Body composition predicts poor outcomes and reveals immunometabolic dysfunction via single-cell profiling in...

Chimeric antigen receptor (CAR) T-cell therapy has transformed the treatment of relapsed or refractory multiple myeloma (RRMM), yet outcomes remain heterogenous. The prognostic role of body composition in this context is unknown. We retrospectively analyzed 108 RRMM patients treated with anti-B-cell maturation antigen (BCMA) CAR T-cell therapy. Pre-treatment Computed tomography imaging was utilized to quantify total adipose tissue (TAT), subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), and skeletal muscle area to assess sarcopenia. Longitudinal flow cytometric and single-cell multi-omic analyses were conducted to characterize the quantitative and qualitative influences of body composition on the immune microenvironment. Patients with BMI < 25 kg/m² experienced significantly worse overall survival (OS) compared to high-BMI patients. Reduced TAT, primarily driven by low SAT, was associated with inferior OS, diminished response, and elevated soluble BCMA. Sarcopenia independently predicted poorer OS, while progression-free survival was unaffected by the respective parameters. Low SAT and sarcopenia correlated with lower bystander T-cell counts at leukapheresis. Longitudinal T-cell receptor sequencing and single-cell transcriptomics revealed diminished cytotoxic and interferon signaling, reduced T-cell clonality, and increased oxidative phosphorylation activity following CAR T-cell infusion. Our findings identify low SAT and sarcopenia as prognostic biomarkers that influence survival, therapeutic response, and immunometabolic profiles. Their quantification through standard imaging techniques offers a cost-effective strategy for early risk stratification and individualized management in CAR T-cell therapy.