From the Cancer Center Clínica Universidad de Navarra, Centro Investigación Medica Aplicada, Instituto de Investigación de Navarra, Centro Investigación Biomédica en Red Cáncer (CIBERONC), Pamplona (J.S.-M.), the University Hospital of Salamanca, Instituto de Investigación Biomédica de Salamanca, Centro Investigación del Cáncer, CIBERONC, Salamanca (M.-V.M.), the Amyloidosis and Myeloma Unit, Department of Hematology, Hospital Clínic of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona (C.F.L.), the Hematological Malignancies Clinical Research Unit, Hospital 12 de Octubre Universidad Complutense, Centro Nacional de Investigaciones Oncológicas, CIBERONC, Madrid (J.M.-L.), and the Institut Català d'Oncologia and Institut Josep Carreras, Hospital Germans Trias i Pujol, Badalona (A.O.) - all in Spain; the Medical College of Wisconsin, Milwaukee (B.D.); the University College London Cancer Institute (K.Y.) and University College London Hospitals, NHS Foundation Trust (R.P.), London, University Hospitals Bristol and Weston NHS Foundation Trust, Bristol (J. Griffin), and Janssen Research and Development, High Wycombe (J. Gilbert) - all in the United Kingdom; Monash University (A. Spencer) and the Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Sir Peter MacCallum Department of Oncology, University of Melbourne (S.J.H.), Melbourne, VIC, and Royal Prince Alfred Hospital and the University of Sydney, Sydney (P.J.H.) - all in Australia; the Vaccine and Infectious Disease Institute, University of Antwerp, Antwerp, and the Division of Hematology and Center for Cell Therapy and Regenerative Medicine, Antwerp University Hospital, Edegem - both in Belgium (S.A.); the Department of Hematology, University Hospital Hôtel-Dieu, Nantes (P.M., C.T.), and Service d'Hématologie et Thérapie Cellulaire, Hôpital La Milétrie, and Centre d'investigation Clinique INSERM 1402, Poitiers University Hospital, Poitiers (X.L.) - both in France; Tel Aviv Sourasky Medical Center (I.A., Y.C.C.) and the Sackler Faculty of Medicine, Tel Aviv University (Y.C.C.) - both in Tel Aviv, Israel; IRCCS Azienda Ospedaliero-Universitaria di Bologna, Seràgnoli Institute of Hematology, and the Department of Medical and Surgical Sciences, Bologna University School of Medicine, Bologna, Italy (M.C.); the Department of Hematology, Japanese Red Cross Medical Center, Tokyo (T.I.); the Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea (S.J.K.); the Department of Hematology, University Medical Center Groningen, Groningen (W.R.), and Amsterdam University Medical Center, Vrije Universiteit Amsterdam, Amsterdam (N.W.C.J.D.) - both in the Netherlands; Poznan University of Medical Sciences, Poznan, Poland (D.D.); Stanford University School of Medicine, Stanford, CA (S.S.); the University of Alabama at Birmingham, Birmingham (L.J.C.); Ohio State University Comprehensive Cancer Center, Columbus (A.M.K.); Janssen Research and Development, Raritan (N.L., J.M.S., C.C.J., K.C., T.Y., S.N.), and Legend Biotech, Somerset (E.F., L.P., N.P.) - both in New Jersey; Janssen, Buenos Aires (C.L.); Cilag International, Zug, Switzerland (A. Slaughter); Janssen Research and Development, Spring House, PA (K.L., E.Z.); Janssen China Research and Development, Shanghai (D.C.); and Universitätsklinikum Würzburg, Medizinische Klinik und Poliklinik II, Würzburg, Germany (H.E.).
N Engl J Med. 2023 Jul 27;389(4):335-347. doi: 10.1056/NEJMoa2303379. Epub 2023 Jun 5.
