A third-generation IMiD for MM.

In this issue of Blood, Lacy et al report that pomalidomide overcomes refractoriness to prior therapy with lenalidomide and bortezomib, thus representing a new and valuable treatment option for patients who have exhausted major novel agent–based strategies for the management of multiple myeloma.1 Over the past decade, increasing use of the immunomodulatory derivatives (IMiDs) thalidomide and lenalidomide and the first-in-class 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 transplant- and 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 β5-proteasome activity, and activation of Wnt/β-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.