Blood Diseases Institute Cancer Institute, Xuzhou Medical University, Xuzhou, China.
Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China.
Am J Hematol. 2024 Dec;99(12):2286-2295. doi: 10.1002/ajh.27469. Epub 2024 Aug 28.
Relapsed/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.
复发/难治性多发性骨髓瘤伴髓外疾病（EMD）患者预后不良，缺乏有效治疗方法。嵌合抗原受体（CAR）T 细胞在 EMD 中的活性尚未确定；EMD 特异性微环境如何影响 CAR T 细胞治疗的临床结局仍然非常重要。在这项前瞻性队列研究中，纳入了经组织学证实有骨髓外 EMD 的患者，并于 2017 年 5 月至 2023 年 9 月接受了联合抗 BCMA 和抗 CD19 CAR T 细胞治疗。研究共纳入 31 例患者。骨髓疾病的总体缓解率为 90.3%，EMD 为 64.5%（p=0.031）。髓内和髓外疾病的治疗反应存在差异，EMD 表现出疗效不佳和延迟，以及缓解持续时间缩短。中位随访 25.3 个月时，中位无进展生存期和总生存期分别为 5.0 和 9.7 个月。里程碑分析表明，输注后 6 个月内进展与死亡风险增加密切相关（HR=4.58；p=0.029）。与非 EMD 患者相比，EMD 患者的生存结局较差。22.6%的患者出现独特的 CAR 相关局部毒性，与全身细胞因子释放综合征的发生和严重程度相关。截至截止日期，65%的治疗患者出现 EMD 进展，主要表现为 BCMA 进展。治疗前 EMD 免疫抑制微环境以耗竭的 CD8 T 细胞浸润为特征，与不良临床结局相关。CAR T 细胞在复发/难治性 EMD 中具有治疗活性，但长期生存获益可能有限。EMD 特异性微环境可能影响治疗效果。需要进一步努力延长 EMD 缓解并改善长期结局。
