Monday, July 31, 2006

IMF Philadelphia MM seminar

New Treatments Keep Philadelphia Woman Alive and Well 13 Years after diagnosis

The International Myeloma Foundation -- a not-for-profit organization supporting research and providing education, advocacy and support for myeloma patients, families, researchers and physicians -- is bringing leading experts to the Doubletree Hotel, August 4 and 5, to discuss the latest trends and developments changing the face of cancer care.

These new developments include the recent approval of the once controversial drug thalidomide for multiple myeloma, the anticipated approval this month of a related drug called Revlimid, and new survival data, just released at a scientific conference.

"When I was first diagnosed with multiple myeloma most patients were given three to five years to live. But for me that was 13 years ago, and here I am leading an active productive life," says Philadelphia resident Marilyn Alexander. "I am in complete remission on a new drug called Revlimid, a pill I take at home that has none of the ravages associated with traditional chemotherapy."

Multiple myeloma is a cancer in the bone marrow that affects production of red cells, white cells and stem cells. With more than 100 drugs in clinical trials, myeloma is leading the way to the new model for cancer treatment. Although it remains incurable, myeloma is fast becoming a chronic cancer, where people will take their medication and go about their lives.

"As I wrote in the New England Journal of Medicine, contrary to a widely held belief, multiple myeloma is not a rare, rapidly fatal disorder that affects only elderly patients," said Edward Stadtmauer, M.D., hematologist at the Hospital of the University of Pennsylvania. "Instead, it is the second most common blood cancer. Half of these patients were diagnosed when they were younger than 60, and increasingly, the disease is detected in patients under the age of 40. The detection of myeloma in patients who are relatively young and otherwise healthy has allowed the use of increasingly aggressive and potentially more efficacious therapies."

The Philadelphia Patient & Family Seminar will be held August 4th and 5th at the Doubletree Hotel, 237 South Broad Street, Philadelphia.

Saturday, July 29, 2006

Cancer agency halts Thalidomide funding in B.C.

VANCOUVER (CP) -- The B.C. Cancer Agency will stop funding the drug thalidomide for new bone cancer patients.

The agency cites the notorious drug's $2-million annual cost as "no longer tenable."

Of the 165 B.C. patients who have been prescribed the drug in the past year for multiple myeloma, those who are still on it will be grandfathered into the new policy effective this month.

They will continue getting the drug for free through the agency, but newly diagnosed patients will have to pay the $1,000 to $4,000 cost per month themselves if they need it.

An estimated 220 patients this year will need the drug.

New patients may also qualify for treatment with a new drug funded by the agency.

The agency, which has been the only cancer centre in Canada paying for thalidomide, has seen its monthly costs jump nearly 1,000% -- from $100 a bottle to nearly $1,000 -- in the past five years.

Scorpion venom fights brain cancer

TransMolecular, Inc. has researched a treatment using scorpion venom to treat malignant brain tumours.

A synthetic version of a protein derived from scorpion venom targeted tumour cells without harming healthy cells of brain cancer patients.

The synthetic scorpion venom was developed by Transmolecular Industries, Inc., a Boston-based company.

Source: www.transmolecular.com

Friday, July 28, 2006

Millennium Pharmaceuticals Inc. 2Q financial results

Millennium Pharmaceuticals Inc. cut its second-quarter loss by more than half as revenue increased and expenses declined.

The Cambridge drug maker lost $17.7 million, or 6 cents per share, compared with a loss of $44.1 million, or 14 cents per share, a year ago. Earnings, excluding charges, amounted to $3.9 million, or a 1-cent gain.

Revenue jumped 9 percent to $120.1 million from $110.6 million, topping analysts' projection of $115.8 million in revenue.

The company attributed improved results to strong sales of multiple myeloma treatment Velcade, more royalties and revenue from strategic alliances, and cutting expenses 16 percent.

MMRF News

A record number of walkers and runners crossed the finish line in the MMRF Race for Research-Seattle in July, raising funds to help find a cure for multiple myeloma, raising more than $65,000!

Thursday, July 27, 2006

Human Genome Sciences Phase 2 Clinical Trial of HGS-ETR1 in Combination With Bortezomib

First clinical study of HGS-ETR1 in combination with another therapeutic agent for the treatment of a hematopoietic cancer

Human Genome Sciences, Inc. (Nasdaq: HGSI - News) announced today that it has initiated dosing of patients in a randomized Phase 2 clinical trial of HGS-ETR1 (mapatumumab) in combination with bortezomib (VELCADE®) in advanced multiple myeloma.

"Clinical and preclinical evidence continues to emerge suggesting that agonistic antibodies to TRAIL receptors 1 and 2 have significant potential to provide novel therapeutic options to patients with multiple myeloma and a variety of other cancer types."

"The results of preclinical studies demonstrate that HGS-ETR1 enhances the tumor-killing activity of bortezomib. These data, along with emerging clinical results, support the evaluation of HGS-ETR1 in combination with bortezomib in a Phase 2 study in patients with relapsed or recurrent multiple myeloma. We look forward to determining whether this combination has the potential to play a role in the treatment of multiple myeloma."

