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Background: CARTITUDE-1 aimed to assess the safety and clinical activity of ciltacabtagene autoleucel (cilta-cel), a chimeric antigen receptor T-cell therapy with two B-cell maturation antigen-targeting single-domain antibodies, in patients with relapsed or refractory multiple myeloma with poor prognosis., Methods: This single-arm, open-label, phase 1b/2 study done at 16 centres in the USA enrolled patients aged 18 years or older with a diagnosis of multiple myeloma and an Eastern Cooperative Oncology Group performance status score of 0 or 1, who received 3 or more previous lines of therapy or were double-refractory to a proteasome inhibitor and an immunomodulatory drug, and had received a proteasome inhibitor, immunomodulatory drug, and anti-CD38 antibody. A single cilta-cel infusion (target dose 0·75 × 10 6 CAR-positive viable T cells per kg) was administered 5-7 days after start of lymphodepletion. The primary endpoints were safety and confirmation of the recommended phase 2 dose (phase 1b), and overall response rate (phase 2) in all patients who received treatment. Key secondary endpoints were duration of response and progression-free survival. This trial is registered with ClinicalTrials.gov, NCT03548207., Findings: Between July 16, 2018, and Oct 7, 2019, 113 patients were enrolled. 97 patients (29 in phase 1b and 68 in phase 2) received a cilta-cel infusion at the recommended phase 2 dose of 0·75 × 10 6 CAR-positive viable T cells per kg. As of the Sept 1, 2020 clinical cutoff, median follow-up was 12·4 months (IQR 10·6-15·2). 97 patients with a median of six previous therapies received cilta-cel. Overall response rate was 97% (95% CI 91·2-99·4; 94 of 97 patients); 65 (67%) achieved stringent complete response; time to first response was 1 month (IQR 0·9-1·0). Responses deepened over time. Median duration of response was not reached (95% CI 15·9-not estimable), neither was progression-free survival (16·8-not estimable). The 12-month progression-free rate was 77% (95% CI 66·0-84·3) and overall survival rate was 89% (80·2-93·5). Haematological adverse events were common; grade 3-4 haematological adverse events were neutropenia (92 [95%] of 97 patients), anaemia (66 [68%]), leukopenia (59 [61%]), thrombocytopenia (58 [60%]), and lymphopenia (48 [50%]). Cytokine release syndrome occurred in 92 (95%) of 97 patients (4% were grade 3 or 4); with median time to onset of 7·0 days (IQR 5-8) and median duration of 4·0 days (IQR 3-6). Cytokine release syndrome resolved in all except one with grade 5 cytokine release syndrome and haemophagocytic lymphohistiocytosis. CAR T-cell neurotoxicity occurred in 20 (21%) patients (9% were grade 3 or 4). 14 deaths occurred in the study; six due to treatment-related adverse events, five due to progressive disease, and three due to treatment-unrelated adverse events., Interpretation: A single cilta-cel infusion at the target dose of 0·75 × 10 6 CAR-positive viable T cells per kg led to early, deep, and durable responses in heavily pretreated patients with multiple myeloma with a manageable safety profile. The data from this study formed the basis for recent regulatory submissions., Funding: Janssen Research & Development and Legend Biotech., Competing Interests: Declaration of interests JGB receives research funding from AbbVie, Amgen, Acetylon, Bluebird, Bristol Myers Squibb, Celgene, Cellularity, Constellation, CRISPR Therapeutics, CURIS, EMD Serono, Genentech, Glenmark, Janssen, Kesios, Lilly, Novartis, Poseida, Teva, Takeda Pharmaceuticals, and Vivolux, and is a consultant for Amgen, Bioclinica, Bristol Myers Squibb, Celgene, CRISPR Therapeutics, Janssen, Karyopharm, Kite Pharma, Legend, Prothena, Servier, Takeda Pharmaceuticals, and SecuraBio. DM is a consultant for and receives honoraria from AbbVie, Celgene, Foundation