CELMoD Potency and Cereblon-Mediated Activity in Multiple Myeloma

Dr. Mikhael asks Dr. Goldsmith to further explain the clinical relevance of the differences in cereblon engagement between CELMoDs and established IMiDs for clinicians treating multiple myeloma. Dr. Goldsmith discusses how differences in cereblon engagement may influence the extent and persistence of degradation of Ikaros and Aiolos, transcription factors important to plasma-cell biology. He describes preclinical observations showing rapid and potent activity of CELMoDs at low concentrations and connects these findings with the clinical development of iberdomide and mezigdomide. The discussion also highlights the relatively low doses used for these agents compared with established IMiDs, illustrating their pharmacologic potency. Dr. Goldsmith further notes that these mechanistic characteristics have supported investigation of CELMoDs in patients with highly treatment-resistant multiple myeloma. The conversation therefore connects molecular pharmacology with the emerging clinical experience while providing community oncologists with context for understanding how next-generation CELMoDs may differ from established IMiDs.