About the Phase 2 Trial Design

The primary objective of the study is to evaluate disease response to HGS- ETR1 in combination with bortezomib, versus bortezomib alone, in patients with relapsed or refractory multiple myeloma. The Phase 2 trial is a randomized, multi-center, open-label study to evaluate the efficacy and safety of HGS-ETR1 in combination with bortezomib in patients with relapsed or refractory multiple myeloma. Approximately 100 patients will be enrolled in the United States and Canada and randomized into two treatment groups, with one treatment group receiving the combination of HGS-ETR1 and bortezomib, and the other treatment group receiving bortezomib alone. Secondary objectives are to evaluate safety and tolerability, and to determine plasma concentrations of HGS-ETR1 for use in a population pharmacokinetic analysis.

About Phase 2 Results to Date

HGS has completed three Phase 2 clinical trials of HGS-ETR1 to evaluate its potential as a single agent for the treatment of specific cancers, including non-Hodgkin's lymphoma, non-small lung cancer, and colorectal cancer.

The results of a Phase 2 clinical trial in patients with non-Hodgkin's lymphoma (NHL) demonstrated that HGS-ETR1 was well tolerated, showed signs of clinical activity in patients with relapsed or refractory NHL, and could be administered safely and repetitively. Of the patients enrolled, 43% (17/40) were diagnosed as having follicular lymphomas. Clinical responses (1 complete response and 2 partial responses) were observed in 3/17 (18%) patients with follicular lymphomas, and 11/17 (65%) of these patients exhibited either response or stable disease. Clinical and preclinical results to date suggest that further clinical evaluation of HGS-ETR1 in combination with other therapeutic agents is warranted in patients with lymphomas and hematologic malignancies.

The results of separate Phase 2 clinical trials of HGS-ETR1 as a single agent in advanced non-small cell lung cancer (NSCLC) and advanced colorectal cancer (CRC) showed that the HGS-ETR1 was well tolerated and could be administered safely and repetitively. Stable disease was observed in approximately 29% of patients participating in the NSCLC study, and in approximately 32% of the patients participating in the CRC study. The results of these studies, along with the interim results of two ongoing Phase 1b trials support further evaluation of HGS-ETR1 in combination with chemotherapeutic agents.

About HGS-ETR1

HGS-ETR1 is an agonistic human monoclonal antibody that specifically binds to the TRAIL receptor-1 protein and triggers programmed cell death, or apoptosis, in cancer cells. HGS-ETR1 does this by mimicking the activity of the natural protein TRAIL (tumor necrosis factor apoptosis-inducing ligand). Human Genome Sciences' own studies, as well as those of others, show that TRAIL receptor 1 is expressed on a number of solid tumors and tumors of hematopoietic origin. It has been demonstrated that cell lines derived from a broad array of solid and hematologic human tumors, including lung, colon, breast, multiple myeloma, prostate, pancreas, and lymphoid, are sensitive to killing by apoptosis induced by either native TRAIL or agonistic antibodies to TRAIL receptors 1 and 2.

HGS-ETR1 was generated through a collaboration between HGS and Cambridge Antibody Technology. GlaxoSmithKline (GSK) has exercised its option under a June 1996 agreement to develop and commercialize HGS-ETR1 jointly with HGS. Under the terms of the agreement, GSK and HGS will share equally in Phase 3/4 development costs, and will share equally in sales and marketing expenses and profits of any commercialized product, under a co-development and co-promotion agreement, the remaining terms of which are being negotiated by the parties.

About Human Genome Sciences

The mission of Human Genome Sciences is to discover, develop, manufacture and market innovative drugs that serve patients with unmet medical needs, with a primary focus on protein and antibody drugs.

The HGS clinical development pipeline includes drugs to treat hepatitis C, lupus, anthrax disease, cancer, rheumatoid arthritis and HIV/AIDS. The Company's primary focus is rapid progress toward the commercialization of its two lead compounds, Albuferon(TM) for hepatitis C, and LymphoStat-B(TM) for lupus. Both compounds are expected to advance to Phase 3 clinical trials in 2006.

In June 2006, HGS announced that the U.S. Government has exercised its option under an existing contract to purchase 20,000 doses of ABthrax(TM), for the treatment of anthrax disease. Other HGS compounds in clinical development include three TRAIL receptor antibodies for the treatment of hematopoietic and solid malignancies, in addition to an antibody to the CCR5 receptor for the treatment of HIV/AIDS.

For more information about Human Genome Sciences, please visit the Company's web site at www.hgsi.com. For more information about HGS-ETR1, see www.hgsi.com/products/ETR1.html.

ABthrax, Albuferon, LymphoStat-B, HGS and Human Genome Sciences are trademarks of Human Genome Sciences, Inc.

Safe Harbor Statement

This announcement contains forward-looking statements within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended. The forward-looking statements are based on Human Genome Sciences' current intent, belief and expectations. These statements are not guarantees of future performance and are subject to certain risks and uncertainties that are difficult to predict. Actual results may differ materially from these forward-looking statements because of the Company's unproven business model, its dependence on new technologies, the uncertainty and timing of clinical trials, the Company's ability to develop and commercialize products, its dependence on collaborators for services and revenue, its substantial indebtedness and lease obligations, its changing requirements and costs associated with planned facilities, intense competition, the uncertainty of patent and intellectual property protection, the Company's dependence on key management and key suppliers, the uncertainty of regulation of products, the impact of future alliances or transactions and other risks described in the Company's filings with the Securities and Exchange Commission. Existing and prospective investors are cautioned not to place undue reliance on these forward-looking statements, which speak only as of today's date. Human Genome Sciences undertakes no obligation to update or revise the information contained in this announcement whether as a result of new information, future events or circumstances or otherwise.

