Doxil®, Oncovin®, Revlimid®, and Dexamethasone Effective in Recurrent Multiple Myeloma

According to a recent report, the combination of Revlimid® (lenalidomide), Oncovin® (vincristine), Doxil® (pegylated doxorubicin), and dexamethasone appears highly effective in multiple myeloma that has recurred or progressed following prior therapies.

Determining optimal treatment choices for patients with multiple myeloma that has recurred (returned following therapy) or for those with refractory disease (stopped responding to therapy) is more challenging than for those who have not received prior therapies.

Researchers from the Cleveland Clinic recently conducted a clinical trial to evaluate the combination of Doxil, Oncovin, Revlimid, and dexamethasone in the treatment of patients with recurrent or refractory multiple myeloma. Both Doxil and Oncovin are chemotherapy agents commonly used for multiple myeloma. This trial included 62 patients, 65% of whom had recurrent or refractory multiple myeloma.

• Seventy-five percent of patients achieved an anticancer response.
• Twenty-nine percent of patients achieved a complete or near complete disappearance of detectable cancer.
• Progression-free survival was one year.
• Overall survival has not yet been reached.
• The main side effect from the addition of Revlimid to this treatment combination was infection.

The researchers concluded that the treatment combination including Revlimid, Doxil, Oncovin, and dexamethasone appears to provide high anticancer activity in recurrent or refractory multiple myeloma. Patients whose multiple myeloma has returned or progressed following prior therapies may wish to speak with their physician regarding participation in clinical trials further evaluating novel treatment combinations.

Reference: Baz R, Walker E, Karam MA, et al. Linalidomide and pegylated liposomal doxorubicin-based chemotherapy for relapsed or refractory multiple myeloma: safety and efficacy. Annals of Oncology. 2006; doi:10.1093/annonc/mdl313.

NPI-0052 another update

Chauhan D, Hideshima T, Anderson KC

Department of Medical Oncology, Harvard Medical School, Dana Farber Cancer Institute, The Jerome Lipper Multiple Myeloma Center, Boston, MA 02115, USA.

Proteasome inhibitor Bortezomib/Velcade has emerged as an effective anticancer therapy for the treatment of relapsed and/or refractory multiple myeloma (MM), but prolonged treatment can be associated with toxicity and development of drug resistance. In this review, we discuss the recent discovery of a novel proteasome inhibitor, NPI-0052, that is distinct from Bortezomib in its chemical structure, mechanisms of action, and effects on proteasomal activities; most importantly, it overcomes resistance to conventional and Bortezomib therapies. In vivo studies using human MM xenografts shows that NPI-0052 is well tolerated, prolongs survival, and reduces tumour recurrence. These preclinical studies provided the basis for Phase-I clinical trial of NPI-0052 in relapsed/refractory MM patients.British Journal of Cancer (2006) 95, 961-965. doi:10.1038/sj.bjc.6603406 www.bjcancer.com.

PMID: 17047643 [PubMed - in process]

Mayo Clinic update on multiple myeloma

Dear Mayo Clinic: Is thalidomide now approved for use in patients with multiple myeloma? My father took it "off label" several years ago and had a very good result. Are there other treatment options for this disease?

Answer (from Dr. S. Vincent Rajkumar in hematology at the Mayo Clinic in Rochester, Minn.): Despite thalidomide's notorious past - having caused numerous cases of severe birth defects when used by pregnant women - the drug is making a comeback as treatment for several conditions.

One of them is multiple myeloma, a cancer of the bone marrow's plasma cells. Abnormal versions of these cells proliferate, leading to anemia, immune deficiency, weakened bones, kidney problems and other symptoms.

At present, there is no cure for multiple myeloma, but we are steadily adding treatments that lengthen patient survival time and improve quality of life.

Until recently, conventional chemotherapy was our only option, and drugs were limited to two types: alkylating agents (such as melphalan and cyclophosphamide) and corticosteroids (prednisone and dexamethasone). These drugs kill abnormal plasma cells, called myeloma cells.

