Clinical outcomes and microenvironment profiling of relapsed/refractory extramedullary disease of multiple myeloma patients with anti-BCMA CAR T cell-based therapy

Abstract Relapsed/refractory (R/R) multiple myeloma (MM) patients with extramedullary disease (EMD) have grim prognoses and lack effective therapy. We conducted a comprehensive study of 31 R/R MM patients with histologically confirmed extra-osseous EMD receiving anti-B-cell maturation antigen (BCMA) CAR T cell-based therapy. The safety/efficacy was assessed; immune microenvironment was analyzed based on multiplex immunofluorescence of pretherapy EMD biopsy samples. Overall response occurred in 90.3% of medullary disease and 64.5% of EMD. Discrepant outcomes between medullary and extramedullary response, with suboptimal and delayed response and shortened response duration in EMD were observed. The median progression-free survival and overall survival were 5.0 and 9.7 months, respectively. Unique CAR-associated local toxicities at EMD were seen in 22.6% patients. Compared with non-EMD patients, patients with EMD showed inferior survival outcomes. To the cutoff date, 65% patients experienced EMD progression post-treatment, and BCMA+ progression constituted the main progression pattern in EMD. The pretherapy EMD immunosuppressive microenvironment, characterized by infiltration of exhausted CD8+ T cells, was reported to associate with adverse clinical outcomes. We show that CAR T cells have favorable activity in EMD, but the long-term survival benefits may be limited; EMD-specific microenvironment potentially impacts treatment. Further efforts are needed to extend EMD remission and improve long-term outcomes.