Source: Human Genome Sciences, Inc.

Wednesday, July 26, 2006

Ontario covers four expensive cancer drugs

Four cancer drugs costing patients tens of thousands of dollars will now be paid for by the province.

It's a victory for Hamilton multiple myeloma patients who have been fighting for more than two years to have OHIP cover Velcade, a last-resort drug that costs patients about $60,000 to buy and have administered intravenously.

The Ministry of Health announced yesterday it will cover Velcade as well as Taxotere for early-stage breast cancer, Tomudex for mesothelioma caused by asbestos, and Tarceva for late-stage lung cancer.

"It's like a gift of life to us," said Lori Borsos, diagnosed with multiple myeloma three years ago. "I'm just shocked."

The 46-year-old Hamilton woman has travelled to Queen's Park, signed petitions and lobbied politicians in a long battle to get funding for Velcade.

Patients turn to Velcade when other therapies fail to treat the blood cancer affecting bone marrow. It prevents reproduction or growth of cancer cells.

Velcade is paid for by other provinces but was originally turned down in Ontario. That left patients, who had no other hope but Velcade, facing bills between $35,000 and $60,000.

"It was devastating," said Borsos, who runs a support group for multiple myeloma patients. "We had people who were going to move out of province to stay alive."

The earlier decision was reversed at the urging of Ontario's Drug Quality and Therapeutics Committee after the drug manufacturer provided new information. "We're delighted these drugs have been approved," said Terry Sullivan, CEO of Cancer Care Ontario, which manages the province's cancer care. "It's good news."

He says the funding will be in effect within days.

Borsos doesn't need the drug right now but says it's a tremendous relief to know she still has hope if her cancer gets worse.

"You can't give up hope. That's all we have," she said. "It's wonderful news."

The four drugs are expected to be used by 1,400 Ontario patients this year and 2,600 patients next year.

"We're committed to helping them in their struggle by providing access to the medications and treatments that will give them the best possible chance of winning their fight," said Health Minister George Smitherman said in a statement.

Cancer Care Ontario plans to make recommendations in the next few weeks regarding drugs that aren't covered. It's expected to advise the government to approve a controversial plan that would allow hospitals to administer intravenous drugs paid for by patients. It would cut the price nearly in half because patients would no longer have to pay private clinics to do it.

But there are concerns it would violate the Canada Health Act because intravenous drugs given in hospital have traditionally been considered medically necessary.

"It's still on the table for discussion," Sullivan said.

Source: The Hamilton Spectator

England refuses to fund Velcade for MM patients

A drug that improves and prolongs the lives of thousands of cancer patients should not be available on the health service, a Government advisory group unexpectedly recommended. Patients described the decision yesterday as a death sentence.

The draft recommendation by the National Institute for Clinical Excellence (Nice) says that Velcade, the only licensed drug for people with multiple myeloma who have relapsed, should be given only to those taking part in clinical trials.

Velcade, also called bortezomib, is recommended for use in Scotland, Wales and Northern Ireland and in countries across Europe and the rest of the world. It costs up to £18,000 per patient and extends life by 18 to 24 months on average.

The International Myeloma Foundation said that only about 4,000 English patients a year would be prescribed the treatment and many would not need the full course, reducing the cost.

Tuesday, July 25, 2006

Ganoderma lucidum causes apoptosis in leukemia, lymphoma and multiple myeloma cells

Leuk Res. 2006 Jul;30(7):841-8. Epub 2006 Jan 19.

Muller CI, Kumagai T, O'Kelly J, Seeram NP, Heber D, Koeffler HP.

Cedars-Sinai Medical Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States. MullerCI@cshs.org

Over many centuries, herbal remedies have treated a variety of ailments. This empiric observational approach has produced a number of leads for formulated medicines. Ganoderma lucidum extract was screened for its anti-proliferative activity using a panel of 26 human cancer cell lines. The six most sensitive hematologic cell lines were: HL-60 (ED50 26 microg/ml), U937 (63 microg/ml), K562 (50 microg/ml), Blin-1 (38 microg/ml), Nalm-6 (30 microg/ml) and RPMI8226 (40 microg/ml). Cell cycle analyses revealed a G2/M arrest, most prominently in HL-60 cells. Four hematopoietic cell lines (HL-60, Blin-1, U937, RPMI8226) were examined for apoptosis, which ranged between 21 and 92%. After exposure to G. lucidum extract, HL-60 cells became multinucleated with an increased DNA content. These results indicate that G. lucidum extract has a profound activity against leukemia, lymphoma and multiple myeloma cells and may be a novel adjunctive therapy for the treatment of hematologic malignancies.

PMID: 16423392 [PubMed - in process]

Ganoderma lucidum causes apoptosis in leukemia, lymphoma and multiple myeloma cells

Leuk Res. 2006 Jul;30(7):841-8. Epub 2006 Jan 19.

Muller CI, Kumagai T, O'Kelly J, Seeram NP, Heber D, Koeffler HP.

