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Background: In CARTITUDE-4, ciltacabtagene autoleucel (cilta-cel) significantly improved progression-free survival (primary endpoint; previously reported) versus standard of care in patients with relapsed, lenalidomide-refractory multiple myeloma. We report here patient-reported outcomes., Methods: In the ongoing, phase 3, open-label CARTITUDE-4 study, patients were recruited from 81 sites in the USA, Europe, Asia, and Australia, and were randomly assigned 1:1 to cilta-cel (target, 0·75 × 10 6 CAR-T cells/kg) or standard of care (daratumumab, pomalidomide, and dexamethasone; pomalidomide, bortezomib, and dexamethasone). Eligible patients had relapsed, lenalidomide-refractory multiple myeloma, received one to three previous treatment lines including a proteasome inhibitor and an immunomodulatory drug, and had an ECOG performance status of 0 or 1. Secondary endpoints reported here include time to sustained worsening of symptoms (Multiple Myeloma Symptom and Impact Questionnaire [MySIm-Q]; a key secondary endpoint) and change in European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life (QoL) Questionnaire Core C30 (intention-to-treat population) and EuroQol 5-Dimension 5-Level (EQ-5D-5L; intention-to-treat population). This study is registered with ClinicalTrials.gov number NCT04181827 and is ongoing., Findings: Patients were enrolled from July 10, 2020, to Nov 17, 2021, and 419 of 516 screened patients were randomly assigned (cilta-cel, n=208; standard of care, n=211; median follow-up, 15·9 months [IQR 12·4 to 17·8]); median age was 61 years. 191 (92%) of 208 patients in the cilta-cel group and 190 (91%) of 209 evaluable patients in the standard- of-care group completed baseline assessments. MySIm-Q compliance post-baseline was 70 to 81% (cilta-cel) and 79 to 89% (standard of care). MySIm-Q median time to sustained symptom worsening with cilta-cel versus standard of care was 23·7 versus 18·9 months (HR 0·42; 95% CI 0·26 to 0·68). 12-month mean changes for EORTC global health status (GHS) were +10·1 (95% CI 7·0 to 13·1) and -1·5 (95% CI -5·3 to 2·3) points and were +8·0 (95% CI 5·2 to 10·7) and +1·4 (95% CI -1·9 to 4·7) points for EQ-5D-5L visual analogue scale (VAS). Rates of clinically meaningful improvements in GHS and VAS were higher with cilta-cel than with standard of care., Interpretation: Health-related QoL improvements and delayed symptom worsening support cilta-cel's clinical efficacy in lenalidomide-refractory disease., Funding: Janssen Research & Development, Legend Biotech USA., Competing Interests: Declaration of Interests RM reports a consulting or advisory role or honoraria for Amgen, BMS–Celgene, GSK, Janssen, Menarini-Stemline, Pfizer, Sanofi, and Takeda. HY reports honoraria for Astellas. WA reports honoraria, research funding, or travel expenses from Affimed, BioNTech, GSK, Immatics, and Janssen. MCM reports consulting or advisory roles, honoraria, speaker's bureau, or research funding from BeiGene, CDR life, GSK, Pfizer, Siemens, and Janssen Medicine, and hospitality from Janssen. LS reports consulting or advisory roles for BMS and Johnson & Johnson. II reports a consulting role for AbbVie, ADC Therapeutics, Beam Therapeutics, Genmab, Gilead, and Incyte; and holds equity in Gilead. SJH reports consulting or advisory roles, honoraria, research funding, or speaker's bureau for AbbVie, Amgen, Celgene–BMS, Eusa, F Hoffmann-La Roche–Genentech, GSK, Haemalogix, Janssen, Novartis, and Terumo BCT. UAS reports research funding from BMS, and Janssen and consulting or advisory roles with BMS, Janssen, and Sanofi. JMS has stock and other ownership interests in Johnson & Johnson; and is employed by Janssen. MV is employed by Janssen. NL has stock options in Janssen; and is employed by Janssen. KSG has equity and stock options in Janssen and is employed by Janssen. EGK has equity and stock options in Janssen and is employed by Janssen. AS has equity and stock options in Janssen and is employed by Janssen. CL is employed by Janssen. JG is employed by Janssen. QL is employed by Janssen. WD is employed by Janssen. OCF has equity in Legend and is employed by Legend. EF is employed by Legend. NP has equity in Legend; and is employed by Legend. LK reports a consulting role or honoraria for AbbVie, Amgen, Celgene, GSK, Janssen, Sanofi, and Takeda. KW reports a consulting role, honoraria, or research funding for AbbVie, Amgen, Adaptive Biotech, AstraZeneca, BeiGene, BMS–Celgene, GSK, Janssen, Karyopharm, Menarini, Novartis, Oncopeptides, Pfizer, Roche, Sanofi, Stemline, and Takeda. AKM and HM declare no competing interests., (Copyright © 2025 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)