions, has now begun analyzing data from the project, and additional genomes are being sequenced, MMRF said.

The Norwalk, Conn.-based foundation is also developing a portal to make the data from the myeloma genomics program available to researchers.

Revlimid survival statistics

2009-08-26T15:59:00.000-06:00

Long-term follow-up on overall survival from the MM-009 and MM-010 phase III trials of lenalidomide plus dexamethasone in patients with relapsed or refractory multiple myeloma.

Dimopoulos MA, Chen C, Spencer A, Niesvizky R, Attal M, Stadtmauer EA, Petrucci MT, Yu Z, Olesnyckyj M, Zeldis JB, Knight RD, Weber DM.

Department of Clinical Therapeutics, University of Athens School of Medicine, Athens, Greece.

We present a pooled update of two large, multicenter MM-009 and MM-010 placebo-controlled randomized phase III trials that included 704 patients and assessed lenalidomide plus dexamethasone versus dexamethasone plus placebo in patients with relapsed/refractory multiple myeloma (MM). Patients in both studies were randomized to receive 25 mg daily oral lenalidomide or identical placebo, plus 40 mg oral dexamethasone. In this pooled analysis, using data up to unblinding (June 2005 for MM-009 and August 2005 for MM-010), treatment with lenalidomide plus dexamethasone significantly improved overall response (60.6 vs 21.9%, P<0.001), complete response rate (15.0 vs 2.0%, P<0.001), time to progression (median of 13.4 vs 4.6 months, P<0.001) and duration of response (median of 15.8 months vs 7 months, P<0.001) compared with dexamethasone-placebo. At a median follow-up of 48 months for surviving patients, using data up to July 2008, a significant benefit in overall survival (median of 38.0 vs 31.6 months, P=0.045) was retained despite 47.6% of patients who were randomized to dexamethasone-placebo receiving lenalidomide-based treatment after disease progression or study unblinding. Low beta(2)-microglobulin and low bone marrow plasmacytosis were associated with longer survival. In conclusion, these data confirm the significant response and survival benefit with lenalidomide and dexamethasone.Leukemia advance online publication, 23 July 2009; doi:10.1038/leu.2009.147.

PMID: 19626046 [PubMed - as supplied by publisher]

New Drug Pomalidomide

2009-08-25T10:27:00.001-06:00

Researchers involved in an international trial have reported that pomalidomide is active for the treatment of anemia associated with myelofibrosis. The details of this study appeared in an early online publication in the Journal of Clinical Oncology on August 3, 2009.

Pomalidomide is an oral analog of thalidomide with significant immunomodulatory effects. It stops the growth of blood vessels, stimulates the immune system, and may directly kill cancer cells. Pomalidomide is also an angiogenesis inhibitor. A Phase I study showed a complete remission rate of 17% in patients with relapsed or refractory myeloma with daily pomalidomide. The main side effects were deep vein thrombosis, which occurred early and late. A Phase II study used an alternate-day regimen of pomalidomide in an attempt to decrease thrombotic side effects. The alternate-day schedule appeared to eliminate thrombotic complications. The complete response rate in patients with relapsed myeloma was 10%, and a greater than 50% reduction in paraprotein was achieved in half the patients.

At ASH 2008 daily pomalidomide and low-dose dexamethasone was evaluated in 37 patients with relapsed or refractory myeloma. The overall response rate was 62%, while 24% had a very good partial response.

It appears that pomalidomide can be added to Revlimid as an active derivative of thalidomide with possibly fewer side effects.

Milatuzumab-doxorubicin conjugate testing

2009-08-19T12:37:00.001-06:00

Immunomedics, Inc. announced that the U.S. FDA has allowed its investigational new drug application to initiate Phase I/II clinical trials of doxorubicin conjugate of milatuzumab. The company noted that this is the first antibody-drug conjugate to enter human testing for the treatment of patients with multiple myeloma.

The company said that the primary objective of the open-label, multi-center study is to evaluate the safety and tolerability of the antibody-drug conjugate in patients with recurrent or refractory multiple myeloma. Preliminary information on efficacy, pharmacokinetics, and immunogenicity will also be obtained.

Milatuzumab is a monoclonal antibody that has been designed to recognise and bind to a specific structure (called an antigen) called CD74. This is a receptor protein that is often found on the surface of multiple myeloma cells and is involved in the growth and survival of the cells. By attaching itself to the CD74 on cancer cells, milatuzumab is expected to stop their development and cause the cells to die.

Milatuzumab is being studied clinically for the treatment of multiple myeloma, non-Hodgkin's lymphoma, and chronic lymphocytic leukemia. Milatuzumab is the first anti-CD74 antagonistic antibody to enter clinical trials.

New Antibiotics May Target Cancer-Causing Proteins

2009-08-18T09:37:00.000-06:00

Scientists are closer to understanding how a recently approved class of antibiotics may work against cancer.

The drugs, called thiazole antibiotics, appear to block a cellular protein called FoxM1, one of the most over-produced proteins in cancer cells, according to researchers at the University of Illinois at Chicago College of Medicine. FoxM1 is believed to play an important role in causing cells to become cancerous and may present a promising target for future anti-cancer treatments.

The researchers also found that thiazoles may inhibit proteasomes, a molecular complex within cells that disposes of old proteins marked for destruction. Recently, a number of proteasome inhibitors have shown promise against cancer. One of these inhibitors, bortezomib (Velcade), has proven effective against a number of cancers, including myeloma and certain forms of lymphoma.

The new research, which appears in the online journal PLoS ONE, points to the possible anti-cancer use of thiazoles in the future. Study author Andrei Gartel, an associate professor of molecular genetics, said that by using thiazole antibiotics in combination with well-known proteasome inhibitors, "we may see a synergy that allows us to markedly reduce the dose of any one of these drugs and still effectively kill the cancer cells."

Multiple Myeloma Genomics Initiative Sequences Myeloma Genomes

2009-07-27T16:41:00.001-06:00

Myeloma Research Foundation (MMRF) and Multiple Myeloma Research Consortium (MMRC) announced the MMRC Multiple Myeloma Genomics Initiative has completed the sequencing of the first multiple myeloma whole genomes. This is the first time multiple myeloma whole genomes have been sequenced and will be used to identify key targets for new treatments.

“Groundbreaking data from the MMRC Multiple Myeloma Genomics Initiative will play an important role in developing better treatment options for individuals who derive little benefit from existing therapies and may ultimately help provide multiple myeloma patients with the most appropriate treatment for his or her disease,” Louise M. Perkins, PhD, Chief Scientific Officer of the MMRF. “Furthermore, knowledge from this effort could also benefit patients with other types of cancer.”

The critical task of analyzing the data from the project, conducted in collaboration with the Broad Institute of MIT and Harvard, is now underway, and additional genomes are also being sequenced. A portal to facilitate data access is being constructed and these first complete multiple myeloma genomes will be made available to researchers everywhere within the next several months.

“Through its extraordinary generosity and vision, the MMRF is enabling the important work of whole genome sequencing for multiple myeloma, and making the data publicly accessible,” said Todd R. Golub, MD, Director of the Broad Institute’s Cancer Program and co-principal investigator of the MMRC Multiple Myeloma Genomics Initiative. “This is a remarkable beginning.”

The Multiple Myeloma Genomics Initiative is a comprehensive genomic analysis program designed to rapidly accelerate progress made against multiple myeloma by significantly improving the understanding of the biology of the disease.

Spearheaded by the MMRF and conducted in collaboration with the Broad Institute and the Translational Genomics Research Institute (TGen), the Multiple Myeloma Genomics Initiative utilizes tissue samples from the MMRC Tissue Bank to advance cutting-edge research and discovery efforts that span the spectrum of genomic science. Data from the Initiative are placed into the public domain in near-real time via the Multiple Myeloma Genomics Portal, the world's only myeloma-specific repository of genomic data, and can be accessed at www.myelomagenomics.org.

The Multiple Myeloma Genomics Initiative has also just completed two other high resolution genomics profiling studies performed at TGen on the full Reference Collection of 250 patient's multiple myeloma tumor tissue. Jeffrey Trent, PhD, President and Scientific Director of TGen and co-principal investigator on the Multiple Myeloma Genomics Initiative, said, “The Multiple Myeloma Genomics Initiative has created an unprecedented opportunity to examine an extraordinary breadth of genomic information to pinpoint the most important genes and cellular processes driving the disease. Such a remarkable dataset exists for very few other cancers; it will no doubt pave the way toward personalized medicine for multiple myeloma patients.”

Pesticide link to MGUS

2009-07-20T17:24:00.002-06:00

(NaturalNews) Just how dangerous are pesticides? No one knows the full answer to that question yet, but research is revealing that exposure to these toxins is clearly a bigger health risk than most people realize.

A new National Cancer Institute (NCI) study just published in Blood, the journal of the American Society of Hematology, has found for the first time that applying pesticides doubles the risk of developing an abnormal blood condition called MGUS (monoclonal gammopathy of undetermined significance). This disorder is characterized by an abnormal level of a plasma protein and requires lifelong monitoring with blood tests. The reason? MGUS can lead to the painful cancer of plasma cells in the bone marrow known as multiple myeloma.

The NCI research involved a study of 678 individuals, culled from a U.S. Agricultural Health Study of over 50,000 farmers who had worked with pesticides. The ages of the study participants ranged from 30 to 94, with an average age of 60. They all lived in either North Carolina or Iowa and were licensed to apply restricted-use pesticides. The research subjects were asked to fill out questionnaires to assess their occupational exposure to a wide range of pesticides and to document how long they had used pesticides. They also answered questions about the pesticide application methods they used, as well as whether they wore protective gear while applying the chemicals.

Information was also obtained about the participants' family history of cancer and their smoking and alcohol usage along with other basic health and medical data. If any research subject had a history of a lymphoproliferative malignancy, such as multiple myeloma or lymphoma, they were excluded from the study. Then, each year for five years the rate of cancer incidence and deaths in the research subject group were documented. At the end of the five year study, interviews were conducted to update the information about participants' occupational exposures, medical histories, and lifestyle factors.

The NCI research team took blood samples from the research subjects and evaluated them for MGUS. No MGUS cases were observed among those who were younger than 50. However, the prevalence of MGUS in those older than 50 was 6.8 percent. And when that figure was compared to a group of men from the general population in Minnesota who did not work with pesticides, the findings showed that the incidence of MGUS was extraordinarily high among those who applied pesticides. Bottom line: the pesticide group had double the risk of having MGUS, placing them at an elevated risk for myeloma.

"Previously, inconclusive evidence has linked agricultural work to an increased multiple myeloma risk. Our study is the first to show an association between pesticide exposure and an excess prevalence of MGUS," said lead author and NCI scientist Ola Landgren, MD, PhD, in a statement to the media. "This finding is particularly important given that we recently found in a large prospective cancer screening study that virtually all multiple myeloma patients experienced a MGUS state prior to developing myeloma.

"What pesticides appear to be the most dangerous? Of the chemicals studied, a significantly increased risk of MGUS was found among the people who used the insecticide dieldrin, the fumigant mixture of carbon tetrachloride and carbon disulfide, and the fungicide chlorothalonil. These pesticides increased the MGUS risk 5.6, 3.9, and 2.4 times, respectively. "As several million Americans use pesticides, it's important that the risks of developing MGUS from the use of pesticides is known," added senior study author and NCI investigator Michael Alavanja, DrPH, in the media statement.

New York Times - Considering Longer Chemotherapy

2009-07-20T17:19:00.000-06:00

http://www.nytimes.com/2009/07/21/health/21canc.html?_r=2

A better way to harvest bone marrow

2009-07-16T13:02:00.001-06:00

http://www.ted.com/talks/daniel_kraft_invents_a_better_way_to_harvest_bone_marrow.html

Study pinpoints novel cancer gene and biomarker

2009-07-09T15:53:00.002-06:00

Research underscores need to combine genomics and basic biology in cancer gene hunt

Dana-Farber Cancer Institute scientists' discovery of a cancer-causing gene — the first in its family to be linked to cancer — demonstrates how the panoramic view of genomics and the close-up perspective of molecular biology are needed to determine which genes are involved in cancer and which are mere bystanders.

The findings are reported in the June 25 issue of the journal Nature.

"In the coming years, we can expect genomic studies [which chart the activity of thousands of cell genes] to generate hundreds or thousands of genetic elements of interest in cancer research," says the study's senior author, Lynda Chin, MD, of Dana-Farber.

"To narrow that group to the genes that actually drive cancer growth and metastasis, it's necessary to do functional studies, which focus on what individual genes do to turn a cell cancerous, and mechanistic studies, which examine how they turn cells cancerous and in what setting. It is a long and intensive effort that will leverage knowledge from different fields and different model systems."

In the study, Chin, lead author Kenneth Scott, PhD, of Dana-Farber, and their colleagues worked their way through a series of experiments — in yeast cells, multiple types of human cancer cells, laboratory cell cultures, and mouse models — to demonstrate that a surplus of a gene known as GOLPH3 can spur cancer cell growth in a variety of tissues.
It is the first gene associated with the Golgi complex, a tiny packaging plant that prepares proteins for their journey within and outside the cell, which has been found to play a role in cancer.

Chin's team also found that the protein made from GOLPH3 may serve as a biomarker for tumors that can be effectively treated with the chemotherapy drug rapamycin: tumors with a high level of the protein are more apt to shrink in response to the drug than those with low levels.

The study began with an observation made years ago that a section of chromosome 5p13 is often duplicated, or amplified, in cancers of the lung, ovary, breast, and prostate gland, as well as melanoma. The presence of this abnormality in so many different types of cancer led Chin and her associates to take a closer look at that stretch of chromosome to see what genes reside there.

Using a method called genomic qPCR that can pick out specific sequences of DNA, they found four genes in the amplified region, two of which, GOLPH3 and SUB1, were expressed at high levels, due to the increase in gene copy. To determine whether both, or either, of these genes are involved in cancer, they conducted "loss of function" tests, in which they lowered each gene's activity in a set of lab-grown tumor cells.

"When we 'knocked down' GOLPH3 expression [or activity] by 95 percent, it significantly inhibited the ability of these cell lines to grow in a semi-solid condition, a cancerous quality that normal cells do not typically share," Chin says. "Knocking down SUB1 to a comparable level had only a minimal effect."

Intriguing as this finding was, it was hardly enough to prove that GOLPH3 is an oncogene — a contributor to cancer when overexpressed within a cell.

Demonstrating that would require several experiments to ensure that GOLPH3 itself, and not a nearby "shadow" gene, is responsible for the effects. Next came gain-of-function studies to see whether revving up GOLPH3 activity can turn a non-cancerous cell cancerous. It did in both mouse and human cells.

"All these results enabled us to build a case that GOLPH3 is an oncogene," Chin states. But there was a problem. "This information wasn't very helpful for achieving our ultimate goal, which is the translation of our findings into a form that is clinically useful for patients."

Despite their discovery that GOLPH3 can promote cancer, researchers didn't know what the gene's role is in normal cells. "There was literally no information on what it does," Chin remarks. The only hint was that the protein it encodes — designated GOLPH3 — is found in the Golgi network.

The team's first attempt to uncover GOLPH3's role — using gene expression profiling to see how protein levels track with various cell functions — was fruitless. So the researchers ran experiments with yeast cells to see which proteins share GOLPH3's cell neighborhood and which proteins it interacts with.

One such partner was found to be VPS35, a component of a structure called the retromer complex. The complex's job is to recycle the antenna-like receptors that dot the cell surface.

From the many genetic screening tests that have been done in yeast, researchers knew that flaws in the retromer complex can cause cells to be vulnerable to rapamycin, just as excess GOLPH3 can. Rapamycin is known to interfere with a protein called TOR, whose job is to control yeast cell size. This suggested that the retromer complex in yeast is important for chemical signals sent to and from TOR.

Chin's team theorized that mammalian GOLPH3 also works with the retromer complex to control the activity of TOR in mammal cells (where it's known at mTOR). To test this idea, the investigators found that knocking down GOLPH3 reduced cell size just as rapamycin did. They followed those experiments with biochemical studies to explore how GOLPH3 affects cell size.

The team next sought to answer whether high GOLPH3 levels cause tumor cells to be more susceptible to rapamycin in animal studies.

They took two sets of human melanoma skin cancer cells — one of which had excess GOLPH3 and the other had normal levels — implanted them in animals, allowed them to grow into tumors, then treated them with rapamycin.

"In the animals where GOLPH3 was overexpressed, the cancer cells grew much faster, but the tumors were much more responsive to rapamycin," Chin notes, "suggesting the tumor-promoting effect of GOLPH3 is dependent on mTOR signaling."

Lastly, the team considered whether the same mechanism might be at work in human cancer cells. An experiment analyzing human tumor tissue for specific proteins suggested yes. The researchers found that non-small cell lung cancer cells with too many copies of the GOLPH3 gene also had abnormally high levels of mTOR activity.

"The mechanistic relationship we'd identified in the mouse system is also at work in human tumors," says Chin, who is also an associate professor at Harvard Medical School.

In addition to identifying GOLPH3 as a bona fide oncogene and an indicator of whether rapamycin is likely to be effective against specific tumors, the study points to the need to follow genomic studies with a rigorous examination of the biological purpose and operation of potential cancer genes, Chin concludes.

"Only then can we turn our intriguing discoveries in the cancer genome into something that is useful to cancer patients."

Co-authors include Omar Kabbarah, Mei-Chih Liang, PhD, Joyce Wu, Sabin Dhakal, Min Wu, PhD, Shujuan Chen, Tamar Feinberg, Joseph Huang, Hans Widlund, PhD, and Kwok-Kin Wong, MD, PhD, Dana-Farber; Elena Ivanova, PhD, Yonghong Xiao, PhD, and Alexei Protopopov, PhD, Dana-Farber and the Broad Institute of Advanced Cancer Science; David E. Fisher, MD, PhD, Massachusetts General Hospital; Valsamo Anagnostou, and David Rimm, MD, PhD,Yale University School of Medicine; Abdel Saci, PhD, Harvard Medical School.

Vegetarian Protection against Multiple Myeloma

2009-07-06T18:08:00.002-06:00

I've asked this question in the past and have always been told that there is no scientific evidence of causality between diet and Multiple Myeloma.

***

Being a vegetarian cuts the risk of developing cancer, especially cancers of the blood, researchers reported today.
The overall benefit enjoyed by vegetarians over carnivores is a 12 per cent reduction in risk, according to Cancer Research UK.

But researchers were surprised to find that a vegetarian diet offers the most protection against cancers of theblood such as leukemia, multiple myeloma and non-Hodgkin lymphoma.

Vegetarians were 45 per cent less likely than meat-eaters to develop these cancers.

The study involved more than 61,000 people studied over a period of 12 years. During that time some 3,350 developed cancer.

The findings are published today in the British Journal of Cancer.

Experts said they were "surprised" at the massive protection against blood cancers enjoyed by vegetarians.

Sara Hiom, of Cancer Research UK, said: "The relatively low number of vegetarians who developed cancer in this study supports Cancer Research UK's advice that people should eat a healthy, balanced diet high in fibre, fruit and vegetables and low in saturated fat, salt and red and processed meat.

"It's understandable that there's a link between what you eat and cancers of the digestive system. But we are surprised to see an association between leukaemia, non-Hodgkin lymphoma and multiple myeloma."

Researcher Professor Tim Key, of Oxford University, said: "In particular vegetarians were much less likely to develop cancers of the blood which include leukaemia and non-Hodgkin lymphoma. More research is needed to substantiate these results and to look for reasons for the differences."

Myeloma Canada Annual Conference

2009-06-24T17:33:00.002-06:00

Myeloma Canada’s fifth annual Patient, Family & Healthcare Professionals Conference will be held in Calgary on
September 11 & 12 at the Delta Bow Valley Hotel.

LIVING WITH MYELOMA:
Advancing knowledge and wellness through education and empowerment

The year’s Conference, hosted by the Southern Alberta Multiple Myeloma Support Group in co-operation with the International Myeloma Foundation, brings together leading researchers, clinicians and healthcare professionals who will address various aspects of living with myeloma.

The sessions will address the changing approaches to myeloma treatment, the complex decisions that must be made before recommending a treatment and the promising developments that are on the horizon.

Presentations will also be made on how to better cope with unwanted side effects, how to understand your bloodwork and how to manage your lab data.

All of this learning will empower you to help you better manage your myeloma, to have a sense of greater control and, we hope, an improved quality of life.

This year’s panel of experts and topics include:

Brian Durie, MD; Cedars Sinai Cancer Centre, Los Angeles, CA
• Philosophy of “Chronic vs. Cure”: How it Impacts Outcomes
• Myeloma Therapy: Future Directions

Nizar Bahlis, MD; Tom Baker Cancer Centre, Calgary, AB
• Myeloma 101: An Introduction

Donna Reece, MD; Princess Margaret Hospital, Toronto, ON
• Understanding Your Bloodwork
• Current Approaches to Relapsed and Refractory Disease

Morie Gertz, MD; Mayo Clinic, Rochester, MN
• Current Approaches to the Newly-Diagnosed Patient

Arthur Bradwell, MD; University of Birmingham, Birmingham, UK
• Clinical Importance of Serum Free Light Chain Analysis in Myeloma

Teresa Miceli, RN, BSN; Mayo Clinic, Rochester, MN
• Management of Side Effects

Linda Watson, RN, MN, CON (c); Tom Baker Cancer Centre, Calgary, AB
• Living When There Is No Cure

Shane Sinclair, PhD (c); Tom Baker Cancer Centre, Calgary, AB
• Beyond the Blood Counts: Finding Meaning Within a Diagnosis of Myeloma

Additional speakers will address quality of life issues and break out sessions will provide the opportunity to attend presentations of specific interest.

For those attending Friday’s session, there will be a reception and dinner on Friday evening. This will provide attendees with the opportunity to meet and network with other conference participants and medical experts.
REGISTER BEFORE JULY 31 TO TAKE ADVANTAGE OF THE SPECIAL EARLY BIRD REGISTRATION FEE

For full agenda details and online registration, go to the Myeloma Canada website www.myelomacanada.ca and click on 2009 Conference.
http://www.myelomacanada.ca/en/2009_conference.htm

Secure credit card payments can be conveniently made online using PayPal.

To register by mail, please download the registration form from the Myeloma Canada site and mail the completed registration form, along with cheque payable to Myeloma Canada and mail to:

Myeloma Canada Conference Registration
5640 Lodge Crescent SW
Calgary, AB
T3E 5Y7

To register by fax, completed registration forms can be faxed to:
(403) 242-1100

Attendees wishing to stay overnight can take advantage of the special Myeloma Canada room rate of $149.00 at the Delta Bow Valley Hotel.
http://www.deltabowvalley.com/gfamcb911

Myeloma Canada / Myélome Canada
Uniquely devoted to Canada's myeloma community
Exclusivement au service de la communauté canadienne du myélome

Mailing Address/Adresse postale:
PO Box / CP 326
Kirkland, QC
H9H 0A4

(514) 570-9769
Email/Courriel: info@myelomacanada.ca
Web: www.myelomacanada.ca

Ottawa seizing Mexican Thalidomide

2009-06-16T11:18:00.001-06:00

First the medical isotope fiasco, now this!?

Canadian patients 'starting to die,' drug firm says

Cancer patients desperate enough to order cheaper, unlicensed versions of the drug thalidomide from Mexico now face another challenge to getting treatment: Federal authorities have reportedly begun seizing supplies of the life-extending medicine at the border.

"Health Canada is stopping every single box of thalidomide," said an official with a Mexican company that makes the pills, who asked not to be named. "Patients are starting to die because of this."

Patient advocates said they had also heard reports that Health Canada and the Canada Border Services Agency have instituted a crackdown on shipments of thalidomide from Mexico and other developing countries.

Health Canada officials would not comment directly on whether they had stepped up seizures, but said their policy has always been to bar unsanctioned imports of such drugs into the country.

The development has nevertheless heightened calls on provincial governments to reimburse the steep costs of the one permitted brand of thalidomide and a similar, newer drug, both of which can add years to the lives of people with multiple myeloma, a rare blood cancer.

Some Ontario patients are even thinking of moving to British Columbia, the one province that covers the newer medicine, said Lori Borsos, a myeloma sufferer in Hamilton.