Cedars-Sinai Medical Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States. MullerCI@cshs.org

Over many centuries, herbal remedies have treated a variety of ailments. This empiric observational approach has produced a number of leads for formulated medicines. Ganoderma lucidum extract was screened for its anti-proliferative activity using a panel of 26 human cancer cell lines. The six most sensitive hematologic cell lines were: HL-60 (ED50 26 microg/ml), U937 (63 microg/ml), K562 (50 microg/ml), Blin-1 (38 microg/ml), Nalm-6 (30 microg/ml) and RPMI8226 (40 microg/ml). Cell cycle analyses revealed a G2/M arrest, most prominently in HL-60 cells. Four hematopoietic cell lines (HL-60, Blin-1, U937, RPMI8226) were examined for apoptosis, which ranged between 21 and 92%. After exposure to G. lucidum extract, HL-60 cells became multinucleated with an increased DNA content. These results indicate that G. lucidum extract has a profound activity against leukemia, lymphoma and multiple myeloma cells and may be a novel adjunctive therapy for the treatment of hematologic malignancies.

PMID: 16423392 [PubMed - in process]

Monday, July 24, 2006

Osteonecrosis of the jaw in patients with multiple myeloma

Osteonecrosis of the jaw (ONJ) has been associated with the use of pamidronate and zoledronic acid. ONJ was assessed prospectively since July 2003 in 202 patients with multiple myeloma who received bisphosphonates since April 1995. Fifteen patients (7.4%) developed ONJ. The median time of exposure to bisphosphonates was 39 months for patients with ONJ compared to 28 months (p=0.048) for patients with no ONJ. The cumulative hazard of developing ONJ was significantly higher in patients treated with zoledronic acid alone than in those treated with pamidronate alone / pamidronate+zoledronic acid / zoledronic acid+ibandronate sequentially (1% at 1 year and 15% at 4 years vs. 0% and 5%, p=0.003). In conclusion, the risk of ONJ is increased with time of exposure and probably with the use of zoledronic acid.

Bisphosphonates are used for the treatment of bone involvement by multiple myeloma and solid tumors. Recently, avascular osteonecrosis of the jaw (ONJ) has been associated with their use. Osteonecrosis refers to the death of bone as a result of impaired blood supply. ONJ has been described in association with the use of zoledronic acid and pamidronate in various malignancies and it has been suggested that its development requires a long period of exposure. The diagnosis of osteonecrosis, in most cases, has been made retrospectively, based on the review of medical records rather than by a specialist. Furthermore, a denominator for the patients who were diagnosed with OJN was not established. In order to define the incidence of ONJ as well possible risk factors we have been prospectively studying the development of ONJ since 2003, while all patients who received bisphosphonates in our department over an 8-year period have been entered into a database. A first analysis, including all patients with malignant bone disease, has already been reported. Nevertheless, such an analysis may not be representative of the problem in each malignancy, since there are differences associated with the duration of treatment. Additionally, biological differences associated with the development of ONJ in different tumors cannot be excluded. That initial report included 111 patients with MM. In our current report, another 91 patients have been included. We, therefore, studied the incidence and possible risk factors associated with bisphosphonate treatment separately in patients with MM.


Source: http://www.haematologica.org/preprint/20060601/03906078_9641.pdf

Tuesday, July 11, 2006

MMRC tissue bank

Patients With Rare Diseases Work to Jump-Start Research

Advocacy Groups Create Their Own Tissue Banks To Aid in Drug Development

By AMY DOCKSER MARCUS

Kathy Giusti, 47 years old, was diagnosed a decade ago with multiple myeloma, an incurable and rare cancer of the blood. With only 16,000 new cases diagnosed a year, Ms. Giusti, a former pharmaceutical-company executive, knew that it would be hard to get drug companies and researchers to study her disease.

When she asked researchers at a 2004 meeting what it would take to speed up the search for treatments, she says they told her that "the biggest obstacle was getting tissue from multiple myeloma patients to study and test." So she decided to give them something to get started: In 2005, the Multiple Myeloma Research Consortium, founded by Ms. Giusti, started its own biospecimen bank.

With more than 600 samples of bone marrow and blood already collected from around the country, the bank's resources are being used to support important new research. The consortium, which now includes 11 academic institutions, earlier this year launched a Multiple Myeloma Genomic Initiative, which will study the tissue samples to look for genes that play a role in the disease. It is also discussing with researchers in France the possibility of setting up a European-based multiple-myeloma bank to further expand the supply of tissue.

Biospecimen banks, which may include tissue samples, blood, spinal fluid or other specimens along with clinical data about patients, are critical to medical research. They offer researchers a way to test new drugs and to study and better understand the biology of a disease. And they offer the best way of finding new targets for experimental drugs.

Major drug companies and medical centers often maintain such banks for a range of diseases. But specimens sometimes sit unused because there isn't money to study them. If a disease is rare, individual centers may not see enough patients to collect a critical mass of samples, and smaller drug companies often don't have the resources to find patients. Patient groups have also found that study results often aren't shared with other researchers, and legal fights have broken out over who owns the rights to potential therapies developed from tissue.

Out of frustration over all these issues, patient groups—especially ones focused on rare, underfunded diseases—are increasingly taking matters into their own hands. They are starting their own biospecimen banks in the hopes of accelerating research and gaining more control over the process.

Ms. Giusti says it cost $2 million to $3 million to set up the multiple-myeloma bank, paid for partly by a grant from the Pioneer Fund, a private family foundation in Denver. Maintaining it costs about $1.5 million a year, which goes mainly to salaries for assistants at major cancer centers who oversee the collection of specimens, the cost of collecting and shipping them, and storage at the Mayo Clinic Scottsdale, in Arizona, where the bank is housed.

