New myeloma drug proves more potent, less toxic than thalidomide

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A designer drug significantly less toxic than thalidomide has shown impressive activity in prolonging survival of patients with advanced multiple myeloma, report researchers from Dana-Farber Cancer Institute.

A multicenter Phase II study of lenalidomide, an altered version of thalidomide, found a response rate of 25 percent among patients with myeloma that had recurred despite multiple prior therapies. Especially important was that long-lasting responses averaging 28 months were seen. When another drug, dexamethasone, was added in patients who were not benefiting from lenalidomide alone, the response rate was improved in a third.

“This is very encouraging,” said Paul Richardson, the Dana-Farber physician who is lead author and principle investigator of the study. “We have already begun testing lenalidomide in combination with both dexamethasone and bortezomib.” The findings, which will be published in the journal Blood, are currently available on the journal’s Web site,

The Phase II study being reported by Richardson and colleagues involved 102 patients, randomly picked to receive the drug in once-daily or twice-daily doses. The patients’ myeloma had relapsed despite having stem cell transplant (61 percent of participants), bortezomib (18 percent), and/or thalidomide (76 percent). The study showed that, when lenalidomide was given as a single dose each day for 21 days, only a few patients reported significant fatigue, neuropathy (nerve damage), and constipation. The once-daily dosing proved better tolerated than the twice-daily regimen.

Troublesome side effects were decreases in blood cell counts caused by the drug’s suppression of bone-marrow function, although these proved manageable with dose reduction and growth factor support. Overall, three cases of deep venous thrombosis were seen, and only when dexamethasone was added. The regimen defined in this study and the observation that the addition of dexamethasone was beneficial provided the basis for the large Phase III trials that led to the drug’s recent approval by the Food and Drug Administration (FDA). The Dana-Farber team participated in these studies and also led the Phase I, II, and preclinical development of this agent.

Multiple myeloma is the second-most-common blood cancer, and results from overproduction of cancerous infection-fighting white cells (known as plasma cells) in the bone marrow. The disease is traditionally treated with chemotherapy agents and often with bone marrow transplants, but, at present, it is incurable.

In the past three years, noted Richardson, the picture has been brightened considerably with two new biologically targeted drugs (bortezomib and lenalidomide) and the new use of an older, but also biologically derived, drug (thalidomide) approved by the FDA for patients with myeloma. Despite its lower rate of responses when used as a single agent when compared with bortezomib, lenalidomide has a different side-effect profile, explained Richardson. “The promise is that you can use each of these drugs sequentially and receive the therapeutic benefits of each, as well as then trying them in combination,” said Richardson, who is also an assistant professor at Harvard Medical School. “Moreover, when you combine them with dexamethasone, the response rates improve dramatically.”

The drugs are now undergoing testing singly and in combination for patients in early stages of the disease.