Cellular and molecular impacts of CELMoDs and IMiD on the induction of myeloid‐derived suppressor cells by myeloma cells

Summary To identify strategies to prevent the induction of monocytic myeloid‐derived suppressor cells (M‐MDSCs) in multiple myeloma (MM), we analysed molecular changes in myeloma and myeloid cells within peripheral blood mononuclear cells (PBMCs) that promote M‐MDSC induction during co‐culture. We then examined the effects of cereblon E3 ligase modulators (CELMoDs), iberdomide (IBER) and mezigdomide (MEZI), compared with pomalidomide (POM), on M‐MDSC induction from PBMCs during co‐culture with human myeloma‐derived cell lines (HMCLs). Co‐culturing PBMCs with HMCLs increased inflammatory, interleukin (IL)‐6‐Janus kinase‐signal transducer and activator of transcription (JAK‐STAT)3 and tumour necrosis factor (TNF)‐α‐associated gene expression in HMCLs, while decreasing interferon‐related genes in myeloid cells. CELMoDs inhibited M‐MDSC induction, with 7.5 nM IBER and 1 nM MEZI as effective as 1 μM POM. In this context, CELMoDs and POM reduced inflammatory genes, including those involved in TNF‐α signalling via nuclear factor‐kappa B (NF‐κB), in HMCLs and lowered pro‐inflammatory genes, including C‐C motif chemokine ligand 5 (CCL5). Conversely, in myeloid cells, CELMoDs and POM enhanced immune‐activating pathways linked to interferon responses. Furthermore, CELMoDs and POM reduced candidate soluble mediators associated with M‐MDSC induction, such as migration‐inhibitory factor (MIF) and IL‐10, in myeloid cells and decreased IL‐10 secretion from IL‐10‐producing HMCLs. In summary, CELMoDs effectively inhibit M‐MDSC induction by altering gene expression in co‐cultured HMCLs and myeloid cells, while also suppressing mediators like IL‐10 and MIF.