At a meeting of patient-advocacy groups last month in Cambridge, Mass., Ms. Giusti recounted some of the challenges she faced in launching the tissue bank. Often, even at major academic centers, the bank wasn't able to get large numbers of samples, so organizers decided they needed more centers. Ms. Giusti estimated that it cost her group $250,000 in legal fees to get a membership agreement written and signed by all the centers.

The Multiple Myeloma Research Consortium has developed stringent standards of its own for collection and storage of samples. At sites around the country that work with the consortium, anytime a patient with multiple myeloma has a bone-marrow draw, he or she is asked to donate an extra sample for the bank. The samples are all drawn, bar-coded, shipped and treated according to a protocol developed and paid for by the consortium. Every week, the consortium sends out a kind of "report card" to each center which tells them how many samples each site has shipped. A system was set up to allow each center to track the specimens and enter patient data in a standard fashion.

The Mayo Clinic storage facility is neutral on how the specimens are used, says Rafael Fonseca, associate professor at the Mayo Clinic and medical director of the tissue bank; such decisions are vetted by the consortium's steering committee.

The multiple myeloma tissue bank has played a key role in several new projects. Nereus Pharmaceuticals of San Francisco plans to start a clinical trial with a new drug, and the tissue bank will collect samples from the patients treated with the drug to allow the company to determine if the drug is working and which patients are responding. Novartis is testing an experimental drug in a group of patients who have an aggressive subtype of the disease that hasn't responded well to standard treatments, and will use tissue from the bank to identify patients in that group.

Source: excerpted from “Wall Street Journal online”

Monday, July 10, 2006

AnorMed begins multiple myeloma trial

AnorMed reports that it has enrolled 300 patients in a phase 3 study of Mozobil in stem-cell transplant for multiple myeloma.

The most recently enrolled patients will receive stem cell transplants over the next four to six weeks, with a subsequent 100-day follow-up period.

Investigators then have up to six months from the first transplant to perform a second or "tandem" transplant if needed, with a 100-day follow-up after the second transplant, AnorMed said.

FDA grants Panzem orphan status

EntreMed's lead drug candidate, Panzem, has been granted orphan drug status by the FDA, the company said.

Panzem (2-methoxyestradiol) is being developed for the treatment of glioblastoma multiforme (GBM), an often fatal form of brain cancer. GBM is the most common type of malignant primary brain tumor, representing approximately 12 to 15 percent of all brain tumors, according to EntreMed.

The FDA accepted the application after reviewing in vitro studies in glioma cell lines that demonstrated anti-proliferative activity of Panzem and in vivo studies in a preclinical model of gliobastoma that demonstrate its anti-tumor activity.

The orphan drug designation is intended to provide incentives to encourage the development of drugs for diseases affecting fewer than 200,000 people in the U.S. and provides the developer with tax credits and marketing exclusivity incentives.

Panzem had previously been granted orphan drug status for the treatment of multiple myeloma — a type of blood cancer — and ovarian cancer.

Source: http://www.fdanews.com

Sunday, July 09, 2006

Green tea effect on Multiple Myeloma cells

Specific killing of multiple myeloma cells by (-)- epigallocatechin-3-gallate extracted from green tea: biological activity and therapeutic implications

Masood A Shammas, Paola Neri, Hemanta Koley, Ramesh B Batchu, Robert C Bertheau, Vidit Munshi, Rao Prabhala, Mariateresa Fulciniti, Yu tzu Tai, Steven P Treon, Raj K Goyal, Kenneth C Anderson, and Nikhil C Munshi*

VA Boston Health Care System, Harvard Medical School, Dana Farber Cancer Institute, Boston, MA
Dana Farber Cancer Institute, Harvard Medical School, Boston, MA
VA Boston Health Care System, Harvard Medical School, Boston, MA
VA Boston Health Care System, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA
VA Boston Health Care System, Boston, MA

* Corresponding author; email: nikhil_munshi@dfci.harvard.edu

Epigallocatechin-3-gallate (EGCG), a polyphenol extracted from green tea is an anti-oxidant with chemopreventive and chemotherapeutic actions. Based on its ability to modulate growth factor mediated cell proliferation, we evaluated its efficacy in multiple myeloma (MM). EGCG induced both dose- and time- dependent growth arrest and subsequent apoptotic cell death in multiple myeloma cell lines including IL-6 dependent cells and primary patient cells; without significant effect on the growth of peripheral blood mononuclear cells (PBMC) and normal fibroblasts. Treatment with EGCG also led to significant apoptosis in human myeloma cells grown as tumors in SCID mice. EGCG interacts with 67Kda laminin receptor 1 (LR1) which is significantly elevated in myeloma cell lines and patient samples relative to normal PBMC. RNAi mediated inhibition of LR1 resulted in abrogation of EGCG-induced apoptosis in myeloma cells, indicating that LR1 plays an important role in mediating EGCG activity in MM while sparing PBMC. Evaluation of changes in gene expression profile indicates that EGCG treatment activates distinct pathways of growth arrest and apoptosis in MM cells by inducing the expression of death-associated protein kinase 2, the initiators and mediators of death receptor dependent apoptosis (Fas ligand, Fas, and caspase 4), p53-like proteins (p73, p63), positive regulators of apoptosis and NF-kappaB activation (CARD10, CARD14), and cyclin-dependent kinase inhibitors (p16 and p18). Expression of related genes at protein level were also confirmed by western blot analysis. These data demonstrate potent and specific anti-myeloma activity of EGCG providing the rationale for its clinical evaluation.

