A third-generation IMiD for MM.

Over the past decade, increasing use of the immunomodulatory derivatives (IMiDs) thalidomide and lenalidomide and the first-inclass proteasome inhibitor bortezomib has dramatically changed the natural history of multiple myeloma (MM).2 Novel agents, initially approved for the treatment of relapsed or refractory (rel/refr) MM, are actually used up-front as part of induction therapy for both transplantand nontransplant-eligible patients, and studies are under way to evaluate their role in additional therapeutic phases, such as consolidation and maintenance.3,4 However, almost all patients treated with these new classes of agents inevitably develop drug resistance over time, and ultimately relapse. Mechanisms leading to resistance are largely unknown. Overexpression and mutation of 5-proteasome activity, and activation of Wnt/ -catenin signaling5 have recently been proposed as possibly related to refractoriness to bortezomib and lenalidomide, respectively. Patients failing bortezomib and lenalidomide have a very dismal clinical outlook, and represent an unmet medical need. Pomalidomide (CC-4047) is a new IMiD (see figure) with increased activity in vitro compared with thalidomide and lenalidomide, which exerts anti-MM effects through multiple mechanisms, including induction of apoptosis via caspase-8, reduction of proliferation, inhibition of NFB activation, reduction of stromal cell stimulatory cytokine secretion, and angiogenesis inhibition. The safety and toxicity profile of pomalidomide as a single agent in patients with rel/ refr MM was initially explored in two pilot phase 1 studies that established the maximum tolerated dose as 2 mg daily on days 1 through 28 of 28-day cycles and 5 mg on alternate days.6,7 In two subsequent studies enrolling patients with rel/refr MM after 1 to 4 prior lines of treatment, including refractoriness to lenalidomide, salvage therapy with pomalidomide at 2 mg/day was given continuously in 28-day cycles combined with low-dose dexamethasone.8,9 In one study, the overall rate of at least partial response (PR) was 63%, including 33% complete response or very good partial response (VGPR), and median progressionfree survival (PFS) was 11.6 months.8 Among patients refractory to prior lenalidomide, PR or better was seen in the 32% to 40% range, suggesting a lack of cross-resistance between lenalidomide and pomalidomide.9 These promising results provided the basis of the study designed by Lacy et al to evaluate the efficacy of two different doses of pomalidomide in patients with dual refractoriness (defined as progression on therapy or within 2 months of stopping treatment) to lenalidomide and bortezomib.1 For this purpose, 70 patients who had received a median of 6 prior therapies (range, 2-11) were enrolled in two sequential phase 2 trials of pomalidomide given continuously at a daily dose of either 4 or 2 mg of 28-day cycles along with 40 mg of dexamethasone on days 1, 8, 15, and 22. The rates of at least minimal response in the 4-mg and 2-mg cohorts were 49% and 43%, respectively, including VGPR and PR rates of 28.5% and 26%, respectively. These values of PR or better appear slightly lower than those observed in previously reported series of lenalidomiderefractory patients,8,9 a finding that reflects the more heavily pretreated population of patients enrolled in the current trial and, importantly, their dual refractoriness to both lenalidomide and bortezomib. Consistent with this interpretation, similar rates of at least PR were seen in the phase 1 and 2 portions (the latter using daily pomalidomide at 4 mg on days 1-21 of 28-day cycles) of MM-002 study that included patients who had been previously treated with bortezomib and lenalidomide and were refractory to their most recent regimen.10 In Lacy et al’s trial, responses to 2-mg and 4-mg doses of pomalidomide combined with dexamethasone were fast, from 1 to 2 months, and durable. With a median follow-up of 14 months, the median duration of response was not reached in the 2-mg cohort. Although a longer follow-up is required, the 6-month overall survival rates of 78% and 67% reported in the 2-mg and 4-mg cohorts are promising in a challenging population of patients for whom Molecular structure of IMiDs.