肿瘤细胞治疗研究
英文原题：Ide-cel or Standard Regimens in Relapsed and Refractory Multiple Myeloma.
对于既往接受过二至四种方案治疗的三类暴露复发/难治性多发性骨髓瘤患者，与标准方案相比，Ide-cel 治疗显著延长了无进展生存期并改善了缓解。
背景：三类药物均暴露后的复发/难治性多发性骨髓瘤患者生存情况较差。靶向 B 细胞成熟抗原的嵌合抗原受体（CAR）T 细胞疗法 idecabtagene vicleucel（ide-cel）此前已使经多线治疗的复发/难治性多发性骨髓瘤患者获得深度且持久的缓解。 方法：在这项国际、多中心、开放标签 III 期试验中，纳入既往接受过 2–4 种方案（包括免疫调节剂、蛋白酶体抑制剂和 daratumumab）且对最近方案难治的复发/难治性多发性骨髓瘤成人患者。患者按 2:1 随机分组，接受 ide-cel（剂量范围为 1.5×10⁸ 至 4.5×10⁸ 个 CAR 阳性 T 细胞）或五种标准方案之一。主要终点为无进展生存期。关键次要终点为总体缓解（部分缓解或更佳）和总生存期，并评估安全性。 结果：共随机分配 386 例患者，其中 254 例接受 ide-cel，132 例接受标准方案。66% 患者为三类药物均难治，95% 对 daratumumab 难治。中位随访 18.6 个月时，ide-cel 组中位无进展生存期为 13.3 个月，标准方案组为 4.4 个月（疾病进展或死亡风险比 0.49；95% 置信区间 0.38–0.65；P<0.001）。ide-cel 组和标准方案组缓解率分别为 71% 和 42%（P<0.001），完全缓解率分别为 39% 和 5%。总生存期数据尚不成熟。ide-cel 组和标准方案组 3–4 级不良事件发生率分别为 93% 和 75%。225 例接受 ide-cel 的患者中，88% 发生细胞因子释放综合征，其中 5% 为 3 级及以上；15% 发生研究者判定的神经毒性，其中 3% 为 3 级及以上。 结论：对于既往接受过 2–4 种治疗的三类药物暴露型复发/难治性多发性骨髓瘤患者，与标准方案相比，ide-cel 显著延长无进展生存期并提高缓解率。ide-cel 毒性与既往报告一致。（本研究由 2seventy bio 和 Celgene［Bristol Myers Squibb 公司］资助；KarMMa-3，ClinicalTrials.gov 注册号 NCT03651128。）
BACKGROUND: Survival is poor among patients with triple-class-exposed relapsed and refractory multiple myeloma. Idecabtagene vicleucel (ide-cel), a B-cell maturation antigen-directed chimeric antigen receptor (CAR) T-cell therapy, previously led to deep, durable responses in patients with heavily pretreated relapsed and refractory multiple myeloma. METHODS: In this international, open-label, phase 3 trial involving adults with relapsed and refractory multiple myeloma who had received two to four regimens previously (including immunomodulatory agents, proteasome inhibitors, and daratumumab) and who had disease refractory to the last regimen, we randomly assigned patients in a 2:1 ratio to receive either ide-cel (dose range, 150 10 6 to 450 10 6 CAR-positive T cells) or one of five standard regimens. The primary end point was progression-free survival. Key secondary end points were overall response (partial response or better) and overall survival. Safety was assessed. RESULTS: A total of 386 patients underwent randomization: 254 to ide-cel and 132 to a standard regimen. A total of 66% of the patients had triple-class-refractory disease, and 95% had daratumumab-refractory disease. At a median follow-up of 18.6 months, the median progression-free survival was 13.3 months in the ide-cel group, as compared with 4.4 months in the standard-regimen group (hazard ratio for disease progression or death, 0.49; 95% confidence interval, 0.38 to 0.65; P<0.001). A response occurred in 71% of the patients in the ide-cel group and in 42% of those in the standard-regimen group (P<0.001); a complete response occurred in 39% and 5%, respectively. Data on overall survival were immature. Adverse events of grade 3 or 4 occurred in 93% of the patients in the ide-cel group and in 75% of those in the standard-regimen group. Among the 225 patients who received ide-cel, cytokine release syndrome occurred in 88%, with 5% having an event of grade 3 or higher, and investigator-identified neurotoxic effects occurred in 15%, with 3% having an event of grade 3 or higher. CONCLUSIONS: Ide-cel therapy significantly prolonged progression-free survival and improved response as compared with standard regimens in patients with triple-class-exposed relapsed and refractory multiple myeloma who had received two to four regimens previously. The toxicity of ide-cel was consistent with previous reports. (Funded by 2seventy bio and Celgene, a Bristol-Myers Squibb company; KarMMa-3 ClinicalTrials.gov number, NCT03651128.).
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