CELMoD Mechanisms and Immune Function in Multiple Myeloma

In this segment, Dr. Joseph Mikhael and Dr. Scott Goldsmith introduce cereblon E3 ligase modulators (CELMoDs) and discuss their dual activity in multiple myeloma. Dr. Mikhael outlines the focus on T-cell activation, immune function, and the potential role of CELMoDs alongside newer myeloma therapies. Dr. Goldsmith explains how CELMoDs promote the degradation of Ikaros and Aiolos, transcription factors involved in plasma cell differentiation and proliferation, contributing to their direct antimyeloma effects. The discussion also explores their effects on the immune microenvironment, including increased T-cell activation, changes in markers associated with T-cell exhaustion, and increased cytokine production by cytotoxic T cells and natural killer (NK) cells, based on preclinical and translational findings. These immunomodulatory effects may support immune-mediated targeting of multiple myeloma cells in addition to direct tumor-cell activity. The segment establishes the biological rationale for examining CELMoDs in the evolving multiple myeloma treatment landscape, particularly as therapies that engage or redirect immune cells become increasingly important.