"If you need this drug to stay alive and you can't afford it, what's your choice?: move to B. C. or move six feet under," she said.

"We all live in Canada and some of us have better health care than others. It's not right."

Thalidomide -- infamous as a morning-sickness remedy that caused widespread birth defects in the 1950s and 1960s -- has proven to be one of the most effective myeloma treatments, but its cost is not officially picked up by any province.

Revlimid, a new drug that acts in a similar way and can cost $100,000 a year, is covered only in British Columbia. Velcade, the other medication widely used by myeloma patients, is financed to at least some extent by most provinces, but is not suitable for all patients.

Private insurance and manufacturers provide some funding, too.

The "core" issue is that provincial governments should pay for all three drugs, said John Lemieux, president of the Myeloma Canada support group. "The patients ... are the sole victims" of the current patchwork of funding policies, he said.

The North American-patented version of thalidomide, made by Celgene Corp. of New Jersey, can cost $40,000 a year, though the firm says it provides it free to about 60% of patients prescribed the medicine. Myeloma Canada says it has been unable to confirm that figure.

Regardless, the rest must either pay out of their own pockets, go without and face shortened lifespans or order versions made in Mexico, Brazil or elsewhere in the developing world.

The cost of one Mexican brand is about one-twentieth of Celgene's. The firm says approximately 100 Canadians have bought thalidomide from it, while other patients have sought supplies from as far afield as India.

Days after a National Post article revealed patients were importing the medicine from overseas, however, Canadian authorities began seizing Mexican shipments of the drug, the pharmaceutical company official said.

Mr. Lemieux said in an e-mailed response that his group has heard reports of as many as 20 patients having their shipments seized, but could not confirm them.

"If they don't have this drug, they will die," said the Mexican company official of her customers.

Some doctors have warned that patients risk consuming substandard product if they order thalidomide from such manufacturers, whichcurrently face no scrutiny from regulators here. Others physicians, though, say the Mexican drug seems to be just as effective and safe as the Celgene product, called Thalomid.

Thalomid is not licensed in Canada, but can be legally ordered by doctors under Health Canada's special-access program, designed to make treatments not yet approved here available on an emergency basis.

It was allowed under the program partly because Celgene, the manufacturer, has an extensive program for dealing with the drug's infamous side effects, Health Canada said in an e-mailed statement. Celgene only provides a month's supply at a time, and requires doctors to submit negative pregnancy tests for female patients of child-bearing age before dispensing more pills, the regulator said.

"Health Canada believes that this care and caution is both necessary and appropriate and is commensurate with the risks associated with the drug," the statement said.

A request for the Mexican thalidomide was made under the special-access program a few years ago, but its maker had no such program in place, the department said.

Source: http://www.nationalpost.com/news/story.html?id=1696051

Proteolix Clinical Data from Two Clinical Studies of Carfilzomib in Multiple Myeloma

2009-06-10T15:46:00.002-06:00

Proteolix, Inc. announced data from ongoing Phase 2 and Phase 1b clinical trials of carfilzomib for the treatment of multiple myeloma at the 14th Congress of the European Hematology Association (EHA) in Berlin, Germany. Carfilzomib is the first in a new class of selective, irreversible proteasome inhibitors being developed by Proteolix for the treatment of hematologic malignancies and solid tumors.

Relapsed Multiple Myeloma Patients Achieve Responses with Single-Agent Carfilzomib

Keith Stewart, M.B., Ch.B., Professor, Division of Hematology/Oncology at the Mayo Clinic, Arizona presented positive data from an ongoing Phase 2 clinical trial of single-agent carfilzomib in relapsed multiple myeloma patients. Patients in the study have relapsed after receiving one to three prior therapies and are stratified according to prior exposure to bortezomib.

A total of 31 patients have been enrolled in the Phase 2 clinical trial to date, of which 45 percent had no prior bortezomib experience and 55 percent relapsed following bortezomib treatment. In both arms, substantial response rates were achieved and sustained. Bortezomib-naive patients achieved an overall response rate of 57 percent with a median duration of response of 8.5 months. The median time to progression in this cohort has not been reached.

Among patients with prior bortezomib exposure, 18 percent achieved partial responses and the median duration of response has not yet been reached in this population. The median time to progression for patients in this cohort was 8.9 months. Ten additional patients achieved stable disease.

"Carfilzomib monotherapy achieves durable responses in relapsed multiple myeloma patients regardless of their prior exposure to bortezomib, and notably, a number of patients remain progression free after twelve cycles," said Dr. Stewart. "Further, carfilzomib has been generally well tolerated, and the compound's selectivity appears to avoid the off-target effects, such as peripheral neuropathy, associated with currently available proteasome inhibitors."

Adverse events were generally mild and manageable and carfilzomib has been well tolerated for up to one year. Of 31 patients treated, 29 percent have received 12 full cycles of treatment.

These data were reported by Dr. Stewart in an oral presentation, titled "# 0474: Safety and Efficacy Update of PX-171-004, an Open-label Phase II Trial of Carfilzomib in Relapsed Multiple Myeloma," on Saturday, June 6, 2009.

Carfilzomib Combination with Lenalidomide is Well-Tolerated; Achieves Responses in Heavily Pre-treated Patients at Low Doses

Positive preliminary data from an ongoing Phase 1b dose-escalating trial of carfilzomib in combination with lenalidomide
and low-dose dexamethasone in relapsed and refractory patients was presented by Michael Wang, M.D., of the University of Texas MD Anderson Cancer Center on Sunday, June 7, 2009. The Phase 1b clinical trial is designed to evaluate safety and to establish a maximum-tolerated dose of carfilzomib in combination with lenalidomide and dexamethasone administered on a 28-day treatment cycle. Lenalidomide in combination with dexamethasone is currently indicated for use in patients with multiple myeloma who have had at least one prior therapy.

To date, the combination of carfilzomib and lenalidomide was well tolerated in heavily pre-treated patients and adverse events were manageable. The most common adverse events reported include anemia and fatigue. No cases of peripheral neuropathy, a common adverse event associated with approved proteasome inhibitors, have been reported. A maximum-tolerated dose has not yet been established and dose-escalation in this trial continues.

Sixty-one percent of the 18 patients evaluable for efficacy achieved very good partial, partial or minor responses. Responses occurred in the first 28-day cycle of treatment at doses well below the maximum-tolerated dose for either lenalidomide or carfilzomib alone. Initial responses improved with continued therapy. Potent inhibition of the proteasome has been observed and the lenalidomide/dexamethasone combination does not appear to interfere with carfilzomib's activity.

"Results observed to date in our Phase 1b combination study of carfilzomib are very promising," said Michael Kauffman, M.D., Ph.D., Chief Medical Officer of Proteolix. "We believe that carfilzomib in combination with lenalidomide and dexamethasone should provide superior activity to lenalidomide and dexamethasone alone. In addition, the lack of overlapping toxicities and absence of peripheral neuropathy may allow for long-term dosing - and ultimately, sustained clinical benefit."

Dr. Wang presented interim data from the Phase 1b clinical trial during the Novel Therapeutics and Drug Resistance session in an oral talk, titled "#1070: PX-171-006: Phase IB Multicenter Dose Escalation Study of Carfilzomib (CFZ) plus Lenalidomide (LEN) and Low Dose Dexamethasone (LODEX) in Relapsed and Refractory Multiple Myeloma (MM) - Preliminary Results."

About Carfilzomib

Carfilzomib is the first in a new class of selective, irreversible proteasome inhibitors. Carfilzomib produces specific and sustained inhibition of the proteasome, leading to apoptosis in cancer cells with minimal off-target effects. In Phase 1 and Phase 2 clinical trials, carfilzomib has demonstrated single-agent activity in hematologic malignancies and solid tumors, including multiple myeloma, Waldenstrom's macroglobulinemia, mantle cell lymphoma and renal cell carcinoma.

Proteolix is conducting a comprehensive clinical development program evaluating carfilzomib for the treatment of multiple myeloma, including an ongoing accelerated approval study in heavily pre-treated relapsed/refractory patients and a Phase 2 clinical trial in relapsed patients stratified by prior treatment with bortezomib. Both Phase 2 clinical trials are being conducted by Proteolix in collaboration with the Multiple Myeloma Research Consortium (MMRC). A Phase Ib clinical trial of carfilzomib in combination with lenalidomide and dexamethasone in patients with relapsed multiple myeloma is also ongoing. In addition, Proteolix is conducting a single-agent Phase 2 clinical trial of carfilzomib in patients with recurrent or advanced solid tumors. For the latest information regarding ongoing carfilzomib clinical trials, please visit www.clinicaltrials.gov.

About Proteolix

Founded in December 2003, Proteolix, Inc. is a privately-held biotechnology company, headquartered in South San Francisco, dedicated to discovering, developing and commercializing novel therapeutics that target protein degradation pathways for cancer and autoimmune diseases. Proteolix's lead product, carfilzomib, is the first in a new class of selective, irreversible proteasome inhibitors. Proteolix is also developing a pipeline of novel proteasome inhibitors, including a selective, oral proteasome inhibitor and a selective immunoproteasome inhibitor. For additional information on Proteolix, please visit www.proteolix.com.

Revlamid Presentations at the 14th Congress of the European Hematology Association

2009-06-08T17:05:00.002-06:00

Celgene announced that data from multiple studies presented at the 14th Congress of the European Society of Hematology demonstrate that REVLIMID provides powerful and sustained responses in patients with multiple myeloma. These key presentations support the advantage of active long-term disease control along with manageable safety profiles, leading to unprecedented survival times.

"Together, the studies presented at this congress demonstrate that the use of REVLIMID early on in the course of the disease allows for rapid and durable responses that lead to the best survival benefits we've seen yet for this patient population," said Jean-Pierre Bizzari, Senior Vice President and Group Head of Global Oncology/Hematology for Celgene. "We are excited that the dual mode of action of REVLIMID, which includes both a direct killing effect against myeloma cells and a unique immune-enhancing effect, controls and manages the disease over the long-term."

Speed of response with lenalidomide and dexamethasone in patients with relapsed or refractory multiple myeloma: First results of the MM-019 German compassionate use protocol

Treatment time required for patients with multiple myeloma to respond to therapy with REVLIMID plus dexamethasone was examined in a phase IIIb, open-label, non-comparative trial. Patients had received at least one previous therapy and were treated in 28-day courses that were repeated until disease progression, toxicity or withdrawal by the physician or patient.
Patients' previous therapies, including transplantations, bortezomib and thalidomide, did not influence response rates. Fifteen patients (12%) had been previously treated with all three regimens, 43 (35%) with two and 42 (34%) with one.
Best response information, measured by levels of M protein and free light chains (FLC), was available for 113 patients, including four patients with a complete response, 80 with a partial response, 28 with stable disease and one with disease progression.

Time to a 50 percent reduction in M-protein or FLC was analysed for 122 patients. For responding patients, median time to response was 28 days, with 39 percent of patients seeing a response in two weeks.

"These data demonstrate that nearly three-quarters of patients achieved a partial response or better, despite having been heavily pretreated," said Dr. Katja Weisel of University Hospital in Tubingen, Germany. "The responses were rapid, with half of the patients responding well within the first treatment course."

Longer duration of treatment and maintenance of best response with lenalidomide plus dexamethasone increases overall survival (OS) in patients with relapsed/refractory multiple myeloma

A subset analysis of updated, pooled data from the MM-009/MM-010 international phase III trials demonstrated a survival benefit upon continued treatment with REVLIMID(R) plus dexamethasone after achieving best clinical response in patients with relapsed or refractory multiple myeloma.

Survival estimates for patients achieving a partial response or better were compared between patients on continuous treatment (those still undergoing treatment or who discontinued due to disease progression) and patients who discontinued treatment early due to adverse events, consent withdrawal or other reasons. Median follow-up time for surviving patients was 48 months.

The estimated median survival time for patients continuing treatment after achieving a partial response or better (N=174) was 50.9 months [95% confidence interval: 43.0-NR], while the median survival time for those who discontinued treatment early (N=38) was 34.95 months [26.4-55.7; P=0.0594].

When differences in the groups' patient characteristics (such as age, number of prior treatments, etc.) were also taken into account, the group that continued treatment had significantly better survival outcomes than did the group that discontinued therapy.

The number of patients who discontinued early due to adverse events was low (N=22, 10%).

"This study suggests that therapy with REVLIMID plus dexamethasone should be prolonged even after the patient achieves an initial response," concluded Dr. Jesus San Miguel of the University Hospital of Salamanca in Salamanca, Spain. "The lasting effects gained by additional rounds of treatment may significantly prolong survival for these patients."

Lenalidomide-based therapy leads to improvement in humoral immune system in relapsed or refractory multiple myeloma patients who respond to the therapy

Dr. Rachid Baz of the Moffitt Cancer Center & Research Institute, in Tampa, FL, USA presented another analysis of MM-009/MM-010, as well as of a large phase II study of REVLIMID(R) as a single agent therapy in patients with relapsed or refractory multiple myeloma, demonstrated that REVLIMID therapy improves patient immunity by boosting immunoglobulin A (IgA) levels.

Levels of IgA, an important antibody for fighting infections, are commonly reduced in patients with multiple myeloma. These low levels are associated with recurrent bacterial infections - the most common cause of death for patients in advanced stages of the disease.

The study measured baseline levels of the antibodies and evaluated antibody responses to therapy on a monthly basis. Improvement was defined as an increase in antibody levels to at least the lower limit of normal and a 25 percent increase in value.

Only patients who responded to therapy showed significant improvement and normalisation of residual IgA levels. At baseline, residual IgA levels were normal in 30 and 17 percent of responders in MM-009/MM-010 and MM-014, respectively. With treatment, normalised IgA levels were found in 56 percent of responders in MM-009/MM-010 by cycle seven and in 50 percent of responders in MM-014 by cycle five.

Patients whose IgA levels normalised had significantly longer progression-free (29-77 weeks) and overall (121-220 weeks) survival times compared to those whose IgA levels did not improve (P=0.0001).

Lenalidomide in combination with dexamethasone at first relapse in comparison with its use as later salvage therapy in relapsed or refractory multiple myeloma

Also of note is a study that was recently published in the European Journal of Hematology. This subset analysis of MM-009/MM-010 demonstrated the benefit of initiating REVLIMID plus dexamethasone at first relapse compared to later salvage therapy.

The study showed that, with REVLIMID plus dexamethasone, patients who had received one prior therapy demonstrated significant improvements compared to those who had received two or more prior therapies in outcomes such as median time to disease progression (17.1 vs. 10.6 months; P=0.026), median progression-free survival (14.2 vs. 9.5 months; P=0.047), complete or very good partial responses (39.8% vs. 27.7%; P=0.025) and median overall survival (42.0 vs. 35.8 months; P=0.041).

"These results suggest that it may be beneficial to patients to be treated with REVLIMID plus dexamethasone earlier on in the treatment course," said Dr. Edward A. Staudtmauer of the Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA. "Based on the findings, the combination of REVLIMID and dexamethasone should be considered as a second-line therapy for patients with multiple myeloma."

REVLIMID is approved in the United States, the European Union, Canada, Argentina, Peru, Bolivia, Columbia, Guatemala, Switzerland, Malaysia, Israel, Singapore and Russia in combination with dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy and in Australia and New Zealand in combination with dexamethasone for the treatment of patients whose disease has progressed after one therapy.

Prunes Promote Bone and Heart Health

2009-06-01T12:29:00.002-06:00

Better Heart and Bones with This Sweet Snack

Looking to satisfy your candy cravings with something tasty and good for you? Try a handful of nature’s guilt-free treats: dried plums. Research shows that they promote both heart and bone health.

Buff Bones

A laboratory study of the polyphenols in prunes showed that they boosted bone formation, density, and strength. How? By affecting the way certain bone-regulating gene cells are expressed.

A Plum Choice for Your Heart

Results from animal studies suggest that dried plums can help keep arteries clear. Researchers suspect that prune flavonoids help reduce the inflammation that plays a big role in artery disease.

Big Benefits, Little Package

If that isn’t enough motivation to pick up a pack of prunes, consider this: Just 10 prunes delivers 20 percent of your daily potassium and copper requirements, 14 percent of your iron requirements, and 10 percent of your manganese and zinc requirements. Prunes also provide a whopping dose of the essential vitamins A, C, E, and B-complex, including folate. And we all know that prunes are a super source of fiber.

Do prunes conjure up a vision of your grandma saying something about regularity? Meet today’s marketing replacement the dried plum! Full of antioxidants, dried plums (okay . . . prunes) are a delicious and sweet treat.

Source: http://www.realage.com/ct/eat-smart/food-and-nutrition/tip/8787

Combination bortezomib and doxorubicin in relapsed/refractory multiple myeloma

2009-05-29T15:55:00.002-06:00

Shah JJ, Orlowski RZ, Thomas SK

The first in class proteasome inhibitor bortezomib (B) received its initial regulatory approval for therapy of patients with multiple myeloma (MM) in the relapsed/refractory setting. Modulation of proteasome function, however, is also a rational strategy for chemosensitization, and a variety of agents have shown synergistic activity with bortezomib pre-clinically, including anthracyclines. This formed the basis for evaluation of a regimen of bortezomib with pegylated liposomal doxorubicin (PLD).

PLD+B, in a phase I study, induced a predictable and manageable toxicity profile, and showed encouraging anti-MM activity. In a recent international, randomized phase III trial, PLD+B demonstrated a superior overall response rate and response quality compared to bortezomib alone, as well as a longer time to progression, duration of response, progression-free survival, and overall survival.

Sub-analyses revealed benefits in almost all clinically relevant subgroups, including several which would be considered to have high-risk disease. These findings have led to the establishment of the PLD+B regimen as one of the standards of care for patients with relapsed and/or refractory myeloma. Efforts are now underway to build on this combination further by adding other active anti-myeloma agents.

Down syndrome reveals key to fighting cancer

2009-05-21T21:30:00.000-06:00

People with Down syndrome rarely get most kinds of cancer, and U.S. researchers have nailed down one reason why — they have extra copies of a gene that helps keep tumours from feeding themselves.

The findings could lead to new treatments for cancer, the researchers reported in the journal Nature on Wednesday, and further study of Down patients might reveal more ways to fight tumours.

The researchers at Harvard University and elsewhere made use of a new kind of embryonic-like stem cell called an induced pluripotent stem cell or iPS cell. These cells, made from ordinary skin, can be transformed to act like powerful stem cells, the body’s master cells.

Using iPS cells from a volunteer with Down syndrome and mice genetically engineered to have a version of the condition, the researchers pinpointed one gene that protects against tumours.

“It is, perhaps, inspiring that the Down syndrome population provides us with new insight into mechanisms that regulate cancer growth,” they wrote. Down syndrome is the most common genetic cause of mental retardation, occurring in one out of 700 live births. The Down syndrome theory had long been explored by Harvard’s Dr. Judah Folkman, who died last year. Folkman, whose name is on the study, developed theories about how tumour cells grow blood vessels to nourish themselves in a process called angiogenesis.

Folkman also noticed how rare cancer is among Down patients, except for leukemia, and he wondered whether the genes explain why. A study of nearly 18,000 Down’s patients showed they had 10 per cent the expected rate of cancer.

People with Down syndrome have a third copy of chromosome 21, where most people have two copies.
The extra copy gives them extra versions of 231 different genes.

“One such gene is Down syndrome candidate region-1 (DSCR1, also known as RCAN1),” Harvard’s Sandra Ryeom and colleagues wrote.

This gene codes for a protein that suppresses vascular endothelial growth factor or VEGF — one of the compounds necessary for angiogenesis.

Genome sequencing of multiple myeloma

2009-05-19T15:06:00.001-06:00

The Multiple Myeloma Research Foundation (MMRF) announced a collaboration with the Broad Institute of MIT and Harvard to systematically uncover the molecular changes underlying multiple myeloma by whole genome sequencing of individual patient tumors. The MMRF will provide both patient samples for analysis as well as funding for the project. All data from this collaboration will be put in the public domain.

"We are delighted to work with the MMRF, which has been a visionary organization in accelerating cancer research for the sake of patients and their families," said Eric S. Lander, PhD, Director of the Broad Institute. "Through our work together on this critical pilot project in whole cancer genome sequencing, we hope not only to advance clinical progress for multiple myeloma, but to build knowledge and technical capabilities that can be applied to many other human cancers."

"Three years ago, the MMRF launched a partnership with the Broad Institute and the Translational Genomics Research Institute — the Multiple Myeloma Genomics Initiative — a comprehensive genome mapping program to identity new targets and eventually new therapies for this incurable disease," said Kathy Giusti, Founder and CEO of the MMRF, and a multiple myeloma patient. "As part of that larger effort, we are confident that this groundbreaking research will accelerate the development of next-generation treatments to extend the lives of multiple myeloma patients. Additionally, we believe that this work will not only ultimately pave the way to a cure for patients with multiple myeloma, but will benefit patients with other types of cancer."

The creation of comprehensive catalogs of all commonly occurring cancer mutations is a current approach of several national and international consortia, including The Cancer Genome Atlas (TCGA) led by the US National Institutes of Health and the International Cancer Genome Consortium (ICGC), to understand major tumor types such as leukemia, lung cancer, glioblastoma and others. To date, only a handful of whole cancer genomes have been sequenced and only one has been published.

"The few cancer genomes sequenced to date have been informative, but we need many more to transform cancer research and ultimately cancer therapy," said Stacey Gabriel, PhD, Co-Director of the Broad Institute's Genome Sequencing and Analysis Program. "This exciting collaboration with the MMRF will advance these goals by contributing public domain data."

Importance of Oral Hygiene

2009-05-13T21:28:00.002-06:00

Good oral hygiene and proper dental care apply to all age groups but the needs of the elderly population can be slightly different than the needs of younger people.

I will try to list several areas of concern and how they pertain to this age group.

Why save your teeth?

A missing tooth affects many things including your oral health, your bite, your speech, your general health and your appearance.

When a tooth is lost, the remaining teeth may drift into the empty space, causing changes in biting and chewing and possibly causing pain in your jaw from the bite being misaligned. Remaining teeth may be more prone to decay if they are misaligned.

Many speech sounds that we make are made because of the position of the tongue against your teeth or the roof of your mouth. Having missing teeth can cause changes in a person's speech.

People with missing teeth often cannot chew their food properly to be digested and subsequently may end up with digestive problems and/or nutritional deficiencies.

Missing tooth will affect your appearance and may have a negative effect on one's self-esteem.

Oral health and your heart
Recent research shows that there is a link between periodontal (gum) disease and heart disease. People who have gum disease may be at a higher risk for heart attacks, although no one is certain how this happens. The current theory is that bacteria present in infected gums can become loose and move throughout the body. The same bacteria that cause gum disease and irritates our gums might travel to your arteries.

What can you do? Proper home care, including brushing and flossing regularly, is essential as well as regular visits to your dentist for periodontal maintenance.

Oral health and bisphosphonates
Patients who have been receiving intravenous bisphosphonates should avoid having teeth pulled at all costs. Many people are being treated with bisphosphonates for a variety of medical problems including osteoporosis, multiple myeloma, breast, lung and other cancers and Paget's disease. While those medications are terrific in treating a number of medical conditions, there is a risk of developing an osteonecrosis (breakdown) of the jaw bone as a result of an invasive dental procedure while taking these medications.

The most important step to prevent these problems is to have a dental consultation before beginning the bisphosphonate therapy and having all invasive procedures done before therapy is initiated.

Oral health and diabetes
It is estimated that one-third of the population in the U.S. has diabetes, yet only one-half of these patients are diagnosed.
The biggest problems for diabetics from a dental point of view are infections, periodontal disease and salivary problems.
Infections can result in improper healing following extractions and other surgical procedures.

Diabetics are very susceptible to periodontal disease and in their case it may be more severe and more difficult to maintain than in a person without diabetes.

Finally, salivary flow can be diminished in diabetics, which will result in a higher rate of caries (cavities).

Proper diet, good oral hygiene and regular dental visits can help keep the oral problems of diabetes in check.

Oral health and tobacco use
While the usage of tobacco has been declining in the last decade, it is still very high in the population and its consequence in the mouth is oral cancer. While the rate of oral cancer isn't as high as with other cancers, it is often devastating and fatal.

