AbstractRelapsed/refractory multiple myeloma patients with extramedullary disease (EMD) have unfavorable prognosis and lack effective therapy. Chimeric antigen receptor (CAR) T‐cell activities in EMD have yet to be determined; how EMD‐specific microenvironment influences the clinical outcomes of CAR T‐cell therapy remains of great interest. In this prospective cohort study, patients with histologically confirmed extra‐osseous EMD were enrolled and treated with combined anti‐BCMA and anti‐CD19 CAR T‐cell therapy from May 2017 to September 2023. Thirty‐one patients were included in the study. Overall response occurred in 90.3% of medullary disease and 64.5% of EMD (p = .031). Discrepancies in treatment response were noted between medullary and extramedullary diseases, with EMD exhibiting suboptimal and delayed response, as well as shortened response duration. With a median follow‐up of 25.3 months, the median progression‐free and overall survival were 5.0 and 9.7 months, respectively. Landmark analysis demonstrated that progression within 6 months post‐infusion is strongly associated with an increased risk of death (HR = 4.58; p = .029). Compared with non‐EMD patients, patients with EMD showed inferior survival outcomes. Unique CAR‐associated local toxicities at EMD were seen in 22.6% patients and correlated with the occurrence and severity of systemic cytokine release syndrome. To the cutoff date, 65% treated patients experienced EMD progression, primarily in the form of BCMA+ progression. The pretherapy EMD immunosuppressive microenvironment, characterized by infiltration of exhausted CD8+ T cells, was associated with inferior clinical outcomes. CAR T cells have therapeutic activity in relapsed/refractory 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.