伊达赛利珠单抗或标准方案治疗复发/难治性多发性骨髓瘤。

Ide-cel or Standard Regimens in Relapsed and Refractory Multiple Myeloma.

机构信息

From Clínica Universidad de Navarra, Pamplona, Spain (P.R.-O.); Mayo Clinic, Jacksonville, FL (S.A.); Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, Université Paris Cité, Paris (B.A.), Centre Hospitalier Universitaire de Lille, Université de Lille, Lille (S.M.), and University Hospital of Nantes, Nantes (P.M.) - all in France; M.D. Anderson Cancer Center, University of Texas, Houston (K.P.); IRCCS Azienda Ospedaliero-Universitaria di Bologna, Seràgnoli Institute of Hematology, and the Department of Experimental, Diagnostic, and Specialty Medicine, Bologna University School of Medicine, Bologna, Italy (M. Cavo); Winship Cancer Institute of Emory University (A.K.N.) and Northside Hospital Cancer Institute (S.R.S.) - both in Atlanta; the University of Wisconsin Carbone Cancer Center, Madison (N.C.); the University of Alabama at Birmingham, Birmingham (L.J.C.); Washington University School of Medicine in St. Louis, St. Louis (R.V.); Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, AB, Canada (N.J.B.); Universitaire Ziekenhuizen Leuven, Leuven, Belgium (M.D.); Sarah Cannon Research Institute and Tennessee Oncology, Nashville (J.B.); 2seventy bio, Cambridge, MA (A.T.-H.); Bristol Myers Squibb, Princeton, NJ (Z.Y., L.F.-K., F.W., J.P., M. Cook); Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom (M. Cook); and Memorial Sloan Kettering Cancer Center, New York (S.G.).

出版信息

N Engl J Med. 2023 Mar 16;388(11):1002-1014. doi: 10.1056/NEJMoa2213614. Epub 2023 Feb 10.

DOI:10.1056/NEJMoa2213614

PMID:36762851

Abstract

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 to 450×10 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.).

摘要

背景

三药暴露复发/难治性多发性骨髓瘤患者的生存率较差。Idecabtagene vicleucel（ide-cel）是一种 B 细胞成熟抗原导向嵌合抗原受体（CAR）T 细胞疗法，此前在接受过多线治疗的复发/难治性多发性骨髓瘤患者中产生了深度、持久的应答。

方法

本研究为国际、开放标签、3 期临床试验，纳入了既往接受过 2 至 4 线治疗（包括免疫调节剂、蛋白酶体抑制剂和达雷妥尤单抗）且对最后一线治疗难治的复发/难治性多发性骨髓瘤成年患者，将患者以 2:1 的比例随机分组，分别接受 ide-cel（剂量范围为 150×10 至 450×10 个 CAR 阳性 T 细胞）或五种标准方案之一的治疗。主要终点为无进展生存期。关键次要终点为总缓解率（部分缓解或更好）和总生存期。评估安全性。

结果

共 386 例患者进行了随机分组：254 例患者接受 ide-cel 治疗，132 例患者接受标准方案治疗。66%的患者存在三药难治性疾病，95%的患者存在达雷妥尤单抗难治性疾病。中位随访 18.6 个月时，ide-cel 组的中位无进展生存期为 13.3 个月，而标准方案组为 4.4 个月（疾病进展或死亡风险比，0.49；95%置信区间，0.38 至 0.65；P<0.001）。ide-cel 组有 71%的患者发生缓解，标准方案组为 42%（P<0.001）；完全缓解率分别为 39%和 5%。总生存期数据不成熟。ide-cel 组 93%的患者和标准方案组 75%的患者发生了 3 级或 4 级不良事件。在接受 ide-cel 治疗的 225 例患者中，细胞因子释放综合征发生率为 88%，其中 5%为 3 级或更高级别，研究者确定的神经毒性发生率为 15%，其中 3%为 3 级或更高级别。

结论

与既往接受 2 至 4 线治疗的三药暴露复发/难治性多发性骨髓瘤患者的标准方案相比，ide-cel 治疗显著延长了无进展生存期，并提高了缓解率。ide-cel 的毒性与既往报告一致。（由 2seventy bio 和 Celgene， a Bristol-Myers Squibb company 资助；KarMMa-3 ClinicalTrials.gov 编号，NCT03651128。）