Novel treatment approaches for relapsed and refractory multiple myeloma

Treatment options for patients with relapsed myeloma are a rapidly moving entity. Although autologous transplantation has improved outcomes for younger patients, the use of a second autologous transplant in the relapsed setting has less benefit. Nonmyeloablative allogeneic transplant is being studied in several large cooperative group trials, but to date early auto/mini-allo does not appear to be superior to tandem autologous transplantation. The greatest benefit in the relapsed setting has been demonstrated using novel targeted agents with biologically based therapies. The response rates from thalidomide with and without dexamethasone, bortezomib, and lenalidomide with and without dexamethasone clearly demonstrate high levels of activity with encouraging durations of remission. More recent studies are combining novel agents, and small phase I/II trials are demonstrating higher overall response and complete remission rates.
The next generation of novel agents targeting heat shock proteins, the mitogen-activated protein kinase pathway, and monoclonal antibodies are further expanding the list of future potential agents. The rapid clinical development of targeting agents will give us more options to treat patients with relapsed or refractory myeloma, thereby improving quality of life and overall survival.

Sinha R, Lonial S.

Winship Cancer Institute, Emory University, 1365 Clifton Road, Building C, Room 4004, Atlanta, GA 30322, USA. sloni01@emory.edu.

PMID: 16615880 [PubMed - in process]

New drug Depsipeptide (FK228)

Data Safety Monitoring Board Recommends Continuation of Gloucester Pharmaceuticals' Pivotal Trial for Depsipeptide in Cutaneous T-Cell Lymphoma

Gloucester Pharmaceuticals, Inc., announced today that an independent Data Safety Monitoring Board (DSMB) has reviewed interim safety data in its international pivotal trial evaluating the Company's depsipeptide product as a treatment for cutaneous T-cell lymphoma (CTCL). The DSMB recommended that Gloucester continue the trial without any modifications.

Data Safety Monitoring Boards are comprised of independent medical experts, including physicians and statisticians, who are not involved in the clinical trial under review. The DSMB 's focus is patient safety and it is responsible for monitoring the safety data from patients participating in the trial and providing feedback and recommendations to the sponsoring organization.

Gloucester's pivotal clinical CTCL trial is a Phase II, non-randomized, open label, single arm study that is being conducted at approximately 20 sites in the US and Europe.

About Depsipeptide (FK228)

Depsipeptide is a novel agent in a new class of anti-cancer drugs known as histone deacetylase inhibitors. The Company is conducting a pivotal study of depsipeptide for patients with cutaneous T-cell lymphoma (CTCL). The U.S. FDA reviewed the trial protocol under its Special Protocol Assessment (SPA) process prior to the initiation of the pivotal study. Depsipeptide has received both Fast Track and Orphan Drug designation by the FDA, and Orphan Drug Designation from the EMEA, as monotherapy for cutaneous T-cell lymphoma patients who have relapsed, or become refractory to, at least one prior systemic therapy. Depsipeptide is also in clinical trials for a variety of other hematologic malignancies and solid tumors including peripheral T-cell lymphoma, hormone refractory prostate cancer and multiple myeloma.

Source: www.gloucesterpharma.com

New drug Bondronat vs. Zometa

New Data Support Bondronat's Superior Renal Safety Profile Against Zometa

New data announced at the 8^th workshop on bisphosphonates in Davos shows Roche's Bondronat® (ibandronate) is associated with significantly less kidney damage than another commonly used bisphosphonate, zoledronic acid (Zometa), in multiple myeloma patients with bone lesions.

Although Bondronat is not currently licensed for use in multiple myeloma, the audit results add to evidence from previous studies which indicate that Bondronat has renal safety similar to placebo, unlike other bisphosphonates.

Multiple myeloma is a cancer of the blood which develops in the bone marrow of patients. Bisphosphonates are used to treat the bone lesions that result from the cancer -- these lesions give rise to a high risk of fractures and considerable bone pain. Approximately 50% of multiple myeloma patients experience kidney problems, making renal safety a key consideration for physicians.

In the audit, rates of renal impairment over a 4 year period were reviewed retrospectively in records of multiple myeloma patients treated with either Bondronat or zoledronic acid. The results showed:

· Patients taking Bondronat were three times less likely to suffer renal impairment than those taking zoledronic acid: 10.8% for Bondronat vs. 39.1% with zoledronic acid (based on serum creatinine levels).

· The incidence rate of renal impairment was significantly higher in patients taking zoledronic acid: 0.87 events with Bondronat versus 2.65 events with zoledronic acid per person-year (indicated by the glomerular filtration rate, a recognized measure of renal function).

