CELMoDs (Cereblon E3 Ligase Modulators) are a new generation of oral drugs for multiple myeloma that may replace older immunomodulatory drugs like lenalidomide and pomalidomide. Both types of drugs target the protein cereblon, but CELMoDs are more powerful. While older drugs mainly slow cancer cell growth, CELMoDs directly trigger cancer cell death. They more effectively destroy key proteins (Ikaros and Aiolos) that myeloma cells need to survive and also strongly activate T cells and natural killer cells.
Clinical trials show encouraging results. Iberdomide combined with daratumumab produced responses in about 46% of heavily pretreated patients, and nearly 95% of newly diagnosed patients responded, with many achieving complete remission. A New Drug Application is under FDA review for relapsed or refractory cases. Mezigdomide has shown response rates above 70% in different treatment combinations, even in patients who had received many prior therapies. Although low blood counts remain a concern, these drugs appear to cause less fatigue and diarrhea than older treatments.
Experts believe CELMoDs could play multiple roles in future treatment. They may enhance the effectiveness of bispecific antibodies, support CAR T-cell therapy, serve as convenient oral options for patients who cannot access specialized centers, and help achieve deeper remissions that allow possible treatment breaks. Overall, CELMoDs both directly kill myeloma cells and strengthen the immune system.