Mechanism of Action and Novel IMiD-Based Compounds and Combinations in Multiple Myeloma

Over the last 2 decades, thalidomide analogs have induced significant antimyeloma effects via immune-modulation, antiangiogenesis and antiproliferative effects. While the exact molecular mechanism of the targets or the mediators of thalidomide activity were not known, a seminal discovery of Cereblon as a thalidomide-binding protein led to explaining the mechanistic basis of antimyeloma activity for this class of agents. Identification of the mechanisms of resistance for immunomodulatory agents (IMiDs), which will have significant clinical implications, remains poorly understood. Newer Cereblon modulators with differential effects and improved increased efficacy in cell lines resistant to the current IMiDs are in development with encouraging preclinical data. In this review, we have summarized the mechanisms of action of IMiDs, clinical development, and potential mechanisms of resistance. We also describe novel IMiD-based combinations and the newer Cereblon modulators as well.