Cilta-Cel Is Associated with Improved Outcomes and Distinct Cellular Dynamics Compared with Ide-Cel for Relapsed or Refractory Multiple Myeloma

Background Both idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) showed substantial progress in the treatment of triple-class exposed relapsed or refractory multiple myeloma (RRMM). Crude comparisons of prospective trials indicated potential differences in efficacy and safety. However, direct comparative data are lacking. This European comparative study endeavors to bridge this gap, to elucidate relative risks and identify different cellular dynamics of cilta-cel versus ide-cel. Methods This is the first international European study on the comparative efficacy and safety cilta-cel versus ide-cel in RRMM. We included only patients infused after 3 or more lines of therapy according to current approval. CAR-T expansion and persistence was measured at day 7, 14, 30, 90, and last follow-up by PCR or FACS, as per center's practice. Co-primary endpoints were overall response rate (ORR) and progression-free survival (PFS). Secondary endpoints were complete response rate, overall survival (OS), incidence of cytokine release syndrome (CRS) or immune effector cell associated neurotoxicity syndrome (ICANS), and non-relapse mortality. Results The total cohort included 162 with ide-cel and 42 with cilta-cel. Median age at time of CAR-T infusion was 61 years (range, 28 to 82 years) for ide-cel versus 61 years (range, 24 to 84 years) for cilta-cel (P=0.32). Median time between diagnosis and CAR-T infusion was 7.5 years for ide-cel versus 6.8 years for cilta-cel (P=0.53), and median turnaround time between apheresis and CAR-T infusion was 47 days for ide-cel versus 68 days for cilta-cel (P<0.001). Median number of prior lines of therapy was 6 for both groups and 15% in the ide-cel group versus 11% in the cilta-cel group had prior exposure to BCMA-directed therapy. Most patient characteristics were well balanced between both groups. Cilta-cel showed deep and significantly higher ORR of 93% versus 79% for ide-cel (P<0.001). Early response appeared to be deeper for cilta-cel, showing complete response at day 30 after CAR-T infusion of 48% in the cilta-cel group versus 26% in the ide-cel group (P<0.001). After a median follow-up of 9.5 months in the cilta-cel group versus 13.4 months in the ide-cel group (P<0.001), the 10-month PFS was 40% in the ide-cel group versus 75% in the cilta-cel group (P<0.001). The 10-month OS was 86% in the cilta-cel group versus 77% in the ide-cel group (P=0.11). Cilta-cel was independently associated with improved PFS and OS after multivariable adjustment. The incidence of CRS was similar between both treatment groups (P=0.51), with 81% in the cilta-cel group versus 84% in the ide-cel group showing CRS of any grade after CAR-T infusion. Half of the patients in both groups had grade 1 CRS, while 9% in the cilta-cel groups versus 4% in the ide-cel group showed CRS grade 3-4. Onset of CRS appeared to be significantly earlier in the ide-cel group (median, 2 days) versus cilta-cel group (median, 4 days; P<0.001). The incidence of ICANS was similar, with ICANS of any grade occurring in 19%, respectively. However, severe ICANS grade 3-4 was seen in 7% of the cilta-cel group versus 2% of the ide-cel group. Non-relapse mortality was similar (P=0.52), being 6% in the cilta-cel group versus 5% in the ide-cel group. All 7 deaths without relapse/progression were due to infection in both groups. Furthermore, we evaluated possible differences in resource utilization. The median length of the hospital stay was 14 days in the ide-cel group versus 17 days in the cilta-cel group (P=0.002). Use of tocilizumab was similar, while use of corticosteroids appeared to be more likely in the cilta-cel group (P=0.04), being used in 35% versus 26% in the ide-cel group. Last, we evaluated CAR-T dynamics, finding that ide-cel was associated with significantly earlier expansion (P<0.001), peaking at day 7 after infusion. In contrast, cilta-cel expansion peaked at day 14 with significantly increased AUC (P<0.001). CAR-T expansion showed stronger association with ORR and PFS for cilta-cel versus ide-cel (P<0.001). Findings were established with PCR and validated in centers with FACS. Conclusion Our study provides real-world evidence that cilta-cel was associated with superior outcomes versus ide-cel in triple-class exposed RRMM. Despite similar non-relapse mortality in both groups, different toxicity profiles of cilta-cel must be taken into account in clinical practice.