Research Summary:
Ciltacabtagene autoleucel (cilta-cel) is a B-cell maturation antigen (BCMA)–targeted chimeric antigen receptor T-cell (CAR-T) therapy that has transformed outcomes for patients with relapsed or refractory multiple myeloma (RRMM), yet head-to-head trials against many commonly used lenalidomide-refractory regimens are not available. This study by Puig et al1 used unanchored matching-adjusted indirect comparisons (MAICs) to contextualize cilta-cel’s efficacy versus standard-of-care options not included in CARTITUDE-4: elotuzumab plus pomalidomide plus dexamethasone (EloPd; ELOQUENT-3), isatuximab plus carfilzomib plus dexamethasone (IsaKd; IKEMA lenalidomide-refractory subgroup), isatuximab plus pomalidomide plus dexamethasone (IsaPd; ICARIA-MM), and selinexor plus bortezomib plus dexamethasone (SVd; BOSTON lenalidomide-refractory subgroup).
Analyses drew on individual patient-level data (IPD) for all apheresed participants randomized to cilta-cel in CARTITUDE-4 (n=208), applied each comparator trial’s key eligibility criteria to the cilta-cel cohort to improve population alignment, and then reweighted the cilta-cel IPD so the weighted means of prespecified prognostic factors matched those reported in each comparator publication. Baseline factors matched in base case models included refractory status to proteasome inhibitor, high cytogenetic risk, and International Staging System (ISS) stage. Additional sensitivity analyses expanded matching sets while preserving an effective sample size (ESS) of at least 20. Outcomes were overall response rate (ORR), very good partial response or better (≥VGPR), complete response or better (≥CR), progression-free survival (PFS), and overall survival (OS). For comparators that only reported Kaplan–Meier curves, individual-level time-to-event data were simulated from digitally extracted curves using a validated algorithm. For the IKEMA lenalidomide-refractory subgroup, PFS was reconstructed by fitting an exponential model through the reported six-, 12-, and 18-month rates because full curves were not available. Weighted logistic regression generated odds ratios and response rate ratios and weighted Cox models estimated hazard ratios (HRs) for PFS and OS.
After population adjustment, cilta-cel was associated with significantly higher ORR than EloPd, IsaPd, and SVd, with relative response ratios of 1.53 (95% confidence interval [CI]: 1.18–1.99), 1.39 (95% CI: 1.15–1.68), and 1.24 (95% CI: 1.02–1.51), respectively. Depth of response favored cilta-cel across all pairwise comparisons. The adjusted odds of achieving ≥VGPR were 15.59 versus EloPd, 2.58 versus IsaKd, 8.63 versus IsaPd, and 7.60 versus SVd, resulting in response rate ratios of 3.98 (95% CI: 2.36–6.72), 1.26 (95% CI: 1.02–1.55), 2.52 (95% CI: 1.90–3.34), and 2.26 (95% CI: 1.56–3.27), respectively. For ≥CR, cilta-cel showed even larger advantages, as adjusted odds ratios were 37.06 versus EloPd, 6.67 versus IsaKd, 78.62 versus IsaPd, and 31.10 versus SVd (all p<0.0001), with response rate ratios of 9.25 (95% CI: 3.93–21.80), 2.09 (95% CI: 1.48–2.95), 17.36 (95% CI: 8.23–36.61), and 8.10 (95% CI: 3.47–18.91), respectively.
For time-to-event outcomes, median PFS was not reached for cilta-cel, whereas observed medians in the comparator trials ranged from 10.2 months (EloPd and SVd) to 19.4 months (IsaKd). After adjustment, cilta-cel significantly reduced the risk of progression or death versus all comparators, with HRs of 0.36 (95% CI: 0.21–0.62) versus EloPd, 0.51 (95% CI: 0.29–0.90) versus IsaKd, 0.31 (95% CI: 0.14–0.68) versus IsaPd, and 0.38 (95% CI: 0.24–0.59) versus SVd, corresponding to relative risk reductions of 64 percent, 49 percent, 69 percent, and 62 percent, respectively. For OS, which was not reported for the IKEMA lenalidomide-refractory subgroup, adjusted HRs favored cilta-cel versus the remaining comparators; HRs were 0.48 (95% CI: 0.29–0.80) versus EloPd, 0.42 (95% CI: 0.21–0.81) versus IsaPd, and 0.40 (95% CI: 0.25–0.67) versus SVd, representing 52-percent, 58-percent, and 60-percent lower hazards of death, respectively. Sensitivity analyses that broadened exclusion criteria for the IsaKd comparison yielded consistent findings, including an adjusted HR for progression or death of 0.45 (95% CI: 0.22–0.94) and maintained advantages for ≥VGPR and ≥CR. Additional sensitivity analyses that matched on more prognostic factors largely corroborated base case estimates, though with wider CIs due to smaller ESSs.
RRMM remains a challenging disease to treat, but emerging CAR-T treatments show promise for patients. While several combination options are now available, guidelines for newer therapies can be broad. In this study, the adjusted comparisons consistently showed that cilta-cel delivered substantially higher response depth and prolonged PFS and OS relative to EloPd, IsaKd, IsaPd, and SVd in patients with at least one prior line of therapy who were refractory to lenalidomide. These findings complement CARTITUDE-4’s prior direct comparison versus physician’s choice of pomalidomide plus bortezomib plus dexamethasone (PVd) or daratumumab plus pomalidomide plus dexamethasone (DPd), and provide decision-relevant context in settings where alternative standard regimens are commonly used. Collectively, the MAIC results support cilta-cel as a highly effective option for previously treated lenalidomide-refractory MM.
References:
- Puig N, Diels J, van Sanden S, et al. Comparative efficacy of ciltacabtagene autoleucel versus standard-of-care treatments for patients with previously treated relapsed or refractory multiple myeloma: a matching-adjusted indirect comparison. Adv Ther. 2025;42(7):3223–3239.