BACKGROUND: Ciltacabtagene autoleucel (cilta-cel), a B-cell maturation antigen (BCMA)-directed CAR T-cell therapy, is effective in heavily pretreated patients with relapsed or refractory multiple myeloma. We investigated cilta-cel in earlier treatment lines in patients with lenalidomide-refractory disease. METHODS: In this phase 3, randomized, open-label trial, we assigned patients with lenalidomide-refractory multiple myeloma to receive cilta-cel or the physician's choice of effective standard care. All the patients had received one to three previous lines of treatment. The primary outcome was progression-free survival. RESULTS: A total of 419 patients underwent randomization (208 to receive cilta-cel and 211 to receive standard care). At a median follow-up of 15.9 months (range, 0.1 to 27.3), the median progression-free survival was not reached in the cilta-cel group and was 11.8 months in the standard-care group (hazard ratio, 0.26; 95% confidence interval [CI], 0.18 to 0.38; P<0.001). Progression-free survival at 12 months was 75.9% (95% CI, 69.4 to 81.1) in the cilta-cel group and 48.6% (95% CI, 41.5 to 55.3) in the standard-care group. More patients in the cilta-cel group than in the standard-care group had an overall response (84.6% vs. 67.3%), a complete response or better (73.1% vs. 21.8%), and an absence of minimal residual disease (60.6% vs. 15.6%). Death from any cause was reported in 39 patients and 46 patients, respectively (hazard ratio, 0.78; 95% CI, 0.5 to 1.2). Most patients reported grade 3 or 4 adverse events during treatment. Among the 176 patients who received cilta-cel in the as-treated population, 134 (76.1%) had cytokine release syndrome (grade 3 or 4, 1.1%; no grade 5), 8 (4.5%) had immune effector cell-associated neurotoxicity syndrome (all grade 1 or 2), 1 had movement and neurocognitive symptoms (grade 1), 16 (9.1%) had cranial nerve palsy (grade 2, 8.0%; grade 3, 1.1%), and 5 (2.8%) had CAR-T-related peripheral neuropathy (grade 1 or 2, 2.3%; grade 3, 0.6%). CONCLUSIONS: A single cilta-cel infusion resulted in a lower risk of disease progression or death than standard care in lenalidomide-refractory patients with multiple myeloma who had received one to three previous therapies. (Funded by Janssen and Legend Biotech; CARTITUDE-4 ClinicalTrials.gov number, NCT04181827.).
背景：靶向 B 细胞成熟抗原（BCMA）的嵌合抗原受体 T 细胞疗法 cilta-cel（西达基奥仑赛）在接受过多线治疗的复发或难治性多发性骨髓瘤患者中具有疗效。我们研究了 cilta-cel 在 lenalidomide 难治性疾病患者中的更早治疗线中的应用。
方法：在这项 3 期、随机、开放标签的临床试验中，我们将 lenalidomide 难治性多发性骨髓瘤患者分配接受 cilta-cel 或医生选择的有效标准护理。所有患者均接受过 1 至 3 线治疗。主要终点为无进展生存期。
结果：共有 419 名患者接受了随机分组（208 名接受 cilta-cel，211 名接受标准护理）。在中位随访 15.9 个月（范围，0.1 至 27.3）时，cilta-cel 组未达到中位无进展生存期，标准护理组为 11.8 个月（风险比，0.26；95%置信区间[CI]，0.18 至 0.38；P<0.001）。cilta-cel 组 12 个月时的无进展生存率为 75.9%（95%CI，69.4 至 81.1），标准护理组为 48.6%（95%CI，41.5 至 55.3）。cilta-cel 组比标准护理组有更多的患者出现总体缓解（84.6% vs. 67.3%）、完全缓解或更好（73.1% vs. 21.8%）和无微小残留病（60.6% vs. 15.6%）。分别有 39 名和 46 名患者报告了任何原因导致的死亡（风险比，0.78；95%CI，0.5 至 1.2）。大多数患者在治疗期间报告了 3 级或 4 级不良事件。在接受治疗的 176 名 cilta-cel 患者中，134 名（76.1%）发生细胞因子释放综合征（3 级或 4 级，1.1%；无 5 级），8 名（4.5%）发生免疫效应细胞相关神经毒性综合征（均为 1 级或 2 级），1 名发生运动和神经认知症状（1 级），16 名（9.1%）发生颅神经麻痹（2 级，8.0%；3 级，1.1%），5 名（2.8%）发生 CAR-T 相关周围神经病（1 级或 2 级，2.3%；3 级，0.6%）。
结论：在接受过 1 至 3 线治疗的 lenalidomide 难治性多发性骨髓瘤患者中，单次 cilta-cel 输注与标准护理相比，疾病进展或死亡的风险降低。（由 Janssen 和 Legend Biotech 资助；CARTITUDE-4 临床试验.gov 编号，NCT04181827。）
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