伊达比星脂质体注射用多柔比星治疗复发/难治性多发性骨髓瘤
Idecabtagene Vicleucel in Relapsed and Refractory Multiple Myeloma.
机构信息
From the Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute (N.C.M.), the Veterans Affairs Boston Healthcare System, Harvard Medical School (N.C.M.), and Massachusetts General Hospital (N.R.), Boston, and bluebird bio, Cambridge (F.P., M.M.) - all in Massachusetts; Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas (L.D.A.); the University of California, San Francisco, San Francisco (N.S.); Icahn School of Medicine at Mount Sinai, New York (D.M.); Sarah Cannon Research Institute and Tennessee Oncology, Nashville (J.B.); Emory School of Medicine, Atlanta (S.L.); Mayo Clinic, Rochester, MN (Y.L.); Hackensack University Medical Center, Hackensack (D.S.), and Bristol-Myers Squibb, Princeton (J.N.C., S.K., P.P., L.H., T.B.C., K.H.) - both in New Jersey; Institut Josep Carreras and Institut Catala d'Oncologia, Hospital Germans Trias i Pujol, Badalona (A.O.), and Clinica Universidad de Navarra, Centro de Investigación Médica Aplicada, Instituto de Investigación Sanitaria de Navarra, Centro de Investigación Biomédica en Red de Cáncer, Pamplona (J.S.-M.) - both in Spain; Centre Hospitalier Universitaire (CHU) de Nantes, Nantes (P.M.), and CHU de Lille, University of Lille, INSERM Unité 1286, Institute for Translational Research in Inflammation, Lille (I.Y.-A.) - both in France; University Hospital Leuven, Leuven, Belgium (M.D.); "Seràgnoli" Institute of Hematology, Bologna University School of Medicine, Bologna (M.C.), the Department of Oncology and Hematology, University of Milan, Milan (A.R.), and Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII, Bergamo (A.R.) - all in Italy; University Hospital of Würzburg, Würzburg (H.E.), University Hospital Heidelberg (H.G.) and the National Center for Tumor Diseases (H.G.), Heidelberg, the University Medical Center Hamburg-Eppendorf, Hamburg (K.W.), and Universitätsklinikum Tübingen, Tübingen (K.W.) - all in Germany; and Princess Margaret Cancer Centre, Toronto (D.R.).
出版信息
N Engl J Med. 2021 Feb 25;384(8):705-716. doi: 10.1056/NEJMoa2024850.
BACKGROUND
Idecabtagene vicleucel (ide-cel, also called bb2121), a B-cell maturation antigen-directed chimeric antigen receptor (CAR) T-cell therapy, has shown clinical activity with expected CAR T-cell toxic effects in patients with relapsed and refractory multiple myeloma.
METHODS
In this phase 2 study, we sought to confirm the efficacy and safety of ide-cel in patients with relapsed and refractory myeloma. Patients with disease after at least three previous regimens including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 antibody were enrolled. Patients received ide-cel target doses of 150 × 10 to 450 × 10 CAR-positive (CAR+) T cells. The primary end point was an overall response (partial response or better); a key secondary end point was a complete response or better (comprising complete and stringent complete responses).
RESULTS
Of 140 patients enrolled, 128 received ide-cel. At a median follow-up of 13.3 months, 94 of 128 patients (73%) had a response, and 42 of 128 (33%) had a complete response or better. Minimal residual disease (MRD)-negative status (<10 nucleated cells) was confirmed in 33 patients, representing 26% of all 128 patients who were treated and 79% of the 42 patients who had a complete response or better. The median progression-free survival was 8.8 months (95% confidence interval, 5.6 to 11.6). Common toxic effects among the 128 treated patients included neutropenia in 117 patients (91%), anemia in 89 (70%), and thrombocytopenia in 81 (63%). Cytokine release syndrome was reported in 107 patients (84%), including 7 (5%) who had events of grade 3 or higher. Neurotoxic effects developed in 23 patients (18%) and were of grade 3 in 4 patients (3%); no neurotoxic effects higher than grade 3 occurred. Cellular kinetic analysis confirmed CAR+ T cells in 29 of 49 patients (59%) at 6 months and 4 of 11 patients (36%) at 12 months after infusion.
CONCLUSIONS
Ide-cel induced responses in a majority of heavily pretreated patients with refractory and relapsed myeloma; MRD-negative status was achieved in 26% of treated patients. Almost all patients had grade 3 or 4 toxic effects, most commonly hematologic toxic effects and cytokine release syndrome. (Funded by bluebird bio and Celgene, a Bristol-Myers Squibb company; KarMMa ClinicalTrials.gov number, NCT03361748.).
背景
Idecabtagene vicleucel（ide-cel，也称为 bb2121）是一种 B 细胞成熟抗原导向的嵌合抗原受体（CAR）T 细胞疗法，在复发和难治性多发性骨髓瘤患者中显示出预期的 CAR T 细胞毒性作用和临床活性。
方法
在这项 2 期研究中，我们旨在确认 ide-cel 在复发和难治性骨髓瘤患者中的疗效和安全性。招募了至少接受过三种先前治疗方案的患者，包括蛋白酶体抑制剂、免疫调节剂和抗 CD38 抗体。患者接受 ide-cel 目标剂量为 150×10 至 450×10 CAR+阳性（CAR+）T 细胞。主要终点为总体反应（部分反应或更好）；关键次要终点为完全缓解或更好（包括完全和严格完全缓解）。
结果
在 140 名入组患者中，有 128 名接受了 ide-cel 治疗。在中位随访 13.3 个月时，128 名患者中有 94 名（73%）有反应，42 名（33%）有完全缓解或更好。33 名患者证实存在微小残留疾病（MRD）阴性状态（<10 个有核细胞），占所有 128 名接受治疗患者的 26%和完全缓解或更好的 42 名患者的 79%。中位无进展生存期为 8.8 个月（95%置信区间，5.6 至 11.6）。128 名接受治疗患者的常见毒性包括 117 名（91%）中性粒细胞减少症、89 名（70%）贫血和 81 名（63%）血小板减少症。107 名患者（84%）报告发生细胞因子释放综合征，包括 7 名（5%）患者发生 3 级或更高级别的事件。23 名患者（18%）出现神经毒性作用，4 名（3%）患者出现 3 级神经毒性作用；没有发生高于 3 级的神经毒性作用。细胞动力学分析证实，在输注后 6 个月时，49 名患者中有 29 名（59%）和 11 名患者中有 4 名（36%）存在 CAR+T 细胞。
结论
Ide-cel 在大多数接受过多重预处理的难治性和复发性骨髓瘤患者中诱导了反应；在接受治疗的患者中，有 26%达到了 MRD 阴性状态。几乎所有患者都有 3 级或 4 级毒性反应，最常见的是血液学毒性反应和细胞因子释放综合征。（由 bluebird bio 和 Celgene，a Bristol-Myers Squibb company 资助；KarMMa ClinicalTrials.gov 编号，NCT03361748。）
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