"These data confirm findings from previous studies and again highlight Bondronat's renal safety advantages over other bisphosphonates. They are especially promising given the particular risk of kidney complications faced by multiple myeloma patients," said Dr. Raoul Bergner from the Klinikum der Stadt Ludwigshafen in Ludwigshafen, Germany. "Patients with multiple myeloma experiencing bone pain may benefit from the loading dose currently under investigation in an international phase III study in cancer patients with bone metastases. The good renal safety profile means Bondronat can be given on 3 consecutive days without causing kidney damage."

In a further two studies also presented today, Bondronat was found to be suitable for use in patients with relapsed or refractory multiple myeloma and well-tolerated in multiple myeloma patients who had reached end stage renal disease, requiring haemodialysis. These promising results are being further evaluated in two multi-centre, multi-national phase III trials in multiple myeloma patients, investigating the efficacy and renal safety of Bondronat in these patients.

New chemotherapy delivery method

A new method for delivering chemotherapy being developed in Britain might result in cancer patients not experiencing hair loss and vomiting.

Researchers at the University of Bath, England, are using tiny fibers and beads soaked in the chemotherapy drug, which are then implanted into the cancerous area in the patient's body.

The fibres are bio-degradable and compatible with body tissue, which means they would not be rejected by the patient's body. They gradually turn from solid to liquid, releasing a regular flow of the chemotherapy chemical into the cancer site and a much lower dose to the rest of the body.

This is a more localized way of killing cancer cells than the current method of injecting the chemical into a cancer sufferer's vein so that it is carried around the body.

The drug's delivery vehicle, known as Fibrasorb, could also cut the numbers of patients who die from the effects of chemotherapy because they need such high doses to tackle their cancer.

Cell division rewind

Scientists have found a way to reverse the process of cell division, previously thought to be unstoppable.

The finding by US researchers could have important implications for cancer, which is caused by cells dividing uncontrollably.

Writing in Nature, the team explained how controlling a key protein can interrupt the process.

UK experts on cancer cell behaviour said the research aided understanding of how cells should divide.

Cell division occurs millions of times each day in the human body.

Each time, the cell is supposed to be in the prime of health - so any DNA damage has to be repaired first - and the 46 pairs of chromosomes in the cell have to be divided equally between its "daughters".

However, both of these things can go wrong in cancer cells.

In the lab, researchers from the Oklahoma Medical Research Foundation were able to control a protein called cyclin which normally plays a key role in instigating cell division before disappearing.

They inactivated it using a chemical, and then washed that chemical out of the cells.

This meant cell cycle went backwards, sending duplicate chromosomes back to the centre of the original cell, which had been thought impossible, rather than continuing the division process.

This appeared to be because the cyclin was still present in the cell when, under natural circumstances, it should not be.

But the team had to act at a particular point, or the intervention failed to reverse cell division.

The team say this suggests many other factors involved in regulating cell division.

Dr Gary Gorbsky, who led the research, said: "No-one has got the cell cycle to go backwards before now.

"This shows that certain events in the cell cycle that have long been assumed irreversible may, in fact, be reversible."

Professor Jonathon Pines, an expert in cancer cell division at the Gurdon Institute in Cambridge, said the research would not lead directly to new cancer treatments.

But he added: "It is useful for us to understand how the cell goes through the process of segregating the chromosomes."

Story from BBC NEWS:
http://news.bbc.co.uk/go/pr/fr/-/1/hi/health/4902908.stm

© BBC MMVI

Osteonecrosis of the Jaw update

Bisphosphonates -- Drugs Used to Treat Osteoporosis, Certain Cancers and Paget's Disease -- May Put Patients at Risk for Deterioration of the Jaw

The American Association of Endodontists (AAE) at its 2006 Annual Session today issued a position statement on an important issue related to the care of patients taking a class of drugs known as bisphosphonates. Each year, more than 30 million Americans take bisphosphonates, which are used to treat cancer, and debilitating bone diseases such as osteoporosis and Paget's disease.

However, these patients may be at risk for osteonecrosis of the jaw (ONJ), a potential side effect of taking bisphosphonates. ONJ is a painful, disfiguring condition, which leads to the breakdown of the jawbone. Symptoms include burning, tingling or localized pain in the jaw, which could lead to serious infections and ultimately jawbone degeneration. While bisphosphonates support the buildup of bone in areas weakened by disease, as a side effect of treatment, patients may experience the opposite in their lower and upper jawbones.