A word to the wise is sufficient with tobacco use, both smoking tobacco and chewing tobacco.

If you currently use tobacco, quit immediately. If you don't use it, don't start.

Older patients' dental needs
In tough economic times such as these, there is concern about the cost of maintaining one's oral health.

One doesn't need to do high-cost elective dental procedures if there are monetary constraints. But there is a need for all patients of all ages to maintain proper oral hygiene and seek regular professional care to prevent the consequences of neglect.

Keep periodontal disease under control with proper brushing and flossing techniques and regular cleanings.

Have broken teeth fixed or extracted before they result in infections.

Have ill-fitting dentures fixed or replaced so they don't cause irritations.

Have an oral cancer screening regularly.

Prevention is more prudent and less costly than repair.

Dr. Francis X. Barra, Doctor of Dental Surgery, is the director of dentistry at FoxCare Dental Associates and is a member of the medical staff at A.O. Fox Memorial Hospital in Oneonta.

Thalidomide sourcing from offshore

2009-05-05T08:26:00.003-06:00

Owing to costs, Canadian myeloma patients are acquiring lower-cost Thalidomide from countries like Mexico, Brazil and India.

Canadians buy the drug over the Internet, in person in Mexico, or friends and relatives bring it back.

The cost is a fraction of that in Canada, athough self-importing Thalidomide is illegal in Canada.

Thalidomide costs in Canada can reach $40,000/year. Provincial drug plans and private insurers do not usually reimburse the expense.

Apparently Health Canada may permit a patient to bring up to a 90-day supply of Thalidomide into Canada.

Although Revlimid and Velcade are approved by Health Canada most provinces refuse to fund them.

A Mexican company, Laboritorios Serral, produces Thalidomide under the brand name Talizer. Apparently the drug can be imported or family members can pick up the drug from an authorized pharmacy in Mexico, if they have the patient's prescription and identification.

However, Canadian doctors are concerned about taking drugs without Health Canada oversight.

New Drug ACE-011 Acceleron Pharma

2009-05-04T21:58:00.003-06:00

Acceleron Pharma eports that it will expand its workforce and build new offices and facilities this year. The company signed a lease in Cambridge, MA, further expanding its research laboratory and office space by 19,700 sq. ft. In conjunction with this, Acceleron will increase its workforce by more than 50% to support growth in R&D and manufacturing.

Acceleron’s lead program, ACE-011, is currently in Phase II studies in multiple myeloma patients with osteolytic bone disease. ACE-011 has been shown to increase bone mineral density and red blood cells and is being jointly developed by Acceleron and Celgene.

Multiple Myeloma Handbook

2009-04-26T16:00:00.002-06:00

At my local Public Library I came across the following interesting book:

Multiple Myeloma -- The plain English Handbook for Patients and Care Givers, by Robert J. Heller

I found it to be a very interesting read that lives up to its title.

Acid/Akaline Interesting Article

2009-04-23T10:38:00.002-06:00

Here's an interesting article on the Acid/Akaline debate, especially the paragraph about too much protein causing the leeching of calcium from your bones.

Acid/Alkaline Theory of Disease Is Nonsense
Gabe Mirkin, M.D.

Have you seen advertisements for products such as coral calcium or alkaline water that are supposed to neutralize acid in your bloodstream? Taking calcium or drinking alkaline water does not affect blood acidity. Anyone who tells you that certain foods or supplements make your stomach or blood acidic does not understand nutrition.

You should not believe that it matters whether foods are acidic or alkaline, because no foods change the acidity of anything in your body except your urine. Your stomach is so acidic that no food can change its acidity. Citrus fruits, vinegar, and vitamins such as ascorbic acid or folic acid do not change the acidity of your stomach or your bloodstream. An entire bottle of calcium pills or antacids would not change the acidity of your stomach for more than a few minutes.

All foods that leave your stomach are acidic. Then they enter your intestines where secretions from your pancreas neutralize the stomach acids. So no matter what you eat, the food in stomach is acidic and the food in the intestines is alkaline.

Dietary modification cannot change the acidity of any part of your body except your urine. Your bloodstream and organs control acidity in a very narrow range. Anything that changed acidity in your body would make you very sick and could even kill you. Promoters of these products claim that cancer cells cannot live in an alkaline environment and that is true, but neither can any of the other cells in your body.

All chemical reactions in your body are started by chemicals called enzymes. For example, if you convert chemical A to chemical B and release energy, enzymes must start these reactions. All enzymes function in a very narrow range of acidity. (The degree of acidity or alkalinity is expressed as "pH."). If your blood changes its acidity or alkalinity for any reason, it is quickly changed back to the normal pH or these enzymes would not function and the necessary chemical reactions would not proceed in your body.

For example, when you hold your breath, carbon dioxide accumulates in your bloodstream very rapidly and your blood turns acidic, and you will become uncomfortable or even pass out. This forces you to start breathing again immediately, and the pH returns to normal. If your kidneys are damaged and cannot regulate the acidity of your bloodstream, chemical reactions stop, poisons accumulate in your bloodstream, and you can die.

Certain foods can leave end-products called ash that can make your urine acid or alkaline, but urine is the only body fluid that can have its acidity changed by food or supplements. ALKALINE-ASH FOODS include fresh fruit and raw vegetables. ACID-ASH FOODS include ALL ANIMAL PRODUCTS, whole grains, beans and other seeds. These foods can change the acidity of your urine, but that's irrelevant since your urine is contained in your bladder and does not affect the pH of any other part of your body.

When you take in more protein than your body needs, your body cannot store it, so the excess amino acids are converted to organic acids that would acidify your blood. But your blood never becomes acidic because as soon as the proteins are converted to organic acids, calcium leaves your bones to neutralize the acid and prevent any change in pH. Because of this, many scientists think that taking in too much protein may weaken bones to cause osteoporosis.

Cranberries have been shown to help prevent recurrent urinary tract infections, but not because of their acidity. They contain chemicals that prevent bacteria from sticking to urinary tract cells.

Taking calcium supplements or drinking alkaline water will not change the pH of your blood. If you hear someone say that your body is too acidic and you should use their product to make it more alkaline, you would be wise not to believe anything else the person tells you.

Dr. Mirkin, who practices medicine in Kensington, Maryland, is board-certified in four specialties: allergy and immunology; sports medicine; pediatrics; and pediatric immunology. He has served as a teaching fellow at Johns Hopkins Medical School, Assistant Professor at the University of Maryland, and Associate Clinical Professor in Pediatrics at the Georgetown University School of Medicine. He has written 16 books on sportsmedicine, weight control, and low-fat eating. His Web site offers broadcasts and reports on thousands of topics. He also offers a free weekly e-mail newsletter.

Source: http://www.quackwatch.org/01QuackeryRelatedTopics/DSH/coral2.html

New Antibody drug

2009-04-20T22:12:00.000-06:00

Australian medical research company Immune System Therapeutics Ltd (IST) has launched a clinical trial to test its breakthrough treatment for blood cancers.

IST has genetically engineered an antibody drug that binds specifically to a target protein found on the surface of some blood cancer cells. Laboratory studies, using cells taken from patients with multiple myeloma, have shown that the antibody works with the human immune system to induce death of the cancer cells. It is anticipated that the antibody will potentially reduce the number of cancerous cells in multiple myeloma patients and improve patient health and wellbeing.

IST has commenced a Phase 1 trial in patients with multiple myeloma and to date six patients have been treated at The Alfred Hospital in Melbourne under the supervision of Dr. Andrew Spencer. Results so far indicate that the antibody has no side effects and final results are expected later this year.

IST's Director of Clinical Development, Dr. Rosanne Dunn, said in order to maintain the recruitment momentum, the Company is seeking to enroll another nine multiple myeloma patients with the kappa form of the disease to be treated over the next few months.

"We are very pleased that the antibody drug is performing as expected with patients suffering no adverse effects. Although this is very rare in cancer treatment it is an indication that the antibody specifically targets cancer cells and not normal cells," she said.

For further information, please contact:

Dr. Rosanne Dunn - +61 2 9514 4060
Alan Liddle - +61 2 9514 7437
Immune System Therapeutics
www.ISTL.com.au

Revlimid funding still under review in Canada

2009-04-15T08:23:00.002-06:00

Jill Lang Ward considers herself lucky: should she ever need the most effective drug on the market to treat
her cancer, her drug plan will cover most of it.

Health Canada approved Revlimid last fall as a treatment for multiple myeloma, a cancer of the plasma
cells, or blood. However, it is still being reviewed by the Joint Oncology Drug Review, the body responsible
for making funding recommendations to the provinces regarding oncology treatment.

Meanwhile, people are dying, warn advocates for publicly funding Revlimid, which comes in pill form, just
as, for example, chemotherapy is covered.

Lang Ward, 56, knows one man in her support group who is foregoing Revlimid for chemo because it would
cost him $10,000 a month. "It would cause too much of a hardship for the family if he dipped into his savings
to extend his life," says the Sault Ste. Marie woman.

Revlimid has been called a miracle drug, because, unlike chemo, "it not only treats the symptoms, it attacks
the disease."

Lang Ward was diagnosed two years ago, some 10 years after her right knee started bothering her. She
took a couple of spills a year apart "and broke both elbows," she says.

She had a knee replacement in February 2007 and soon began experiencing fatigue so extreme that she
couldn't return to her job at the Great Lakes Forestry Centre. The cancer was at Stage 3 when they did a
bone marrow biopsy in September.

"They said at that point it was very likely I had it for 10 years."

Fortunately, checkups reveal little of the typical lesions and erosion on the bones that are a hallmark of
myeloma. Lang Ward takes care of herself, staying active and taking an aquafit class four times a week.
But she's no Pollyanna about her disease, which affects about 6,000 Canadians and is expected to kill
1,350.

"It's always in the back of your mind."

A retired federal civil servant, she estimates that would cover 80 per cent of the cost of the drug.
But nobody should have to choose between living or breaking the bank in a country where health care is
ostensibly publicly funded, she says.

She has collected approximately 150 signatures and has spoken to Sault MPP David Orazietti, who has
promised to bring the petition to Queen's Park.

"If it comes back, as it most likely will at some point, then I'd be considered for Revlimid. But not everybody
has a drug plan."

Source: Frank Dobrovnik, The Sault Star

21st Century Cancer Access legislation proposed

2009-04-09T14:34:00.002-06:00

Dana-Farber Cancer Institute president comments on Senators Kennedy and Hutchison's cancer legislation

Senators Edward M. Kennedy (D-Mass.) and Kay Bailey Hutchison (R-Texas) introduced the 21st Century Cancer Access to Life-Saving Early detection, Research and Treatment (ALERT) Act, a bill to comprehensively address the challenges our nation faces in battling this disease.

This is the first sweeping cancer legislation introduced since the National Cancer Act in 1971, authored by Kennedy.

Senators Kennedy and Hutchison first proposed the idea for comprehensive cancer legislation last May, when the Health, Education, Labor and Pensions Committee held a hearing to discuss the need for a renewed focus on the deadly disease.

Dana-Farber Cancer Institute's president Edward J. Benz, Jr., MD, testified at the hearing and offers the following comments on the bill:

"We are extremely grateful for the leadership of Senators Kennedy and Hutchison in bringing this important legislation forward.

"Despite the great progress that has been made against cancer in the past quarter century, the burden of the disease on patients and their families around the world remains unacceptably high.

"This legislation holds significant promise. It stands to improve access to latest advances in cancer care. It places much needed focus on national initiatives in cancer prevention. It outlines a strong set of priorities to improve patient participation in clinical trials. It acknowledges that more people are surviving cancer and addresses the need for greater cancer survivorship care and services. It calls for reducing disparities in cancer mortality. It provides the resources for workforce development to help ensure that we have the highly skilled caregivers needed to expertly and compassionately care for patients.

"It also recognizes that current research has immense potential to lessen that burden for future generations and provides a powerful impetus for continued progress. We will be working closely with Senators Kennedy and Hutchison and their staffs to refine the bill and work for its passage."

Edward J. Benz, Jr., MD
President of Dana-Farber Cancer Institute
Co-Chair of the Research Working Group for the 21st Century Cancer Act
President of the Association of American Cancer Institutes

Velcade with Salubrinal

2009-04-01T13:26:00.001-06:00

Velcade is a drug that was approved as the first line treatment for MM in June 2008, after having been used as a treatment for recurrences since 2003. However, many patients do not respond and among those that do, virtually all eventually experience a recurrence of the MM. Most cancer fatalities are caused by recurrences rather than the initial diagnosis.

The mechanism by which Velcade fights MM cells can also cause a cell to become dormant rather than die. Dr. Julio Aguirre-Ghiso's lab identified a response that protected the multiple myeloma cells from the Velcade and enabled some of them to become dormant. The scientists speculated that these dormant cells were responsible for the later recurrence. They demonstrated that simultaneous treatment with another drug, salubrinal, which has no effect on the survival of MM cells, still dramatically enhanced the impact of the Velcade, raising the proportion of cells killed from 50% to 90%. This is achieved by preventing the MM cells from reversing the signals changed by Velcade. Further, the use of salubrinal after treatment with Velcade eradicated the dormant cells surviving the initial therapy. Salubrinal is notable for its lack of toxicity in preclinical models.

Denis M. Schewe and Julio A. Aguirre-Ghiso Inhibition of eIFα Dephosphorylation Maximizes Bortezomib Efficiency and Eliminates Quiescent Multiple Myeloma Cells Surviving Proteasome Inhibitor Therapy Cancer Research, Feb. 2009; 69: 1545-1552.

Gene identified in 10% of multiple myeloma cases

2009-03-30T15:52:00.002-06:00

Combining the number-crunching potency of computers with an exploration of the genetic code, scientists have identified a new master gene in cancer.

The research, published by separate teams in the journal Nature Genetics, could open up avenues to identify people at risk and, potentially, new drugs to block the mechanisms that let cancers proliferate, they hope.

British-based researchers said a gene called UTX, found in the X gender chromosome, played the role of ringmaster in 10 percent of cases of multiple myeloma and one in 12 cancers of the oesophagus.

UTX controls an enzyme that contributes to the structure of DNA in our cells. The enzyme also acts as a switch, turning other genes on and off.

In a massive genetic trawl through tissue samples from patients with a form of kidney cancer, the scientists found a rare but telling signature among a mutated form of UTX.

By expanding the search to other cancer types, they also found the variant gene played a part in multiple myeloma -- cancer of the immune cells -- and in throat tumours.

"It influences some of the most fundamental mechanisms controlling gene activity in our cells," said Andy Futreal, co-leader of the Cancer Genome Project at Britain's Wellcome Trust Sanger Institute, which led the study.

"Unlike many cancer genes, UTX does not appear to be directly involved in cell division or cell death but in basic regulation, and shows the depths to which cancers will plumb in order to get themselves ready to go."

Biomarkers for Drug Effectiveness

2009-03-30T15:41:00.002-06:00

Micromedic Technologies Ltd. has found two successes in a preliminary trial together with the University of Florida for the development of innovative biomarkers for pharmacogentics, the improvement of drug effectiveness. The trial tested 47 patients with multiple myeloma receiving Aredia and Zometa.

The trial objective was to test whether the use of Micromedic's genetic biomarker could predict which patients will develop side effects from the drugs; namely significant deterioration in bones of the mouth. Currently, 13% of multiple myeloma patients receiving these two drugs develop this side effect.

Professor Joseph Katz, Director of the University of Florida's College of Dentistry, Department of Oral Diagnostic Science oversaw the trial. Micromedic's genetic biomarker found a group of patients that were 11.6 times more likely to develop the side effects, compared with the control group. Micromedic's goal is for its test to be conducted on every patient who is a candidate for the drugs, so that patients who are predicted to develop the side effect can be given alternative treatment or be given treatments in advance to prevent the side effect.

Micromedic will now conduct a further trial to confirm the findings.

BioKine $1.2M grant for new BKT140 drug

2009-03-23T18:08:00.001-06:00

Biokine Therapeutics, Ltd. has received a $1.2 million research grant to support a Phase I/IIa clinical study to test the safety and the efficacy of the company’s flagship product, cancer drug BKT140.

In experimental models of chemotherapy treatments and bone-marrow transplants BKT140 caused the death of myeloma and leukemia cells, while encouraging the production of normal cells.

BioKine founder and CEO Dr. Amnon Peled said, “This is an exciting and significant time for the scientists, development staff, and investors who have supported the project. It is our goal to help cure and relieve the suffering of those struck by this cruel disease. Early data indicates that BKT140 may help us realize this goal."

Biokine develops pharmaceuticals that control the activity of receptors for molecules called chemokines, which play a key role in the development of cancer and inflammatory diseases.

Novel Agents and Multiple Myeloma

2009-03-19T14:07:00.000-06:00

Improved survival of patients with multiple myeloma after the introduction of novel agents and the applicability of the International Staging System (ISS): an analysis of the Greek Myeloma Study Group (GMSG).

Kastritis E, Zervas K, Symeonidis A, Terpos E, Delimbassi S, Anagnostopoulos N, Michali E, Zomas A, Katodritou E, Gika D, Pouli A, Christoulas D, Roussou M, Kartasis Z, Economopoulos T, Dimopoulos MA.

1Department of Clinical Therapeutics, Alexandra Hospital, University of Athens School of Medicine, Athens, Greece.

When the novel agents thalidomide, bortezomib and lenalidomide are administered to patients with myeloma in the context of clinical trials, they are associated with a significant improvement in response, progression-free survival and in some studies, overall survival (OS); however, their effect on the outcome of unselected myeloma patients has not been fully assessed. We compared the outcome of 1376 unselected patients with symptomatic myeloma, who started treatment before or after the introduction of thalidomide. The median OS in patients who started treatment after the introduction of novel agents increased by 12 months (48 vs 36 months, P<0.001).>70 years (from 26 to 33 months, P=0.27). In patients treated after the introduction of novel agents, the international staging system (ISS) could discriminate three groups with significantly different outcomes (5-year survival for ISS stage I, II and III was 66, 45 and 18%, respectively, P<0.001). ISS was also valid in patients who actually received upfront treatment with novel drugs (4-year survival rate was 85, 61 and 26% for ISS stage I, II and III patients, P=0.001).Leukemia advance online publication, 19 February 2009; doi:10.1038/leu.2008.402.

PMID: 19225533 [PubMed - as supplied by publisher]

Green tea polyphenols block the anticancer effects of bortezomib

2009-03-04T17:18:00.000-07:00

Golden EB, Lam PY, Kardosh A, Gaffney KJ, Cadenas E, Louie SG, Petasis NA, Chen TC, Schonthal AH.

Department of Pathology, University of Southern California (USC) Keck School of Medicine (KSOM), Los Angeles, CA, United States.

The anticancer potency of green tea and its individual components is being intensely investigated, and some cancer patients already self-medicate with this 'miracle herb' in hopes of augmenting the anticancer outcome of their chemotherapy. Bortezomib (Velcade((R))) is a proteasome inhibitor in clinical use for multiple myeloma. Here, we investigated whether the combination of these compounds would yield increased antitumor efficacy in multiple myeloma and glioblastoma cell lines in vitro and in vivo. Unexpectedly, we discovered that various green tea constituents, in particular (-)-epigallocatechin gallate (EGCG) and other polyphenols with 1,2-benzenediol moieties, effectively prevented tumor cell death induced by bortezomib in vitro and in vivo. This pronounced antagonistic function of EGCG was only evident with boronic acid-based proteasome inhibitors (bortezomib, MG-262, PS-IX), but not with several non-boronic acid proteasome inhibitors (MG-132, PS-I, nelfinavir). EGCG directly reacted with bortezomib and blocked its proteasome inhibitory function; as a consequence, bortezomib could not trigger endoplasmic reticulum stress or caspase-7 activation, and did not induce tumor cell death. Taken together, our results indicate that green tea polyphenols may have the potential to negate the therapeutic efficacy of bortezomib and suggest that consumption of green tea products may be contraindicated during cancer therapy with bortezomib.

PMID: 19190249 [PubMed - as supplied by publisher]

MMRF and LLS Fund $500,000 In Cancer Stem Cell Research

2009-03-03T10:56:00.000-07:00

The Multiple Myeloma Research Foundation (MMRF) and the Leukemia & Lymphoma Society (LLS) have partnered to award William Matsui, MD, Johns Hopkins University, and Irving Weissman, MD, Stanford University, research grants totaling $500,000 to study the multiple myeloma cancer stem cell. Each individual grant is valued at $250,000.

These grants, developed in response to input from leading cancer stem cell experts who participated in the 2008 MMRF Myeloma Cancer Stem Cell Research Roundtable, provide an unprecedented opportunity to apply existing knowledge of cancer stem cells to multiple myeloma.

Ultimately, the identification and characterization of the multiple myeloma cancer stem cell will advance our understanding of drug resistance and relapse in patients with multiple myeloma and potentially lead to the development of targeted therapies that effectively treat the disease. Many researchers believe that cancer stem cells, although few in number, are responsible for cancer's development, metastases, and recurrence.

About Multiple Myeloma: Multiple myeloma is an incurable cancer of the plasma cell. The five-year relative survival rate for multiple myeloma is approximately 35%, one of the lowest of all cancers. In 2008, an estimated 19,920 adults (11,190 men and 8,730 women) in the United States were diagnosed with multiple myeloma and an estimated 10,690 people died from the disease.

Alcohol increases cancer risk in women in UK

2009-03-02T15:56:00.002-07:00

A glass of wine each evening is enough to increase your risk of developing cancer, women are being warned.

Consuming just one drink a day causes an extra 7,000 cancer cases - mostly breast cancer - in UK women each year, Cancer Research UK scientists say.

The risk goes up the more you drink, whether spirits, wine or beer, the data on over a million women suggests.

Overall, alcohol is to blame for about 13% of breast, liver, rectum, mouth and throat cancers, the researchers say.

They estimate that about 5,000 cases of breast cancer in the UK - 11% of the 45,000 cases diagnosed each year - can be attributed to women's consumption of alcohol.

The study looked specifically at women who consumed low to moderate levels of alcohol - defined as three drinks a day or fewer.

Over the seven years of the study, published in the Journal of the National Cancer Institute, a quarter of the 1.3 million women reported drinking no alcohol.

Of those who did drink, virtually all consumed fewer than 21 drinks per week, and an average of 10g of alcohol per day, which is equivalent to just over one unit of alcohol found in half a pint of lager, a 125 ml glass of wine or a single measure of spirits.

Nearly 70,000 of the middle-aged women developed cancer and a pattern emerged with alcohol consumption.

Consuming one drink a day increased the risk of all types of cancer by 6% in women up to the age of 75.

The rates for individual cancers varied, with one drink a day causing a 12% rise in the risk of breast cancer, a 10% rise in rectal cancer, a 22% rise in gullet cancer, a 29% rise in mouth cancer and a 44% rise in throat cancer.

On a population scale, this would mean 15 extra cases of these cancers diagnosed for every 1,000 women - comprising 11 breast, one mouth, one rectal cancer and 0.7 each for cancers of the gullet, throat and liver.
Breast cancer is now the most common cancer in the UK. Each year almost 45,000 women are diagnosed with breast cancer. A woman's lifetime risk for breast cancer in the UK is one in nine.

Source: http://news.bbc.co.uk/go/pr/fr/-/1/hi/health/7906355.stm

Prostate treatment 95% effective, study shows

2009-01-30T14:47:00.000-07:00

A study of early diagnosed prostate cancer patients suggests that 95 per cent of men treated using brachytherapy-- the planting of a radioactive particle in the prostate -- have had their cancer cured.

The results of the study of 1,006 consecutive patients treated through the BC Cancer Agency's prostate brachytherapy program from 1998 to 2003 will be published in this week's edition of the medical journal Urology.

The cancer agency said 95 per cent of men did not experience a biochemical recurrence--a rise in the blood level of PSA (prostate-specific antigen)--following brachytherapy,"which indicates a likely cure of prostate cancer."

"These are excellent results, demonstrating that brachytherapy should be considered the gold-standard treatment for men with localized prostate cancer,"Dr. Mira Keyes, head of the BC Cancer Agency's brachytherapy program, said Wednesday.
"We have only had one patient whose cancer reoccurred after five years."

