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

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.