See also http://myelomic.blogspot.com/2005/12/beneficial-effects-of-green-tea.html

Thursday, July 06, 2006

State of the art therapy in multiple myeloma and future perspectives

Denz U, Haas PS, Wasch R, Einsele H, Engelhardt M.

Hematology and Oncology Department, University of Freiburg Medical Center, Hugstetter Strasse 55, 79106 Freiburg, Germany.

Treatment for multiple myeloma (MM) has changed beyond recognition in the past decades. While until the early 1980s, MM caused a slow progressive decline in quality of life until death after about two years, today's patients can expect a 50% chance of achieving a complete remission, a median survival time of five years and a 20% chance of surviving longer than ten years. State of the art therapy comprises: evidence-based supportive care; highly effective and well tolerated chemotherapeutic regimens; and for patients qualifying for intensive high-dose conditioning, autologous haematopoietic stem cell transplantation (HSCT) is an option. Maintenance therapy has become increasingly important since a majority of patients are able to achieve a good remission after front-line therapy which is aimed to be preserved as long as possible. In addition, improved understanding of the disease biology has led to the development of novel biological treatment agents, such as thalidomide, bortezomib and others, targeted at cellular mechanisms and interactions, e.g. with the bone marrow microenvironment. These strategies are incrementally integrated into modern MM care. This review considers recent clinical advancements in anti-myeloma strategies and provides an overview of the state of the art management of MM patients.

PMID: 16815703 [PubMed - as supplied by publisher]

State of the art therapy in multiple myeloma and future perspectives

Denz U, Haas PS, Wasch R, Einsele H, Engelhardt M.

Hematology and Oncology Department, University of Freiburg Medical Center, Hugstetter Strasse 55, 79106 Freiburg, Germany.

Treatment for multiple myeloma (MM) has changed beyond recognition in the past decades. While until the early 1980s, MM caused a slow progressive decline in quality of life until death after about two years, today's patients can expect a 50% chance of achieving a complete remission, a median survival time of five years and a 20% chance of surviving longer than ten years. State of the art therapy comprises: evidence-based supportive care; highly effective and well tolerated chemotherapeutic regimens; and for patients qualifying for intensive high-dose conditioning, autologous haematopoietic stem cell transplantation (HSCT) is an option. Maintenance therapy has become increasingly important since a majority of patients are able to achieve a good remission after front-line therapy which is aimed to be preserved as long as possible. In addition, improved understanding of the disease biology has led to the development of novel biological treatment agents, such as thalidomide, bortezomib and others, targeted at cellular mechanisms and interactions, e.g. with the bone marrow microenvironment. These strategies are incrementally integrated into modern MM care. This review considers recent clinical advancements in anti-myeloma strategies and provides an overview of the state of the art management of MM patients.

PMID: 16815703 [PubMed - as supplied by publisher]

Wednesday, July 05, 2006

Cancer from X-rays kills hundreds a year

X-ray-induced cancers kill 780 to 2,500 Canadians a year and many new procedures that use X-rays to guide thin tubes and other devices into blood vessels and arteries have not been tested for radiation safety, Health Canada says.

And as the use of ionizing radiation in medicine grows, so do concerns that patients are not being told of rare but potential hazards.

An internal Health Canada document provided to CanWest News Service estimates that even a five-per-cent reduction in radiation dose "would translate in the saving of 125 lives per year."

Nearly three million Canadians will have a CT scan of their brain, lungs, joints, stomachs or other organs this year. Tens of thousands more will have an angioplasty or other X-ray guided procedure to prop open clogged coronary arteries, shrink uterine fibroids, and diagnose stomach ulcers and other illnesses.

Interventional radiology allows doctors to do through tiny incisions what once required major surgery. People recover sooner, with less risk of infection and death.

In almost all cases, the benefit to patients far outweighs the potential risk of a downstream cancer, experts say, but as the procedures become more common, and more complex, concerns about excessive radiation exposure are increasing.

"In general, these procedures are of benefit to Canadians since they allow a shorter stay in hospital and reduce the need for surgery," says a Health Canada document obtained by Ottawa researcher Ken Rubin. "However, the risks of cancer and deterministic effects (injuries) are not negligible.

"With the increased complexity of these procedures, the irradiation time has also increased, giving rise to concern about patient doses."

Some abdominal CT scans expose people to 250 times the radiation of an ordinary X-ray. A single chest scan can deliver radiation to the breast -- one of the most radiosensitive tissues in the body-- roughly equal to 10 to 25 mammograms, or 100 to 400 chest X-rays.

Last week, researchers reported that chest X-rays may double or triple the risk of breast cancer in women genetically predisposed to the disease. The risk was highest in women who had five or more X-rays or who were exposed before age 20.

The use of CT scans for concussions has doubled or tripled over the last 10 years in large Canadian hospitals, and scans of the head and pelvis in children are also increasing rapidly.

The International Atomic Energy Agency says radiation doses could be reduced by half or more without jeopardizing safety or image quality.

The National Academy of Sciences estimates that one in 1,000 people who receive 10 millisieverts of medical radiation exposure -- roughly equal to one CT scan of the chest or abdomen -- will develop a solid tumour or leukemia.

But patients receive minimal information about CT scans, says Dr. Richard Semelka, professor and vice-chair of research in University of North Carolina's department of radiology.

"They undergo a CT, but nobody says to them that there is a small but definite risk you could get cancer. And I think that is wrong."

Writing last month in the British medical journal Lancet, Semelka and co-author Diego Martin say radiation cancer may take five to 20 years to develop.

