The autologous anti–B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell therapy LCAR-B38M has been approved for the treatment of relapsed and refractory multiple myeloma in many countries across the world under the name ciltacabtagene autoleucel. LEGEND-2 was the first-in-human trial of LCAR-B38M and yielded deep and durable therapeutic responses. Here, we reported the outcomes in LEGEND-2 after a minimal 5-year follow-up. Participants received an average dose of 0.5 × 106 cells/kg LCAR-B38M in split or single unfractionated infusions after cyclophosphamide-based lymphodepletion therapy. Investigator-assessed response, survival, safety and pharmacokinetics were evaluated. Seventy-four participants enrolled and had a median follow-up of 65.4 months. The 5-year progression-free survival (PFS) and overall survival (OS) rates were 21.0% and 49.1%, with progressive flattening of the survival curves over time. Patients with complete response (CR) had longer PFS and OS, with 5-year rates of 28.4% and 65.7%, respectively. Twelve patients (16.2%) remained relapse-free irrespective of baseline high-risk cytogenetic abnormality and all had normal humoral immunity reconstituted. An ongoing CR closely correlated with several prognostic baseline indices including favorable performance status, immunoglobulin G subtype, and absence of extramedullary disease, as well as a combination cyclophosphamide and fludarabine preconditioning strategy. Sixty-two (83.8%) suffered progressive disease (PD) and/or death; however, 61.1% of PD patients could well respond to subsequent therapies, among which, the proteasome inhibitor-based regimens benefited the most. Concerning the safety, hematologic and hepatic function recovery were not significantly different between non-PD and PD/Death groups. A low rate of second primary malignancy (5.4%) and no severe virus infection were observed. The patients who tested positive for COVID-19 merely presented self-limiting symptoms. In addition, a sustainable CAR T population of one case with persistent remission was delineated, which was enriched with indolently proliferative and lowly cytotoxic CD4/CD8 double-negative functional T lymphocytes. These data, representing the longest follow-up of BCMA-redirected CAR T-cell therapy to date, demonstrate long-term remission and survival with LCAR-B38M for advanced myeloma. LEGEND-2 was registered under the trial numbers NCT03090659, ChiCTRONH-17012285.

中文翻译：

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LCAR-B38M CAR T 细胞治疗后复发或难治性多发性骨髓瘤患者的长期缓解和生存：LEGEND-2 试验的 5 年随访

自体抗 B 细胞成熟抗原 (BCMA) 嵌合抗原受体 (CAR) T 细胞疗法 LCAR-B38M 已在世界许多国家被批准用于治疗复发性和难治性多发性骨髓瘤，名称为 ciltacabtagene autoleucel。 LEGEND-2 是 LCAR-B38M 的首次人体试验，产生了深入而持久的治疗反应。在这里，我们报告了 LEGEND-2 经过至少 5 年随访后的结果。参与者在基于环磷酰胺的淋巴细胞清除疗法后，接受平均剂量为 0.5 × 106 个细胞/kg 的 LCAR-B38M 分次或单次普通输注。对研究者评估的反应、生存、安全性和药代动力学进行了评估。 74 名参与者入组，中位随访时间为 65.4 个月。 5 年无进展生存率 (PFS) 和总生存率 (OS) 分别为 21.0% 和 49.1%，随着时间的推移，生存曲线逐渐变平。完全缓解 (CR) 患者的 PFS 和 OS 较长，5 年率分别为 28.4% 和 65.7%。无论基线高危细胞遗传学异常如何，12 名患者 (16.2%) 仍保持无复发，并且所有患者都重建了正常的体液免疫。持续的 CR 与多项预后基线指标密切相关，包括良好的体能状态、免疫球蛋白 G 亚型、无髓外疾病，以及环磷酰胺和氟达拉滨联合预处理策略。 62 人 (83.8%) 患有进行性疾病 (PD) 和/或死亡；然而，61.1%的PD患者对后续治疗有良好反应，其中以蛋白酶体抑制剂为基础的治疗方案受益最大。就安全性而言，非 PD 组和 PD/死亡组之间的血液学和肝功能恢复没有显着差异。第二原发恶性肿瘤发生率低（5.4%），无严重病毒感染。 COVID-19 检测呈阳性的患者仅出现自限性症状。此外，还描绘了一个持续缓解病例的可持续 CAR T 群体，其中富含惰性增殖和低细胞毒性的 CD4/CD8 双阴性功能性 T 淋巴细胞。这些数据代表了迄今为止 BCMA 重定向 CAR T 细胞疗法最长的随访数据，证明了 LCAR-B38M 对晚期骨髓瘤的长期缓解和生存。 LEGEND-2 注册号为 NCT03090659、ChiCTRONH-17012285。