Localized prostate cancer is early-stage cancer which has not spread outside of the prostate.

Men in the study group also experienced low rates of metastasis--spread of cancer--and death from cancer, she said.

To date, over 2,500 men have been treated by the agency using brachytherapy.

Other forms of treatment for prostate cancer are surgery to remove the cancer mass, or external beam radiation to destroy it.

Keyes said the agency has developed a fourth method called active surveillance, in which a man diagnosed in the early stages of prostate cancer will have his condition monitored and will be treated only if the cancer advances.

Keyes said the sexual potency rate is higher with brachytherapy than with surgery.

Phase II Trial Of Zolinza With Velcade

2009-01-30T14:19:00.001-07:00

The Multiple Myeloma Research Consortium (MMRC) announced a Phase IIb study of Zolinza®, an oral histone deacetylase (HDAC) inhibitor, in combination with Velcade® for Injection, a proteasome inhibitor, in patients with relapsed and refractory multiple myeloma. The study is open for enrollment. This international, multicenter, open-label clinical trial is sponsored by Merck & Co. and is part of the VANTAGE (Vorinostat Clinical Trials in Hematologic and Solid Malignancies) program.

The trial will enroll 142 patients from more than 60 clinical centers including the following MMRC Member Institutions: City of Hope, Dana-Farber Cancer Institute, Emory University's Winship Cancer Institute, Hackensack University Medical Center, St. Vincent's Comprehensive Cancer Center of Saint Vincent Catholic Medical Centers of New York, and University Health Network (Princess Margaret Hospital). Patients must be refractory to Velcade taken alone or in combination with other anti-myeloma therapies and have been exposed to prior immunomodulatory therapies, such as Revlimid® (lenalidomide, Celgene Corporation) or Thalomid® (thalidomide, Celgene Corporation). The study will assess the objective response rate as well as progression-free survival, overall survival, time to disease progression and tolerability of the combination.

"Vorinostat is one of a promising class of drugs that may offer a new treatment option for patients with multiple myeloma, particularly when combined with bortezomib," said Kenneth Anderson, MD, a member of the MMRC Steering Committee and Chief of the Division of Hematologic Neoplasia and Director of the Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute.

For more information about this and other clinical trials, please visit http://www.myelomatrials.org or call 866-603-MMCT (6628).

About Zolinza Zolinza is approved in the United States for treatment of cutaneous manifestations in patients with cutaneous T-cell lymphoma (CTCL) who have progressive, persistent or recurrent disease on or following two systemic therapies. In addition to the Phase II-b study, Merck has also initiated a Phase III, global, randomized, double-blind, placebo-controlled, multi-center trial (Vantage 088) investigating Zolinza in combination with Velcade in patients with relapsed multiple myeloma after 1-3 prior anti-myeloma regimen. The Phase III trial will enroll 742 patients at more than 200 centers. The study will compare progression-free survival in patients taking Velcade in combination with either Zolinza or placebo. The study is open for enrollment.

Clinical features associated with a response to bortezomib

2009-01-30T14:16:00.001-07:00

Dawson MA, Opat SS, Taouk Y, Donovan M, Zammit M, Monaghan K, Horvath N, Roberts AW, Prince HM, Hertzberg M, McLean CA, Spencer A.

Clinical Haematology/Bone Marrow Transplant Department, The Alfred Hospital, Commercial Road, Prahran, Melbourne, Victoria, Australia 3181.

PURPOSE: Multiple myeloma is an incurable disease with heterogeneous clinical behavior. Bortezomib has offered some patients with relapsed and refractory disease an opportunity for prolonged survival. However, there remains a paucity of data in patients treated with bortezomib that accurately delineates and identifies such patients. This information is crucial to guide management. EXPERIMENTAL DESIGN: In this study, we aimed to identify the patients most likely to respond to bortezomib salvage therapy. We analyzed the baseline clinical variables and profiled the baseline expression of a broad range of immunohistochemical markers of cell cycle activity, apoptosis, and angiogenesis in a large cohort of multiply relapsed myeloma patients recruited to one of two prospective multicentre trials assessing the efficacy of bortezomib salvage therapy. RESULTS: Using the European Group for Bone Marrow Transplantation criteria, response (complete or partial) to bortezomib salvage therapy was associated with a previous history of complete response to alternative antimyeloma treatment. Patients who expressed cyclin D1 were more likely to achieve a response. In contrast, patients who expressed p16(INK4A), cytoplasmic p53, and the highest intensity of Bcl-2 staining had a poor response. Patients who achieved a response to bortezomib and those patients who expressed cyclin D1 at baseline showed a significant survival advantage. Patients who expressed FGFR3, a poor prognostic marker, responded equally well and had similar outcomes with bortezomib compared with FGFR3-negative patients. CONCLUSIONS: Baseline clinical variables and selective immunohistochemical markers expressed by patients may be used effectively to identify patients that are most likely to achieve a meaningful clinical response to bortezomib salvage therapy.

PMID: 19147779 [PubMed - in process]

Expected long-term survival of patients diagnosed with multiple myeloma in 2006-2010

2009-01-28T21:33:00.001-07:00

Brenner H, Gondos A, Pulte D.

German Cancer Research Center, Heidelberg, Germany.

New therapeutic options have led to substantial increases in survival expectations of younger patients with multiple myeloma in recent years. In the past, the impact of these innovations on long-term survival has been disclosed only with substantial delay. We aimed to derive up-to-date estimates of long-term survival expectations of concurrently diagnosed multiple myeloma patients. Using data from the 1973-2005 database of the Surveillance, Epidemiology, and End Results (SEER) Program, we employed a novel model-based projection method to project 5-and 10-year relative survival expectations of multiple myeloma patients in the United States diagnosed in 2006-2010. Preliminary empirical evaluation of the method using historical data indicated good performance. Projected 5-year relative survival for patients diagnosed in 2006-2010 below 45 years of age is 68.0%, which exceeds the most up-to-date estimates obtained from traditional cohort and period analysis by 15.5 and 7.0 percent units respectively. Ten-year relative survival projection for patients in this age group is 55.3%, exceeding the most up-to-date estimates from traditional cohort and period analysis by 19.7 and 7.4 percent units respectively. By contrast, survival projections remain much lower and hardly exceed estimates from traditional survival analysis for older patients. Patients diagnosed with multiple myeloma in 2006-2010, especially those diagnosed at younger ages, are expected to have much higher long-term survival perspectives than suggested by previously available survival statistics.
PMID: 19144659 [PubMed - as supplied by publisher]

Videos from ASH 2008 on the Web

2009-01-28T15:47:00.001-07:00

http://myeloma.org/main.jsp?source=link&source_link_id=3768&type=index&tab_id=1&menu_id=0&id=175

The IMF is pleased to provide you with a broad sampling of myeloma presentations and posters from the 2008 annual meeting of the American Society of Hematology in San Francisco, California. They report significant progress in myeloma research. IMF Scientific Advisor, Dr. Morie Gertz said, "This is the most exciting ASH meeting that I've been to, and I've been a member for over 25 years."

Nifuroxazide inhibits survival of multiple myeloma cells

2009-01-27T13:19:00.000-07:00

Erik A. Nelson1, Sarah R. Walker1, Alicia Kepich1, Laurie B. Gashin1, Teru Hideshima1, Hiroshi Ikeda1, Dharminder Chauhan1, Kenneth C. Anderson1,2, and David A. Frank1,2

1 Department of Medical Oncology, Dana-Farber Cancer Institute, and 2 Departments of Medicine, Harvard Medical School and Brigham and Women's Hospital, Boston, MA

Constitutive activation of the transcription factor STAT3 contributes to the pathogenesis of many cancers, including multiple myeloma (MM). Since STAT3 is dispensable in most normal tissue, targeted inhibition of STAT3 is an attractive therapy for patients with these cancers. To identify STAT3 inhibitors, we developed a transcriptionally based assay and screened a library of compounds known to be safe in humans. We found the drug nifuroxazide to be an effective inhibitor of STAT3 function. Nifuroxazide inhibits the constitutive phosphorylation of STAT3 in MM cells by reducing Jak kinase autophosphorylation, and leads to down-regulation of the STAT3 target gene Mcl-1. Nifuroxazide causes a decrease in viability of primary myeloma cells and myeloma cell lines containing STAT3 activation, but not normal peripheral blood mononuclear cells. Although bone marrow stromal cells provide survival signals to myeloma cells, nifuroxazide can overcome this survival advantage. Reflecting the interaction of STAT3 with other cellular pathways, nifuroxazide shows enhanced cytotoxicity when combined with either the histone deacetylase inhibitor depsipeptide or the MEK inhibitor UO126.
Therefore, using a mechanistic-based screen, we identified the clinically relevant drug nifuroxazide as a potent inhibitor of STAT signaling that shows cytotoxicity against myeloma cells that depend on STAT3 for survival.

New Agents for Multiple Myeloma treatment presented at ASH 2008

2009-01-26T20:41:00.002-07:00

At the 2008 meeting of the American Society of Hematology in San Francisco in December, there were several oral presentations of new and promising agents for the treatment of patients with multiple myeloma.

Zolinza™ (vorinostat) and Velcade®
Zolinza is a histone deacetylase inhibitior that is being tested in a variety of lymphoid malignances. On October 6, 2006, the U.S. Food and Drug Administration approved Zolinza for the treatment of the cutaneous manifestations of cutaneous T-cell lymphoma (CTCL) in patients with progressive, persistent, or recurrent disease following two systemic therapies. At ASH 2008, U.S. researchers reported that the combination of Zolinza™ (vorinostat) and Velcade® (bortezomib) is active for the treatment of relapsed/refractory myeloma.[1] There were 34 patients with relapsed/refractory myeloma in this study. The partial response rate was 26%, with an additional 21% having a minimal response and 53% having stable disease. Dexamethasone was added to Zolinza and Velcade in 21 additional patients. Two achieved a very good partial response, seven had a partial response, and 10 had stable disease. These authors concluded that the combination of Zolinza and Velcade was active even in patients previously treated with Velcade.

Carfilzomib and Dexamethasone
Carfilzomib is a novel, irreversible, epoxomicin-related proteasome inhibitor. Carfilzomib currently has orphan drug status for the treatment of multiple myeloma. Preclinical studies have shown that carfilzomib can overcome the resistance of myeloma cells to conventional agents and acts synergistically with dexamethasone.[2] At ASH 2008 researchers involved in a U.S. multi-center trial (PX-171-004) reported that carfilzomib and dexamethasone was a promising new agent for the treatment of myeloma.[3] There were 31 patients with relapsed myeloma in this study. Eighty-seven percent had received a prior stem cell transplant. For 13 patients who had not received Velcade, the overall response rate was 54%, including one complete response, two very good partial responses, and four partial responses; four patients had stable disease. Sixteen patients had received prior treatment with Velcade, and 19% achieved a partial response. One patient had a minimal response, and nine had stable disease.
A second study (PX-171-003) evaluated carfilzomib in 39 patients, all of whom had received prior treatment with Velcade; in addition, 89% had received a prior stem cell transplant.[4] The clinical benefit rate was 26%, including five patients with a partial response.
Carfilzomib will undoubtedly be evaluated in patients with less advanced disease and probably compared with Velcade for up-front treatment of myeloma.

Pomalidomide (CC4047)
Pomalidomide is an oral analog of thalidomide with significant immunomodulatory effects. It stops the growth of blood vessels, stimulates the immune system, and may directly kill cancer cells. Pomalidomide is also an inhibitor of angiogenesis. A Phase I study showed a complete remission rate of 17% in patients with relapsed or refractory myeloma with daily pomalidomide.[5] Fifty-four percent of patients in this study had a 50% or greater decrease in paraprotein. The main side effects were deep vein thrombosis, which occurred early and late. A Phase II study used an alternate day regimen of pomalidomide in an attempt to decrease thrombotic side effects.[6] The alternate day schedule appeared to eliminate thrombotic complications. There were 20 patients in this study, and the complete response rate was 10%; a greater than 50% reduction in paraprotein was achieved in half the patients. At ASH 2008 daily pomalidomide and low-dose dexamethasone were evaluated in 37 patients with relapsed or refractory myeloma.[7] All patients receive aspirin for prophylaxis against thrombotic complications. Seventy-six percent of patients had received a prior stem cell transplant, and 62% had received Thalomid® (thalidomide) or Revlimid® (lenalidomide). The overall response rate was 62%, and 24% had a very good partial response. The response was 29% in patients who had received prior Revlimid. Pomalidomide promises to be a rival of Revlimid and Thalomid in the treatment of patients with myeloma.

CNTO 328
CNTO 328 is a chimeric monoclonal antibody that specifically binds to and neutralizes human IL-6 with high affinity. A Phase I study has been performed in patients with lymphoma and myeloma. Preclinical studies suggest synergy of CNTO with Velcade.[8] At ASH 2008 researchers involved in a U.S. multi-center trial reported that the combination of Velcade and CNTO 328 was active in patients with relapsed or refractory myeloma.[9] This study included 21 patients, of whom 11 had received a prior stem cell transplant and eight had received prior Velcade or Thalomid. Fifty-seven percent achieved a partial or complete remission, and the median time to disease progression was 280 days. These authors will be performing a trial of Velcade plus CNTO 328 versus Velcade and placebo.

Velcade® and Perifosine
Researchers from several U.S. institutions have reported a 40% overall response rate to the combination of perifosine and Velcade® (bortizomib) in patients with multiple myeloma who had been previously treated with Velcade.[10] Perifosine belongs to a new class of anti-tumor drugs that targets cell membranes, inhibits Akt activation, and induces apoptosis.
The current study involved the treatment of 76 patients with relapsed/refractory multiple myeloma treated with perifosine and Velcade with or without dexamethasone. All patients had received prior therapy with Velcade and 35 were deemed refractory to Velcade. Fifty-seven patients in this study were evaluable for response. The overall response rate was 40%, with 30% having stable disease. The median time to tumor progression for all patients was 19 weeks, while the median time to tumor progression for responders had not been achieved. The overall response rate for patients deemed refractory to Velcade was 37%, and the median time to tumor progression was 23 weeks. The combination of Velcade and perifosine was described as well tolerated. These data suggest that pirifosine may be a new useful agent for the treatment of patients with myeloma.
Comments: It appears that new and novel agents for the treatment of multiple myeloma are continuing to be developed at a relatively rapid rate; many of these may have a major impact on future therapy.

References:
[1] Weber D, Badros AZ, Jagannath S, et al. Vorinostat plus bortezomib for the treatment of relapsed/refractory multiple myeloma: Early clinical experience. Blood. 2008;112:322, abstract number 871.
[2] Kuhn DJ, Chen O, Voorhees PM, et al. Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquin-proteasome pathway, against preclinical models of multiple myeloma. Blood. 2008;110:3281-3290.
[3] Vij R, Wang M, Orlowski R, et al. Initial results of PX-171-004, an open-label, single-arm, phase II study of carfilzommib (CFZ) in patients with relapsed myeloma (MM). Blood. 2008;112:320, abstract number 865.
[4] Jagannath S, Vij R, Stewart AK, et al. Initial results of PX-171-003, an open-labele, single-arm, phase II study of carfilzomib (CFZ) in patients with relapsed and refractory multiple myeloma (MM). Blood. 2008;112:319, abstract number 864.
[5] Schey SA, Field SP, Bartlett JB, et al. Phase I study of an immunomodulator thalidomide analog, CC-4047, in relapsed or refractory multiple myeloma. Journal of Clinical Oncology. 2008;22:3269-3276.
[6] Streetly MJ, Gyertson K, Daniel Y, et al. Alternate day pomalidomide retains anti-myeloma effect with reduced adverse events and evidence of in vivo immunomodulation. British Journal of Haematology. 2008;141:41-51.
[7] Lacy MQ, Hayman SR, Gertz MA, et al. Pomalidomide (CC4047) plus low-dose dexamethasone (Pom/dex) is highly effective therapy in relapsed multiple myeloma. Blood. 2008;112:320, abstract number 866.
[8] Voorhees PM, Chen O, Kuhn DJ, et al. Inhibition of interleukin-6 signaling with CNTO 328 enhances the activity of bortezomib in preclinical models of multiple myeloma. Clinical Cancer Research. 2007;13:6469-6478.
[9] Rossi J-F, Manges RF, Sutherland HJ, et al. Preliminary results of CNTO 328, an anti-interleukin-6 monoclonal antibody, in combination with bortezomib in the treatment of relapsed or refractory multiple myeloma. Blood. 2008;112:320, abstract number 867.
[10] Richardson P, Wolf J, Jakubowiak et al. Phase I/II results of a multicenter trial of perisosine (KRX-0401) + bortezomib in patients with relapsed or relapsed/refractory multiple myeloma who were previously relapsed from or refractory to bortezomib. Blood. 2008;112:321, abstract number 870.

1.2 Million Dollars Awarded to Institute for Myeloma and Bone Cancer Research

2009-01-26T16:52:00.000-07:00

FJC, a foundation of philanthropic donor-advised funds and the Myeloma Research Foundation are the latest major donors to the "Cure Myeloma Project", an ongoing research initiative at the Institute for Myeloma and Bone Cancer Research, (IMBCR), in Los Angeles, CA.

IMBCR's "Cure Myeloma Project" is the nation's foremost effort to find a cure for multiple myeloma, a blood cancer that resides in bone marrow. Led by premier scientists in the world of myeloma research, James R. Berenson, M.D., Haiming Chen, M.D., Ph.D. and Zhi-Wei Li, Ph.D., this multi-phase research project's overall goal is to specifically target myeloma cells while leaving surrounding healthy cells untouched.

Over the past five years, researchers and scientists at IMBCR have been responsible for creating many of the novel therapeutics currently used to extend the quality of life and lifespan of myeloma patients throughout the world.
About Multiple Myeloma and Blood Cancers: The American Cancer Society predicts that over 80,000 people are currently living with myeloma in the US and over 20,000 new cases are diagnosed each year. Approximately 10,000 people die each year from multiple myeloma. The Leukemia & Lymphoma Society estimates that 894,543 people in the US are presently battling blood cancers that include leukemia, lymphoma and myeloma. Blood cancers are the second most fatal form of cancer, second only to lung cancer.

About IMBCR: Headquartered in Los Angeles, California, IMBCR is the only independent non-profit cancer research institute working to find improved treatment, and ultimately a cure for multiple myeloma and other forms of blood cancer. IMBCR research findings have been presented at numerous scientific meetings throughout the world and its research has been published in most major oncology journals. www.imbcr.org

Acidic diet eats away at your health, author says (Edmonton Journal, 19 Jan 2009, Page D2)

2009-01-19T11:20:00.001-07:00

Acidic diet eats away at your health, author says
MICHELLE MAGNAN
Edmonton Journal
19 Jan 2009

How acidic are you today? Pee on a piece of pH test paper, which tells you whether your body is acidic or alkaline based on the pH scale of 14, and you’ll find out. If your diet consists of typical foods — foods that are high in starch, fat and sugar...read more...

Cylene Initiates Phase I Trial of CX-4945

2009-01-17T17:53:00.001-07:00

Cylene Pharmaceuticals announced that it has initiated a Phase I clinical trial of its oral CK2 protein kinase
inhibitor, CX-4945, in patients with advanced solid tumors, Castleman's disease, or multiple myeloma. The primary endpoints of the oral dose escalating trial are determination of safety, tolerance and PK properties of CX-4945 and to select the appropriate dose for Phase II trials. In addition, multiple mechanism-related pharmacodynamic biomarkers that were validated in preclinical studies will also be evaluated in the trial to assess the ability of CX-4945 to hit its target in patients.

CX-4945 is a first-in-class, orally administered small molecule anticancer agent that delivers highly selective and potent inhibition of CK2, a constitutively active protein kinase that is overexpressed in a wide range of cancers. CK2 drives the excessive proliferation phenotype of cancer cells through its potentiating role in key cell survival pathways and angiogenesis. CX-4945 demonstrates potent tumor regression activity in murine xenograft models, as well as favorable PK/ADMET and safety properties in preclinical studies.

"CK2 overexpression drives key cell survival pathways and proliferation of cancer cells, but it has been notoriously difficult to inhibit because it has an unusual active site. CX-4945 represents the first potent and selective inhibitor of CK2 with a favorable safety profile and the ability to promote tumor regressions as a single agent in preclinical studies. We are delighted to have advanced CX-4945 into the clinic ahead of schedule, and we are thoughtfully planning our Phase II program in particular CK2 driven cancers."

The primary objectives of the study will be to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLTs) of CX-4945, and to define the phase II dose. The secondary objectives are to characterize the pharmacokinetics, as well as observe for signs of anti-tumor activity via pharmacodynamic as well as radiographic assessments.

About CX-4945: an oral CK2 protein kinase inhibitor, CX-4945 is a first-in-class small molecule that has been optimized to selectively inhibit CK2 activity. The CK2 protein kinase plays a multifunctional role in cell cycle regulation, signal transduction, transcriptional control, angiogenesis, apoptosis and inflammation. Because CK2 contributes to the cancer phenotype via multiple cellular events, CX-4945 has been designed with the objective of creating a multifunctional inhibitor by targeting a single protein and affecting potentially many cancers. CX-4945 demonstrates broad spectrum anti-proliferative activity against diverse cancer cell lines, and the data attribute the anti-tumor activity of CX-4945 to intracellular inhibition of the CK2 enzyme.

Source: Cylene Pharmaceuticals

Trial of 'accurate' radiotherapy

2009-01-07T17:33:00.001-07:00

Clinical trials are being carried out in the UK using radiotherapy that is highly targeted so can be given at much greater doses to destroy cancerous cells in the bone marrow without harming healthy cells.

Pauline Pain, 58, became the first patient in the world to receive the radiotherapy. Mrs Pain, who has multiple myeloma, was able to return home after her radiotherapy to await her bone marrow transplant. A conventional total body irradiation would have meant a long stay in hospital.

She said: "The only side-effects were a little temporary tiredness and mild sickness; other than that I felt very, very well. It was incredible to be walking around knowing that something inside me was fighting the cancer, but I couldn't feel it at all.
"The beauty of it was that I had the big dose of radiotherapy in the morning and I was at home by 5pm the same evening."

The two-year trial at Southampton General Hospital will involve 80 patients, half of whom will receive the new radiotherapy with chemotherapy and the other half will have chemotherapy alone.

The early results are "very encouraging", doctors said.

The radiotherapy is used to kill the cancer cells in the system before a transplant of healthy stem cells to replace the lost ones. The same dose of traditional radiotherapy would cause severe or even fatal damage to the body, proving toxic to the liver and kidneys. But because the new system delivers a radioisotope that attaches only to the surface of cancer cells, the healthy tissue is not affected.

Dr Kim Orchard, a senior lecturer at the University of Southampton's School of Medicine who is leading the trial, said: "Radiotherapy is used to clear the bone marrow of myeloma cells before a stem-cell transplant. Current treatment uses high doses of radiation, which are delivered by X-rays, but the sensitivity of healthy organs limits the dose that can be tolerated.

"Previous attempts to use antibodies to deliver the radioactivity have been frustrated by their accumulation in the liver, lungs and kidneys, which can cause grave complications. The key to this new treatment is that the antibody accumulates only in the bone marrow.

"We hope that the trial will show a clear benefit in better and longer remissions from myeloma. If we are successful, this approach offers great promise for the treatment of a range of other blood cancers."

Dr David Grant, Scientific Consultant at Leukaemia Research, which is funding the study, said: "This trial is very exciting. One of the main reasons why stem cell transplants have been less successful in the long-term treatment of myeloma is that patients are not cleared of all the cancer cells before the transplant.

"This new radiotherapy is not only more effective and potentially cheaper than existing treatments, it is far less toxic for the patient. It also enables patients to go home immediately after the procedure, reducing time spent in hospital."

Xencor to Present Data from Pre-Clinical Antibody Programs at ASH

2008-12-02T17:33:00.000-07:00

Xencor, Inc., a company developing protein and antibody therapeutics, will present new data from its pre-clinical anti-CD19 and anti-CD40 programs, XmAb®5574 and XmAb®5485 respectively, for lymphoma and leukemias at the 50th Annual Meeting of the American Society of Hematology (ASH) being held at the Moscone Convention Center in San Francisco December 6-9, 2008.

