Myeloma Genome Sequencing

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

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

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

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

Revlimid survival statistics

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

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

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

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

PMID: 19626046 [PubMed - as supplied by publisher]

New Drug Pomalidomide

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

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

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

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

Milatuzumab-doxorubicin conjugate testing

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

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

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

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

New Antibiotics May Target Cancer-Causing Proteins

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

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

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

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