"The AAE is at the forefront of this emerging complication because endodontists have special expertise in finding the cause of oral and facial pain that has been difficult to diagnose," said AAE President Marc Balson, D.D.S. "With this position statement, we hope to ensure the highest quality care and safety for patients taking bisphosphonates."

"Until further information becomes available, the AAE recommends that all patients taking bisphosphonates be considered at some risk for ONJ, recognizing that the magnitude of the risk varies by patient," he added. "The AAE also encourages patients taking bisphosphonates to inform their dental care providers and consult with specialists as needed."

The position statement was based on the findings of a special committee of leading endodontic educators and researchers assembled by the AAE. The group reviewed scientific data on the relationship between bisphosphonates and ONJ, including information published in the October and November 2005 issues of the Journal of Endodontics, the association's scientific journal. Case reports suggest that problems in patients using bisphosphonates may be triggered by tooth extractions and other dental surgical events, or even occur spontaneously.

The committee recommends that those taking bisphosphonates receive counsel before undergoing any elective dental surgical procedures, and that any non-elective dental work -- especially extractions -- be completed before starting bisphosphonate therapy. When dental work is required after starting bisphosphonate therapy, it is essential that patients and general dentists consult with medical and dental specialists who can provide information on appropriate treatments. Endodontists are especially important participants in treatment planning, since nonsurgical root canal treatment has been shown to be safer for patients taking bisphosphonates.

What to do if you think you have ONJ

Patients who think they may be experiencing ONJ symptoms should contact their general physicians and oncologists, and inform their dentists, endodontists and other dental professionals that they are undergoing treatment with bisphophonates. When dental work is required after starting bisphosphonate therapy, patients, physicians and general dentists should consult with appropriate dental specialists, including endodontists, because nonsurgical root canal treatment may be a safer alternative to extraction.

Who may be at risk?

-- People taking one in a class of drugs called bisphosphonates,

including:

-- Alendronate (Fosamax®)

-- Clodronate (Bonefos®, Ostac®)

-- Etidronate (Didronel®)

-- Ibandronate (Boniva®)

-- Pamidronate (Aredia®)

-- Risedronate (Actonel®)

-- Tiludronate (Skelid®)

-- Zoledronate (Zometa®)

What are the symptoms of ONJ?

-- Irregular sore with exposed bone in the mandible or maxilla

-- Pain or swelling in the infected jaw

-- Infection, possibly with pus

-- Altered sensation (e.g., numbness or heavy sensation)

According to the AAE's position statement, risk factors associated with the development of bisphosphonate-associated ONJ include:

-- History of taking bisphosphonates, especially I.V. formulations. The concurrent use of steroids appears to contribute to this risk.

-- Previous history of cancer (e.g., multiple myeloma or metastatic disease to bone), osteoporosis, Paget's disease or other indications for bisphosphonate treatment.

-- A history of a traumatic dental procedure. Most complications occur after a tooth extraction, although other traumatic dental procedures may be associated with the occurrence of ONJ. One case report describes bisphosphonate-associated ONJ occurring six months after placement of five dental implants, with the subsequent loss of all implants.

-- Several reports indicate the spontaneous development of bisphosphonate-associated ONJ without a prior traumatic dental procedure.

Velcade clinical trial for NHL

Millennium Pharmaceuticals, Inc. along with co-development partner Johnson & Johnson Pharmaceutical Research & Development, today announced the initiation of a Phase III clinical trial of VELCADE in combination with rituximab in patients with relapsed or refractory follicular lymphoma, a subtype of non-Hodgkin's lymphoma (NHL). This study builds on clinical data observed in previous trials of VELCADE that showed high objective response rates and a favorable safety profile across a variety of lymphomas.

The Phase III study is expected to enroll approximately 670 patients with relapsed or refractory, rituximab naïve or sensitive follicular NHL. Patients will be randomized to either the combination regimen of once-weekly VELCADE plus rituximab or rituximab alone. The primary endpoint is progression-free survival. Secondary endpoints of the study include the overall response rate and duration of response.

