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
Authors: Puig Noemi , Diels Joris , van Sanden Suzy , Mendes João , Hernando Teresa , Lee Seina , Lendvai Nikoletta , Patel Nitin , Sanchez-Pina José 
Published: December 2024

Background:
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. Recently, cilta-cel demonstrated significant overall survival (OS) benefit in an updated prespecified CARTITUDE-4 analysis with median follow-up of 34 months. This analysis aims to compare efficacy of cilta-cel vs elotuzumab, isatuximab and selinexor-based regimens, using the latest data from CARTITUDE-4 and published data from the comparator trials.
Methods:
Comparators for the matching adjusted indirect comparisons (MAICs) were identified a priori based on regimens used in the target population including: SVd, EloPd and IsaPd. 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). We report here on comparison of cilta-cel (CARTITUDE-4) vs. EloPd (ELOQUENT-3), IsaPd (ICARIA-MM), and SVd (BOSTON len-refractory subgroup). 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=53) using simulated IPD from published Kaplan-Meier (KM) curves for OS and progression-free survival (PFS), and reconstructed IPD for response endpoints. 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 OS, PFS, overall response rate (ORR), very good partial response or better (≥VGPR) rate and complete response or better (≥CR) rate. For OS and PFS, HRs including 95% CIs were estimated using a weighted Cox proportional hazards model. For binary endpoints, relative effects were quantified using relative response ratios (RRs) with 95% confidence intervals (CIs) derived from a weighted logistic regression analysis.
Results:
After adjustment, OS was significantly superior in patients treated with cilta-cel vs IsaPd (HR: 0.42, 95% CI: 0.21-0.81; p=0.0105), vs EloPd (HR: 0.48, 95% CI: 0.29-0.80; p=0.0051) and vs SVd (HR: 0.40, 95% CI: 0.25-0.67; p=0.0004). Patients treated with cilta-cel showed statistically significant PFS benefit vs IsaPd (HR: 0.31, 95% CI: 0.14-0.68; p=0.0034), vs EloPd (HR: 0.36, 95% CI: 0.21-0.62; p=0.0003) and vs SVd (HR: 0.38, 95% CI: 0.24-0.59; p&lt;0.0001). In terms of response outcomes, patients in the cilta-cel arm demonstrated significantly superior ORR [vs IsaPd (RR: 1.39, 95% CI: 1.15-1.68; p= 0.0077), vs EloPd (RR: 1.53, 95% CI: 1.18-1.99; p= 0.0003) and vs SVd (RR: 1.24, 95% CI: 1.02-1.51; p= 0.0102)], ≥VGPR [vs IsaPd (RR: 2.52, 95% CI: 1.90-3.34; p&lt;0.0001), vs EloPd (RR: 3.98, 95% CI: 2.36-6.72; p&lt;0.0001) and vs SVd (RR: 2.26, 95% CI: 1.56-3.27; p&lt;0.0001)] and ≥CR [vs IsaPd (RR: 17.36, 95% CI: 8.23-36.61; p&lt;0.0001), vs EloPd (RR: 9.25, 95% CI: 3.93-21.80; p&lt;0.0001) and vs SVd (RR: 8.10, 95% CI: 3.47-18.91; p&lt;0.0001)] vs patients in all other comparators arms.
Conclusion:
In this comparative analysis, cilta-cel demonstrated statistically significant clinical benefit over IsaPd, EloPd and SVd for OS, PFS and response outcomes, 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 current treatment practice may be different from DPd or PVd.