Research Summary:
Approved by the United States Food and Drug Administration and the European Commission to treat relapsed/refractory multiple myeloma (RRMM) after 1 or more previous lines of therapy, ciltacabtagene autoleucel (cilta-cel) is a B-cell maturation antigen-directed chimeric antigen receptor T-cell (CAR T) therapy. Prior to the CARTITUDE-4 trial, there were no published studies examining the effect of CAR T therapy for the treatment of patients with RRMM. In this study, Einsele et al1 reported overall survival (OS) and updated safety and efficacy outcomes at the second interim analysis of the phase 3 CARTITUDE-4 trial.
The CARTITUDE-4 trial is an ongoing, randomized, multicenter, phase 3 trial. Between July 10, 2020, and November 17, 2021, 419 adult patients with lenalidomide-refractory multiple myeloma with 1 to 3 previous lines of therapy, including a proteasome inhibitor and an immunomodulatory agent, were randomly assigned 1:1 using a computer-generated randomization sequence to receive either a single cilta-cel infusion (n=208) or standard of care (physician’s choice of pomalidomide-bortezomib-dexamethasone or daratumumab-pomalidomide-dexamethasone; n=211). The primary endpoint was progression-free survival (PFS), which was met in the first interim analysis, as cilta-cel showed a significant and clinically meaningful improvement in PFS compared to standard of care. In addition to reporting OS and updated PFS data in the intention-to-treat population, this interim analysis reported on secondary endpoints, including minimal residual disease (MRD) negativity rate, the rate of complete response (CR) or better, PFS on next-line therapy, and time to symptom worsening, measured with the Multiple Myeloma Symptom and Impact Questionnaire (MySIm-Q).
At final data cutoff on May 1, 2024, the median follow-up duration was 33.6 months (interquartile range [IQR]: 20.3–35.0). There were a total of 242 PFS events, 89 in the cilta-cel group and 153 in the standard-of-care group. Median PFS was not reached (95% confidence interval [CI]: 34.5 months–not evaluable) in the cilta-cel group and 11.8 months (95% CI: 9.7–14.0 months) in the standard-of-care group (hazard ratio [HR]: 0.29; 95% CI: 0.22–0.39). Estimated 30-month PFS rates were longer in the cilta-cel group (59.4%; 95% CI: 52.3–65.7) compared to the standard-of-care group (25.7%, 95% CI: 19.8–31.9). In the subgroup analysis, a PFS benefit was documented across prespecified subgroups based on demographic and disease characteristics in the cilta-cel vs standard-of-care groups.
There were 133 OS events at final data cutoff, 50 in the cilta-cel group and 83 in the standard-of-care group. Median OS was not reached in either group (cilta-cel group, 95% CI: not evaluable; standard-of-care group, 95% CI: 37.7 months–not evaluable; HR: 0.55, 95% CI: 0.39–0.79, P=0.0009), and there was a significant advantage in OS with cilta-cel vs standard of care. In the cilta-cel and standard-of-care groups, estimated 30-month OS was 76.4% (95% CI: 70.0–81.6%) and 63.8% (95% CI: 56.9–69.9%), respectively. OS benefit with cilta-cel was consistent in prespecified subgroups.
A smaller proportion of patients in the cilta-cel group (31%) received 1 or more subsequent antimyeloma therapies vs the standard-of-care group (69%) at final data cutoff. Overall MRD negativity at a 10–5 threshold at any time during the study occurred in 62% of the cilta-cel group and 18% of the standard-of-care group. Overall MRD negativity at a 10–6 threshold occurred in 57% of the cilta-cel group and 9% of the standard-of-care group. In the cilta-cel group, CR or better occurred in 77% of patients vs 24% in the standard-of-care group. A treatment response occurred in 85% of the cilta-cel group vs 67% of the standard-of-care group. The cilta-cel group was more likely to have a sustained (ie, ≥12 months) MRD-negative CR or better (52%) vs the standard-of-care group (10%) in patients who were evaluable for MRD at a 10–5 threshold. Median PFS on next-line therapy was 25.3 months (95% CI: 21.6–32.9 months) in the standard-of-care group and was not reached (95% CI: not evaluable) in the cilta-cel group (HR: 0.46; 95% CI: 0.34–0.63).
In the cilta-cel and standard-of-care groups, 30 and 49 MySIm-Q symptom worsening events, respectively, occurred. The cilta-cel group had a significantly longer time to symptom worsening, as median time to worsening was not reached (95% CI: not evaluable) vs 34.3 months (95% CI: 32.2 months–not evaluable) in the standard-of-care group (HR: 0.38; 95% CI: 0.24–0.61; P<0.0001).
In the safety population, treatment-emergent adverse events (TRAEs) at a maximum grade of 3 or 4 occurred in 89% of patients in the cilta-cel group and 93% of patients in the standard-of-care group, with grade 3 to 4 cytopenias cited as the most frequent TRAE in both groups. Mortality from disease progression was reported in 21 patients (10%) in the cilta-cel group (8 of whom did not receive cilta-cel) and 51 (25%) in the standard-of-care group.
Overall, survival outcomes and quality of life was significantly improved with cilta-cel vs standard of care in adult patients with lenalidomide-refractory MM. These findings show that cilta-cel led to improved outcomes for patients with RRMM as early as the second line of therapy.
References:
- Einsele H, San-Miguel J, Dhakal B, et al. Cilta-cel in lenalidomide-refractory multiple myeloma (CARTITUDE-4): an updated analysis including overall survival from an open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 2026;27(2):254–268.