Review of recent developments in Multiple Myeloma treatment

Not all patients who fulfill the minimal criteria for diagnosis of multiple myeloma should be treated. If doubt exists about beginning therapy, one should wait and re-evaluate the patient in 2 or 3 months. There is no evidence that early treatment of multiple myeloma is advantageous. All patients should be considered possible candidates for an autologous stem cell transplantation. If they are deemed to be eligible, they should be treated for 3 to 4 months with therapy that does not damage the hematopoietic stem cells. Currently, most physicians use thalidomide plus dexamethasone or dexamethasone alone for induction. Vincristine, doxorubicin (Adriamycin), and dexamethasone (VAD) have been used in the past. Autologous stem cell transplantation prolongs disease-free survival and overall survival. The treatment-related mortality rate is 1% to 2%. Melphalan, 200 mg/m(2), is the most widely used preparative regimen. Although allogeneic transplantation is attractive, the mortality rate (about 20%) is too high to recommend conventional allogeneic transplantation. Non-myeloablative transplantation is currently under investigation. If the patient is not a candidate for autologous stem cell transplantation, therapy with melphalan and prednisone is a good choice. Patients with relapsed or refractory disease may be treated with dexamethasone, thalidomide and dexamethasone, bortezomib (Velcade, PS-341), or lenalidomide (Revlimid, not yet approved by the Food and Drug Administration).

Kyle RA, Vincent Rajkumar S.

Division of Hematology, Mayo Clinic, Rochester, Minnesota, U S A.

PMID: 16581696 [PubMed - in process]

Advances in oral therapy for multiple myeloma

Conventional intravenous chemotherapy regimens are toxic, cumbersome, and negatively affect patients' quality of life, with oral treatment preferable to most patients with cancer. Multiple myeloma is the second most common haematological malignant disease, but cannot be cured with conventional and high-dose chemotherapy. New oral treatments that target myeloma cells or bone marrow are being developed that are highly effective yet have low toxic effects, such as the immunomodulatory drugs thalidomide and lenalidomide. Several treatments in early development have shown antimyeloma activity, including: CHIR-258, which inhibits fibroblast growth factor receptor 3; NVP-ADW742, which inhibits insulin-like growth factor receptor 1; and PTK787, which inhibits vascular endothelial growth factor. Additional drugs aimed at switching off silenced genes include histone deacetylase inhibitors. The availability of these various oral treatments is hoped to improve regimens that, if used sequentially or in combination, offer the potential of making multiple myeloma a chronic disease, thereby extending patient lifespans and improving quality of life.

Morgan GJ, Krishnan B, Jenner M, Davies FE

Royal Marsden Hospital and Institute of Cancer Research, London, UK. gareth.morgan@rmh.nhs.uk

PMID: 16574547 [PubMed - in process]

SCT importance of complete response

Complete response in multiple myeloma: clinical trial E9486, an Eastern Cooperative Oncology Group study not involving stem cell transplantation.

BACKGROUND: The importance of obtaining a complete response (CR) in multiple myeloma (MM) treated with chemotherapy is unclear.

METHODS: The Eastern Cooperative Oncology Group evaluated 653 previously untreated patients with active MM randomized to vincristine, carmustine (BCNU), melphalan, cyclophosphamide, and prednisone (VBMCP), to VBMCP and recombinant interferon alfa-2 (INFalpha-2), or to VBMCP and high-dose cyclophosphamide.

RESULTS: Objective response was achieved in 420 (67%) of the 628 eligible patients, and 85 (14%) achieved a CR. Patients receiving VBMCP and recombinant INFalpha-2 had a significantly higher CR (18%) than those receiving VBMCP alone (10%) (P = .02). The CR rate for VBMCP and high-dose cyclophosphamide was 12%. Median duration of survival was 3.5 years for all eligible patients, and the estimated 5-year survival rate was 31%. The median duration of survival from the date of objective response was 5.1 years for those who achieved a CR and 3.3 years for those with a partial response (P < .0001). The median postresponse survival was 6.6 years in the 21 patients in CR with nonclonal disease and 4.4 years in the 11 patients in CR who had persistent clonal disease. All patients with negative immunofixation results and nonclonal plasma cells in whom polymerase chain reaction was performed had a positive result (presence of tumor DNA).

CONCLUSION: Patients in whom a CR was achieved had a longer survival than those who had a partial response. Cancer 2006. (c) 2006 American Cancer Society.

Kyle RA, Leong T, Li S, Oken MM, Kay NE, Van Ness B, Greipp PR

Mayo Clinic, Rochester, Minnesota.

PMID: 16565956 [PubMed - as supplied by publisher]

Fighting for medicare coverage for Velcade in Ontario

Ontario Health Minister George Smitherman defends the province's decision to deny payment for the cancer drug velcade, which is available worldwide and throughout the rest of Canada, by stating that velcade treatment for multiple myeloma offers marginal benefit. This is indeed news to me and my colleagues who specialize in treating this bone marrow cancer.

