Management of the relapsed/refractory myeloma patient: strategies incorporating lenalidomide.
The immunomodulatory drug (IMiD) lenalidomide is a more potent immunomodulator than thalidomide with respect to its effects on cytokine modulation and increased T-cell proliferation. Of all the IMiDs, clinical trial data are most mature for lenalidomide. In phase I studies, dose-limiting toxicities of lenalidomide were limited to myelosuppression and a response rate of 72% was seen in relapsed/refractory patients. Three phase II studies subsequently evaluated the efficacy of single-agent lenalidomide or lenalidomide in combination with dexamethasone. As a single agent for post-transplant salvage therapy, lenalidomide 25 mg every 3 weeks has shown response rates as high as 44%. For patients with relapsed/refractory multiple myeloma, the MM-007 study has shown that lenalidomide alone or in combination with dexamethasone provides response rates between 37% and 41%. In MM-007, median progression-free survival was 5.5 months at early analysis and the median overall survival has yet to be reached. Preliminary data for the single-arm, multicenter, open-label MM-014 study showed that median time to progression was 5.6 months. Response rates indicate that 70% of patients had stable disease or better as the best response to treatment. Two randomized, phase III trials (MM-009 and MM-010) evaluated lenalidomide with high-dose dexamethasone versus high-dose dexamethasone alone for the treatment of relapsed/refractory multiple myeloma. Both MM-009 and MM-010 provided remarkably similar response rates for patients receiving lenalidomide and dexamethasone. In both trials response rates with the combination were greater than twice the response rates seen with high-dose dexamethasone alone. Indeed, an independent Data Monitoring Committee determined that both trials exceeded the prespecified efficacy value of P<.0015, recommending that the trials be discontinued and that lenalidomide be offered to patients on the dexamethasone arm of the trial if clinically indicated. Toxicities observed in studies of lenalidomide alone were low; the incidence of peripheral neuropathy was significantly lower than those noted in trials using thalidomide. Thrombocytopenia was a significant grade 3 or 4 toxicity observed; however, it was manageable with dose reduction. In contrast with high-dose dexamethasone, deep vein thrombosis has emerged as an important toxicity. Lenalidomide is currently being tested in combination with both standard and novel agents, including bortezomib, for patients with relapsed/refractory multiple myeloma.
Richardson
Paul
P
Jerome Lipper Myeloma Center, Division of Hematologic Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA. paul_richardson@dfci.harvard.edu
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D003907:Dexamethasone / Q000627:therapeutic use; D018572:Disease-Free Survival; D006801:Humans; D000077269:Lenalidomide; D009101:Multiple Myeloma / Q000188:drug therapy*; D012008:Recurrence; D012189:Retrospective Studies; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000627:therapeutic use
D013792:Thalidomide; D003907:Dexamethasone; D000077269:Lenalidomide