PFAS penetrate the bone marrow microenvironment and alter immunometabolic homeostasis.

Per- and polyfluoroalkyl substances (PFAS) are persistent environmental contaminants associated with cancer risk, but their relevance to multiple myeloma remains poorly understood. In an unmatched case-control study of 173 participants, we integrated PFAS biomonitoring, immunoglobulin profiling, and untargeted metabolomics to characterize PFAS-associated immune and metabolic alterations. Higher circulating concentrations of perfluorodecanoic acid and perfluoroheptane sulfonate were associated with increased odds of multiple myeloma and lower polyclonal immunoglobulin G (IgG). Metabolomic analyses identified candidate alterations involving glycolysis, pentose phosphate pathway-related metabolism, redox homeostasis, lipid peroxidation, and arachidonic acid-derived mediators. Several PFAS-IgG and PFAS-metabolic associations were also observed among controls, suggesting that these patterns were not solely attributable to diagnosed multiple myeloma. Complementary PFAS mixture experiments showed lower circulating IgG, reduced bone marrow plasma-cell frequency, and increased serum lactate dehydrogenase activity in mice; experiments in human bone marrow-derived mesenchymal stromal cells showed disrupted redox homeostasis and enhanced oxidative stress. Exploratory mediation analysis further prioritized metabolites potentially mediating the associations between PFAS exposure and multiple myeloma. Together, these findings identify the bone marrow immunometabolic environment as a biologically relevant interface for PFAS-associated effects and support further prospective and targeted experimental investigation.