In reality, velcade has been universally hailed as a breakthrough drug in this disease, working in one of three patients when all else fails, the first such drug approved in 40 years by Health Canada, the FDA and the European Union for this purpose. The drug is even more effective used earlier in the disease course. Does the minister really believe that oncologists worldwide, the editorial staff at the New England Journal of Medicine and 50,000 patients treated to date are so gullible as to be swayed by "shrewd marketing campaigns"?

Ontario and its advisors must indeed be much smarter to have discovered something that those of us who treat and research the disease every day have missed. I no longer practise in Ontario but since leaving last year have heard regularly from my former colleagues and patients who are outraged but seemingly unable to overturn this well-intentioned but totally inappropriate decision.

The government should revisit the mistaken position it has adopted. In my opinion, myeloma and lymphoma patients in Ontario should seek any available legal recourse to overturn this state of affairs before more patients die prematurely.

On the other hand, perhaps the intelligent public of Ontario will demand better and the government will overturn this illogical decision with the haste that desperate patients require.

I acknowledge that I have been a consultant and an invited lecturer for the manufacturers of this drug and was actively engaged in clinical trials that proved its worth. Nevertheless, I am swayed only by the irrefutable evidence of clinical benefit in my patients.

---

Dr. A. Keith Stewart, Professor of Medicine,University of Toronto

Source: The Toronto Star

Altiprimod clinical trial update

Callisto Pharmaceuticals, a New York biopharmaceutical company, has received approval from three of its clinical research sites to test its anticancer drug candidate at higher doses.

Atiprimod is being developed as a treatment for the serious blood cancer multiple myeloma. So far the phase I/IIa studies have not demonstrated a maximum tolerated dose for the treatment. Therefore, Callisto amended the trial protocols to study Atiprimod at the higher doses.

The continuation of the studies will enable the researchers to use higher doses of Atiprimod as they study the drug's efficacy as a treatment for multiple myeloma. Callisto said some positive therapeutic effects were observed even at the first dosage levels.

"This next wave of research is where we'll expect to see Atiprimod showing some significantly positive activity against multiple myeloma along with further safety data," said Dr Donald Picker, Callisto's executive vice president of R&D.

Atiprimod is presently in two phase I/IIa clinical trials; the first for relapsed or refractory multiple myeloma patients, while the second is in advanced cancer.

Gene therapy corrects immune-system disease

London - A team of international scientists has used gene therapy to successfully treat two patients with a rare but deadly disease of the immune system, marking a small but significant step in the push toward DNA-based medicine.

In a study published in the journal Nature Medicine, researchers described how they introduced a corrective gene to undo the damage caused by a form of chronic granulomatous disease, or CGD. The rare affliction, which is more commonly inherited by men, makes patients extremely vulnerable to infections.

In the latest gene-therapy experiment, two adult men with CGD were treated with gene therapy for 1-1/2 years. Each of the two patients had inherited a defective gene that makes it difficult for their bodies to produce a particular enzyme. As a result, their myeloid cells, a form of white blood cell, can't mount the appropriate response against fungal or bacterial infection.

To fix the problem, researchers used a virus to ferry corrective genes for the enzyme into the patients. The appropriate genes got switched on. But in a surprise to the scientists, the gene-corrected blood cells also tripled in number, improving the performance of the therapy.

The experiment is one of the first to show that gene therapy can successfully treat diseases of the myeloid system. Scientists refrain from pronouncing their achievement a cure, until they verify that the effects last over time.

Source: Gautam Naik in "The Telegraph"

New genetic subtypes of Multiple Myeloma

Scientists have identified four distinct genetic subtypes of multiple myeloma, that have different prognoses and might be treated most effectively with drugs specifically targeted to those subtypes.

A new computational tool based on an algorithm designed to recognize human faces plucked the four distinguishing gene patterns out of a landscape of many DNA alterations in the myeloma genome, the researchers report in the April issue of Cancer Cell.

These results "define new disease subgroups of multiple myeloma that can be correlated with different clinical outcomes," wrote the authors, led by Ronald DePinho, MD, director of Dana-Farber's Center for Applied Cancer Science.

Not only do the findings pave the way for treatments tailored to a patient's specific form of the disease, they also narrow down areas of the chromosomes in myeloma cells likely to contain undiscovered genetic flaws that drive myeloma, and which might turn out to be vulnerable to targeted designer drugs.

Kenneth Anderson, MD, medical director of the Jerome Lipper Multiple Myeloma Center at Dana-Farber and an author of the paper, said the findings "allow us to predict how patients will respond to current treatments based on a genetic analysis of their disease." In addition, the findings "identify many new genes implicated in the cause and progression of myeloma, and the product of those genes can be targeted with novel therapies."

