Microbiome modulation uncouples efficacy and toxicity induced by immune checkpoint blockade in mouse multiple myeloma

Smoldering multiple myeloma (SMM), which is in principle curable, may develop into life-threatening MM. Intestinal microbiota and gut-born T helper-17 (Th17) lymphocytes may contribute to this development, but the mechanisms are unclear. Here we demonstrate that administering the human commensal Prevotella melaninogenica to transgenic Vk*MYC mice that exhibit SMM-like phenotypes delays the evolution to full-blown MM. Mechanistically, P. melaninogenica increases the production of short-chain fatty acids (SCFA), thereby preventing the skewing of dendritic cells towards a pro-Th17 phenotype and subsequently accumulation of Th17 cells in the bone marrow of treated mice. P. melaninogenica or butyrate synergizes with anti-PD-L1 or anti-TIGIT to suppress myeloma progression by restraining Th17 cell expansion while inducing effector CD8⁺ T cells. P. melaninogenica also attenuates IL-17-mediated skin lesions that mimic anti-PD-L1-induced adverse events. Our results thus suggest that gut microbiota modulation or SCFAs administration may represent treatment options for patients affected by plasma cell dyscrasias.