Novel Therapy for Relapsed Myeloma

The immunomodulatory drug lenalidomide is more potent than thalidomide in preclinical studies, targeting multiple myeloma (MM) cells in the bone marrow (BM) and overcoming cell-adhesion-mediated drug resistance to conventional therapy by directly inducing apoptosis, even of MM cells resistant to conventional and novel therapies; downregulating adhesion molecules and binding of MM cells to the BM milieu; inhibiting secretion of cytokines mediating MM cell growth, survival, and drug resistance; inhibiting angiogenesis as well as upregulating natural killer and cytolytic T-cell responses against autologous tumor cells.¹  Phase I trials rapidly established the maximal tolerated dose of 25 mg for 21 of 28-day cycles, the low incidence of neuropathy, somnolence, and constipation attendant to thalidomide use, and, even more remarkably, evidence of anti-MM activity in the majority of patients.²  Phase II trials then established single daily dosing and the addition of dexamethasone to optimize tolerability and anti-tumor activity, respectively,³  setting the stage for these two randomized phase III trials comparing lenalidomide plus high-dose dexamethasone versus high-dose dexamethasone plus placebo in 353 and 351 patients with relapsed or refractory MM.

Remarkably, response frequency and extent, as well as time to progression and overall survival, were statistically significantly improved in the lenalidomide-plus-dexamethasone-treated cohorts, with nearly identical data in both studies strengthening the validity of the data. Specifically, in the North American study, rates of partial response or better, complete response, time to progression, and overall survival were statistically significantly improved (p<0.001) in patients treated with lenalidomide plus dexamethasone at 61 percent, 14.1 percent, 11.1 months, and 29.6 months, respectively, versus 19.9 percent, 0.6 percent, 4.7 months, and 20.2 months, respectively, in the dexamethasone-treated cohort. In the other study, rates of partial response or better, complete response, and time to progression were statistically significantly improved (p<0.001) in patients treated with lenalidomide plus dexamethasone at 60.2 percent, 15.9 percent, and 11.3 months, respectively, versus 19.9 percent, 0.6 percent, and 4.7 months, respectively, in the dexamethasone-treated cohort. Overall survival was also significantly improved, with a hazard ratio for death of patients treated with lenalidomide of 0.66 (p=0.03). Side effect profiles in both studies were also remarkably similar, with grade 3 or 4 thrombocytopenia and thromboembolism more common in the lenalidomide groups than in the placebo groups.

These studies represent a major advance, further validating the paradigm of targeting the MM cell in its BM microenvironment to overcome drug resistance, and have established a new treatment option for these patients. They are a remarkable example of rapid, collaborative bench-to-bedside research. Responses occurred in patients who had received prior thalidomide and high-dose therapy and stem cell transplant. Most importantly, both the FDA and EMEA have approved lenalidomide plus dexamethasone for treatment of patients who have had one prior therapy for their MM. Remaining issues now to be defined include the utility of high versus low dexamethasone plus lenalidomide, given the survival advantage of the latter when this combination is used as initial therapy for newly diagnosed MM patients, as well as optimal anticoagulation prophylaxis. Going forward, lenalidomide is already showing great promise when used in combination with conventional agents to treat newly diagnosed patients, including its combination with dexamethasone for transplant candidates and melphalan and prednisone for non-transplant patients. In addition, it is being combined with novel agents predicated upon preclinical rationale, with bortezomib to induce dual apoptotic signaling or with monoclonal antibody therapy to enhance antibody-dependent cellular cytotoxicity. Finally, given that it is an oral and well-tolerated agent, multiple studies are now evaluating its utility as a maintenance therapy.