Myeloma cells' genomes are scenes of rampant chaos: extra or missing chromosomes; pieces of broken chromosomes randomly reattached; genes that are mutated or amplified -- present in too many copies -- or are overexpressed or absent. The roles played by these myriad abnormalities in the initiation and progression of myeloma are only beginning to be understood, but it's been observed that different abnormalities are often found from one patient to the next.

Previously, scientists had identified two genetic subtypes of myeloma. One, called hyperdiploid MM, is characterized by extra copies of entire chromosomes, and patients with this subtype appear to fare better. The non-hyperdiploid form lacks these extra chromosomes and instead has abnormal rearrangements between different chromosomes, and the outlook is generally worse for these patients.

The collaborating researchers sought to cast a wide net to capture as many of the genetic flaws in myeloma cells as possible, creating a comprehensive atlas of this cancerous genome. First, they used a technique called high-resolution array CGH (comparative genomic hybridization) to analyze samples from 67 newly diagnosed patients. The CGH technique compared the genomes of a normal blood cell with various myeloma cells in search of differences. The goal was to identify recurrent copy number alterations -- hotspots on the chromosomes where genes were abnormally duplicated or lost across many different tumors.

The CGH analysis netted a large number of areas showing such alterations in the myeloma cells from patients. Then the scientists asked whether any specific pattern or combination of these aberrations in an individual patient might help predict how aggressive the disease would be.

For this deeper analysis, the researchers created an algorithm based on a recently developed computational method designed to recognize individuals by facial features. It is called non-negative matrix factorization, or NMF. In the myeloma study, the algorithm was used to group the results in a way that yielded distinctive genomic features from the CGH data.

Four distinct myeloma subtypes based on genetic patterns emerged: Two of them corresponded to the non-hyperdiploid and hyperdiploid types, and the latter was found to contain two further subdivisions, called k1 and k2 When these subgroups were checked against the records of the patients from whom the samples were taken, it showed that those with the k1 pattern had a longer survival than those with k2.

Digging still deeper, the scientists found evidence suggesting that certain molecular signatures within the subgroups are responsible for the differences in outcomes, providing a clear and productive path for further research.

This narrowing down of potential genes and proteins within the subgroups "is a huge advance," comments DePinho. "If you know that a certain gene is driving the disease and influences the clinical behavior of the disease in humans, it immediately goes to the top of the list as a prime candidate for drug development."

The research was supported by grants from the National Cancer Institute, the Fund to Cure Myeloma, and the Belfer Foundation for Innovative Science at Dana-Farber.

SOURCE: Dana-Farber Cancer Institute

Thalidomide news

Thalidomide derivative CC-4047 inhibits osteoclast formation by down-regulation of PU.1

CC-4047, an immunomodulatory analog of thalidomide, inhibits multiple myeloma with unknown effects on the human osteoclast lineage. Early osteoclast progenitors are of hematopoietic origin and differentiate into mature bone resorbing multinucleated osteoclasts. We investigated the effects of CC-4047 and thalidomide on human osteoclastogenesis, using in vitro receptor activator of NF-B ligand/macrophage colony-stimulating factor–stimulated bone marrow cell cultures. Treating bone marrow cultures with CC-4047 for 3 weeks decreased osteoclast formation accompanied by complete inhibition of bone resorption. The inhibitory effect was similar when cultures were treated for 3 weeks or for only the first week (90% inhibition), indicating that CC-4047 inhibits early stages of osteoclast formation. Inhibition of osteoclastogenesis by CC-4047 was mediated by a shift of lineage commitment to granulocyte colony-forming units at the expense of granulocyte-macrophage colony-forming units. Further studies revealed that this shift in lineage commitment was mediated through down-regulation of PU.1. Treatment with thalidomide resulted in significantly less potent inhibition of osteoclast formation and bone resorption. These results provide evidence that CC-4047 blocks osteoclast differentiation during early phases of osteoclastogenesis. Therefore, CC-4047 might be a valuable drug for targeting both tumors and osteoclastic activity in patients with multiple myeloma and other diseases associated with osteolytic lesions.

Gülsüm Anderson, Margarete Gries, Noriyoshi Kurihara, Tadashi Honjo, Judy Anderson, Vera Donnenberg, Albert Donnenberg, Irene Ghobrial, Markus Y. Mapara, David Stirling, David Roodman, and Suzanne Lentzsch

From the University of Pittsburgh Cancer Institute, Division of Hematology/Oncology, Pittsburgh, PA; the University Medical Center Charité, Robert-Rössle-Klinik, Department of Hematology, Oncology and Tumorimmunology, Humboldt University Berlin, Germany; and Celgene Corporation, Warren, NJ.

