Mezigdomide combined with bortezomib disrupts the cell cycle and elicits superior antitumor effects in multiple myeloma

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). Mezigdomide (MEZI; CC-92480) is a cereblon E3 ubiquitin ligase modulator that is being clinically investigated in combination with bortezomib (BTZ) and low-dose dexamethasone (DEX) for safety and efficacy in pretreated R/RMM. The single-agent mechanism of action (MOA) of MEZI has been defined by the recruitment and degradation of essential MM transcription factors Ikaros and Aiolos, leading to cell autonomous antitumor effects and immune modulation. These effects were confirmed in patients based on pharmacodynamic measurements of Ikaros/Aiolos degradation in biomarker evaluations of immune subsets. However, the MOA of triplet regimens, including that of MEZI/BTZ/DEX remain poorly defined. To better understand the MOA of this triplet combination, we compared the mechanistic contributions of MEZI, BTZ, or DEX alone, or in combination, in preclinical MM models in vitro and in vivo. 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.