Comparative Effectiveness of Ciltacabtagene Autoleucel from the Cartitude-4 Trial Vs Real-World Physician's Choice of Therapy from the Flatiron Registry in Lenalidomide-Refractory Multiple Myeloma - an Updated Overall Survival Analysis
Authors: Touzeau Cyrille , Lipe Brea , Khan Abdullah Mohammad , Dhakal Binod , Nair Sandhya , He Jianming , Mendes João , Lee Seina , Lonardi Carolina , Slaughter Ana , Lendvai Nikoletta , Schecter Jordan M. , Chen Diana , Zhao Man , Yeh Tzu-min , Leleu Xavier , Puig Noemi , Dytfeld Dominik , Zamagni Elena , Weisel Katja C. , Karlin Lionel , Delforge Michel , Corradini Paolo , Mina Roberto , Roeloffzen Wilfried , Sidana Surbhi 
Published: December 2024

Introduction: CARTITUDE-4 is a phase 3 randomized controlled trial (RCT) assessing the efficacy and safety of citacabtagene 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 1-3 prior line(s) of therapy (LOT) that included an immunomodulatory agent (IMiD) and a proteasome inhibitor (PI), and who are refractory to lenalidomide. This updated analysis compares the relative efficacy of cilta-cel from the CARTITUDE-4 study with Real-World Physician's Choice (RWPC) using an external control arm from the Flatiron Health MM cohort registry.
Methods: Data from Jan 2020 until May 2024 were extracted from the Flatiron Health US MM cohort registry of deidentified patient-level electronic health records for patients who matched key eligibility criteria for CARTITUDE-4 (1-3 prior LOT, Eastern Cooperative Oncology Group performance status [ECOG PS] of 0-1, lenalidomide refractory, PI and IMiD exposed, eGFR ≥40 mL/min/1.73 m2, and hemoglobin ≥8 g/dL).
The clinical cut-off for the updated prespecified analysis of CARTITUDE-4 was 1 May 2024, and the index date of Flatiron was restricted to trial enrollment period 2020-2021. As the base case, inverse probability of treatment weighting (IPTW) was used to adjust for unbalanced baseline covariates: PI-refractory status, anti-CD38-refractory status, cytogenetic profile, International Staging System (ISS) stage, time to progression on last regimen, number of prior LOT, years since diagnosis, age, and hemoglobin level; additionally, prior transplant, ECOG PS, race, sex, and MM type were added in the fully adjusted sensitivity analyses. Comparative effectiveness was estimated for progression-free survival (PFS), overall survival (OS) and time to next treatment (TTNT). Sensitivity analyses conducted were multivariate regression, doubly robust method, and first observation vs all observations.
Results: The CARTITUDE-4 cohort consisted of 208 patients in the cilta-cel arm (median follow-up of 34 months) and the Flatiron cohort consisted of 423 patients, corresponding to 667 eligible LOTs (external control arm; median follow-up, 37.6 months). Baseline characteristics were similar between the two cohorts after adjustment. According to National Comprehensive Cancer Network guidelines (NCCN) categorization, the most commonly used regimens in RWPC were NCCN recommended for 1-3 PL len-refractory (42.7%), NCCN 1-3 PL other (10.3%) and NCCN 1-3 PL useful in certain circumstances (19.5%). There is a significant number of regimens used that are not recommended by NCCN (25.6%). Among NCCN recommended for 1-3 PL len-refractory category (N=285), daratumumab, pomalidomide ± dexamethasane (41.1%), daratumumab, bortezomib ± dexamethasone (16.8%) and daratumumab, carfilzomib ± dexamethasone (12.6 %) are the most common regimens. In this updated analysis, cilta-cel demonstrated significant OS benefit, the adjusted HR (95% CI) for cilta-cel vs RWPC was 0.52 (0.36, 0.75); median (95% CI) OS for cilta-cel and RWPC was not reached and 44.81 (33.91, NE) months, respectively. Cilta-cel also improved PFS (adjusted hazard ratio [HR], 0.28 (0.22, 0.36)) vs RWPC; median (95% CI) PFS for cilta-cel was not reached (NR; 34.5−NE) vs 7.43 (6.37, 9.40) months for RWPC. The adjusted HR (95% CI) for cilta-cel vs RWPC was 0.32 (0.25, 0.42) for TTNT; median (95% CI) TTNT for cilta-cel and RWPC was NR (33.7−NE) and 9.33 (6.83, 11.07) months, respectively. Cilta-cel treatment benefit was robust and consistent across all sensitivity analyses including full models.
Conclusions: These results consistently demonstrate a superior clinical benefit for cilta-cel vs RWPC on all measured outcomes. Cilta-cel reduced the risk of progression or death by 72% vs RWPC and reduced the risk of death or moving to the next treatment by 68%. In this update, cilta-cel further demonstrates superior overall survival benefit vs. RWPC, with a reduction of the risk of death by 48%. Results of the full model and sensitivity analyses were consistent with the base case. This data highlight the value of cilta-cel as an effective therapy in PI-exposed, len-refractory MM as early as first relapse.
References: Touzeau C, et.al, EHA Library. Touzeau C. 06/13/2024; 421031; P967