Updated Comparative Efficacy of Ciltacabtagene Autoleucel Versus Idecabtagene Vicleucel in Patients with Relapsed or Refractory Multiple Myeloma Previously Treated with 2-4 Prior Lines of Therapy Using a Matching-Adjusted Indirect Comparison

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 initially approved for heavily pre-treated relapsed/refractory multiple myeloma (RRMM) based on the CARTITUDE-1 and KarMMa-1 studies. An extension of indication has been recently approved by the FDA and EMA (2024) for the treatment of adult patients with RRMM who have received at least 1 prior line of therapy (LOT), including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD), and are refractory to lenalidomide (cilta-cel; CARTITUDE-4); and in patients with RRMM after 2 or more prior LOT, including an IMiD, a PI, and an anti-CD38 monoclonal antibody (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. Since the initial publication of this MAIC, data from longer follow-ups became available for both CARTITUDE-4 and KarMMa-3, reporting overall survival (OS) outcomes, allowing for an updated assessment of the comparative efficacy between cilta-cel and ide-cel. Methods: While both KarMMa-3 and CARTITUDE-4 included DPd in the physician's choice control arm, no data were published on this subgroup from KarMMa-3, which could be used as common arm in anchored indirect comparisons between both studies. Therefore, an unanchored MAIC was performed utilizing individual patient-level data (IPD) from all apheresed patients from the cilta-cel arms (N=245), including 208 patients from CARTITUDE-4 who had received 1-3 prior LOT and 37 patients from CARTITUDE-1 with 3-4 prior LOT. From this cohort, 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) and OS. 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, R-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, PFS and OS. 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 and OS, 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]=41) were significantly more likely to achieve an overall response (RR: 1.20 [95% CI: 1.06, 1.36]; p=0.0167), and to reach deeper levels of response as demonstrated by ≥VGPR (RR: 1.36 [95% CI: 1.18, 1.57]; p= 0.0010), and ≥CR (RR: 1.79 [95% CI: 1.48, 2.17]; p<0.0001) compared to the ide-cel patients. In addition, a statistically significant reduction of 56% in the risk of disease progression or death was observed with cilta-cel versus ide-cel (HR: 0.44 [0.27, 0.70], p=0.0007) as well as a 40% reduction for the risk death (HR: 0.60 [0.35, 1.02], p=0.06). Conclusions: This unanchored MAIC demonstrated clinical benefit of cilta-cel over ide-cel across response outcomes, PFS and OS for patients with triple-class exposed RRMM treated with 2-4 prior LOT. These results are consistent with previously published comparative results between both CAR-T treatments, and the new OS results highlight the added value of cilta-cel in this patient population. These comparisons provide valuable information to contextualize the efficacy of cilta-cel compared to ide-cel for the treatment of multiple myeloma.