Medicine, GlaxoSmithKline, Janssen, Legend, Takeda, and Kinevant, and is a member of the Board of Directors or advisory committee and part of the Speaker's Bureau for GlaxoSmithKline, Legend, and Kinevant. SZU is a consultant for AbbVie, Amgen, Array Biopharma, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Merck, Sanofi, Seattle Genetics, SkylineDX, and Takeda Pharmaceuticals; receives honoraria from Amgen, Bristol Myers Squibb, Celgene, Janssen, Pharmacyclics, Sanofi, MundiPharma, and Takeda Pharmaceuticals; receives speaking fees from Amgen, Janssen, and Takeda Pharmaceuticals; and receives research funding from Amgen, Array Biopharma, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Incyte, Janssen, Merck, Pharmacyclics, Sanofi, Seattle Genetics, SkylineDX, and Takeda Pharmaceuticals. AJ receives consulting fees and honoraria from AbbVie, Adaptive, Amgen, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Juno, Karyopharm, and Sanofi, and is a member of the Board of Directors or advisory committee for AbbVie, Amgen, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Karyopharm, and Sanofi. ADC reports personal fees from Janssen, Takeda, Bristol Myers Squibb/Celgene, AstraZeneca, Genentech/Roche, Seattle Genetics, Kite Pharma, and Oncopeptides, and personal fees and grants from GlaxoSmithKline and Novartis. AKS receives honoraria from Aventis, Janssen, Amgen, Oncopeptides, Bristol Myers Squibb, GlaxoSmithKline, and Sanofi, and is a member of the Board of Directors or advisory committee for Genomics England and Tempus. PH receives consulting fees and honoraria from AbbVie, Bristol Myers Squibb, Celgene, Janssen, Kite, Sanofi Genzyme, Spectrum, and Takeda Pharmaceuticals; receives research funding from Amgen, Bristol Myers Squibb, Celgene, Sanofi Genzyme, and Spectrum. MH is a current employee of City of Hope Medical Center. AD is a consultant for Novartis and Kite, a Gilead Company. AL receives consulting fees and honoraria from Bristol Myers Squibb, GenMab, Takeda Pharmaceuticals, Janssen, Amgen, and Boehringer Ingelheim; receives research funding from Bristol Myers Squibb, Genentech, Pfizer, Trillium, and Janssen; and receives royalties from patents from Serametrix. IS was an employee of Janssen at the time the study was conducted, and is a current employee of Gilead Sciences. EZ, T-MY, AJA, YO, AB, JDG, JMS, WD, SHZ, and JI are employed by Janssen. CCJ is employed by Janssen, and is a consultant physician at the Memorial Sloan Kettering Cancer Center (New York, NY, USA). DG, XW, and MAk are employed by Legend Biotech. MJC-A was an employee of Legend Biotech at the time the study was conducted, and owns stock in Adaptimmune Therapeutics, Allogene Therapeutics, Atara Biotherapeutics, Bellicum Pharmaceuticals, BioNTech, Bluebird Bio, Cellectis, CRISPR Therapeutics, Editas Medicine, Fate Therapeutics, Iovance Biotherapeutics, Intellia Therapeutics, Juno Therapeutics, Kite Pharma, Legend Biotech, Moderna Therapeutics, NantKwest, Neon Therapeutics, Novartis, AG Pharma, Sana Biotechnology, Sangamo Therapeutics, Sorrento Therapeutics, Tcr2 Therapeutics, Verstem Oncology, and Ziopharm Oncology. FH was an employee of Legend Biotech at the time the study was conducted, and is a current employee of Genentech. SR was an employee of Legend Biotech at the time the study was conducted. FF is employed by Nanjing Legend Biotechnology. YL is a consultant for Bluebird Bio, Celgene, Gamida Cells, Janssen, Huno, Kite, Novartis, Sorrento, Legend BioTech, and Vineti, and receives research funding from Bluebird Bio, Celgene, Janssen, Kite, Merck, and Takeda Pharmaceuticals. TM receives research funding from Janssen. SJ is a consultant for Bristol Myers Squibb, Janssen, Karyopharm Therapeutics, Merck, Sanofi, Legend Biotech, and Takeda Pharmaceuticals. MAg, EO'D, NCM, and DA declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)