Targeting degradation of IKZF1 and IKZF3 through modulation of the E3 ligase substrates in the context of cellular therapies for multiple myeloma

Abstract Multiple myeloma (MM) is a blood cancer characterized by the clonal evolution of plasma cells. In 2022, there were an estimated 118 000 MM cases and 121 000 deaths worldwide. The treatment landscape of MM has undergone a dramatic transformation in recent decades, shifting from conventional chemotherapy to more targeted approaches. In order to overcome intrinsic and acquired resistance mechanisms that frequently restrict the efficacy of single-agent therapies, drug combination strategies have been developed to simultaneously target multiple pathogenetic pathways. Building on the success of immunomodulatory agents, CRBN E3 ligase modulators (CELMoDs), iberdomide (CC-220) and mezigdomide (CC-92480), have been designed as promising and more selective agents. CELMoDs demonstrate a 10–20 times higher binding capacity and they promote a more profound and rapid breakdown of Ikaros and Aiolos compared to traditional immunomodulatory agents. According to the National Cancer Institute Surveillance Program, the median survival for fit patients is greater than ten years, and the 5-year survival for the general MM patient population in the US approaches 60%. Despite these encouraging numbers, MM is still an incurable disease, and the majority of patients eventually relapse and require additional lines of therapy. Combining CELMoDs with cellular therapies significantly improves the response rate in MM patients. In this paper, based on the literature presented at the Annual Meeting of the American Society of Hematology (ASH), the American Society of Clinical Oncology (ASCO), the International Myeloma Society (IMS), and the European Hematology Association (EHA) in the 2020–2025 timeframe, we explore the rationale and emerging evidence of combining CELMoDs with immunotherapies, and their use as a bridge to transplant or as post-ASCT maintenance therapy in MM.