Musculoskeletal Adverse Events Following BCMA CAR T-Cell Therapy in Multiple Myeloma: Clinical Characteristics and...

Chimeric antigen receptor T-cell (CAR-T) therapy targeting B-cell maturation antigen (BCMA) has revolutionized treatment for relapsed/refractory multiple myeloma (RRMM). While life-threatening toxicities like cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome are well-characterized, musculoskeletal adverse events (MSK AEs) remain poorly understood despite their potential to significantly impact quality of life. To characterize the incidence, clinical features, temporal patterns, and immunological correlates of MSK AEs following commercial BCMA CAR-T therapy in patients with RRMM. We conducted a single-center retrospective cohort study of 69 consecutive patients with RRMM who received commercial BCMA CAR-T therapy (ciltacabtagene autoleucel or idecabtagene vicleucel) between December 2022 and February 2025 with minimum 3-month follow-up. MSK AEs were defined as new-onset or worsening arthralgias, myalgias, or bone pain documented in clinical notes. We performed comprehensive immune profiling including flow cytometry analysis of immune cell populations and cytokine measurements at multiple timepoints. Twenty patients (29%) developed MSK AEs with median onset 39 d (range 18 to 76) post-CAR-T and median duration 61 d (range 14 to 299). Grade 3 events occurred in 6 (30%) of affected patients, with 5 (83%) of these patients requiring opioids and 3 (50%) requiring corticosteroids. Seventy percent had polyarticular involvement, with hip being the most commonly affected joint (70%), followed by knee and shoulder (35% each). MSK AEs occurred significantly more frequently in Black patients compared to other races (55% versus 18%, P = .0095) and were paradoxically associated with absence of ICANS (0% versus 31% in unaffected patients, P = .0139). Patients developing MSK AEs had significantly lower baseline polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) prior to lymphodepletion (P = .0187) and demonstrated a distinct inflammatory signature at 6 months post-CAR-T with elevated IL-12 (589 versus 423 pg/mL, P = .0003), TNFα (P = .0015), IFNγ (P = .013), and MIP-1β (P = .011). No associations were observed with CAR-T product, treatment response, or CAR-T persistence markers. MSK AEs represent a common, under-recognized toxicity affecting nearly one-third of BCMA CAR-T recipients, often causing severe and prolonged disability. The identification of predictive baseline PMN-MDSC reduction and persistent inflammatory cytokine elevation provides insights into pathophysiology and suggests potential for risk stratification and targeted therapeutic intervention. These findings warrant prospective validation and development of standardized assessment and management protocols.