Comparative Efficacy of Ciltacabtagene Autoleucel Versus Elotuzumab, Isatuximab, and Selinexor-Based Regimens in the Treatment of Patients with Relapsed or Refractory Multiple Myeloma with 1-3 Prior Lines of Therapy Using a Matching-Adjusted Indirect Comparison

Introduction: Ciltacabtagene autoleucel (cilta-cel; Carvykti) was assessed in the phase 3 randomized controlled trial CARTITUDE-4 for adult patients with relapsed and refractory multiple myeloma (RRMM) who have received 1-3 prior line(s) of therapy (LOT) that included an immunomodulatory agent (IMiD), and a proteasome inhibitor (PI) and are refractory to lenalidomide. Other therapies used to treat patients with multiple myeloma who have received at least one other therapy and are lenalidomide-refractory vary by country, but broadly include doublet and triplet regimens based on daratumumab, pomalidomide, bortezomib, and carfilzomib. This analysis aims to compare efficacy outcomes in patients randomized to the cilta-cel arm of CARTITUDE-4 versus relevant comparators based on their target trial populations. Methods: Comparators for the matching adjusted indirect comparisons (MAICs) were identified a priori based on regimens used in the target population including; SVd, EloPd, IsaKd, DKd, DVd, Kd, Vd, Pd, and Ide-cel. PVd and DPd were not of interest given their inclusion in the CARTITUDE-4 trial. Melflufen+d, PanVd, VenVd, PCd, IxaKd, D-monotherapy, V-monotherapy, CyVd, and DVCd were not of interest for the US, EU-5, the Netherlands, and Canada. A systematic literature review identified publications of relevant clinical trials for these treatments, which were assessed for feasibility of an indirect treatment comparison. Feasibility was determined based on study design and degree of overlap with the CARTITUDE-4 population (prior LOT, lenalidomide-refractoriness, and exclusion criteria around previous therapies, i.e., prior daratumumab). We report here on comparisons vs. EloPd (ELOQUENT-3), IsaPd (ICARIA-MM), and SVd (BOSTON). Due to differences in methods for the comparisons versus ide-cel (KarMMa-3) and versus DKd, Kd, DVd, Vd, and Pd, these are reported separately. Comparison to IsaKd was not feasible due to a lack of published data in the lenalidomide-refractory subgroup (baseline characteristics and efficacy data), and key differences in exclusion criteria. Given the lack of a common comparator between CARTITUDE-4 and the comparator trials, unanchored MAICs were performed utilizing individual patient-level data (IPD) from patients randomized to the cilta-cel arm of CARTITUDE-4 (N=208). The eligibility criteria from each of the comparator trials were applied to the cilta-cel IPD, and outcomes for the matched population were compared against published summary data for EloPd (N=60), IsaPd (N=154), and SVd (N=195) 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 by weighting the cilta-cel data to match the reported baseline characteristics of the comparator trials in terms of refractory status, cytogenetic risk, ISS stage, 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, HRs including 95% CIs were estimated using a weighted Cox proportional hazards model. Results: After adjustment, patients in the cilta-cel arm were significantly more likely to achieve an overall response than patients in EloPd or IsaPd arms, and to achieve ≥VGPR and ≥CR versus patients in all other comparators arms ( Table 1). In addition, cilta-cel was associated with a significant reduction in the risk of disease progression or death (PFS) versus all comparators, ranging from 39% (versus SVd) to 68% (versus IsaPd) ( Table 2). Conclusions: Cilta-cel demonstrated clinical benefit over EloPd, IsaPd, and SVd for response outcomes and PFS, highlighting its potential as an effective treatment option for patients with RRMM who have received at least one other therapy and are lenalidomide-refractory. These comparisons provide valuable information to contextualize the efficacy of cilta-cel in countries where treatment for these patients may be different from DPd or PVd.

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