New data from the XmAb5574 program will be presented in a poster session titled, “XmAb®5574, an Fc-Engineered Humanized Anti-CD19 Monoclonal Antibody, has Potent In Vitro and In Vivo Activities, and has the Potential for Treating B Cell Malignancies.”

The Company will present XmAb5485 data in an oral presentation titled, “An Fc-Engineered Humanized Anti-CD40 Monoclonal Antibody, XmAb5485, Exhibits Potent Activity In Vitro and In Vivo Against Non-Hodgkin Lymphoma, Chronic Lymphocytic Leukemia and Multiple Myeloma.”

About XmAb®5574
XmAb®5574 is a humanized monoclonal antibody that targets the antigen CD19 for treatment of B cell malignancies and autoimmune diseases. XmAb®5574 contains a proprietary Xencor XmAb Fc domain that enhances cytotoxic potency and also downregulates B cell activation.

About XmAb®5485
XmAb®5485 is a humanized monoclonal antibody that targets the antigen CD40 for treatment of B cell malignancies and autoimmune diseases, and contains a proprietary Xencor XmAb® Fc domain that enhances cytotoxic potency.

About Xencor
Xencor, Inc. engineers superior biotherapeutics using its proprietary Protein Design Automation® technology platform and is a leader in the field of antibody Fc engineering to significantly improve antibody potency and half-life. The company is advancing XmAb® antibody drug candidates optimized for activity against biologically validated targets and its XPro™ protein therapeutic candidate into the clinic. Xencor's product development is led by an antibody candidate, XmAb®2513, in a Phase I clinical trial for the treatment of Hodgkin lymphoma and anaplastic large cell lymphoma, and a protein therapeutic drug candidate, XPro™1595 DN-TNF, for the treatment of inflammatory disease. With multiple partners, such as industry leaders Genentech, Boehringer Ingelheim, MedImmune and Human Genome Sciences, Xencor is applying its suite of XmAb antibody Fc domains to improve antibody drug candidates for traits such as potency and sustained half-life.

Source: www.xencor.com

IMF Announces Research Agreement with Nobel Prize Winner Luc Montagnier and Howard Urnovitz of Chronix Biomedical

2008-11-18T11:30:00.001-07:00

--Will Study Circulating DNA as a Marker for and Potential Cause of Disease Recurrence--

The International Myeloma Foundation (IMF) today announced plans to establish a research partnership between IMF chairman Brian G.M. Durie, M.D.; Luc Montagnier, M.D., co-recipient of the 2008 Nobel Prize in medicine; and Howard Urnovitz, Ph.D., CEO of Chronix Biomedical. The collaboration will study cancers that affect the immune system including multiple myeloma. The partnership will build on Dr. Montagnier's pioneering work with HIV; both AIDS and myeloma involve white blood cells in the immune system, and to date cannot be cured. Dr. Urnovitz studies genetic changes that take place over the course of a disease and uses the findings to aid in the diagnosis of cancer.

Their collaborative work will focus on circulating nucleic acids -- genomic sequences of DNA and RNA that travel in the blood stream - and the emerging understanding of their role in disease. In an abstract published in connection with the upcoming annual meeting of the American Society of Hematology, Drs. Durie and Urnovitz report they have identified specific DNA sequences circulating in the blood of myeloma patients that increase or decrease as the myeloma moves in and out of remission. While they look at DNA sequences that originate within the body, Dr. Montagnier will contribute new technology to the collaboration that can detect external DNA sequences related to infectious agents.

"These are intriguing biomarkers that point to processes underlying disease states," said Dr. Montagnier who is best known for his role in discovering the virus that causes AIDS. "They may be a sign of a persistent infectious process or may even be the cause. New technology I am developing to detect infectious disease agents at a new level of sensitivity is one of the key factors that will advance our ability to study diseases such as myeloma."

Dr. Durie added: "Tests for these DNA sequences circulating in the blood may become an important tool for physicians, telling them when disease is starting to recur so they know when to intervene. A greater understanding of these DNA sequences may also tell us whether we should be attacking the cancer cells, as we do now, or whether we should be looking for an underlying agent that may be the cause of the cancer and its recurrence."

Plans for the collaboration will allow all three partners to support each other, while each group will retain the rights to their own specific areas of research. For Dr. Montagnier this is the role of infectious agents, for Dr. Urnovitz the role of genetic changes, and for Dr. Durie this is applications of the findings to cancer.

Dr. Urnovitz says, "This work is made possible by powerful new technology. At Chronix we are publishing a paper about the first application of new mass-sequencing technology in the detection of chronic illnesses. Our approach coupled with Dr. Montagnier's new technology will give us new opportunities to measure genomic biomarkers while detecting infectious agents. This research partnership will utilize the combination of these new biotechnologic tools, allowing us to design new approaches in the treatment and prevention of cancer."

The relationship will be a global collaboration with Dr. Durie in the U.S., Dr. Montagnier based in France and Dr. Urnovitz based at Chronix Biomedical in Germany.

Using Computers to match drugs with genes

2008-11-06T08:57:00.002-07:00

RevolutionariesMerck's Free RadicalMatthew Herper 11.10.08
Cancer drugs don't help 75% of the people who take them. Stephen Friend says he can use science to end the crapshoot

In the downtrodden drug industry, Merck cancer guru Stephen Friend may be one of the last great dreamers. His latest idea is one that would completely change the secretive and siloed way the pharmaceutical business fights cancer: create a giant, open-to-the-public database that will include every cancer drug and every patient and how that patient is doing. Track everything and over time we might be able to raise the abysmal success rate of treatment.

Friend, 54, has been a doctor who treated kids with cancer, an academic, an entrepreneur and a biotech chief executive. He helped develop a diagnostic test that predicts whether breast cancer will return after surgery. For five years he has been in charge of getting cancer drugs invented at Merck. Now 8 are in clinical trials, up from one, with 15 more preparing to enter trials. Friend is still unsatisfied. Why is it that, on average, three out of every four people who take a cancer medicine get lots of side effects but no benefit?

Researchers have been too willing to bet on hunches, he says, yet the technology to understand the complex biology of cancer is at hand. Spurred by Friend, Merck has spent billions on an arsenal of technologies for understanding how genes work. The resulting data stream is sent through the fastest supercomputer in the drug industry, a beast that consumes 64 kilowatts of power and is capable of 16 trillion calculations a second. Friend thinks he can accurately predict how groups of proteins in tumors work together and use that information to kill the cancer. He's trying to drag the secretive world of drug-discovery chemistry into the computer age.

The Friend way would take all the data collected each year from the thousands of cancer patients entered in trials, make it anonymous and put it into one database, preferably held by the government but definitely accessible to any physician or scientist. Right now those data are lost to the wind once the trial is over. But by keeping track of patients' genes, the genes in their tumors and what drugs they take, scientists will be able to discern patterns. Instead of trying drugs in order, from the ones that work most often to those that work least often, doctors will be able to pick the medicine that is most likely to help a particular patient. New medicines will get to market faster, along with diagnostic tests that will predict what will work. Friend predicts, somewhat optimistically, that prescribing decisions won't be based on "a promotional campaign." The database will decide.

"That future world is coming," says Friend. "And pharmaceutical companies can live in that world. If you develop the best drug and develop it for the right patient, all this does is get it to that right
patient."

Merck has not done much so far to open its trial data to the world, nor have its rivals, but Merck has less to lose here and more to gain. It has fewer cancer drugs in human tests than Pfizer or AstraZeneca, and its shares have dropped by half this year. Friend is powering ahead, building a first stab at the big database with the H. Lee Moffitt Cancer Center in Tampa, Fla. Over the next five years every patient who walks through Moffitt's door will be asked to put genes and tumor samples in a database that will number 100,000 patients; 5,000 are already in. The database will provide information to the doctors doing research there and, eventually, to patients. If it turns out you have a gene that tells researchers what drug will work for you, Merck and Moffitt plan to let you know. Experiments that would have required weeks of thawing tumor samples now take a matter of hours.

"Right now most of medicine is based on a bunch of gray-haired guys who say, 'This is the way I do it and it seems to work,'" says Moffitt Director Bill S. Dalton. "We need to determine over time what is useful and what isn't. The only way to do that is to study 100,000 patients."

The database idea is taking root elsewhere. The U.S. government is funding a Cancer Genome Atlas, in order to figure out how a large database would work. The Multiple Myeloma Research Consortium has funded the collection of 1,900 patients' bone marrow samples that are being studied by the mit-Harvard Broad Institute, a genetic research center. New data from that effort will be available within months.

A megadatabase "could save me months or years of trying to collect patient information," says Oregon Health & Science University oncologist Brian Druker, who helped get Novartis' potent tumor-fighter Gleevec to the market. But he questions whether researchers understand cancer biology well enough for Friend's highly computational approach to pay off in the short term. "Over the long term the Merck strategy will be the winning strategy," says Druker. "But right now I don't think we're quite there."

Merck has spent the past few years trying to dig out of one of the toughest periods of its 120-year history. In 2003 several experimental drugs for various diseases failed, all at once. In 2004 the blockbuster painkiller Vioxx was yanked because it caused heart problems. Merck settled its Vioxx liability claims last year for $5 billion.

The stock recovered as eight drugs were approved in two years, but the revival was short-lived. Sales of its Vytorin cholesterol pill, produced with Schering-Plough, have crashed under doubts about its effectiveness at preventing heart attacks. Cervical cancer vaccine Gardasil has hit a growth wall, and the Food & Drug Administration rejected a promising cholesterol drug because Merck had not collected enough safety data.

Merck hopes fighting cancer is one way out of this funk. Friend was put in charge of Merck's cancer research efforts in 2003, two years after Merck bought the company he was running, Rosetta Inpharmatics. Friend had cofounded Rosetta in 1996 with Leland Hartwell, now director of the Fred Hutchinson Cancer Research Center in Seattle, and Leroy Hood, now president of the nearby Institute for Systems Biology. Like rival Affymetrix, Rosetta began selling tiny DNA chips that could be used to figure out how often cells were accessing their genes.

Merck bought Rosetta in 2001 for $620 million. Hood and Hartwell gave their shares to their institutions. Hartwell won the Nobel Prize six months later for other work. Friend made $10 million on the sale and built himself a solar-powered, off-the-grid house on Stuart Island.

The first fruits of Rosetta's technology began to emerge with a 2002 article in the New England Journal of Medicine. Dutch researchers using Rosetta's software found a particular pattern of genetic signals within breast cancer tumors that could predict whether or not the cancer would return after surgery. The test is not a significant product for Merck but was approved by the FDA in 2007. It and a similar test made by a rival, Genomic Health of Redwood City, Calif., are widely used to guide post-op treatment strategy.

Merck has been making big acquisitions to augment Friend's technology. In 2006 Merck spent $1.1 billion in cash to buy tiny Sirna Therapeutics, a leader in a field called RNA silencing, which uses small molecules to shut off genes. These molecules can't be used as drugs because the body destroys them. But they can be used in petri dishes to turn genes on and off to find out which are important.

This technology identified a gene last year called KRAS that predicts whether targeted cancer drugs like ImClone Systems' Erbitux will work in a given cancer patient. Clinical trials confirmed this finding this year, and it turned out that 40% of the patients who were receiving Erbitux were getting no benefit. In the past this would have hurt the chances for a drug like Erbitux, but the new test makes doctors more eager to use the drug when it makes sense. Eli Lilly is now buying ImClone for $6.5 billion.

Friend has identified three families of cancer drugs that he thinks his technology can accurately understand: drugs that destroy DNA; those that mess up cell division; and drugs that block some of the most important signals in cancer cells. Noticeably absent are drugs such as Genentech's $2 billion (annual sales) Avastin, which stanches tumor blood supply. These are too complicated to understand.

He's been buying the rights to drugs that fit his interests. In 2004 Merck bought Aton Pharmaceuticals for its drug Zolinza, used to treat cutaneous T cell lymphoma. In 2007 it pledged up to $1 billion for a cancer pill from Ariad Pharmaceuticals.

All of these bets are based on what Friend's giant computer tells him. "This is going to have to be the path taken by pharma in the future," says Hood of Friend's current work. "It's a gamble, but I think it's one that if Merck sticks with it, they'll win big."

Recently Friend took a detour on his way to a research conference in Chicago. He flew to Florida, rented a 1972 Chevy Chevelle and drove to Cape Canaveral to watch the space shuttle launch. He says it wasn't just that he wanted to recapture the feeling of the space race, when scientists were treated like heroes, but that he wanted to get a sense of a project that massive and complex. Creating a cancer drug is not that different.

"The puzzle's gotten big," he says of the cancer drug hunt. "But I think there is only one way to solve it."

Curcumin, a cancer chemopreventive and chemotherapeutic agent, is a biologically active iron chelator

2008-10-26T10:14:00.000-06:00

Yan Jiao, John Wilkinson IV, Xiumin Di, Wei Wang, Heather Hatcher, Nancy D. Kock, Ralph D'Agostino Jr., Mary Ann Knovich, Frank M. Torti, and Suzy V. Torti*

Department of Cancer Biology, Wake Forest University Health Sciences, Winston-Salem, NC, United StatesDepartment of Pathology, Wake Forest University Health Sciences, Winston-Salem, NC, United StatesPublic Health Sciences, Wake Forest University Health Sciences, Winston-Salem, NC, United StatesSection of Hematology/Oncology, Wake Forest University Health Sciences, Winston-Salem, NC, United StatesComprehensive Cancer Center, Wake Forest University Health Sciences, Winston-Salem, NC, United StatesDepartment of Biochemistry, Wake Forest University Health Sciences, Winston-Salem, NC, United States
* Corresponding author; email: storti@wfubmc.edu

Curcumin is a natural product currently in human clinical trials for a variety of neoplastic, preneoplastic and inflammatory conditions. We previously observed that in cultured cells, curcumin exhibits properties of an iron chelator. To test whether the chelator activity of curcumin is sufficient to induce iron deficiency in vivo, mice were placed on diets containing graded concentrations of both iron and curcumin for 26 weeks. Mice receiving the lowest level of dietary iron exhibited borderline iron deficiency, with reductions in spleen and liver iron, but little effect on hemoglobin, hematocrit, transferrin saturation or plasma iron. Against this backdrop of subclinical iron deficiency, curcumin exerted profound effects on systemic iron, inducing a dose-dependent decline in hematocrit, hemoglobin, serum iron and transferrin saturation, the appearance of microcytic anisocytotic red blood cells, and decreases in spleen and liver iron content. Curcumin repressed synthesis of hepcidin, a peptide that plays a central role in regulation of systemic iron balance. These results demonstrate that curcumin has the potential to affect systemic iron metabolism, particularly in a settling of subclinical iron deficiency. This may affect the use of curcumin in patients with marginal iron stores or those exhibiting the anemia of cancer and chronic disease.

MMRC announces Phase 1B Study of Elotuzumab (HuLuc63) Monoclonal Antibody in combination with REVLIMID and dexamethasone

2008-10-13T19:50:00.001-06:00

The Multiple Myeloma Research Consortium (MMRC) today announced the initiation of a three-drug combination study of elotuzumab (also known as HuLuc63), a humanized anti-CS1 monoclonal IgG1 antibody administered intravenously, in combination with REVLIMID(R) (lenalidomide), and dexamethasone for the treatment of multiple myeloma in patients who are experiencing a relapse.

Emory University's Winship Cancer Institute, Washington University, and St. Vincent's Comprehensive Cancer Center of Saint Vincent Catholic Medical Centers of New York will evaluate the maximum tolerated dose of elotuzumab in combination with label dosing of lenalidomide and dexamethasone. The multi-center, open-label, dose-escalation Phase Ib study will enroll up to 26 patients.

"This three drug combination study is a pivotal study for patients with relapsed multiple myeloma as they may benefit from the synergistic effects of a new monoclonal antibody with two currently available drugs", said Principal Investigator, Sagar Lonial, MD, Associate Professor of Medicine, at Emory University's Winship Cancer Institute. "We look forward to testing this promising new combination."

About Elotuzumab
Elotuzumab (or HuLuc63) is a humanized monoclonal antibody under development by PDL BioPharma that binds to human CS1, a cell-surface glycoprotein that is highly and universally expressed on multiple myeloma cells but minimally expressed on normal cells. The antibody is currently being evaluated in Phase I clinical studies as a monotherapy and combination therapy for the treatment of relapsed multiple myeloma.

REVLIMID approved in Canada

2008-10-06T17:43:00.001-06:00

Celgene announced that its oral cancer drug REVLIMID (lenalidomide) has received marketing authorization approval from Health Canada for use in combination with dexamethasone as a treatment for patients with multiple myeloma who have received at least one prior therapy. Multiple myeloma is the second most commonly diagnosed blood cancer worldwide.

Approximately 6,000 Canadians have the disease and another 2,000 are diagnosed each year.

The authorization from Health Canada was based upon the safety and efficacy results of two large, randomized pivotal Phase III special protocol assessment trials, North American Trial MM-009 and International Trial MM-010 evaluating REVLIMID plus dexamethasone in multiple myeloma patients who have received at least one prior therapy--both published in the New England Journal of Medicine in November 2007.

REVLIMID is currently approved in the United States, the European Union, Argentina and Switzerland in combination with dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy and in Australia in combination with dexamethasone for the treatment of patients whose disease has progressed after one therapy. REVLIMID is also approved in Canada, the United States and Argentina for transfusion-dependent anemia due to low- or intermediate-1-risk MDS associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities. REVLIMID has obtained Orphan Drug designation in the EU, U.S., Switzerland and Australia.

EUropean trial of free LIght chain removal by exTEnded haemodialysis

2008-09-29T12:39:00.001-06:00

Renal failure is a frequent complication of multiple myeloma and when severe is associated with a greatly increased morbidity and mortality. The principal cause of severe renal failure in this setting is cast nephropathy, a direct consequence of high concentrations of monoclonal free light chains (FLCs) in the patient's serum.

FLC removal by extended haemodialysis, using a high cut-off dialyser, has recently been described as a novel therapeutic option in this setting.

Methods: The EUropean trial of free LIght chain removal by exTEnded haemodialysis in cast nephropathy (EuLITE) trial is a prospective, randomised, multicentre, open label clinical trial to investigate the clinical benefit of FLC removal haemodialysis in patients with cast nephropathy, dialysis dependent acute renal failure and de novo multiple myeloma. Recruitment commenced in May 2008, in total 90 patients will be recruited. Participants will be randomised, centrally, upon enrolment, to either trial chemotherapy and FLC removal haemodialysis or trial chemotherapy and standard high flux haemodialysis. Trial chemotherapy is a modified PAD regime, consisting of bortezomib, doxorubicin and dexamethasone. FLC removal haemodialysis is undertaken using two Gambro HCO 1100 dialysers in series, over an intensive treatment schedule. The primary outcome for the study is independence of dialysis at 3 months. Secondary outcomes are: duration of dialysis, reduction in serum FLC concentrations; myeloma response and survival.

Hypothesis: FLC removal haemodialysis will increase the rate of renal recovery in patients with severe renal failure secondary to cast nephropathy and de novo multiple myeloma.

Trial Registration: ISRCTN45967602

Author: Colin A Hutchison, Mark Cook, Nils Heyne, Kataja Weisel, Lucinda Billingham, Arthur R Bradwell and Paul Cockwell

Economist Article: The root of all evil?

2008-09-19T18:04:00.002-06:00

Cancer may be caused by stem cells gone bad. If that proves to be correct, it should revolutionise treatment.

MUCH of medical research is a hard slog for small reward. But, just occasionally, a finding revolutionises the field and cracks open a whole range of diseases. The discovery in the 19th century that many illnesses are caused by bacteria was one such. The unravelling of Mendelian genetics was another. It now seems likely that medical science is on the brink of a finding of equal significance. The underlying biology of that scourge of modern humanity, cancer, looks as though it is about to yield its main secret. If it does, it is possible that the headline-writer’s cliché, “a cure for cancer”, will come true over the years, just as the antibiotics that followed from the discovery of bacteria swept away previously lethal infectious diseases.

The discovery—or, rather, the hypothesis that is now being tested—is that cancers grow from stem cells in the way that healthy organs do. A stem cell is one that, when it divides, produces two unequal daughters. One remains a stem cell while the other multiplies into the sorts of cells required by its organ. This matters for cancer because, at the moment, all the cells of a tumour are seen as more or less equivalent. Therapies designed to kill them do not distinguish between them. Success is defined as eliminating as many of them as possible, so those therapies have been refined to do just that. However, if all that the therapies are doing is killing the descendants of the non-stem-cell daughters, the problem has not been eliminated. Instead of attacking the many, you have to attack the few. That means aiming at the stem cells themselves.

Not all investigators support the cancer-stem-cell hypothesis, but the share who do so is growing rapidly. A mere five years ago, few research papers on the subject were presented at big academic meetings. This year there were hundreds at one such meeting alone. Moreover, data from clinical trials based on the hypothesis suggest that it has real value for patients. As a result, drug companies have taken notice and are trying to develop substances that will kill cancer stem cells.

The virtues of self-restraint

The root cause of both cancer and stem cells is multicellularity. In the distant past, when all living things had only one cell, that cell’s reproduction was at a premium. In the body of an animal, however, most cells have taken a vow of self-denial. Reproduction is delegated to the sex cells. The rest, called somatic cells, are merely supporting actors, specialised for the tasks needed to give the sex cells a chance to get into the next generation. For this to happen required the evolution of genes that were able to curb several billion years’ worth of instinct to proliferate without killing that instinct entirely. Only then could somatic cells do their job, and be present in appropriate numbers.

The standard model of tumour formation was based on the fact that somatic cells slowly accumulate mutations. Sometimes these disable the anti-proliferation genes. If enough of the brakes come off in a somatic cell, so the theory went, it will recover its ancestral vigour and start growing into a tumour. Cancer, then, is an inevitable cost of being multicellular.

The discovery of stem cells changed this picture subtly, but importantly. Blood stem cells were found a long time ago, but only recently has it become apparent that all tissues have stem cells. The instincts of stem cells lie halfway between those of sex cells and ordinary body cells. They never stop reproducing, but they cannot look forward to making the generational leap. When the body dies, so do they. However, they are few in number, and because at cell division only one daughter continues to be a stem cell, that number does not grow.

This division of labour may even be another type of anti-cancer mechanism. It allows stringent locks to be put on somatic cells (which, for example, strictly limit the number of times they can divide), yet it permits tissue to be renewed. Without stem cells, such tissue-renewal would be the province of any and every somatic cell—a recipe, as the traditional model observes, for tumorous disaster. The obverse of this, however, is that if a stem cell does mutate into something bad, it is likely to be very bad indeed. That, in essence, is the stem-cell hypothesis of cancer.

One obvious prediction of this hypothesis is that tumours will have at least two sorts of cell in them: a dominant population of daughter cells and a minority one of stem cells. The first person to show that to be true was John Dick, a molecular biologist at the University of Toronto. In 1997 he isolated what looked like stem cells from a blood cancer called acute myeloid leukaemia (AML). Blood cancers are easier to deal with in this context than solid tumours because their cells do not have to be separated from one another before they are examined. One characteristic of AML cells is that they have two sorts of a protein, called CD34 and CD38, on their surfaces. Dr Dick thus used two sets of special antibodies for his experiment. One sort stuck only to the CD34 molecule, the other only to CD38. Each sort was also attached to a fluorescent tag.

By mixing the AML cells from his patients with the two antibodies and running them through a machine that sorted them according to how they fluoresced, he showed that most were positive for both proteins. However, a small fraction (as low as 0.2%) were positive only for CD34. These, he suspected, were the stem cells.

He was able to confirm this by injecting the minority cells into mice. The resulting tumours had the same mix of cells as those from human patients. However, when he injected mice with samples from the majority cells, with both sorts of the protein, no tumours resulted. The CD34-only cells thus acted as cancer stem cells.

Moreover, this phenomenon was not confined to leukaemia. In 2003 a group of researchers at the University of Michigan in Ann Arbor, led by Max Wicha and Michael Clarke, used a similar trick on breast-cancer cells. In this case the surface proteins were known as CD24 and CD44, and the minority were those positive only for CD44. As with AML, these minority cells produced cancers in mice, whereas the majority cells did not.