"That really explains why nothing really is told to patients, because people consider it so far in the future," Semelka said in an interview. "It's not like surgery. ... We're talking about something that may be 20 years down the road."

That may not be of concern to older people who may have only a decade or two of life left, but the risks are higher for children and young adults, Semelka says.

Every year in Canada, about 600,000 adults with a concussion are seen in emergency rooms. Eighty per cent were sent to radiology for a CT scan in 2002; in 1997, just 30 per cent were scanned.

The tests are ordered to detect blood clots in the brain, which are rare in patients who are "wide awake and talking," says Dr. Ian Stiell, professor and chair of emergency medicine at the University of Ottawa. Still, they can happen, and they can be disastrous.

The tendency has been to order a CT scan for every minor head injury, even though Stiell and his colleagues have determined only a third to half of concussion patients need one.

Radiologists use as little radiation as necessary to get an answer to a clinical question, says Michael Bronskill, a professor in the department of medical biophysics at the University of Toronto.

But doses during interventional procedures can vary substantially, based on the procedure.

"A regular diagnostic angiogram exposed patients to about 2.5 to five millisieverts of radiation," says Dr. Benjamin Chow, a cardiologist at the University of Ottawa Heart Institute. For angioplasties, it could be an extra 2.5 millisieverts, or as high as 20 millisieverts, during one procedure.

Health Canada is also concerned about dental X-rays, although the radiation doses are substantially lower. Christian Lavoie, chief of Health Canada's medical X-ray and mammography division, says the dose from one dental X-ray is equivalent to a few hours of flying, and that there are "not that many cancer-sensitive organs" close to the teeth.

"Why do we care if it's that small of a dose? The reason is it's probably the single most numerous type of X-ray you could get."

It also comprises the largest number of X-rays given to children. "About 50 per cent of my calls are from parents who are concerned about dental X-rays."

The Canadian Dental Association says the number of dental X-rays should be kept to a minimum, and should be based on a clear medical need.

Chow says the small, one-in-1,000 risk of cancer in patients exposed to 10 millisieverts of radiation, needs to be put in perspective.

"Twenty-five per cent of the population will get cancer -- one in four. So you're increasing their risk of cancer from 25 per cent to 25.001 per cent," he says. "From a medical perspective, we don't think this is a significant increase in risk."

The risks of stroke, heart attack and death during angiography "are actually higher than the cancer risk, and they're also more significant. As physicians, we quote what we believe are the most significant and most relevant risks."

But Lavoie of Health Canada says the risk-benefit needs to be weighed as the procedures grow.

"We do uterine artery embolization (for fibroids), which means a woman doesn't have to have her uterus removed, but we're then putting a whole lot of radiation around the ovaries. Will it mean that we're going to actually create cancer in those women in 10 years?"

The U.S. Food and Drug Administration has passed regulations that will require all fluoroscopy equipment sold in the U.S. to be fitted with displays that monitor X-ray time and track the radiation dose to patients in real-time.

But Semelka says hospitals should also develop permanent patient records as a way to track how much radiation people are exposed to from CT scans and X-ray guided procedures, and to consider alternative tests, such as ultrasounds or an MRI, where appropriate.

"First of all, the general public has the right to know. It may then also be beholden on them that they keep track of their radiation and going into emergency, maybe even having a card showing this is what I've had done before."

Adds Semelka: "What I don't want the public to come away with is the concept that CT is terrible. It's not. It's a terrific modality. It's very fast, it's very accurate.

"The risk is small, but think twice about getting the second one. Think three times about getting the third."

© The Edmonton Journal 2006

MMRF genomics initiative update

The Multiple Myeloma Genomics Iniative is now underway! To date, the MMRC has accrued the first 60 untreated myeloma tissue samples and has transferred these tissues to its collaborators -- the Eli and Edythe L. Broad Institute of MIT and Harvard, and the Translational Genomics Research Institute.

This exciting genome-mapping program is comprised of several related research and discovery efforts that aim to determine what genes and molecular pathways play a role in the onset and progression of myeloma, learn how patients will respond to therapies, and identify new druggable targets for the disease. Taken together, these findings will lead to the development of better, more effective therapies for myeloma.

The success of Multiple Myeloma Genomic Initiative hinges on researchers' ability to study, analyze, and characterize a large number of untreated myeloma patient tissue samples in great detail. This kind of research has been made possible only recently with the development of the MMRC Tissue Bank.

If you are interested in contributing a tissue sample to the MMRC Tissue Bank, please contact Alicia Sabel-Hunt, RN, MMRC Program Manager, at sablehunt@themmrc.org

Tuesday, July 04, 2006

Multiple Myeloma diagnosis: Plasma cell quantification in bone marrow by computer-assisted image analysis

Went P, Mayer S, Oberholzer M, Dirnhofer S.

Institute for Pathology,
University of Basel, University Hospital, Switzerland. pwent@uhbs.ch

BACKGROUND: Minor and major criteria for the diagnosis of multiple myeloma according to the definition of the WHO classification include different categories of the bone marrow plasma cell count: a shift from the 10-30% group to the >30% group equals a shift from a minor to a major criterium, while the <10% group does not contribute to the diagnosis. Plasma cell fraction in the bone marrow is therefore critical for the classification and optimal clinical management of patients with plasma cell dyscrasias. The aim of this study was (i) to establish a digital image analysis system able to quantify bone marrow plasma cells and (ii) to evaluate two quantification techniques in bone marrow trephines i.e. computer-assisted digital image analysis and conventional light-microscopic evaluation. The results were compared regarding inter-observer variation of the obtained results.

