Targeting Ikaros and Aiolos: Next‐Generation Cereblon E3 Ligase Modulators in MM

Multiple myeloma (MM) remains an incurable plasma cell malignancy characterized by recurrent relapses and eventual refractoriness to standard agents, including proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and anti-CD38 monoclonal antibodies. With frontline therapeutic strategies increasingly employing quadruplet induction regimens and prolonged lenalidomide maintenance, resistance to traditional IMiDs has become more prevalent, creating an urgent need for next-generation cereblon E3 ligase modulators (CELMoDs) capable of overcoming IMiD refractoriness and enhancing the immunologic microenvironment. Iberdomide (CC-220) and mezigdomide (CC-92480) are rationally engineered CELMoDs designed to achieve deeper degradation of Ikaros (IKZF1) and Aiolos (IKZF3), restore cereblon-mediated activity, and potentiate immune effector responses. This review explores the core biological features of these agents, detailing their mechanisms of action, preclinical and clinical activity, as well as safety profile. We examine how their pharmacodynamic properties differ from classical IMiDs, their relevance in triple-class and penta-refractory MM, and their integration into emerging combination strategies with monoclonal antibodies and T-cell–redirecting immunotherapies. Special emphasis is placed on ongoing and future trials that may refine their therapeutic positioning, alongside a critical appraisal of the limitations and future directions of this rapidly advancing drug class.