Comparative Efficacy of Ciltacabtagene Autoleucel Versus Idecabtagene Vicleucel in the Treatment of Patients with Relapsed or Refractory Multiple Myeloma Previously Treated with 2-4 Prior Lines of Therapy Using a Matching-Adjusted Indirect Comparison
Authors: Bar Noffar , Diels Joris , van Sanden Suzy , Mendes João , Hernando Teresa , Cost Patricia , Schecter Jordan M. , Lendvai Nikoletta , Patel Nitin , Ishida Tadao , Er Jeremy , Harrison Simon J. , Lopez-Muñoz Nieves 
Published: December 2023

Introduction: Two novel B-cell maturation antigen (BCMA)-targeting chimeric antigen receptor T-cell (CAR-T) therapies, ciltacabtagene autoleucel (cilta-cel; Carvykti) and idecabtagene vicleucel (ide-cel; Abecma), were recently developed and approved in 2022 and 2021, respectively, for heavily pre-treated relapsed/refractory multiple myeloma (RRMM) based on the CARTITUDE-1 and KarMMa studies. A previous comparison of these therapies in triple-class exposed patients demonstrated improved efficacy with cilta-cel versus ide-cel (Martin T, et al. Curr Med Res Opin. 2023;39(1):81-89). More recently, the efficacy and safety of these CAR-Ts were demonstrated earlier in the treatment pathway in lenalidomide-refractory, proteasome inhibitor (PI)-exposed patients with 1-3 prior line(s) of treatment (LOT; cilta-cel; CARTITUDE-4), and in triple-class exposed patients with 2-4 prior LOT (ide-cel; KarMMa-3). In the absence of a head-to-head comparison of these two therapies, an unanchored matching-adjusted indirect comparison (MAIC) was used to estimate their relative efficacy using data from CARTITUDE-4, CARTITUDE-1, and KarMMa-3.

Methods: While KarMMa-3 and CARTITUDE-4 both included DPd in the physician's choice control arm, there is no published data on this subgroup from KarMMa-3. As such, an unanchored MAIC was performed utilizing individual patient-level data (IPD) from 245 patients who received cilta-cel; 208 patients from CARTITUDE-4 who had received 1-3 prior LOT and 37 patients from CARTITUDE-1 who had received 3-4 prior LOT. From these data, cilta-cel patients who fulfilled the inclusion criteria from KarMMa-3 (2-4 prior LOT and triple-class exposed) were selected, and their outcomes were compared against published summary data for ide-cel (N=254) from KarMMa-3 using reconstructed IPD for response endpoints and simulated IPD from published Kaplan-Meier (KM) curves for progression-free survival (PFS). Further imbalances in patient characteristics were adjusted for by weighting the cilta-cel IPD to match the reported baseline characteristics of KarMMa-3 in terms of refractory status, ISS stage, time to progression on prior LOT, cytogenetic risk, and presence of extramedullary disease. Comparative efficacy was estimated for overall response rate (ORR), very good partial response or better (≥VGPR) rate, complete response or better (≥CR) rate, and PFS. For binary endpoints, relative effects were quantified using relative response ratios (RRs) with 95% confidence intervals (CIs) derived from a weighted logistic regression analysis. For PFS, the hazard ratio (HR) with 95% CIs for cilta-cel versus ide-cel was estimated using a weighted Cox proportional hazards model.

Results: After applying the KarMMa-3 inclusion and exclusion criteria to the CARTITUDE-1 and CARTITUDE-4 IPD (excluding patients with only 1 prior LOT or no prior daratumumab), 36 patients and 49 patients were included from the cilta-cel trials, respectively. After adjustment, patients in the cilta-cel group (effective sample size [ESS]=46) were significantly more likely to achieve an overall response (RR: 1.18 [95% CI: 1.04, 1.33]; p=0.0404), and to reach deeper levels of response as demonstrated by ≥VGPR (RR: 1.34 [95% CI: 1.16, 1.56]; p=0.0027), and ≥CR (RR: 1.91 [95% CI: 1.56, 2.34]; p&lt;0.0001) compared to patients in the ide-cel group ( Table). In addition, a statistically significant reduction of 49% in the risk of disease progression or death was observed with cilta-cel versus ide-cel (HR: 0.51 [95% CI: 0.31, 0.84]; p=0.0078; Figure).

Conclusions: This unanchored MAIC showed that cilta-cel provides clinical benefit over ide-cel across response outcomes and PFS for patients with triple-class exposed RRMM treated with 2-4 prior LOT. These results are consistent with the previous comparison in later line, triple-class exposed patients, continuing to highlight the value of cilta-cel for these patients. Furthermore, these comparisons provide valuable information to contextualize the efficacy of cilta-cel compared to other available CAR-Ts for multiple myeloma.