MATERIAL AND METHODS: Eighty-seven patients, 28 with multiple myeloma, 29 with monoclonal gammopathy of undetermined significance, and 30 with reactive plasmocytosis were included in the study. Plasma cells in H&E- and CD138-stained slides were quantified by two investigators using light-microscopic estimation and computer-assisted digital analysis. The sets of results were correlated with rank correlation coefficients. Patients were categorized according to WHO criteria addressing the plasma cell content of the bone marrow (group 1: 0-10%, group
2: 11-30%, group 3: >30%), and the results compared by kappa statistics.

RESULTS: The degree of agreement in CD138-stained slides was higher for results obtained using the computer-assisted image analysis system compared to light microscopic evaluation (corr.coeff.=0.782), as was seen in the intra- (corr.coeff.=0.960) and inter-individual results correlations (corr.coeff.=0.899). Inter-observer agreement for categorized results (SM/PW: kappa 0.833) was in a high range.

CONCLUSIONS: Computer-assisted image analysis demonstrated a higher reproducibility of bone marrow plasma cell quantification. This might be of critical importance for diagnosis, clinical management and prognostics when plasma cell numbers are low, which makes exact quantifications difficult.

PMID: 16763944 [PubMed - in process]

Research: Bone cell science

Though we think of them as solid and permanent, our bones are actually constantly being rebuilt throughout our lives. A team of scientists at the Weizmann Institute of Science have revealed how cells that work at remodeling the bones play a direct part in the ongoing renewal of another system – the blood. Their findings were published in the June issue of Nature Medicine.

Bones are really two systems in one. The cavities inside bones are filled with spongy bone marrow, in which stem cells divide and their daughter cells differentiate into all kinds of blood cells, including large numbers of immune cells for the body’s defense. The hematopoietic (literally, blood-creating) stem cells, which can give rise to any kind of blood cell, reside in special ‘stem cell niches’ nestled in the bones’ inner walls. Inside these sheltered nurseries, the stem cells remain undifferentiated; with the help of other nearby cells, they hang onto their juvenile qualities. Only when they leave the niches do they morph into specialized blood cells, possibly becoming immune cells for fighting infection or cells for blood clotting and healing after injury. They can even respond to calls for help from organs such as the liver, migrating through the bloodstream to assist in repairing damage.

The inner walls of the bones are also sites of intensive reconstruction. While one type of cell, the osteoblast, is busy building bone, its partner, the osteoclast, breaks it down and reassimilates the material. Osteoclasts are formed when several cells (which themselves originate from hematopoietic stem cells) fuse together at a signal from the osteoblasts, and the two work together in a sort of ‘urban renewal’ scheme to keep the bones healthy and strong.

The Weizmann Institute team headed by Prof. Tsvee Lapidot of the Immunology Department, which included Dr. Orit Kollet and colleagues, found that the bone-dismantling osteoclasts are instrumental in releasing hematopoietic stem cells into the bloodstream. As they wear away the bone, they allow the stem cells out of the niches and into the bloodstream. Although some hematopoietic stem cells can always be found circulating in the blood, when there is bleeding or inflammation in the body, more stem cells are needed to deal with the situation and restore balance. The team’s study showed that the bone marrow response to the body’s call for help involves stepping up production of osteoclasts, putting machinery that normally operates at a leisurely pace into high gear. The osteoclasts not only clear away bone, they also break up ‘nurturing’ substances in the niche that attract and hold the stem cells to that spot, thus allowing more stem cells into the bloodstream.

The team carried out their research on mice, including some developed in the lab of Prof. Ari Elson of the Molecular Genetics Department, in which the osteoclasts carried a mutation that rendered them only partially functional in the young females. They found abnormally low stem cell levels in the blood of these mice even when they tried to encourage their mobilization, giving them solid evidence of the connection. In normal mice, using a chemical compound that stimulates osteoclast formation, they were able to boost osteoclast levels and thus manage the release of stem cells into the blood in a variety of stress situations. This finding may have implications for bone marrow transplant techniques: The drugs given today to donors to increase the supply of stem cells in their bloodstream before they are harvested for transplantation cause the release of many other mature cells as well. Injecting the osteoclast-promoting substance into the mice, on the other hand, resulted in an increase mainly in stem cell release. These findings add a new dimension to our understanding of the processes of renewal and breakdown in the body, and the relationship between blood-forming stem cells, bone, and the immune system. In some forms of osteoporosis, autoimmune arthritis, and cancer that has metastasized to the bone, for instance, the osteoclasts demolish bone faster than it is built up. This study suggests the effects of such an imbalance may reach well beyond the bone.

Saturday, July 01, 2006

FDA grants REVLIMID approval for Multiple Myeloma

A number of news reports the past few days have announced a landmark decision for Multiple Myeloma patients -- FDA approval for Revlimid to treat multiple myeloma in patients who have failed to respond to a previous treatment.

Last month the FDA approved Thalomid to treat patients with newly diagnosed multiple myeloma.

In June 2006, Celgene presented data demonstrating improved survival with Revlimid in previously treated patients with multiple myeloma by at least a year compared with those receiving chemotherapy plus a placebo. About half of the patients in the placebo group had died within two years, while more than half the patients in the Revlimid group were still alive after three years.

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