Immunomodulatory Drugs and Cereblon E3 Ligase Modulators in Multiple Myeloma: 30 Years in the Making
Cet article retrace l'évolution clinique des immunomodulateurs pour le traitement des myélomes multiples (thalidomide, lénalidomide, pomalidomide et modulateurs de la ligase E3 du cereblon : iberdomide, mezidomide), présente les mécanismes d'action, résume les premières expériences cliniques ainsi que les programmes randomisés en cours, examine les combinaisons rationnelles avec les anticorps monoclonaux, les anticorps bispécifiques engageant les lymphocytes T et les thérapies par lymphocytes CAR-T puis propose un cadre pour l'intégration des CELMoD dans les immunothérapies
Immunomodulatory drugs (IMiDs) have fundamentally reshaped multiple myeloma therapy, extending survival and establishing durable backbones across induction, relapse, and maintenance. Cereblon's identification as a druggable E3 ligase substrate receptor created the mechanistic path to next-generation modulators, whereas widespread frontline lenalidomide exposure created the clinical need for scalable oral agents active in IMiD-refractory, triple-class–exposed disease. In this review, we link the clinical evolution of the IMiD class to its mechanistic foundation. We trace the path from thalidomide's serendipitous repurposing to lenalidomide's establishment of the Rd backbone and maintenance paradigm and to pomalidomide's ability to retain efficacy after lenalidomide failure. We integrate structural and biochemical insights showing how medicinal chemistry reshaped cereblon engagement and selective neosubstrate degradation, producing tumor-intrinsic and immune-mediated effects. We then focus on next-generation cereblon E3 ligase modulators (CELMoDs), including iberdomide and mezigdomide, designed to deepen cereblon modulation and overcome resistance. We summarize early clinical experience and ongoing randomized programs, discuss rational combinations with monoclonal antibodies, bispecific T-cell engagers, and chimeric antigen receptor T-cell therapies, and propose a pragmatic framework for positioning CELMoDs in an immunotherapy-rich treatment era.
Journal of Clinical Oncology , résumé, 2026