Standard-of-care ciltacabtagene autoleucel in earlier versus later lines of therapy for relapsed or refractory multiple myeloma: a nationwide registry analysis

BACKGROUND: Ciltacabtagene autoleucel (cilta-cel) is a BCMA-directed chimeric antigen receptor (CAR) T-cell therapy approved for relapsed or refractory multiple myeloma (RRMM). Following the CARTITUDE-1 results in heavily pretreated patients, the randomized phase 3 CARTITUDE-4 trial demonstrated superior progression-free survival (PFS) and overall survival for cilta-cel compared with standard of care in lenalidomide-refractory patients after one to three prior lines, leading to label expansion in 2024. However, real-world data characterizing outcomes in this earlier-line indication are lacking. METHODS: We analyzed all patients with RRMM receiving standard-of-care cilta-cel between 2022 and 2025 from the German Registry for Stem Cell Transplantation and Cellular Therapy. Patients were stratified by prior lines of therapy into an Early group (1-3 prior lines) and a Late group (> 3 prior lines). The primary endpoint was PFS. Secondary endpoints included overall response rate, response conversion, and safety outcomes including cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome (ICANS), non-ICANS neurotoxicity, and non-relapse mortality. Prognostic associations were assessed using restricted cubic spline Cox regression and univariable Cox models. RESULTS: Of 606 patients, 177 (30%) were treated in the Early and 429 (70%) in the Late setting. The overall response rate was 91% and 88%, with complete response in 63% and 54%, respectively. The 12-month PFS was 79% for Early and 70% for Late cilta-cel. Depth of response was the strongest predictor of PFS in both cohorts, with patients maintaining complete response showing 100% PFS at 12 months irrespective of treatment line. Extramedullary disease was adversely prognostic in both groups, whereas high-risk cytogenetics were not associated with inferior PFS in the Early group. Non-ICANS neurotoxicity occurred less frequently in the Early group (3% versus 8%), while non-relapse mortality was comparable (6% versus 7%). CONCLUSIONS: This analysis demonstrates that cilta-cel in earlier lines of therapy achieves deep responses and high PFS consistent with the CARTITUDE-4 trial. These results provide real-world evidence for the deployment of cilta-cel as early as first relapse and may be a benchmark outside prospective trials.