CELMoDs: A Distinct Therapeutic Class for Relapsed Multiple Myeloma

In an interview with Targeted Oncology, Sagar Lonial, MD, Professor and Chair in the Department of Hematology and medical oncology at the Emory University School of Medicine and Chief Medical Officer for the Winship Cancer Institute of Emory University, discussed the evolving role of cereblon E3 ligase modulators (CELMoDs) in the treatment of multiple myeloma. He spoke following the FDA priority review acceptance of iberdomide based on the EXCALIBER-RR trial (NCT04975997), which evaluates the combination of iberdomide, daratumumab (Darzalex), and dexamethasone. Lonial explains that while CELMoDs are often compared to traditional immunomodulatory imide drugs (IMiDs) such as thalidomide, lenalidomide (Revlimid), and pomalidomide—(Pomalyst), they represent a distinct and more potent class of agents.

Superior Potency and Mechanism of Action

Lonial identifies 3 primary pillars that differentiate CELMoDs from their predecessors. The first is their binding affinity; CELMoDs bind to the cereblon protein with significantly higher potency than the IMiD class. This results in a much more rapid degradation of the key transcription factors Ikaros (IKZF1) and Aiolos (IKZF3).

Unlike IMiDs, which typically induce cytostatic growth arrest, the accelerated degradation achieved by CELMoDs leads directly to cell death. This shift from stopping growth to actively killing myeloma cells marks a major step forward in efficacy for heavily pretreated patients.

Enhanced Synergy with Immunotherapy

The second advantage of CELMoDs involves their superior "immune-stimulatory" engineering. Lonial explains that these agents are specifically designed to increase T-cell activation, bolstering the body’s natural defense against malignant cells, reduce T-cell exhaustion, allowing for a more sustained immune response, and activate Natural Killer (NK) cells. These characteristics make CELMoDs such as iberdomide and mezigdomide ideal partners for monoclonal antibodies and other immunotherapies, as they optimize the patient’s own immune environment to support the treatment's success.

Improved Safety and Tolerability Profiles

Finally, Lonial addresses the clinical tolerability of these agents. Although they are not without adverse events (AEs), the CELMoD class demonstrates a markedly different adverse event profile compared to lenalidomide or pomalidomide. Specifically, the frequency of grade 3 and grade 4 non-hematologic AEs is significantly lower. This improved safety profile is critical for maintaining quality of life and treatment adherence in patients with relapsed/refractory disease.