mezigdomide (CC-92480)

P2/3, N=322, Active, not recruiting, Celgene Corp. | Recruiting --> Active, not recruiting

P1/2, N=24, Recruiting, Celgene Corp.

P3, N=525, Active, not recruiting, Bristol-Myers Squibb | Recruiting --> Active, not recruiting

P1/2, N=200, Terminated, Celgene | Trial completion date: Jan 2028 --> Oct 2025 | Active, not recruiting --> Terminated; Business objectives have changed

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...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.

P1, N=27, Recruiting, Abdullah Khan | Trial completion date: Dec 2025 --> Dec 2026 | Trial primary completion date: Dec 2025 --> Dec 2026

Triplet regimens that include an immunomodulatory agent, proteasome inhibitor, and dexamethasone are widely used in newly diagnosed and relapsed/refractory (R/R) multiple myeloma (MM)...Additionally, we have compared these results with similar combinations with the immunomodulatory agent pomalidomide (POM). Our studies indicate that the MEZI/BTZ/DEX triplet is superior to all single agents and POM/BTZ/DEX in terms of potency of antiproliferative and proapoptotic activities, substrate degradation depth and kinetics in the presence of BTZ, and in vivo efficacy. We show that the combination of MEZI with BTZ increases cell death through disruption of multiple phases of the cell cycle and this thereby enhances the direct cytotoxic effects of the combination treatment.

P1, N=24, Not yet recruiting, Massachusetts General Hospital

P1/2, N=52, Recruiting, Memorial Sloan Kettering Cancer Center

P2, N=70, Not yet recruiting, Assistance Publique - Hôpitaux de Paris

P2, N=28, Recruiting, Roswell Park Cancer Institute | Suspended --> Recruiting

P1, N=125, Recruiting, K36 Therapeutics, Inc. | Trial completion date: Jun 2026 --> Jun 2028 | Trial primary completion date: Dec 2025 --> Dec 2027