Microenvironmentally derived fatty acid-binding proteins 4 and 5 are novel therapeutic vulnerabilities in multiple myeloma.

Multiple myeloma (MM) is an incurable cancer of monoclonal plasma cells. Despite its dependency on the bone marrow (BM), therapies targeting the BM microenvironment are lacking, barring immunotherapies. Obesity is associated with worse outcomes in MM, and although antiobesity treatments may benefit patients with MM, this is not yet known. Moreover, those treatments have side effects, and their specific mechanisms of action are elusive because of the interconnectedness of obesity, metabolic syndrome, diet, fiber intake, gut microbiome, inflammation, and the immune system. Fatty acid-binding proteins (FABPs) play a role in obesity and other diseases, but no studies of microenvironmentally derived FABPs' effects on cancer progression exist. Therefore, we tested the hypothesis that microenvironmentally derived FABPs support MM progression using single-cell sequencing data, in vivo models, and MM Research Foundation Relating Clinical Outcomes in MM to Personal Assessment of Genetic Profile data. We found that global Fabp4/Fabp5 double-knockout (Fabp4/5 dKO) mice have modifications in body composition, immune cells, and skeletal parameters. Murine myeloma cell (Vk12598) engraftment and growth (tumor incidence) were higher in wild-type (WT) vs Fabp4/5 dKO mice. High-fat diet-fed Fabp4/5 dKO mice were further protected from metabolic and skeletal diseases, and tumor incidence was reduced, whereas survival was increased in Fabp4/5 dKO vs WT mice. Finally, low FABP5 expression in granulocyte-monocyte progenitors, typically considered immunosuppressive, is associated with improved survival of patients with MM, implicating reduced immunosuppression and improved immune-mediated tumor eradication as one mechanism of action. Overall, the data suggest that tumor-extrinsic FABP4/5 support MM progression, which, combined with previous myeloma cell-intrinsic findings, suggests targeting FABP4/5 may cause a 2-pronged attack in MM.