Mezigdomide Combined with Bortezomib Disrupts Cell Cycle and Elicits Superior Anti-Tumor Effects in Multiple Myeloma Open Access

• The combination of MEZI with BTZ increases cell death through disruption of the cell cycle.

• The combination of MEZI/BTZ/DEX demonstrates superior efficacy compared to POM/BTZ/DEX in the preclinical setting.

Triplet regimens that include an immunomodulatory agent, proteasome inhibitor (PI) and dexamethasone are widely used in newly diagnosed and relapsed/refractory (RR) multiple myeloma (MM). Mezigdomide (MEZI; CC-92480) is a cereblon E3 ubiquitin ligase modulator (CELMoD) that is being clinically investigated in combination with bortezomib (BTZ) and low-dose dexamethasone (DEX) for safety and efficacy in pre-treated RRMM. 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 anti-tumor 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 pre-clinical MM models in vitro and in vivo. Additionally, we have compared these results to 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 anti-proliferative and pro-apoptotic activities, substrate degradation depth and kinetics in the presence of BTZ, and in vivo efficacy. We show 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.