Since these two pieces of work, the list of cancer stem cells has multiplied. It now includes tumours of the breast, brain, prostate, colon, pancreas, ovary, lung, bladder, head and neck, as well as melanoma, sarcoma, AML, chronic myelogenous leukaemia, Hodgkin’s lymphoma and myeloma.

That is quite a list. The question is, what can be done with it? Jeremy Rich, a neurologist at Duke University in Durham, North Carolina, has one idea. He created mice that had human glioblastoma tumours, a form of brain cancer, growing in them. Then he treated these mice with radiation (the standard therapy for such cancer in people). He found that the cancer stem cells were more likely to survive this treatment than the other cells in the tumour. That turned out to be because, although all the tumour cells suffered equal amounts of DNA damage from the radiation, the stem cells were better able to repair this damage. When he treated the mice simultaneously with radiation and with a drug that interferes with DNA repair, however, the stem cells no longer had an advantage. They were killed by the radiation along with the other cells.

If that result applies to people as well as rodents, it opens up a whole avenue of possibility. In fact, Dr Rich is now in negotiations with several companies, with a view to testing the idea in humans. That “if” is a real one, though. A mouse is not a human being.

Indeed, the stem-cell hypothesis is often criticised for its reliance on animal models of disease. Some researchers worry that the experiments used to identify putative cancer stem cells are too far removed from reality—human tumour cells do not naturally need to survive in mice—and thus may not reflect human cancer biology at all.

Proponents of the hypothesis are alive to that concern, but they think that the same pattern has been seen so often in so many different cancers that it is unlikely to be completely wrong. The practical test, though, will be whether the hypothesis and ideas that emanate from it, such as Dr Rich’s combination therapy, actually help patients survive.

Searching for the suspects

As a step towards discovering whether they do, William Matsui, an oncologist at Johns Hopkins University School of Medicine in Baltimore, looked for cancer stem cells in pancreatic-tumour samples taken from nearly 300 patients. His team found that patients whose tumours did contain such stem cells survived for an average of 14 months. Those whose tumours lacked them survived for 18 months.

That finding is consistent with the idea that cancer stem cells contribute to the most aggressive forms of the disease, though it does not prove they cause tumours in the first place. And although the absence of detectable stem cells in some tumours may be seen as casting doubt on the whole idea, it may instead be that they are too rare to be easily detected. If the stem-cell idea is confirmed, it may help doctors and patients choose how to treat different tumours. Those with detectable stem cells might be candidates for aggressive chemical and radiation therapies, while those without might best be treated with the surgeon’s knife alone.

Breast-cancer researchers are also testing the stem-cell hypothesis in the clinic. Jenny Chang’s group at Baylor College of Medicine, in Texas, took samples of tumours from women before and after standard chemotherapy. When they counted the cells in the tissue they found that the proportion of stem cells in a tumour increased after treatment. That suggests the chemotherapy was killing the non-stem tumour cells and leaving the stem cells behind. When the group repeated the experiment using a modern drug called Tykerb that blocks what is known as the HER2 pathway, they got a different result. HER2 is a gene which encodes a protein that acts as a receptor for molecules called growth factors which, as their name suggests, encourage cell growth and proliferation. After the HER2-blocking treatment, cancer stem cells formed the same proportion of the residual tumour as beforehand. That suggests they, too, were being clobbered by the new treatment. It is probably no coincidence that another drug, Herceptin, which also goes after HER2, is one of the few medicines that is able to prolong the lives of people with advanced cancer.

The stem-cell hypothesis has also changed the way people do basic research. For example, over the past few years cancer researchers have been grinding up pieces of tumour and using what are known as gene-expression microarrays to work out which genes are active in them. However, if the hypothesis is correct, this approach will probably yield the wrong result, because the crucial cells make up but a small part of a tumour’s bulk and the activity of their genes will be swamped by that of the genes of the more common non-stem cells. The answer is to isolate the stem cells before the grinding starts.

This approach has already yielded one important finding. When Dr Chang used microarrays to study gene expression in the CD44-positive cells from breast tumours, she noticed that they did not look like those of the epithelial cells that make up the bulk of such a tumour. Epithelial cells are immobile, grow in “cobblestone” patterns and produce proteins that help them stick together. The gene expression of the putative stem cells, however, resembled that of a mesenchymal cell. Mesenchymal cells rarely stick together. Indeed, they are mobile and are able to slip through the matrix of proteins that holds epithelial cells together.

That finding is important because mobile cells are more likely to escape from a tumour and form secondary cancers elsewhere in the body. Once such secondaries are established, successful treatment is much harder. And the CD44-positive cells also expressed genes that are important for stem-cell self-renewal, particularly one called Notch that controls the flow of chemical signals within a cell.

Researchers at OSI Pharmaceuticals, a firm that makes a drug called Tarceva, found a similar pattern in lung cancer. Several years ago, they started looking for gene-expression patterns that correlated with response to Tarceva. They found that tumours with a pattern that resembled epithelial cells were sensitive to the drug. By contrast, those that had a mesenchymal pattern were not. They hypothesised that as tumours develop, some of their cells actually switch from a sticky, epithelial state to a mobile, mesenchymal one. This epithelial-to-mesenchymal transition, or EMT, is well known to biologists who study embryonic development, but OSI’s results, and those of other researchers, suggest that cancers may have hijacked it for their own use.

Robert Weinberg, a molecular biologist at the Massachusetts Institute of Technology, and his colleagues have come to the same conclusion but they have taken the hypothesis one step further. They think that tumour cells which have undergone EMT have acquired many of the characteristics of cancer stem cells. Experiments in his laboratory, employing a variety of animal models of breast cancer, suggest that communication between tumour cells and surrounding non-cancerous support cells can lead some of the cancer cells to undergo EMT.

That is intriguing. If this transition really can be induced in tumour cells, then any of them might be able to become a cancer stem cell. So it may be that the fundamentalist version of the stem-cell hypothesis is wrong, and the stem cells are a result of a cancer, rather than its cause. That could be another reason why Dr Matsui found that pancreatic cancers do not always seem to contain stem cells.

Dr Weinberg is sensitive to this point, and is cautious when talking about these experiments. He refers to the cells that have undergone EMT as “having the qualities of stem cells” but avoids actually calling them cancer stem cells. If his idea is correct, though, it means that finding drugs which block the signals that induce EMT could reduce the stem-cell population and prolong the survival of the patient. It also means that both the epithelial cells and the mesenchymal ones will have to be attacked. And OSI is now testing a drug that does just that.

Notch up a victory?

Breast-cancer researchers, too, are testing drugs that hit molecular targets highlighted by cancer-stem-cell studies. Merck, for example, has turned to a drug it originally developed to treat Alzheimer’s disease. Although this drug, code-named MK0752, did not slow that disease, it does block activity of Notch, the stem-cell self-renewal gene, and might thus be an appropriate weapon against breast-cancer stem cells. Dr Chang and Dr Wicha have started a clinical trial which uses MK0752 in combination with standard chemotherapy. By the end of the year they hope to have some idea of whether the combination kills cancer cells in human tumours.

Attacking Notch is a high-risk approach, because this gene is used by healthy stem cells as well as cancerous ones; healthy organs as well as tumours could be damaged. Some researchers are therefore taking a different tack and looking for drugs that hit only the unhealthy stem cells. Craig Jordan, a biologist at the University of Rochester Medical Centre, in New York state, is one such. He has discovered that a chemical called parthenolide, found in feverfew, a medicinal plant, kills AML stem cells. Normal stem cells, however, seem to be able to tolerate the drug without difficulty. The reason is that the leukaemia cells are reliant on a biochemical pathway that parthenolide blocks, whereas normal stem cells are not. If all goes well, a trial to test the safety of a modified form of parthenolide will start in a few months.

If the safety issues can be dealt with—and most researchers think they can—then attacking cancer stem cells really could help patients survive. If, that is, the stem-cell hypothesis is correct.

At the moment, scientists being scientists, few are willing to be anything other than cautious. They have seen too many past cures for cancer vanish in a puff of smoke. The proof needs to come from patients—preferably with them living longer. But if the stem-cell hypothesis is indeed shown to be correct, it will have the great virtue of unifying and simplifying the understanding of what cancer is.

And that alone is reason for hope.

Source: http://www.economist.com/science/displaystory.cfm?story_id=12202589

Denosumab Osteoporosis Trial Results

2008-09-18T17:33:00.001-06:00

Amgen (NASDAQ:AMGN) announced full data results from a non-pivotal Phase 3 head-to-head, double-blind trial comparing bone mineral density (BMD) gains in postmenopausal women with low bone mass who transitioned from weekly oral alendronate (Fosamax(R)) to denosumab versus those who continued alendronate therapy.

Additional Data From Separate Head-to-Head Trial Showed More Than 75 Percent of Patients Prefer the Administration and Frequency of Twice-Yearly Subcutaneous Injection Compared to Weekly Oral Pill.

Data presented from the bisphosphonate transition study, also known as the STAND (Study of Transitioning from AleNdronate to Denosumab) trial, demonstrated that subcutaneous injections of denosumab every six months achieved significantly greater increases in BMD versus those achieved with alendronate at all sites measured. For the primary endpoint, denosumab resulted in significant increases in BMD at the total hip compared with alendronate (1.9 percent vs. 1.05 percent, p less than 0.0001). Treatment with denosumab also resulted in significant increases in BMD compared with continued alendronate treatment at all secondary endpoints including the lumbar spine, femoral neck, hip trochanter and 1/3 radius. Top-line results of this trial were previously released in May 2008.

The incidence and types of adverse events observed in the study, including neoplasm and infection, were well-balanced between the denosumab and alendronate treatment groups. The most common adverse events across both treatment arms were back pain, arthralgia, and nasal pharyngitis.

About the 234 Bisphosphonate Transition Study (STAND)

The 234 bisphosphonate transition Phase 3 study was a randomized, double-blind, active controlled, parallel group study. Eligible patients had T-scores of less than -2.0 and greater than -4.0 at the lumbar spine or total hip, and had previously been treated with alendronate. A total of 504 women with low BMD participated in the study, with approximately 250 patients in each arm.
The study's primary endpoint was to evaluate the effect of denosumab treatment (twice-yearly 60 mg) on total hip BMD in women with low bone mass compared to patients continuing alendronate therapy (weekly 70 mg) at 12-months. The secondary endpoints included evaluation of the effects of transitioning to denosumab compared to continuing treatment with alendronate on percent change from baseline in BMD at the lumbar spine, hip trochanter, femoral neck, and 1/3 radius.

About the 141 Head-to-Head Study (DECIDE)

In this Phase 3 double-blind, double-dummy, active controlled study, 1,189 healthy postmenopausal women (T-score less than or equal to -2.0 total hip or spine), were randomized 1:1 to receive either denosumab injection (subcutaneous 60 mg, Q6M) plus placebo tablet (oral weekly), or placebo injection and oral alendronate (70 mg weekly). Patients were followed for one year to assess changes in BMD at the total hip compared to alendronate. Secondary endpoints were to evaluate the effect of denosumab on percent change from baseline in BMD at the lumbar spine, hip trochanter, femoral neck, and 1/3 radius compared to alendronate. Preference and satisfaction were assessed after 12-months of treatment, with patients being asked to complete a 34-item questionnaire to rate their preference and satisfaction with each mode and frequency of administration.

About Denosumab
Denosumab is the first fully human monoclonal antibody in late stage clinical development that specifically targets RANK Ligand, an essential regulator of osteoclasts (the cells that break down bone). Denosumab is being investigated for its potential to inhibit all stages of osteoclast activity through a targeted mechanism. Denosumab is being studied in a range of bone loss conditions including postmenopausal osteoporosis, rheumatoid arthritis, and cancer treatment-induced bone loss (in breast cancer and prostate cancer patients), as well as for its potential to delay bone metastases and inhibit and treat bone destruction across many stages of cancer.

Source: http://www.amgen.com/media/media_pr_detail.jsp?year=2008&releaseID=1197250

IT impact on DNA sequencing

2008-09-11T12:01:00.001-06:00

The mystery behind why some have a genetic disposition to a certain disease, or why a medicine works for some and not for others, might be revealed sooner than many had anticipated. Several significant breakthroughs in DNA sequencing technology have been made, giving hope that the coveted $1,000 genome is just around the corner.

Since the completion of the Human Genome Project in 2003, which took over a decade and cost over $300 million, the idea of personalized medicine and using genetic testing for medical procedures has become much more of a reality. Decoding a human genome is far too costly, and, as a result, several companies are in a race to develop the next-generation DNA sequencer that will drive down the costs of sequencing a person's genome to $1,000, and to win the $10 million Archon X Prize, which is awarded to the company that successfully sequences 100 human genomes in 10 days for $10,000 per genome.

In February 2008, Illumina claimed to sequence a human genome in four weeks for $100,000, only to be outdone five weeks later by its competitor, Applied Biosystems (ABI), which announced the sequencing of a whole human genome for less than $60,000. ABI also mentioned that its next-generation DNA sequencer is capable of generating up to nine gigabases per run, which is the highest throughput reported to date.

Also in February 2008, Pacific Biosciences (PacBio) presented a revolutionary technology which, within five years, could produce a three-minute raw sequence, and a complete, high-quality sequence in 15 minutes - all for under $1,000. PacBio plans to introduce a sequencing machine in 2010, but an instrument capable of performing the $1,000 whole genome sequencing will not be available until 2013.

The rapid advancement of next-generation DNA sequencers has been possible due to vast improvements in computer technology, specifically in speed and size. These new systems produce enormous amounts of data - one run could generate close to one terabyte of data - and bioinformatics and data management tools have to play catch-up to handle the analysis and storage of this data.

The $1,000 genome has the potential to bring the genomic age to the physician's office. At this price tag, DNA sequencing could become common for certain medical procedures - such as testing for cancer and developing treatments specifically for the patient and, one day, routine decoding at birth could provide parents with a genetic instruction guide to their children's future ailments.

However, this concept of genome sequencing as a standard medical procedure raises several privacy issues, as there is nothing more personal than genetic code. Important questions raised will include who should have access to this information, and how easily attainable would this data be for others? For example, should only the patient and physician share this knowledge, or should health insurance companies be privy to this valuable genome report?

Technology vendors will have to work with the healthcare and medical industries to establish the answers to these questions and then develop the appropriate security protocols. Healthcare and life science IT vendors should utilize the expertise of other industries, such as the banking and credit card industry, which also require high levels of security in their day-to-day workflow to aid in the development of software to ensure patient privacy.

Phase II clinical trial of Trail receptor antibody HGS-ETR1 in combination with bortezomib

2008-09-11T11:57:00.001-06:00

Human Genome Sciences has reported initial topline results from an ongoing randomized Phase II clinical trial of its Trail receptor antibody HGS-ETR1 in combination with bortezomib in patients with advanced multiple myeloma.

The initial data from the multiple myeloma study show that HGS-ETR1 was well tolerated and suggest that disease response was comparable for this combination versus bortezomib alone. The trial in advanced multiple myeloma is a randomized, multi-center, open-label Phase II study to evaluate the efficacy and safety of HGS-ETR1 (mapatumumab) in combination with bortezomib in these patients.

Approximately 104 patients are being treated in the study, which is being conducted in the US, Canada, Australia and India. Patients were randomized into three treatment groups, with one group receiving bortezomib alone and two groups receiving bortezomib in combination with mapatumumab (10mg/kg or 20mg/kg). Approximately 43% (15/35) of the patients in the group receiving bortezomib alone were randomized contemporaneously with randomization of the group receiving a combination of bortezomib and mapatumumab at 10mg/kg.

The remaining 57% (20/35) of the patients in the group receiving bortezomib alone were randomized contemporaneously with randomization of the group receiving a combination of bortezomib and mapatumumab at 20mg/kg. The primary objective of the study is to evaluate disease response to mapatumumab in combination with bortezomib, versus bortezomib alone, in patients with relapsed or refractory multiple myeloma.

Patients participating in the study had received a median of two previous cancer treatment regimens. At baseline, 17.1% (6/35) of patients in the treatment group receiving bortezomib alone had stage 3 disease, versus 40.6% (13/33) in the group receiving the combination of bortezomib and mapatumumab at 10mg/kg, and 19.4% (7/36) in the group receiving the combination of bortezomib and mapatumumab at 20mg/kg.

The initial data show that mapatumumab was well tolerated and could be administered safely and repetitively in combination with bortezomib, with no evidence of increased toxicity in patients receiving the combination of bortezomib and mapatumumab, versus patients receiving bortezomib alone.

VELCADE for multiple myeloma receives front-line approval in Canada

2008-09-08T13:38:00.000-06:00

VELCADE* (bortezomib) for Injection has received Health Canada approval for front-line (first) treatment of multiple myeloma. As part of combination therapy, VELCADE is indicated for the treatment of patients with previously untreated multiple myeloma who are unsuitable for stem cell transplantation. With this new approval, patients with multiple myeloma can now receive VELCADE earlier following initial disease diagnosis, which may help to slow, reverse or halt disease progression.

VELCADE’s front-line approval is based on the phase III VISTA (VELCADE as Initial Standard Therapy in Multiple Myeloma: Assessment with Melphalan and Prednisone) trial, recently published in the New England Journal of Medicine.

VELCADE Approved Across all Disease Stages

2008-09-08T13:35:00.001-06:00

Janssen-Cilag / Ortho Biotech, today announced the European Commission's approval of VELCADE in combination with melphalan and prednisone for the treatment of patients with previously untreated multiple myeloma (MM) who are not eligible for high-dose chemotherapy with bone marrow transplant.

In more than 87 countries worldwide, VELCADE monotherapy had already been approved for the treatment of relapsed and / or refractory MM in patients who have received at least one prior therapy.
"VELCADE has already made an important contribution for patients with multiple myeloma at first relapse," said Professor Jesus San Miguel, M.D., University of Salamanca in Spain, the principal investigator for the VISTA trial. "The marketing authorisation from the EMEA is encouraging as it suggests that more patients may benefit from earlier treatment."

The frontline approval is based on phase III results from the VISTA trial, recently published in the New England Journal of Medicine, which demonstrated statistically superior results across all efficacy endpoints compared to melphalan and prednisone. In particular, complete response (CR) rates were similar to those that have been achieved in the transplant setting. VISTA stands for: VELCADE as Initial Standard Therapy in Multiple Myeloma.

Myeloma Research Web Portal at Dana Farber

2008-09-05T12:29:00.001-06:00

Researchers can view genetic information from multiple databases with a specially designed Web portal.

The Dana-Farber Cancer Institute in Boston is harnessing the dual power of business intelligence and Web 2.0-based scientific search tools to gather complex, scattered data to better treat patients and work toward a cure for this formidable disease.

Dana-Farber physicians and researchers regularly slog through complex calculations to find connections between data gleaned from tumor biopsies and other clinical samples and the vast genetic research housed within the organization or spread among three massive public-domain databases.

Dana-Farber officials are using data warehousing capabilities with Web-based data- collection tools, since vital connections between patient samples and analytical data will almost certainly prove the crux of both effective patient treatment and any potential breakthroughs tied to the disease, according to researchers.

Not only is data on multiple myeloma and other diseases often far-flung and fiercely guarded, it is also incredibly complex, says Joseph White, a senior research scientist at Dana-Farber. "A single gene may be represented by several different name sequences," he explains. "To gather all of the information on any one particular gene, a researcher must look at many sources and different expressions for the gene."

"You can't engineer serendipity," says White. "You want to be able to ask questions such as 'How do I cure cancer?' and not be limited to questions that are too specific, such as 'Does eating beets have a correlation to curing cancer?'"

Drug research: Cyproheptadine

2008-09-03T21:13:00.001-06:00

Xinliang Mao1, Sheng-ben Liang1, Rose Hurren1, Marcela Gronda1, Sue Chow1, G. Wei Xu1, Xiaoming Wang1, Reza Beheshti Zavareh1, Nazir Jamal1, Hans Messner1, David W. Hedley1, Alessandro Datti2, Jeff L. Wrana2, Yuanxiao Zhu3, Chang-xin Shi3, Kyle Lee1, Rodger Tiedemann3, Suzanne Trudel1, A. Keith Stewart3, and Aaron D. Schimmer1

1 Princess Margaret Hospital and the Ontario Cancer Institute, Toronto, ON; 2 Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON; and 3 Mayo Clinic, Scottsdale, AZ

D-cyclins are regulators of cell division that act in a complex with cyclin-dependent kinases to commit cells to a program of DNA replication. D-cyclins are overexpressed in many tumors, including multiple myeloma and leukemia, and contribute to disease progression and chemoresistance. To better understand the role and impact of D-cyclins in hematologic malignancies, we conducted a high throughput screen for inhibitors of the cyclin D2 promoter and identified the drug cyproheptadine. In myeloma and leukemia cells, cyproheptadine decreased expression of cyclins D1, D2, and D3 and arrested these cells in the G0/G1 phase. After D-cyclin suppression, cyproheptadine induced apoptosis in myeloma and leukemia cell lines and primary patient samples preferentially over normal hematopoietic cells. In mouse models of myeloma and leukemia, cyproheptadine inhibited tumor growth without significant toxicity. Cyproheptadine-induced apoptosis was preceded by activation of the mitochondrial pathway of caspase activation and was independent of the drug's known activity as an H1 histamine and serotonin receptor antagonist.

Thus, cyproheptadine represents a lead for a novel therapeutic agent for the treatment of malignancy. Because the drug is well tolerated and already approved in multiple countries for clinical use as an antihistamine and appetite stimulant, it could be moved directly into clinical trials for cancer.

Immunotherapy targets NHL

2008-08-30T15:34:00.001-06:00

Four of 38 patients with non-Hodgkin's lymphoma have seen "complete regressions" following immunotherapy treatment, while five others saw reductions of 50 per cent in their tumours.

The drug works by activating the body's own defences to attack the cancer.

The results have been described as an "exciting" and "significant" development in the use of immunotherapy, the process of using the body's own immune system to fight disease.

Professor Peter Johnson, Cancer Research UK's chief clinician, said: "These exciting preliminary results come from using them to harness the body's own immune response in a new way. Although the side effects need to be monitored carefully, we hope that this type of treatment will prove to be active in larger trials in the future"

"This a significant study," said Dr Cassian Yee, Fred Hutchinson Cancer Research Center, Seattle, who has had significant results using the alternative method of treating patients with white blood cells grown in the lab. "It remains to be seen if most of the responses are longlasting. Certainly the results are very promising."

The drug, which has been developed by Micromet, in Bethesda, Maryland, was trialled by a team led by Dr Ralf Bargou at University of Würzburg in Würzburg, German.

The results, published in the journal Science, are encouraging because they suggest that the bigger the dose, the bigger the effect.
Coauthor of the study Dr Patrick Baeuerle, of Micromet, said all seven who received the highest dose responded to the drug.

"Two of the seven had a complete response, and five a partial regression (greater than 50 per cent reduction of tumour)."

The longest duration of a response was so far seen in a patient who received one quarter of their dose. After 13 months, he remains free of the blood cancer.

There are adverse side effects involved, however, such as fevers and chills, occasionally with confusion and tremor, though all stopped after treatment ceased.

Now a further trial is investigating how the drug works in patients with another form of blood cancer, called acute lymphoblastic leukaemia.

Micromet targets the body's own white blood cells on the cancer, using a fraction of a millionth of a gram of a specialised protein called a "bispecific antibody".

The company has created antibodies, called BiTE antibodies, which are able to stick to sites with exquisite precision, in this case to activate specialized white blood cells (T cells) to attack cancer.

The antibodies overcome a key problem with immunotherapy that as tumours become more advanced they become more "invisible" to the T cells because the cancer cells lack molecules for white blood cells to hang on to and stage their attack.

Normal antibodies are designed to latch on to one molecular target but the bispecific antibody developed by Micromet, given the name blinatumomab, binds to two, the cancer cell and the T cell, and bring the two together to target the immune system on the cancer.

The team tried varying doses of blinatumomab in patients, and found that among 38 patients, at doses from 0.0005 to 0.06 milligrams (millionths of a gram) per square metre of body surface per day, 11 of them exhibited major responses and tumour shrinking. The disease was cleared from bone marrow, spleen and liver too.