But now our arsenal is being supplemented by other medications such as thalidomide, bortezomib and lenalidomide, which target the myeloma cells as well as the microenvironment that nurtures them. The new drugs may suppress the blood supply or growth factors on which the abnormal cells depend. As a result, we are achieving greater success rates, especially when new and conventional drugs are used in combination.

A recent large French study showed that adding thalidomide to standard chemotherapy prolonged survival in multiple myeloma. In another study, my colleagues and I found that average time to progression was more than twice as long in patients on thalidomide and dexamethasone compared to those on dexamethasone alone. Thus they enjoyed longer periods of being relatively symptom-free.

The FDA recently approved thalidomide in combination with dexamethasone for treatment of newly diagnosed multiple myeloma.

New options don't necessarily displace old treatments but can be additive and even synergistic.

We are now planning three-drug trials and look forward to four-drug trials. The individual agents, by themselves, are not panaceas, but in combination they lengthen survival. Our hope is to find the ultimate combination - from currently available drugs as well as newer ones now being tested - that will constitute a cure for multiple myeloma.

Thalidomide use in Multiple Myeloma - past, present and future

Harousseau JL.

Service d'Hematologie, Hotel Dieu, Place Alexis Ricordeau, 44093 NANTES CEDEX 01, France. jean-luc.harousseau@univ-nantes.fr.

Thalidomide was introduced in the treatment of multiple myeloma in the late 1990s. Following the initial results, which demonstrated dramatic response rates in heavily pretreated patients, a number of Phase II studies have confirmed the efficacy of this agent in relapsed patients. However, a high incidence of side effects at the dosage initially recommended (400 mg/day) justified further studies with lower doses of thalidomide given alone or in combination with dexamethasone or chemotherapy. Thalidomide is currently considered as one of the most active agents in relapsed myeloma. Recent studies have demonstrated that thalidomide could also be used as part of frontline therapy. The combination of thalidomide plus dexamethasone as initial therapy appears to be slightly superior to dexamethasone alone or to vincristine-doxorubicine-dexamethasone, but with an increased risk of deep vein thrombosis. Maintenance with thalidomide after autologous transplantation appears to increase the complete remission rate and to prolong progression-free survival. The combination of thalidomide plus melphalan and prednisone is superior to the classical melphalan-prednisone regimen in elderly patients, and will become the standard of care. Thalidomide has been registered in the USA in combination with dexamethasone in newly diagnosed patients, but is not yet registered in the European Union. Its use is currently challenged by bortezomib and by thalidomide's analog lenalidomide.

PMID: 17026450 [PubMed - in process]

Band From TV supports IMF

By day, Los Angeles financial planner Rich Winer provides comprehensive wealth management and financial planning services to a select group of high net worth individuals and families throughout the United States and overseas. By night, he plays guitar for Band From TV alongside television stars Hugh Laurie (House), James Denton (Desperate Housewives), Greg Grunberg (Heroes), Bonnie Somerville (Kitchen Confidential) and Bob Guiney (The Bachelor) in an effort to raise millions of dollars for charity. In August, Band From TV followed Pink at TV GUIDE’s Emmy After Party in Hollywood and raised $200,000 for some of the band members’ favorite charities including UCLA’s Pediatric Epilepsy Project, Cure Autism Now, The Guitar Center Music Foundation, Save The Children and The International Myeloma Foundation.

“My cousin, Bob, is battling Multiple Myeloma” Winer explains, “a cancer of the bone marrow that took the life of one of my closest friends back in 1997. Medical science's ability to fight Multiple Myeloma has come a long way in the past 9 years, but there’s still no cure. Band From TV is a great way to bring attention to insidious diseases like Multiple Myeloma, Autism and Epilepsy, and hopefully raise enough money to someday find cures for these diseases. It’s also been a lot of fun playing with such a great group of individuals and humanitarians."

Although his career is in financial planning, Winer is no amateur musician. A graduate of the Studio Music and Jazz Program at the University of Miami, he worked as a sideman, session guitarist, composer and music producer in Miami, Nashville, and Los Angeles in the 1980’s and 90’s and has performed with a number of major recording artists.