Apoptosis through rATG

Current monoclonal antibody therapies for multiple myeloma have had limited success, perhaps due to narrow target specificity. We have previously described the ability of polyclonal rabbit antithymocyte globulin (rATG) to induce caspase- and cathepsin-mediated apoptosis in human B and plasma cells. We now extend this observation to myeloma cells. Complement independent cell death was measured after addition of rATG (1-1000 µg/mL) to cultures of myeloma cell lines or primary CD138⁺ isolates from patient bone marrow aspirates. rATG induced significant levels of apoptosis in myeloma cells as assayed by caspase induction, annexin V binding, subdiploid DNA fragmentation, plasma-membrane permeability, and loss of mitochondrial-membrane potential. Addition of complement greatly augmented myeloma-cell death. Binding of rATG to individual myeloma cell-surface proteins, primarily CD38, CD52, CD126, and CD138, was demonstrated by competitive inhibition experiments with targeted monoclonal antibodies. Three pathways of cell death were identified involving caspase activation, cathepsin D, and the genistein sensitive tyrosine kinase pathway. F(ab')₂ fragments of rATG had reduced proapoptotic activity, which was restored by coincubation with Fc fragments, and anti-CD32 or anti-CD64 antibodies. We conclude that rATG is an effective agent for in vitro induction of apoptosis in multiple myeloma, and that exploratory clinical trials may be warranted.

Martin S. Zand, Thuong Vo, Tina Pellegrin, Raymond Felgar, Jane L. Liesveld, Jainulabdeen J. Ifthikharuddin, Camille N. Abboud, Ignacio Sanz, and Jennifer Huggins

From the Division of Nephrology, Department of Surgery; Division of Allergy, Immunology and Rheumatology; Department of Pathology; and Hematology and Oncology Unit; University of Rochester Medical Center, NY.

Rituximab shows effectiveness against chronic GVHD

Research points to the benefit of using the drug rituximab to combat chronic graft-versus-host disease (GVHD) after allogenic bone marrow transplants (BMT).

Researchers at the Dana Farber Cancer Center have published results on the largest clinical trial to date (30 patients) of this treatment.

Chronic GVHD is a leading cause of death among allogenic BMT survivors. About 50% of allogenic BMT patients develop a GVHD – their body’s immune system identifies the transplanted cells as foreign invaders.

Transplant rejections that occur within the first 100 days of the transplant are called Acute GVHD. Later rejections are called Chronic GVHD. Chronic GVHD is life threatening and can effect all organs.

The theory behind using rituximab - a drug widely used against B-cell lymphoma and some inflammatory diseases - arose from earlier lab experiments that suggested GVHD involved the B-cells of the immune system, not just T-cells.

Quadramet update

Preclinical data presented at AACR indicate that exposure to radiation from QUADRAMET increases the expression of surface molecules involved in the identification and killing of cancer cells by the immune system

Cytogen Corporation reported results of a preclinical study indicating that exposure to ionizing radiation with QUADRAMET(R) (samarium Sm-153 lexidronam injection) increases the expression of surface molecules on cancer cells, potentially improving the ability of the body's immune system to recognize and kill tumor cells. QUADRAMET is currently marketed for the relief of pain associated with cancer progression to bone in a variety of tumor types. The findings were presented today by researchers from the National Cancer Institute (NCI) at the 97th Annual Meeting of the American Association for Cancer Research (AACR) in Washington, D.C.

"Recent research has provided new insights showing how dying tumor cells, such as those killed by exposure to radiation or chemotherapy, engage with antitumor immune responses," stated Michael D. Becker, president and chief executive officer of Cytogen. "Building on this research, these new preclinical findings presented by researchers at the NCI further support ongoing efforts to investigate therapeutic options that combine QUADRAMET with synergistic agents for the treatment of a wide range of cancer types."

In the study, 10 human tumor cell lines, including four prostate, two breast, and four lung, were treated with increasing doses of QUADRAMET. Ninety-six hours following exposure, fluorescence activated cell sorting (FACS) analysis was performed for five surface molecules. Ten out of 10 tumor cell lines (100%) upregulated Fas (CD95) and carcinoembryonic antigen (CEA), while 70% upregulated MUC-1, 40% upregulated MHC class I and 30% upregulated ICAM-1. In addition, the HLA-A2 prostate cell line, LNCaP, was analyzed to determine whether treatment with QUADRAMET rendered the tumor cells more susceptible to killing by CTLs. This line demonstrated enhanced killing by tumor-specific CTL following exposure to QUADRAMET.

