Efficacy of Carvykti in Cartitude-4 Versus Other Conventional Treatment Regimens for Lenalidomide-Refractory Multiple Myeloma Patients Using Inverse Probability of Treatment Weighting

Introduction: CARTITUDE-4 is a phase 3 randomized controlled trial (RCT) assessing the efficacy and safety of CARVYKTI (ciltacabtagene autoleucel; cilta-cel) versus pomalidomide, bortezomib and dexamethasone (PVd) or daratumumab, pomalidomide and dexamethasone (DPd) in patients with relapsed and refractory multiple myeloma (RRMM) with one to three prior line(s) of therapy that included an immunomodulatory agent (IMiD) and a proteasome inhibitor (PI), and who are refractory to lenalidomide. Based on the latest reported results from CARTITUDE-4, cilta-cel demonstrated superiority over PVd and DPd on progression-free survival (PFS), overall survival (OS) and response rates (overall response rate [ORR], very good partial response [VGPR] or better, and complete response [CR] or better [CR or better]). In 2023, an initial analysis was performed to compare the efficacy outcomes between all apheresed patients from the cilta-cel arm in CARTITUDE-4 vs doublet (Pd and Kd) and daratumumab-based triplet (DKd and DVd) therapy regimens in the same target population using available patient level data. Data from an updated prespecified data-cut of CARTITUDE-4 with median follow-up of 34 months became available, allowing for an updated assessment of the comparative efficacy, including OS, between cilta-cel and these treatment regimens. Methods: Individual patient data were collected from the CARTITUDE-4 (cilta-cel), CASTOR (DVd), CANDOR (DKd and Kd), and APOLLO (Pd) RCTs, from which patients who met CARTITUDE-4 eligibility criteria were identified. As no patients in the comparative trials had prior treatment with anti-CD38, patients with prior exposure to anti-CD38 therapies in the cilta-cel cohort were excluded. Key prognostic baseline covariates including refractory status, ISS stage, presence of extramedullary disease (EMD), and time to progression on prior line, were adjusted for using inverse probability of treatment weighting (IPTW), with average treatment effect in the treated weights. Differences in baseline characteristics were assessed using standardized mean differences. PFS, OS and response rates (ORR, ≥VGPR and ≥CR) were compared between cilta-cel versus the comparator regimens. Relative efficacy for PFS and OS was estimated with Hazard ratios (HRs) and 95% confidence intervals (CIs) using weighted Cox proportional hazards regression. Response endpoints were analyzed using weighted logistic regression estimating response rate ratios (RRs) and 95% CIs. Sensitivity analyses using alternative statistical approaches and including additional covariates were explored. Results: After the exclusion of 53 patients with prior exposure to an anti-CD38 therapy, 155 patients in the cilta-cel arm remained, and were compared to patients treated with DVd (n=44), DKd (n=98), Kd (n=46) and Pd (n=92) who met the CARTITUDE-4 inclusion criteria. Baseline covariates were well balanced across the cohorts after IPTW. Patients from the cilta-cel arm showed significant improvements in PFS versus all comparators, with adjusted HRs ranging from 0.21 vs DVd to 0.58 vs DKd (all p ≤0.01). Also, OS was significantly longer for cilta-cel versus all other regimens, with adjusted HRs ranging between 0.31 vs Pd to 0.55 vs DKd (all p ≤0.05). While comparative estimates for ORR and VGPR did not change versus the previously reported results, the relative benefit for cilta-cel versus other regimens further increased on deeper levels of response, with adjusted RR for ≥CR from 2.71 vs DKd to 31.47 vs Pd (all p≤0.001). Treatment with DKd consistently yielded the best results out of all comparator regimens but results were still significantly in favor of cilta-cel. Results of cilta-cel benefit were generally consistent across sensitivity analyses. Conclusions: Results from this updated analysis confirm the previously observed significant superiority of PFS and response outcomes of cilta-cel, whilst showing significant OS benefit compared to commonly used treatment regimens for this patient population. These findings provide valuable information to support cilta-cel as a highly effective treatment for RRMM patients who received 1-3 prior lines of therapy, including a PI and IMiD, and who are refractory to lenalidomide, particularly in countries where standard of care may be different from DPd/PVd.