MMRC announces clinical trial of pomalidomide CC-4047

2008-08-27T11:09:00.000-06:00

Paul Richardson, MD, Clinical Director of the Jerome Lipper Center for Multiple Myeloma at DanaFarber Cancer Institute, is leading the multicenter, randomized, open-label, dose-escalation study. A Phase 1 study is designed to determine maximum tolerated dose of single-agent pomalidomide while a Phase 2 randomized study will compare the oral compound's efficacy alone against its combination with dexamethasone.

"This potent new immunomodulator, which is in the same class as thalidomide and lenalidomide, will hopefully be successful in treating patients who have relapsed or who don't respond to currently available treatment options. We are excited to be testing pomalidomide in this context and are optimistic that it will meaningfully add to our therapeutic options for our patients," said Dr. Richardson.

Pomalidomide is an IMiDs compound, a member of Celgene's proprietary group of novel oral immunomodulatory agents that impede or stabilize disease through several mechanisms of action, including anti-angiogenic activity.

Celgene's lead IMiDs compound, REVLIMID (lenalidomide) continues to demonstrate unprecedented overall survival in multiple myeloma as well as significant clinical potential across a broad range of blood cancers.

IMiDs compounds are proprietary novel small molecule, orally available compounds that modulate the immune system and other biologically important targets through multiple mechanisms of action, including angiogenesis inhibition, modulation of the levels of key pro-inflammatory and regulatory cytokines and immune cell co-stimulation.

Proteolix Initiates Phase 1b Clinical Trial of Carfilzomib

2008-08-25T15:28:00.000-06:00

Patient dosing has commenced in a Phase 1b clinical trial to evaluate the safety and efficacy of Proteolix's lead anti-cancer agent, carfilzomib (PR-171), in combination with lenalidomide and dexamethasone in patients with relapsed multiple myeloma. Carfilzomib selectively blocks proteasome activity, causing apoptosis in cancer cells. In single agent Phase 1 studies carfilzomib has demonstrated encouraging anti-tumor activity and has been generally well tolerated.

The Phase 1b clinical trial is designed to evaluate safety and to establish a maximum-tolerated dose of carfilzomib in combination with lenalidomide and dexamethasone on a twenty-eight day treatment cycle. Lenalidomide in combination with dexamethasone is indicated for use in patients with multiple myeloma who have had at least one prior therapy. Patients will be divided into four cohorts and will receive escalating doses of carfilzomib and lenalidomide, combined with a set dose of dexamethasone. A secondary endpoint for the trial is overall response rate at four months.

"Carfilzomib has been generally well-tolerated in patients and we believe that the product's selectivity and potency provide a solid rationale for use in combination with existing treatment protocols," said Lori Kunkel, M.D., Proteolix's Chief Medical Officer. "Initiating our first combination trial of carfilzomib complements our multi-pronged strategy to thoroughly explore carfilzomib's potential in the treatment of patients with multiple myeloma for whom treatment options may be limited."

In addition to the Phase 1b clinical trial announced today, Proteolix is currently evaluating carfilzomib as a single agent for the treatment of multiple myeloma in two Phase 2 clinical trials.

A Phase 2 clinical trial of single-agent carfilzomib in patients with relapsed and refractory multiple myeloma recently began enrolling its second cohort of approximately 40 patients to explore safety, tolerability and activity using a higher dose schedule. This trial is being conducted in collaboration with the Multiple Myeloma Research Consortium (MMRC) and is designed to evaluate patients' overall response rate after four cycles of carfilzomib. All patients enrolled in the trial have received prior treatment(s) with bortezomib and either lenalidomide or thalidomide and are refractory to their last treatment.

A second open-label, multi-center Phase 2 trial of single-agent carfilzomib in relapsed multiple myeloma patients is also currently enrolling patients. The goal of this study is to evaluate carfilzomib's activity based on a patient's prior treatment with bortezomib. The company plans to present interim data from both of these Phase 2 trials by year end. A complete list of Proteolix's ongoing clinical trials of carfilzomib may be found at http://www.clinicaltrials.gov.

About Carfilzomib

Carfilzomib is a structurally- and mechanistically-novel proteasome inhibitor that exhibits a high level of selectivity for a single active site in the proteasome with minimal cross reactivity to other protease classes.

Bristol-Myers Squibb and PDL BioPharma Alliance to Develop Novel Treatment for Multiple Myeloma

2008-08-24T22:43:00.000-06:00

Bristol-Myers Squibb Company (NYSE: BMY) and PDL BioPharma, Inc. (NASDAQ: PDLI) today announced an agreement for the global development and commercialization of PDL BioPharma's anti-CS1 antibody, elotuzumab, previously known as HuLuc63, currently in Phase I development for multiple myeloma.

Elotuzumab provides a novel approach to treating multiple myeloma because it is an antibody that binds to the CS1 glycoprotein, allowing the immune system to selectively kill myeloma cells with minimal effects on other cell types. CS1 is a cell surface glycoprotein that is widely expressed on multiple myeloma cells but is minimally expressed on normal cells. Elotuzumab is currently being investigated in Phase I studies as a monotherapy and in combination with other therapies. There are currently no approved monoclonal antibodies on the market to treat multiple myeloma.

"Elotuzumab provides us with the opportunity to develop and market an innovative therapy that has the potential to meaningfully address the significant unmet medical need in multiple myeloma," said Francis Cuss, MD, senior vice president, Discovery and Exploratory Clinical Research, Bristol-Myers Squibb.

Review of new drugs in multiple myeloma

2008-08-21T14:33:00.000-06:00

Berenson JR, Yellin O.

PURPOSE OF REVIEW: Advances in the understanding of multiple myeloma pathogenesis have led to the development of innovative targeted therapies and improved management of this aggressive hematological neoplasia. This review will focus on the clinical trials that have reinforced the use of these new agents. Also, we will briefly take a look at the newer drugs making their way out of the laboratory and into early phase studies.

RECENT FINDINGS: During the past decade new multiple myeloma therapies featuring bortezomib and lenalidomide have come to light, whereas known agents such as thalidomide and arsenic trioxide have been reintroduced as key factors in multiple myeloma management. These new agents and their combinations have shown increased response rates and have added more options for patients with multiple myeloma whose disease has become resistant to conventional therapy. With these drug therapies has come a more targeted approach to treatment enabling not only improved antimyeloma efficacy but also the use of decreased dosing enhancing the safety and tolerability of these regimens. Newer agents including the histone deacetylase, hsp90, mammalian target of rapamycin and Akt inhibitors are showing promise preclinically and are now being assessed in phase I/II trials.

SUMMARY: This new antimultiple myeloma arsenal has shown its worth in both the relapsed/refractory and frontline setting and provides valuable options for patients with this debilitating disease.

PMID: 18685422 [PubMed - in process]

SymBio Pharmaceuticals and Eisai Sign License Agreement for bendamustine hydrochloride (SyB L-0501)

2008-08-18T20:52:00.001-06:00

Tokyo – SymBio Pharmaceuticals Limited and Eisai Co., Ltd. announced today that the companies have concluded the license agreement for the co-development and commercialization of bendamustine hydrochloride in Japan.

In Germany, bendamustine hydrochloride has been used extensively for the treatment of non-Hodgkin's lymphoma, multiple myeloma and chronic lymphocytic leukemia. The drug has been on the market in the United States since April of this year after receiving FDA approval in March 2008 for the treatment of chronic lymphocytic leukemia. In Japan, bendamustine hydrochloride is currently being investigated in patients with low-grade non-Hodgkin's lymphoma, and is in the pivotal stage of clinical development prior to submission for approval.

In a collaborative effort to address unmet medical needs, SymBio and Eisai will work in tandem to expedite the development of bendamustine hydrochloride in Japan.

Molecules Out Of Balance Lead to Multiple Myeloma

2008-08-11T11:51:00.002-06:00

An international team of scientists has identified processes that are heavily implicated in human multiple myeloma and other B cell cancers.

B cells, the white blood cells that produce antibodies, form a key part of our 'immune response'. To remain healthy, we need to maintain the right number of B cells, not too many and not too few. This in turn relies on an intricate interplay of molecules within our bodies, and inside our B cells.

Professor Fabienne Mackay, Professor Klaus Rajewsky and Dr Marc Schmidt-Supprian, from Sydney's Garvan Institute of Medical Research, Harvard Medical School and Germany's Max Planck Institute of Biochemistry respectively, have identified two processes that appear to influence B cell driven cancers. Their findings are published online in the international journal, Proceedings of the National Academy of Sciences.

"We already know that the over-expression or mutation of molecules known as NIK and TRAF3 in B cells is associated with multiple myeloma," said Professor Mackay. "Our collaborative research uncovered two distinct processes involving these molecules that help explain why."

The first process involves NIK, an enzyme that acts closely with BAFF, the substance that regulates the number of B cells in our bodies. Work done previously by Professor Mackay on BAFF showed that levels correlate with B cell hyperplasia (expansion) and cancer. The current study shows that if we have too much NIK in our systems, then our B cells will also expand, and we will be prone to cancer.

The second process, associated with the first, involves TRAF3, the molecule that negatively regulates NIK.

Professor Mackay explained that in a healthy person, NIK and TRAF3 work together, helping to maintain the right number of B cells for survival. "But when there are mutations in either molecule, they become uncoupled. In other words, TRAF 3 no longer represses the action of NIK when necessary."

"The important thing to note is that when you uncouple NIK from TRAF3 action, its levels are not necessarily going to go up, but its function is going to be changed. This can lead to B cell hyperplasia and cancer."

"Our paper is saying 'be careful'! Sometimes you can find a patient without high expression of NIK, so you think NIK is not implicated, where it might be."

"In the very near future, we will have the capacity to do blood tests and test for specific gene mutations in patients. Once you identify a mutation, you can bypass the action of that gene, with targeted medications."

Bottom of Form

"Both NIK and TRAF3 are molecules, so can potentially be targeted by pharmaceuticals. We anticipate that new treatments for cancers may emerge from our findings."

Aplidin, a marine organism-derived compound with potent antimyeloma activity

2008-07-10T14:35:00.000-06:00

Mitsiades CS, Ocio EM, Pandiella A, Maiso P, Gajate C, Garayoa M, Vilanova D, Montero JC, Mitsiades N, McMullan CJ, Munshi NC, Hideshima T, Chauhan D, Aviles P, Otero G, Faircloth G, Mateos MV, Richardson PG, Mollinedo F, San-Miguel JF, Anderson KC.

Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. Constantine_Mitsiades@dfci.harvard.edu

Despite recent progress in its treatment, multiple myeloma (MM) remains incurable, thus necessitating identification of novel anti-MM agents. We report that the marine-derived cyclodepsipeptide Aplidin exhibits, at clinically achievable concentrations, potent in vitro activity against primary MM tumor cells and a broad spectrum of human MM cell lines, including cells resistant to conventional (e.g., dexamethasone, alkylating agents, and anthracyclines) or novel (e.g., thalidomide and bortezomib) anti-MM agents. Aplidin is active against MM cells in the presence of proliferative/antiapoptotic cytokines or bone marrow stromal cells and has additive or synergistic effects with some of the established anti-MM agents. Mechanistically, a short in vitro exposure to Aplidin induces MM cell death, which involves activation of p38 and c-jun NH(2)-terminal kinase signaling, Fas/CD95 translocation to lipid rafts, and caspase activation. The anti-MM effect of Aplidin is associated with suppression of a constellation of proliferative/antiapoptotic genes (e.g., MYC, MYBL2, BUB1, MCM2, MCM4, MCM5, and survivin) and up-regulation of several potential regulators of apoptosis (including c-JUN, TRAIL, CASP9, and Smac). Aplidin exhibited in vivo anti-MM activity in a mouse xenograft model. The profile of the anti-MM activity of Aplidin in our preclinical models provided the framework for its clinical testing in MM, which has already provided favorable preliminary results.

PMID: 18593922 [PubMed - in process]

One Gene May Be Key to Myeloma

2008-06-23T16:12:00.000-06:00

Cancerous myeloma cells are so "addicted" to a gene known as IRF4, they simply can't live without it, new research has revealed.

Reducing the activity of the gene by only 50 percent is enough to kill myeloma cells without compromising other healthy activities, said scientists reporting in the current issue of Nature.

"This pathway is so critical to the growth of myeloma that, potentially, if you turn it off, you've found a chink in the armor," said Dr. Bart Kamen, executive vice president and chief medical officer at The Leukemia & Lymphoma Society.

The gene could present a target for future drug development.

"IRF4 is absolutely a target in myeloma. This is not an easy target but not an impossible target," said Dr. Louis Staudt, senior author of the paper and chief of the Lymphoid Malignancies Section, Metabolism Branch, Center for Cancer Research at the U.S. National Cancer Institute.

"It's obviously a little bit away, but we have the ability to fairly quickly figure out how to block [genes]," added Dr. Mitchell Smith, head of the lymphoma service at Fox Chase Cancer Center in Philadelphia.

Multiple myeloma, a cancer of the white blood cells, primarily affects older adults and, partly for that reason, often doesn't have a good prognosis.

What's more, there are least seven different "flavors" of multiple myeloma, each having its own unique genetic abnormalities, Staudt said. "One worries that would mean we'd need different drugs for each of these."

While there has been an explosion in new drugs to treat the disease over the past five to 10 years, there is still no cure, Smith said.

The authors took advantage of a genetic screen devised several years ago. This "Achilles' heel screen" uses RNA interference to spot particularly vulnerable parts of cancer cells

"It allows you to inactivate one gene at a time in a cancer cell and then ask what happens," Staudt explained. "We looked simultaneously at thousands of different genes . . . and then asked which one prevents the proliferation and survival of cancer cells."

In this study, the screen identified one gene, IRF4, which surfaced no matter what type of multiple myeloma the investigators looked at.

"Basically, every type of myeloma cell for which we have in vitro models is completely dependent on IRF4, such that, when we inhibit it, they die a swift death within a few days in the lab," Staudt said. "This is better than we hoped."

Interestingly, however, the gene is not mutated when cancer is present. "In the vast majority of cases, there was absolutely nothing different between the IRF4 gene in cancer cells compared to any normal cells," Staudt said. "They were completely normal, yet the cells were totally dependent."

Of course, this begged the question, why?

IRF4 turns out to be a transcription factor, meaning it regulates gene expression -- how a gene produces proteins. In this case, IRF4 regulated the expression of about 35 other genes, including MYC, a well-known cancer-causing gene.

"We found that this IRF4 transcription factor was turning on MYC, which itself is a transcription factor that was turning on IRF4. So, you can see that this is a vicious cycle," Staudt explained. "They cycle out of control, and so this is at least part of how it works."

IRF4 is in charge of so many processes, in fact, that the study authors described knocking it out as "death by a thousand cuts."

"If IRF4 is a master regulator of the working of a myeloma cell, this would be a great drug," Staudt said. "We want people to sit up and take notice of IRF4, because it would be effective across the board in all types of myeloma."

First thalidomide clinical trial in multiple myeloma: a decade later

2008-05-29T11:20:00.000-06:00

van Rhee F, Shaughnessy Jr JD, Anaissie E, Siegel D, Hoering A, Zeldis J, Jenkins B, Singhal S, Mehta J, Crowley J, Jagannath S, Barlogie B.

Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock.

The clinical outcomes of 169 patients, enrolled in the first clinical trial of thalidomide for advanced or refractory myeloma, are updated. Seventeen patients remain alive and 10 event-free, with a median follow-up of 9.2 years. According to multivariate analysis of pre-treatment variables, cytogenetic abnormalities (CA), present in 47% of patients within 3 months of enrollment, and lambda light chain isotype both affected overall survival and event-free survival adversely. Forty percent of the 58 patients lacking these 2 unfavorable features, one-half of whom had no disease recurrence, survived at least 6 years, in contrast to fewer than 5% among those with 1 or 2 risk features (P<0.0001).>

PMID: 18502827 [PubMed - as supplied by publisher]

Lenalidomide raises clot risk in multiple myeloma patients

2008-05-27T17:11:00.000-06:00

Thromboembolic events are increased in patients undergoing lenalidomide-based therapy for multiple myeloma. Aspirin prophylaxis appears to reduce this risk.

"There is a real risk of blood clots with the use of lenalidomide in myeloma," according to Dr. S. Vincent Rajkumar, "particularly in combination with other chemotherapeutic drugs."

To investigate these and other risk factors, Dr. Rajkumar of the Mayo Clinic College of Medicine, Rochester, Minnesota and colleagues conducted a pooled analysis of data from three clinical trials involving 125 patients who had previously untreated multiple myeloma.

Along with lenalidomide-based therapy, 52 received high-dose dexamethasone (40 mg 12 days a month) and 73 received prednisolone or dexamethasone 40 mg, 4 times per month. In addition, 110 were given thromboprophylactic treatment, primarily aspirin.

Overall, 10 patients (8%) developed deep vein thrombosis (DVT), the investigators report in the April 1 issue of Cancer. Four were not receiving thromboprophylactic treatment at the time of the event.

There was no significant difference in the incidence of DVT in patients receiving concomitant erythropoietin therapy and those not receiving this treatment. The rate of DVT was higher in the high-dose corticosteroid group compared with the low-dose group (12% versus 6%, respectively), but this difference did not reach statistical significance.

The rate of thrombosis was lower than the range reported in the literature, the investigators point out, possibly because most patients were receiving anticoagulant prophylaxis and 58% received low-dose corticosteroid.

"The best prophylaxis," Dr. Rajkumar concluded, "should take into account all the risks and benefits. By using a low dose of steroids, and using aspirin as a preventive measure, the risk of blood clots can be minimized to less than 10%."

CS1, a Potential New Therapeutic Antibody Target for the Treatment of Multiple Myeloma

2008-05-15T11:15:00.001-06:00

Hsi ED, Steinle R, Balasa B, Szmania S, Draksharapu A, Shum BP, Huseni M, Powers D, Nanisetti A, Zhang Y, Rice AG, van Abbema A, Wong M, Liu G, Zhan F, Dillon M, Chen S, Rhodes S, Fuh F, Tsurushita N, Kumar S, Vexler V, Shaughnessy JD Jr, Barlogie B, van Rhee F, Hussein M, Afar DE, Williams MB.

Authors' Affiliations: Clinical Pathology, Cleveland Clinic Foundation, Cleveland, Ohio.

PURPOSE: We generated a humanized antibody, HuLuc63, which specifically targets CS1 (CCND3 subset 1, CRACC, and SLAMF7), a cell surface glycoprotein not previously associated with multiple myeloma. To explore the therapeutic potential of HuLuc63 in multiple myeloma, we examined in detail the expression profile of CS1, the binding properties of HuLuc63 to normal and malignant cells, and the antimyeloma activity of HuLuc63 in preclinical models. EXPERIMENTAL DESIGN: CS1 was analyzed by gene expression profiling and immunohistochemistry of multiple myeloma samples and numerous normal tissues. HuLuc63-mediated antimyeloma activity was tested in vitro in antibody-dependent cellular cytotoxicity (ADCC) assays and in vivo using the human OPM2 xenograft model in mice. RESULTS: CS1 mRNA was expressed in >90% of 532 multiple myeloma cases, regardless of cytogenetic abnormalities. Anti-CS1 antibody staining of tissues showed strong staining of myeloma cells in all plasmacytomas and bone marrow biopsies. Flow cytometric analysis of patient samples using HuLuc63 showed specific staining of CD138+ myeloma cells, natural killer (NK), NK-like T cells, and CD8+ T cells, with no binding detected on hematopoietic CD34+ stem cells. HuLuc63 exhibited significant in vitro ADCC using primary myeloma cells as targets and both allogeneic and autologous NK cells as effectors. HuLuc63 exerted significant in vivo antitumor activity, which depended on efficient Fc-CD16 interaction as well as the presence of NK cells in the mice. CONCLUSIONS: These results suggest that HuLuc63 eliminates myeloma cells, at least in part, via NK-mediated ADCC and shows the therapeutic potential of targeting CS1 with HuLuc63 for the treatment of multiple myeloma.

PMID: 18451245 [PubMed - in process]

Complete remission sustained 3 years from treatment initiation is a powerful surrogate for extended survival in multiple myeloma

2008-05-15T11:13:00.000-06:00

Barlogie B, Anaissie E, Haessler J, van Rhee F, Pineda-Roman M, Hollmig K, Alsayed Y, Epstein J, Shaughnessy JD Jr, Crowley J.

Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, Arkansas.

BACKGROUND.: Complete response (CR) has been considered a necessary although not sufficient early clinical endpoint for extended survival in multiple myeloma. METHODS.: By using Total Therapy 2 (TT2) clinical outcome data in 668 patients, whether sustained CR (SUS-CR) was potentially a superior surrogate for survival than attaining CR status per se was evaluated. RESULTS.: Compared with not achieving CR (NON-CR) and especially achieving and subsequently losing CR status (LOS-CR) within a 3-year landmark from treatment initiation, SUS-CR was associated with highly superior postlandmark survival (P < .0001). These results were validated in 231 untreated patients enrolled in the predecessor trial, TT1 (hazard ratio [HR] = 0.54, P = .013) and in 1103 previously treated patients on other transplant protocols (HR = 0.49; P < .001). CONCLUSIONS.: In all 3 trial settings the survival benefit of SUS-CR was independent of metaphase abnormalities as a dominant adverse parameter. Given its bleak prognosis despite high CR rates, SUS-CR should be evaluated as a primary trial endpoint in high-risk myeloma. Cancer 2008. (c) 2008 American Cancer Society.

PMID: 18470907 [PubMed - as supplied by publisher]

Impact of genetic abnormalities on survival after allogeneic stem cell transplantation in multiple myeloma

2008-04-24T11:02:00.001-06:00

Schilling G, Hansen T, Shimoni A, Zabelina T, Simon-Perez JA, Gutierrez NC, Bethge W, Liebisch P, Schwerdtfeger R, Bornhäuser M, Otterstetter S, Penas EM, Dierlamm J, Ayuk F, Atanackovic D, Bacher U, Bokemeyer C, Zander A, Miguel JS, Nagler A, Kröger N.

1Department of Oncology and Hematology, Medical Clinic II, University Hospital Hamburg-Eppendorf, Hamburg, Germany.

We analyzed the prognostic impact of the most frequent genetic abnormalities detected by fluorescence in situ hybridization in 101 patients with multiple myeloma, who underwent allogeneic hematopoietic stem cell transplantation (HSCT) after melphalan/fludarabine-based reduced conditioning. The incidences of abnormalities in the present analysis were as follows: del(13q14) (61%), t(11;14)(q13;q32) (14%), t(4;14)(p16.3;q32) (19%), MYC-gain gains (8q24) (21%), del(17p13) (16%) and t(14;16)(q32;q23) (5%). None of the patients had t(6;14)(p25;q32). The overall complete remission (CR) rate was 50% with no differences between the genetic abnormalities except for patients with del(17p13) who achieved less CR (7 vs 56%; P=0.001). Univariate analysis revealed a higher relapse rate in patients aged >50 years (P=0.002), patients with del(13q14) (P=0.006) and patients with del(17p13) (P=0.003). In multivariate analyses, only del(13q14) (HR: 2.34, P=0.03) and del(17p13) (HR: 2.24; P=0.04) significantly influenced the incidence of relapse, whereas for event-free survival, only age (HR 2.8; P=0.01) and del(17p13) (HR: 2.05; P=0.03) retained their negative prognostic value. These data show that del(17p13) is a negative prognostic factor for achieving CR as well as for event-free survival after HSCT. Translocation t(4;14) might be overcome by allogeneic HSCT, which will have implication for risk-adapted strategies.Leukemia advance online publication, 17 April 2008; doi:10.1038/leu.2008.88.