“Both my day job as a financial planner and the charitable work I’m doing with Band From TV are labors of love” Winer says. “I’m fortunate that my wife, my children and I are all healthy and financially secure. I get a wonderful feeling helping others build wealth and become financially secure through my work as a financial planner and an equally wonderful feeling raising money for worthwhile causes in my free time with Band From TV. And from the feedback we've received through our website on Myspace (myspace.com/bandfromtv), I think the public really appreciates what we're trying to do and they've given us a lot of support. That's very gratifying."

Edelfosine and perifosine

Edelfosine and perifosine induce selective apoptosis in multiple myeloma by recruitment of death receptors and downstream signaling molecules into lipid rafts

Consuelo Gajate and Faustino Mollinedo^*

Universidad de Salamanca-CSIC, Salamanca, Spain

^* Corresponding author; email: fmollin@usal.es.

Multiple myeloma (MM) is an incurable B-cell malignancy, requiring new therapeutic strategies. We have found that synthetic alkyl-lysophospholipids (ALPs) edelfosine and perifosine induced apoptosis in MM cell lines and patient MM cells, whereas normal B and T lymphocytes were spared. ALPs induced recruitment of Fas/CD95 death receptor, Fas-associated death domain-containing protein and procaspase-8 into lipid rafts, leading to the formation of the death-inducing signaling complex (DISC) and apoptosis. TNF-related apoptosis-inducing ligand receptor-1/death receptor 4 (TRAIL-R1/DR4) and TRAIL-R2/DR5, as well as Bid were also recruited into lipid rafts, linking death receptor and mitochondrial signaling pathways. ALPs induced mitochondrial cytochrome c release. Bcl-X_L overexpression prevented cytochrome c release and apoptosis. A Fas/CD95-deficient MM subline expressing DR4 and DR5 was resistant to edelfosine. Fas/CD95 retrovirus transduction bestowed edelfosine sensitivity in these cells. A Fas/CD95 mutant lacking part of the intracellular domain was ineffective. Lipid raft disruption prevented ALP-induced Fas/CD95 clustering, DISC formation and apoptosis. ALP-induced apoptosis was Fas/CD95 ligand (FasL/CD95L)-independent. ALP-induced recruitment of death receptors in lipid rafts potentiated MM cell killing by FasL/CD95L and TRAIL. These data uncover a novel lipid raft-mediated therapy in MM involving concentration of death receptors in membrane rafts, with Fas/CD95 playing a major role in ALP-mediated apoptosis.

Patients, Physicians and Scientists Call for Greater Action in the Fight Against Multiple Myeloma

ISTANBUL, Turkey -- Myeloma Euronet, the European network of myeloma patient groups, the European Group for Blood and Marrow Transplantation (EBMT), a group of scientists and physicians involved in clinical bone marrow transplantation, and the European Myeloma Network (EMN), an interdisciplinary network of 421 myeloma experts, have issued a manifesto today calling for greater action in the fight against multiple myeloma.

Multiple Myeloma, an incurable but treatable cancer of the bone marrow, currently affects more than 77,000 people in Europe. It is one of the fastest growing cancers in the western world. Only about 35% of people in Europe living with myeloma are alive five years after diagnosis. This is in contrast to recent advances in early detection and treatment of some other cancers.

The three groups therefore call on the European Commission, national governments, medical societies, patient groups, the media, and the pharmaceutical and biotechnology industries to take action to address the six key needs of people living with multiple myeloma:

- Equity in biomedical and clinical research.

- Multidisciplinary care from trained professionals.

- Increased information and support services.

- Access to optimal treatment.

- Policies that put patients and their needs at the centre of treatment and care.

- Reduction in the isolation that characterises the lives of people living with myeloma and other rare cancers.

The Multiple Myeloma Manifesto is also endorsed by the Lymphoma Coalition. Organisations and individuals can show their support for this initiative by signing the Multiple Myeloma Manifesto at www.myeloma-euronet.org.