Metabolic biomarkers for predicting onset and severity of CAR-T therapy-induced cytokine release syndrome in multiple myeloma

Chimeric antigen receptor T-cell (CAR-T) therapy has been successfully applied in clinical treatment, especially for hematologic malignancies such as multiple myeloma (MM), but its broad application is limited by cytokine release syndrome (CRS), a potentially life-threatening complication. Although metabolic alterations are known to accompany CRS, predictive biomarkers for its onset, severity, and associated metabolic remodeling remain unknown, hindering proactive clinical management. Here, we analyzed longitudinal serum metabolic profiles from 19 patients with relapsed/refractory MM receiving CAR-T therapy, with validation in an independent cohort of 23 patients. We observed dysregulated arginine metabolism that progressed alongside clinical CRS. At pre-lymphodepletion (Day-5), over half of differentially abundant metabolites were enriched in unsaturated fatty acid (UFA) synthesis pathways, which were exclusively upregulated in patients who later developed severe CRS. Furthermore, two lysophosphatidylcholines, namely, lysoPC(16:0) and lysoPC(15:0), were significantly associated with delayed CRS onset, with elevated concentrations correlated with a prolonged time to onset; this association was independently validated. These findings revealed that arginine metabolism was a pathological axis in CRS, UFAs were severity predictors, and specific lysoPCs were modulators of onset time. Collectively, they provide proactive CRS management, addressing critical gaps in predictive biomarkers to advance the safe, broad CAR-T application in MM.