• May 18, 2010
    Trio of drugs makes major mark against multiple myeloma

    paul-richardson-lab.jpgTrial results show that a new three-drug regimen reduces multiple myeloma by more than 90 percent in some patients. The treatment is based on research by a team in Paul Richardson's (center, seated) lab. 

    Initial results of a novel three-drug combination therapy in patients with multiple myeloma have been so encouraging that researchers believe the treatment may delay the need for a stem cell transplant in some cases, Dana-Farber investigators reported in a recent paper.

    When used together, the three agents – lenalidomide, bortezomib, and dexamethasone – trigger protein circuits within myeloma cells that cause the cells to die. The drugs boost one another's effect against myeloma cells themselves and the surrounding tissue. In the study, posted online by the journal Blood, every patient who received the combination had a significant reduction in the extent of cancer in his or her body.

    "The rate and quality of response to this combination is unprecedented for newly diagnosed myeloma patients," says the study's lead author, Paul Richardson, MD, of Medical Oncology. "We're especially encouraged that it produced responses in patients regardless of chromosomal differences in their myeloma cells, was very active in both older and younger patients, and was generally well tolerated."

    The standard treatment for patients newly diagnosed with multiple myeloma – a highly malignant and incurable blood cancer which arises in the bone marrow – has been conventional chemotherapy, either to control the disease or to prepare younger patients for a stem cell transplant.

    In recent years, the introduction of novel agents like bortezomib, which shuts down a vital "garbage disposal" system in cancer cells, as well as thalidomide and lenalidomide, which influence the immune system's attack on disease and affect the tumor and its surroundings, have dramatically increased survival rates of myeloma patients.

    The new study involved a phase I and II clinical trial to determine the safety, proper dosage, and effectiveness of the three-drug regimen in 68 newly diagnosed myeloma patients. Participants received eight, three-week cycles of lenalidomide, bortezomib, and dexamethasone on an outpatient basis, followed by maintenance therapy, and were followed for at least the next two years.

    While all patients had at least a partial response to the therapy, meaning a greater than 50 percent decrease in the extent of their disease, a striking 74 percent of those who completed the phase II portion of the trial had at least a "very good partial response," meaning a greater than 90 percent reduction in disease. Of these patients, 52 percent achieved a complete response. The results were lasting as well; 18 months after completing the first phase of the trial, 75 percent of the patients remained in remission and 97 percent were alive.

    Although most patients experienced side effects from the treatment, these proved relatively mild and reversible. Eighty percent of participants experienced neuropathy, including tingling or numbness in their extremities; 64 percent felt fatigue; 14 percent had a reduction in the number of circulating lymph cells; 9 percent had a decline in the number of white blood cells called neutrophils; and 6 percent had clots form in blood vessels. No patients died as a result of the treatment.

    "This combination enabled us to keep the option of stem cell transplantation in reserve for a number of patients in the trial," Richardson states. "With early follow-up, we saw no difference in progression-free survival [patients living with no worsening of their disease] in those who went on to receive a stem cell transplant versus in those who did not. In addition, while the numbers are small, patients whose chromosome abnormalities usually indicate a poorer response to treatment did as well as those without them."

    While the new study is cause for optimism, no definite conclusions can be drawn until the three-drug regimen proves itself in a phase III trial involving many hundreds of patients, Richardson cautions. That trial opens this summer. When completed, it will help researchers determine which patients benefit the most, and the least, from the three-drug therapy, and which can therefore defer the need for a stem cell transplant until later in their course of treatment, or should have it performed early.

    Other Dana-Farber authors of the study include senior author Ken Anderson, MD, and co-authors Edie Weller, PhD; Wanling Xie; Irene Ghobrial, MD; Robert Schlossman, MD; Nikhil Munshi, MD; Deborah Doss, RN, OCN; Diane Warren; Laura Lunde; Teru Hideshima, MD, PhD; and Constantine Mitsiades, MD, PhD.

    – Rob Levy
    Robert_Levy@dfci.harvard.edu 

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