Real-World Efficacy Outcomes of Ciltacabtagene Autoleucel in Relapsed Refractory Multiple Myeloma: A Comparative Study with the Cartitude-1 Trial

Introduction: The CARTITUDE-1 (C-1) trial, a Phase Ib/II global single-arm pivotal trial, resulted in the approval of ciltacabtagene autoleucel (cilta-cel), a BCMA-directed CAR-T cell therapy, in 2022 for patients with relapsed refractory multiple myeloma (RRMM) who had progressed after at least 4 lines of therapy. The inclusion criteria for C-1 may not fully represent the real-world (RW) patient (pt) population. This study highlights a RW cohort of pts who may not have met the C-1 trial's eligibility criteria, to evaluate the effectiveness of cilta-cel in RRMM and compare the outcomes with those of the C-1 trial. Method: This multi-center retrospective study from 5 centers included 73 RW pts who had received cilta-cel. The International Myeloma Working Group (IMWG) criteria was used to assess the responses. ORR was defined as at least ≥ PR as best response. Baseline characteristics, ORR, DOR, progression-free survival (PFS), and overall survival (OS) were evaluated and compared to the C-1 population to identify any statistically significant differences. Individual pt data was estimated from the C1 publication (Martin T et al. J Clin Oncol. doi:10.1200/JCO.22.00842) and compared with RW using the Kaplan-Meier method with a regression model for survival analysis. Group comparisons were performed using the Wilcoxon rank sum test and Pearson's Chi-squared test. Results: In the RW cohort, there were 73 pts, while there were 97 pts in C-1. The median age in the RW cohort was 65.5 years, with the majority being white (78%) and male (52%). Thirty-three percent of patients had R-ISS III, 29% had extramedullary disease (EMD), 15% had del 17p, 6.8% had t (4;14) and 2.7% had t (14:16). The majority of patients were refractory to lenalidomide (74%), pomalidomide (74%), carfilzomib (63%), anti-CD38 monoclonal antibody (88%). Additionally, 47% of patients were refractory to bortezomib, and 14% had prior BCMA exposure. The median LOT was 5 (4-12), and 79% had prior stem cell transplants. RW baseline demographics, such as age, ethnic minorities, gender, prior therapies, disease characteristics including high-risk cytogenetics were broadly similar compared to the C-1 population. Notably, in the RW cohort, fewer patients had ECOG 0 (16% vs 40%, p=0.0006), and more patients had EMD compared to C-1 (29% vs 13%, p = 0.02). Furthermore, fewer RW pts were refractory to bortezomib (47% vs 68% p=0.007) and anti-CD38 monoclonal antibody (88% vs 97%, p = 0.03). In the RW cohort, 37% of patients did not meet the inclusion criteria for C-1. Reasons for not meeting C-1 inclusion criteria were as follows: ejection fraction (EF) < 45% (n=1, 1.4%), Creatinine clearance < 45ml/min (n=4, 5.5%), and fewer than three lines of therapy (n=11,15%). Nine pts9 (13.5%) patients had ECOG ≥2. Additionally, 10 (14%) patients had previous BCMA exposure, 1 (1.4%) patient had co-existing plasma cell leukemia, and 1 (1.4%) patient had co-existing amyloidosis. The median follow-up for the real-world (RW) cohort was 11.67 months (4.9 -16.6). Rates of stringent complete responses (sCR) were lower in RW compared to C-1 cohort (30% vs 67%, p<0.0001), while complete response (CR) rates were higher (30% vs 0%, p<0.001). Partial response (PR) was higher (14% vs 4%, p=0.034) while very good partial response (VGPR) was similar in RW (14% vs 26%, p=0.1). Best response as ≥VGPR was lower in the RW cohort compared to C-1 (74% vs 93%, p<0.0001). Disease progression as best response was higher in RW (7.8% vs 1%, p=0.038), and the ORR in RW was lower (88% vs 97%, p=0.015) The 2-year PFS and OS for the RW cohort compared to the 2-year outcomes in C-1 were similar (PFS: 58% in RW vs 62% in C-1, p=0.98, and OS: 72% vs 74%, p=0.9). Conclusions: A significant proportion of RW patients did not meet the criteria for enrollment in the C-1 trial. Although the overall response rate was lower in the real-world setting, the progression-free survival and overall survival outcomes were similar, indicating comparable efficacy. These findings suggest that despite a higher percentage of patients with more significant comorbidities, lower performance status, and more advanced disease in the real-world compared to the C-1 trial, cilta-cel in real world setting demonstrates similar effectiveness to CARTITUDE-1 in the treatment of relapsed or refractory multiple myeloma.