Based on these positive preclinical results, a clinical trial evaluating the effect of combining QUADRAMET with immunotherapy in patients with solid tumors is now in the NCI review process.

"In addition to the direct cytotoxic effects normally associated with ionizing radiation, these data suggest that it also increases the expression of surface molecules on certain cancer cells known to be important in the recognition and destruction of these cells by the body's immune system," said William Goeckeler, Ph.D., senior vice president of operations at Cytogen. "The ability to enhance the anti-cancer effects of various immunotherapy approaches could be of great benefit to patients with many different forms of cancer that have spread to bone."

About QUADRAMET

QUADRAMET is indicated for the relief of pain in patients with confirmed osteoblastic metastatic bone lesions that enhance on radionuclide bone scan. This press release describes clinical applications that differ from that reported in the QUADRAMET package insert.

QUADRAMET is an oncology product indicated for pain relief that pairs the targeting ability of a small molecule, bone-seeking phosphonate (EDTMP) with the therapeutic potential of radiation (samarium Sm-153). Skeletal invasion by prostate, breast, multiple myeloma, and other cancers often creates an imbalance between the normal process of bone destruction and formation. QUADRAMET selectively targets such sites of imbalance, thereby delivering radioactivity to areas of the skeleton that have been invaded by metastatic tumor.

QUADRAMET has demonstrated a range of characteristics that may be advantageous for the treatment of pain arising from metastatic bone disease, including early onset of pain relief (patients may experience pain relief within the first week with maximal relief generally occurring at three to four weeks after injection), predictable and reversible bone marrow toxicity or myelosuppression that tends to return to pretreatment levels after eight weeks, ease of administration, and length of pain relief, lasting an average of four months in responding patients. QUADRAMET is administered as a single intravenous injection, usually on an outpatient basis, and exhibits selective uptake in areas of bone formation with little or no detectable accumulation in soft tissue.

QUADRAMET Safety Profile

QUADRAMET causes bone marrow suppression. In clinical trials, white blood cell counts and platelet counts decreased to a nadir of approximately 40% to 50% of baseline in 123 (95%) patients within 3 to 5 weeks after QUADRAMET, and tended to return to pretreatment levels by 8 weeks. Because of the unknown potential for additive effects on bone marrow, QUADRAMET should not be given concurrently with chemotherapy or external beam radiation therapy unless the clinical benefits outweigh the risks. Blood counts should be monitored weekly for at least 8 weeks, or until recovery of adequate bone marrow function. Non-hematologic adverse events that occurred in 5% or more of patients and greater than placebo were plain flare (7%), diarrhea (6%), infection (7%), spinal cord compression (6.5%), arrhythmias (5%), and hematuria (5%). Patients who receive QUADRAMET should be advised that for several hours following administration, radioactivity will be present in excreted urine. To help protect themselves and others in their environment, precautions need to be taken for 12 hours following administration.

A copy of the full prescribing information for QUADRAMET, including warnings, precautions, adverse events and other safety information, may be obtained in the U.S. from Cytogen Corporation by calling toll-free 800-833- 3533 or by visiting the Web site at http://www.cytogen.com, which is not part of this press release.

About Cytogen Corporation

This press release contains certain "forward-looking" statements within the meaning of the Private Securities Litigation Reform Act of 1995 and Section 21E of the Securities Exchange Act of 1934, as amended. All statements, other than statements of historical facts, included in this press release regarding our strategy, future operations, financial position, future revenues, projected costs, prospects, plans and objectives of management are forward-looking statements. Such forward-looking statements involve a number of risks and uncertainties and investors are cautioned not to put any undue reliance on any forward-looking statement. There are a number of important factors that could cause Cytogen's results to differ materially from those indicated by such forward-looking statements. In particular, Cytogen's business is subject to a number of significant risks, which include, but are not limited to: the risk of obtaining additional capital; the risk of obtaining the necessary regulatory approvals; the risk of whether products result from development activities; the risk of shifts in the regulatory environment affecting sales of Cytogen's products such as third-party payor reimbursement issues; the risk associated with Cytogen's dependence on its partners for development of certain projects, as well as other factors expressed from time to time in Cytogen's periodic filings with the Securities and Exchange Commission (the "SEC"). As a result, this press release should be read in conjunction with Cytogen's periodic filings with the SEC. The forward-looking statements contained herein are made only as of the date of this press release, and Cytogen undertakes no obligation to publicly update such forward-looking statements to reflect subsequent events or circumstances.

Web site: http://www.cytogen.com/