Dr Banerjee on the Potential Role of CELMoDs in the Multiple Myeloma Treatment Paradigm

“CELMoDs work harder, faster, better, stronger…than the traditional IMiD. Anything an IMiD can do, a CELMoD can do better, and that's not just efficacy. That is also in terms of safety and tolerability as well, and that is supremely important for our patients. [CELMoDs] will replace IMiDs, I think there's no doubt about that.”

Rahul Banerjee, MD, FACP, an assistant professor in the Clinical Research Division of Fred Hutchinson Cancer Center, as well as an assistant professor in the Division of Hematology and Oncology at the University of Washington, discussed the potential role of cereblon E3 ligase modulators (CELMoDs) in the multiple myeloma treatment paradigm, emphasizing how continued positive results from early-phase prospective clinical trials poise these agents to reshape standard therapy.

According to Banerjee, CELMoDs represent an evolution of immunomodulatory drug (IMiD) biology, offering greater potency, deeper target engagement, and potentially improved tolerability compared with earlier-generation agents such as lenalidomide (Revlimid). Mechanistically, CELMoDs retain and amplify the core functions of IMiDs—immune activation, direct antimyeloma activity, and modulation of the tumor microenvironment—while achieving more efficient cereblon binding and downstream protein degradation.

Banerjee noted that one of the longstanding limitations of prolonged IMiD exposure has been concern regarding cumulative toxicities, including cytopenias and the risk of secondary primary malignancies. Although definitive long-term data are not yet available for CELMoDs, emerging preclinical and early clinical evidence suggests that these novel agents may not carry the same degree of secondary malignancy risk observed with lenalidomide-based maintenance strategies. Although this hypothesis requires validation in long-term follow-up studies, the increased selectivity of CELMoDs provides a biologic rationale for improved long-term safety.

From a regulatory and practical standpoint, Banerjee highlighted unresolved questions regarding implementation, including whether CELMoDs will require Risk Evaluation and Mitigation Strategy (REMS) programs if they reach clinical practice. Even if regulatory safeguards remain necessary, he emphasized that enhanced tolerability, fewer dose-limiting adverse effects (AEs), and potentially reduced cumulative toxicity could meaningfully improve adherence and quality of life for patients.

Looking ahead, Banerjee suggested that if ongoing and future trials confirm durable efficacy and improved safety of these agents, CELMoDs could progressively replace IMiDs across multiple lines of therapy. This shift could begin in relapsed or refractory disease, where unmet need is greatest, and ultimately extend into earlier treatment settings, including maintenance strategies. In that scenario, the rationale for continuing lenalidomide-based therapy would diminish, particularly if CELMoDs demonstrate superior disease control with fewer AEs.

Overall, Banerjee framed CELMoDs as a platform with the potential to redefine foundational treatment in multiple myeloma. Although he cautioned that longer follow-up and randomized data are essential, he concluded that the trajectory of current evidence supports CELMoDs as likely successors to IMiDs, with implications for efficacy, tolerability, and long-term disease management.