PMID: 18418408 [PubMed - as supplied by publisher]

Autologous SCT (ASCT) remains an effective therapy for eligible patients with myeloma

2008-04-07T19:44:00.000-06:00

Bone Marrow Transplantation advance online publication 10 March 2008; doi: 10.1038/bmt.2008.24

Impact of pretransplant therapy in patients with newly diagnosed myeloma undergoing autologous SCT

S K Kumar¹, D Dingli¹, A Dispenzieri¹, M Q Lacy¹, S R Hayman¹, F K Buadi¹, S V Rajkumar¹, M R Litzow¹ and M A Gertz¹

¹Department of Internal Medicine, Division of Hematology, Mayo Clinic, Rochester, MN, USA

Correspondence: Dr SK Kumar, Department of Internal Medicine, Division of Hematology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. E-mail: kumar.shaji@mayo.edu

Abstract

Autologous SCT (ASCT) remains an effective therapy for eligible patients with myeloma. Previous studies have suggested a lack of impact of the initial therapy on the outcome after ASCT. It is not clear if incorporation of new agents in the initial treatment regimens will have any impact on the outcome after ASCT. We studied 472 patients undergoing ASCT within 12 months of diagnosis to assess the effect of initial therapy on the outcome after ASCT. Patients received initial therapy with vincristine, adriamycin and dexamethasone (VAD), dexamethasone, thalidomide and dexamethasone or lenalidomide and dexamethasone. While patients treated with dexamethasone alone had higher disease burden at ASCT, no differences were observed in the response rates to ASCT, post transplant complications or treatment-related mortality among the groups. The median time to progression after ASCT was 27.1, 24.7, 21.1 months and did not reach the VAD, Dex, Thal–Dex and Len–Dex group, respectively, P=0.11. The median overall survival from ASCT was 62 months for VAD, 69.6 months for Dex and were not reached for Thal–Dex and Len–Dex groups, P=0.2. For patients undergoing early ASCT for myeloma, the nature of initial treatment utilized has no long-term impact on the outcome of ASCT.

Carfilzomib Receives Orphan Drug Designation for Treatment of Multiple Myeloma

2008-04-07T19:33:00.001-06:00

Proteolix, Inc., a clinical-stage company engaged in the development of novel pharmaceutical therapies for the treatment of cancer and immunological conditions, announced today that the U.S. FDA has granted orphan drug designation to carfilzomib, a selective blocker of proteasome activity for the treatment of multiple myeloma.

"I am very pleased by our receipt of this designation for carfilzomib," said Susan Molineaux, Ph.D., the Company's President and CEO. "To date we have been encouraged by carfilzomib's early-stage clinical results in multiple myeloma, and we continue to believe it has the potential to offer cancer patients a new and effective treatment for their disease."

The Orphan Drug Act of 1983 allows the FDA to grant orphan drug status to novel drugs or biologics that treat a rare disease or condition affecting fewer than 200,000 patients in the U.S. According to the SEER Database of the National Cancer Institute (2004), the U.S. prevalence of multiple myeloma was 53,712 patients. The Orphan Drug Act provides the drug developer with several financial benefits and incentives related to the orphan drug, including tax credits for clinical research costs, ability to apply for annual grant funding, clinical research trial design assistance, waiver of Prescription Drug User Fee Act (PDUFA) filing fees, and a seven-year period of U.S. marketing exclusivity if the drug is the first of its type approved for the specified indication.

For more information on multiple myeloma go to http://www.cancer.gov/cancertopics/types/myeloma.

About Proteolix
Proteolix, Inc. is a privately-held biopharmaceutical company, headquartered in South San Francisco, and dedicated to discovering, developing and commercializing pharmaceutical therapies that target certain cancers and immunological conditions by inhibiting the proteasome and thereby disrupting protein turnover in cells. Phase 1 clinical studies with carfilzomib, the Company's lead product, have shown that patients with hematologic malignancies who have relapsed or progressed following multiple therapies can achieve durable anti-tumor responses. Carfilzomib is currently in Phase 2 clinical studies to evaluate its safety and efficacy in multiple myeloma, lymphoma and solid tumor malignancies. Proteolix is also developing a pipeline of next-generation proteasome inhibitors, including an oral proteasome inhibitor and a selective immunoproteasome inhibitor. For more information, visit http://www.proteolix.com/

Bone and Cancer Foundation New Online Resource

2008-03-24T10:18:00.001-06:00

New York City, New York, March 20, 2008 – The Bone and Cancer Foundation announced today the launch of a new online resource for the 400,000 patients whose cancers spread to their bones.

The Web site, www.boneandcancerfoundation.org, provides medically reviewed information for cancer patients unaware of treatment options and new discoveries which can improve a thier quality of life and possibly prolong survival.

The information is relevant for those who have or are treating breast cancer, prostate cancer, and osteonecrosis of the jaw. General information about bone metastasis and myeloma bone disease is also available.

Dr. David Roodman, Chairman of the Foundation’s Advisory Medical Panel stated, “Bone is one of the most frequent sites of metastasis and is responsible for severe pain, fractures with little or predisposing injury and a poor quality of life. Many patients and professionals are unaware of treatment options and new discoveries which can improve a patient’s quality of life and possibly prolong the survival. The Bone and Cancer Foundation’s major focus is to provide up to date information for patients and professionals to treat and ameliorate this devastating complication of cancer”. Dr. Roodman is Professor of Medicine and Vice Chair for Research, Department of Medicine, University of Pittsburgh School of Medicine and Director of the Myeloma Program at the University of Pittsburgh Cancer Institute.

About the Bone and Cancer Foundation and Paget Foundation

The Bone and Cancer Foundation is a program of The Paget Foundation for Paget’s disease of Bone and Related Disorders (www.paget.org), a national voluntary health agency founded in 1978. The Paget Foundation addresses several benign bone conditions and has also worked in the cancer and bone field for ten years, primarily in the area of medical education and research.

For additional information please contact the Bone and Cancer Foundation at 212-509-5188, toll free 888-862-0999 or send an email to bcfdn@aol.com

Oncolytics Biotech Inc. Presents Reovirus Research at AACR

2008-03-17T09:56:00.001-06:00

Oncolytics Biotech Inc. (TSX: ONC, NASDAQ: ONCY) announced preclinical work with reovirus are available today on the American Association for Cancer Research (AACR) website at www.aacr.org, and on the Oncolytics website at www.oncolyticsbiotech.com.

The first abstract, entitled "Targeting Multiple Myeloma with Oncolytic Viral Therapy" covers preclinical work using reovirus as a purging agent during autologous (harvested from the patient themselves) hematopoietic stem cell transplants for multiple myeloma. The results demonstrated that up to 70% of multiple myeloma cell lines tested showed reovirus sensitivity and reovirus induced cell death mediated through apoptosis. An oral presentation is scheduled to be delivered by Dr. Chandini Thirukkumaran of the Tom Baker Cancer Centre, Calgary, AB on Tuesday, April 15, 2008.

"This exciting work highlights the potential of expanding the use of the reovirus to include being used as a purging agent during autologous blood stem cell transplants, as well as a treatment for childhood sarcomas," said Dr, Matt Coffey, Chief Scientific Officer of Oncolytics.

About Oncolytics Biotech Inc.

Oncolytics is a Calgary-based biotechnology company focused on the development of oncolytic viruses as potential cancer therapeutics. Oncolytics' clinical program includes a variety of Phase I/II and Phase II human trials using REOLYSIN(R), its proprietary formulation of the human reovirus, alone and in combination with radiation or chemotherapy. For further information about Oncolytics, please visit www.oncolyticsbiotech.com.

This press release contains forward-looking statements, within the meaning of Section 21E of the Securities Exchange Act of 1934, as amended. Forward-looking statements, including the implication of the abstract and materials presented on the AACR website and at this meeting with respect to REOLYSIN(R), the Company's expectations related to the results of trials investigating delivery of REOLYSIN(R), and the Company's belief as to the potential of REOLYSIN(R) as a cancer therapeutic, involve known and unknown risks and uncertainties, which could cause the Company's actual results to differ materially from those in the forward-looking statements. Such risks and uncertainties include, among others, the availability of funds and resources to pursue research and development projects, the efficacy of REOLYSIN(R) as a cancer treatment, the success and timely completion of clinical studies and trials, the Company's ability to successfully commercialize REOLYSIN(R), uncertainties related to the research and development of pharmaceuticals, uncertainties related to the regulatory process and general changes to the economic environment. Investors should consult the Company's quarterly and annual filings with the Canadian and U.S. securities commissions for additional information on risks and uncertainties relating to the forward-looking statements. Investors are cautioned against placing undue reliance on forward-looking statements. The Company does not undertake to update these forward-looking statements.

%SEDAR: 00013081E

For further information: Oncolytics Biotech Inc., Cathy Ward, 210, 1167 Kensington Cr NW, Calgary, Alberta, T2N 1X7, Tel: (403) 670-7377, Fax: (403) 283-0858, cathy.ward@oncolytics.ca; The Equicom Group, Nick Hurst, 325, 300 5th Ave. SW, Calgary, Alberta, T2P 3C4, Tel: (403) 538-4845, Fax: (403) 237-6916, nhurst@equicomgroup.com; The Investor Relations Group, Erika Moran, 11 Stone St, 3rd Floor, New York, NY, 10004, Tel: (212) 825-3210, Fax: (212) 825-3229, emoran@investorrelationsgroup.com

Combination Therapy Effective Against Multiple Myeloma

2008-03-17T09:40:00.001-06:00

Treatment with a combination of clarithromycin, lenalidomide and dexamethasone is successful in most patients with newly diagnosed symptomatic multiple myeloma, according to New York-based researchers.

"This paper," lead investigator Dr. Ruben Niesvizky told Reuters Health, "reports the efficacy and safety of a novel induction regimen, which has shown higher complete and overall response rates than other induction therapies."

In a phase II trial, Dr. Niesvizky of the New York Presbyterian Hospital-Cornell Medical Center and colleagues treated 72 patients in 28-day cycles. The patients were given dexamethasone 40 mg once weekly, clarithromycin 500 mg twice daily and lenalidomide 25 mg daily on days 1 to 21.

With response defined as a decrease in monoclonal protein of at least 50% in serum and 90% in urine, 65 of the patients (90.3%) had an objective response, the authors report in the February 1st issue of Blood. In total, 73.6% of the subjects achieved a decrease in monoclonal protein of 90% or greater.

The 52 patients who did not undergo hematopoietic stem cell transplant continued on therapy, and 37% of these patients had a complete response and 33% had a "very good" partial response. "The median event-free survival has not been reached," the researchers added, "and the actuarial 2-year event-free survival has reached 97.2%."

These results, Dr. Niesvizky said, are "comparable to high-dose chemotherapy programs." In the transplant patients, the investigators were able to "collect stem cells after lenalidomide therapy with successful engraftment after transplant."

Among other new findings, Dr. Niesvizky added, was "the safety and efficacy of dexamethasone in a once-weekly schedule" rather than the more toxic pulsing approach.

"Most adverse events were manageable," the researchers report. "The most common grade 3 or higher hematologic toxicities were neutropenia (19.4%), anemia (13.8%) and thrombocytopenia (22.2%). The most serious non-hematologic side effect was myopathy."

The results support further exploration of the approach for induction therapy, the researchers conclude, "because it produces high response rates and may increase disease-free and overall survival when used in conjunction with autologous transplantation."

SOURCE: Blood 2008;111:1101-1109.

Alternate day pomalidomide retains anti-myeloma effect with reduced adverse events and evidence of in vivo immunomodulation

2008-03-14T13:37:00.000-06:00

Streetly MJ, Gyertson K, Daniel Y, Zeldis JB, Kazmi M, Schey SA.

Department of Haematology, Guys Hospital, Guys and St. Thomas' NHS Foundation Trust, London, UK.

We previously reported that daily dose pomalidomide (CC-4047), a thalidomide analogue, has excellent anti-myeloma activity but is associated with myelosuppression and deep vein thrombosis. We report here a phase 1 study to determine the maximum tolerated dose (MTD) of pomalidomide at 1 mg, 2 mg, 5 mg and 10 mg on alternate days (ad). Twenty patients with relapsed myeloma were treated. Grade 4 neutropenia occurred in all patients receiving 10 mg and the MTD was defined as 5 mg ad. No thrombotic events were observed. Pomalidomide was continued following the 4-week MTD study in 17/20 patients for a median of 14 months. 10% of patients had a complete response and >50% reduction in paraprotein was achieved in 50% of subjects. Progression-free survival was 10.5 months and median overall survival was 33 months. A significant rise was observed in the proportion of CD8(+) cells. Alternate day pomalidomide was associated with a marked reduction in the incidence of thrombosis whilst maintaining excellent anti-myeloma activity. This trial provides further in vivo evidence that pomalidomide modulates the immune system in myeloma patients. Phase 2 studies to further assess the optimal schedule of administration and anti-myeloma activity of this agent are planned.

PMID: 18324965 [PubMed - in process]

Anti-CD20 monoclonal antibody therapy in multiple myeloma

2008-03-14T13:36:00.000-06:00

Kapoor P, Greipp PT, Morice WG, Rajkumar SV, Witzig TE, Greipp PR.

Division of Hematology, Mayo Clinic, Rochester, MN, USA.

CD20 is a particularly appealing target that is expressed on the surface of almost all B cells, with no significant shedding, secretion or internalization. In contrast to the demonstrated efficacy of anti-CD20 strategies in various B-cell lymphoproliferative disorders, the role of such therapy in multiple myeloma is undetermined and controversial. The expression of CD20 by myeloma cells is heterogeneous, and can be detected only in 13-22% of patients. However, there is increasing interest in testing anti-CD20 therapy in myeloma because of recent studies suggesting the existence of clonogenic CD20-positive precursor B cells in the disease. This article reviews the rationale, preclinical and clinical activity of anti-CD20 therapy in myeloma. Clinical trials show that anti-CD20 therapy with rituximab elicits a partial response in approximately 10% of CD20(+) patients with multiple myeloma. In addition, there is preliminary evidence of disease stabilization in 50-57% of CD20(+) patients for a period of 10-27 months. Further large-scale clinical trials are therefore needed to establish the role of this promising strategy in the treatment of myeloma.

PMID: 18318769 [PubMed - as supplied by publisher]

Drug Research: ACE-011 Bone Forming Agent

2008-03-11T15:15:00.000-06:00

Acceleron Pharma, Inc., a biopharmaceutical company developing therapeutics that modulate the growth of tissues including bone and muscle, was recently selected to receive a Biotech Investment Award from the Multiple Myeloma Research Foundation to support the research and development of ACE-011, a bone forming agent, for the treatment of multiple myeloma.

In addition, Acceleron announced that it began an additional study of ACE-011.

“With this grant, we will continue to aggressively pursue the development of ACE-011, which has shown encouraging preclinical and clinical effects on bone formation, to treat the complications of bone loss associated with multiple myeloma,” said John Knopf, chief executive officer of Acceleron.

The multiple dose study will be conducted in healthy, post-menopausal women. Subjects will receive four monthly subcutaneous doses of either ACE-011 or placebo. The primary objective of the study is to assess the safety, tolerability and pharmacokinetics of ACE-011. The pharmacodynamic effects of ACE-011 on bone will also be measured.

In numerous preclinical models of bone loss, ACE-011 increased bone mineral density, improved bone architecture, increased the mineral apposition and bone formation rates and improved bone mechanical strength. These effects have been demonstrated in therapeutic models of bone loss in which ACE-011 stimulated bone formation — a significant unmet medical need that is underserved by current treatments for bone loss, according to Acceleron.

New Biological Agents Added to Treatment Algorithm for Multiple Myeloma

2008-03-11T13:33:00.000-06:00

Novel therapy using several targeted agents has been incorporated into new guidelines from the National Comprehensive Cancer Network (NCCN) for treatment of multiple myeloma, presented at the NCCN 13th Annual Conference: Clinical Practice Guidelines and Quality Cancer Care.

The new agents that have been added to the NCCN's guidelines for treating cancer patients include:
· The proteasome inhibitor bortezomib. Proteasomes are enzymes that play a role in regulating cell function and growth.
· Thalidomide, which appears to inhibit the growth and survival of myeloma cells and to inhibit the growth of new blood vessels. Its precise mechanism of action is unknown. In the 1960s thalidomide was found to be responsible for birth defects and must not be taken by women who may become pregnant.
· Lenalidomide, an analog of thalidomide, which acts as an immune modulator, reducing cytokine proliferation that occurs in multiple myeloma.
· The anthracycline doxorubicin hydrochloride liposome injection, a cytotoxic agent.

"The effect on overall survival with these drugs is as yet unknown," said Kenneth C. Anderson, MD, the Kraft Family Professor of Medicine, Harvard Medical School, Boston, Massachusetts. "New drug combinations for front-line therapy are under evaluation using bortezomib, thalidomide, and lenalidomide."

In the updated guidelines for treatment of multiple myeloma, the drugs are indicated for use in advanced multiple myeloma patients along with cyclophosphomide and the combination of etoposide, dexamethasone, cytarabine, and cisplatin, Dr. Anderson said in a presentation on March 7th.

The guidelines suggest that other therapies for the treatment of relapse include thalidomide, lenalidomide, and bortezomib either as single agents or in combination with dexamethasone. Dr. Anderson also said that bortezomib can be used in combination, including with doxorubicin hydrochloride liposome injection.

"Other novel therapies to be conducted in clinical trials should also be considered," he added. The use of the drugs in the salvage setting is only for patients who have opted against transplantation to try to cure the disease. Thalidomide, bortezomib, and lenalidomide are mentioned in the guidelines for maintenance in transplantation.

Reduced-intensity conditioning allogeneic SCT as salvage treatment for relapsed multiple myeloma

2008-02-28T12:22:00.000-07:00

de Lavallade H, El-Cheikh J, Faucher C, Fürst S, Stoppa AM, Coso D, Bouabdallah R, Chabannon C, Gastaut JA, Blaise D, Mohty M.

1Unité de Transplantation et de Thérapie Cellulaire (UTTC), Institut Paoli-Calmettes, Marseille, France.

The aim of this retrospective analysis was to assess the benefit of reduced-intensity conditioning allo SCT (RIC allo-SCT) in a cohort of 32 relapsed multiple myeloma (MM) patients. A total of 19 patients had an HLA-identical sibling donor ('donor' group), while 13 patients had no donor ('no-donor' group). There were no significant differences between these two groups as for prognosis risk factors. Eighteen patients from the 'donor' group could actually proceed to RIC allo-SCT. With a median follow-up of 36 (range, 21-60) months, six patients died from transplant-related toxicity (cumulative incidence, 33% (95% CI, 11-55%)). Only 4 patients from the 18 transplanted patients (22%; 95% CI, 7-48%) progressed after RIC allo-SCT, as compared to 12 (86%; 95% CI, 56-98%; P=0.0003) among the nontransplanted patients. In an 'intention-to-treat' analysis, the Kaplan-Meier estimate of PFS was significantly higher in the 'donor' group as compared to the 'no-donor' group (P=0.01; 46 versus 8% at 3 years). There was no difference in terms of overall survival. However, in multivariate analysis, actual performance of RIC allo-SCT was associated with better PFS (relative risk, 0.35; 95% CI, 0.15-0.82; P=0.01). These data suggest a potential benefit for RIC allo-SCT in the management of relapsed MM warranting further prospective investigations.Bone Marrow Transplantation advance online publication, 25 February 2008; doi:10.1038/bmt.2008.22.

PMID: 18297115 [PubMed - as supplied by publisher]

Phase I trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) in patients with advanced multiple myeloma

2008-02-28T12:18:00.000-07:00

Richardson P, Mitsiades C, Colson K, Reilly E, McBride L, Chiao J, Sun L, Ricker J, Rizvi S, Oerth C, Atkins B, Fearen I, Anderson K, Siegel D.

Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.

A Phase I trial (NCT00109109) of oral vorinostat 200, 250 or 300 mg twice daily for 5 days/week/4-week cycle or 200, 300, or 400 mg twice daily for 14 days/3-week cycle until progressive disease or intolerable toxicity was conducted. Patients with measurable, relapsed/refractory multiple myeloma were eligible. The objectives were to determine maximum tolerated doses (MTDs) and assess activity and safety. Thirteen patients (median age, 63 years; median prior therapies, 3) were enrolled. MTDs were not determined due to early study termination by sponsor decision. One patient (250 mg twice daily 5 days/week) developed dose-limiting toxicity (DLT; grade 3 fatigue). There were no other DLTs and the maximum administered doses were 250 mg twice daily for 5 days/week/4-week cycle and 200 mg twice daily for 14 days/3-week cycle. Drug-related adverse experiences included fatigue, anorexia, dehydration, diarrhea, and nausea and were mostly grade less than or equal to 2. Of 10 evaluable patients, 1 had a minimal response and 9 had stable disease, demonstrating modest single-agent activity in relapsed/refractory multiple myeloma.

PMID: 18297527 [PubMed - in process]

Mayo Clinic announces genetically engineered model of multiple myeloma progression

2008-02-26T15:13:00.000-07:00

The first successful model able to mimic the genetic properties of multiple myeloma (MM) has been presented by Mayo Clinic researchers. The new model, announced in the February 2008 edition of Cancer Cell magazine, is expected to speed development of more effective treatments for myeloma.

"This model helps us understand the genetic properties that lead to multiple myeloma and provides a framework for developing better therapies," said Leif Bergsagel, M.D., a Mayo Clinic physician and lead investigator for the study. "We will now be able to test new treatments on models."

Multiple myeloma is the second most common form of blood cancer after lymphoma, with 15,000 new reported cases per year. It affects the bone marrow cells, called plasma cells, which produce antibodies. MM eventually leads to destruction of bone marrow and painful osteoporosis — an important indicator that malignant cancer is present.

Myeloma is typically preceded by the development of a benign tumor called MGUS (monoclonal gammopathy of undetermined significance). MGUS is the most common lymphoid tumor in humans, and develops in an estimated 3 percent of all individuals over age 50.

In a small percentage of patients, the harmless MGUS progresses to a fully malignant cancer. The agent of change is a cancer-causing gene known as MYC, first identified 25 years ago and suspected of involvement in MM. Dr. Bergsagel and his team proved conclusively that MYC is positively linked to converting MGUS into myeloma.

"We've proven that MYC can cause the conversion," he notes. "Now we can move forward and target new therapies to prevent that from happening."

The genetically engineered mouse model is a critical step in moving researchers past the "one size fits all" approach to treating MM, and into the realm of understanding the specific development of the disease. Until this project, previous efforts to produce models able to simultaneously repeat the precise timing, tissue specificity and nature of oncogenic events had failed.

"Some aspects of the progression of myeloma are due to the acquisition of genetic mutations over time," said Dr. Bergsagel. "With this model we can identify those mutations more quickly, and better understand what's happening with the patient."

The successful development of the mouse model is the end result of six years of research for Dr. Bergsagel, a pioneer of myeloma genetics and an internationally recognized authority on the genetic roots of the disease. Also participating in the project were Marta Chesi, Ph.D., of Mayo Clinic Cancer Center, and 12 others.

Myeloma in patients under age 50 shows better survival

2008-02-25T12:10:00.000-07:00

Ludwig H, Durie BG, Bolejack V, Turesson I, Kyle RA, Blade J, Fonseca R, Dimopoulos M, Shimizu K, San Miguel J, Westin J, Harousseau JL, Beksac M, Boccadoro M, Palumbo A, Barlogie B, Shustik C, Cavo M, Joshua D, Attal M, Sonneveld P, Crowley J.

Department of Medicine I, Wilhelminenspital, Vienna, Austria.

We analyzed the presenting features and survival in 1,689 patients with multiple myeloma aged <50>/= 50 years of age. 7,765 of the total 10,549 patients received conventional and 2,784 high-dose therapy. Young patients were more frequently male, had more favorable features such as low ISS and D/S stage as well as less frequently adverse prognostic factors including high CRP, low hemoglobin, increased serum creatinine and poor performance status. Survival was significantly longer in young patients (median 5.2 years versus 3.7 years; P<.001) both after conventional (median: 4.5 years versus 3.3 years; P<.001) or high-dose therapy (median: 7.5 years versus 5.7 years; P=.04). Ten-year survival rate was 19% after conventional and 43% after high-dose therapy in young, and 8% and 29%, respectively, in older patients. Multivariate analysis revealed age as an independent risk factor during conventional therapy, but not after autologous transplantation. Five of the 10 independent risk factors identified for conventional therapy were also relevant for autologous transplantation. After adjusting for normal mortality, lower ISS stage and other favorable prognostic features seem to account for the significantly longer survival of young patients with multiple myeloma with age remaining a risk factor during conventional therapy.

PMID: 18268097 [PubMed - as supplied by publisher]