Efficacy of Carvykti in Cartitude-4 Versus Alternative Treatments from Daratumumab Clinical Trials for the Treatment of Patients with Lenalidomide-Refractory Multiple Myeloma
Authors: Delforge Michel , Avivi Mazza Irit , Mateos Maria- Victoria , Carlson Kristina , Qi Keqin , Mendes João , Lee Seina , Schecter Jordan M. , Deraedt William , Lonardi Carolina , Slaughter Ana , Chen Diana , Zhao Man , Connors Kaitlyn , Patel Nitin , Florendo Erika , Einsele Hermann , Dhakal Binod , Roeloffzen Wilfried 
Published: December 2024

Background:
In CARTITUDE-4, a phase 3 open-label randomized controlled trial, CARVYKTI (ciltacabtagene autoleucel; cilta-cel), demonstrated superior progression-free survival (PFS) and response rates over physician's choice of daratumumab, pomalidomide and dexamethasone [DPd], or pomalidomide, bortezomib and dexamethasone [PVd].Recently an updated prespecified analysis of CARTITUDE-4 with median follow-up of 34 months demonstrated significant overall survival (OS) benefit of cilta-cel vs physician's choice in patients with relapsed and refractory multiple myeloma (RRMM) who are refractory to lenalidomide and have received 1-3 prior line(s) of therapy (LOTs) including an immunomodulatory agent (IMiD) and a proteasome inhibitor (PI). The objective of this abstract is to evaluate the comparative efficacy of cilta-cel vs. a combined group of alternative treatments pooled from daratumumab clinical trials in this target population.
Methods:
Patient-level data were available for patients from CARTITUDE-4 who received cilta-cel, and from nine daratumumab trials (CASTOR, CANDOR, APOLLO, ALCYONE, MAIA, GRIFFIN, CASSIOPEIA, POLLUX and EQUULEUS) who received active or subsequent treatments with or without daratumumab. Patients from the daratumumab clinical trials had either newly diagnosed MM (NDMM) or RRMM at study enrolment. Patients were included in the comparator cohort if they satisfied the key eligibility criteria of CARTITUDE-4 at enrollment or at a subsequent line of therapy. Inverse probability of treatment weighting was used to adjust for imbalances between cohorts on key patient characteristics. OS, PFS, real-world PFS (RW-PFS), time to next treatment (TTNT), overall response rate (ORR), very good partial response or better rate (≥VGPR), complete response or better rate (≥CR), were assessed. Sensitivity analyses were conducted using different analytical methods and additional patient characteristics.
Results:
The cilta-cel cohort consisted of 208 patients in the CARTITUDE-4 trial and the combined comparator cohort included 800 patients from the daratumumab trials (who fulfilled the key eligibility criteria for CARTITUDE-4). In this combined comparator cohort, the most frequent treatment regimens used were carfilzomib and dexamethasone [Kd], daratumumab with Kd [DKd], pomalidomide and dexamethasone [Pd], and DPd, among others. After adjustment, baseline covariates were similar across the cohorts. In this updated analysis, Cilta-cel demonstrated significant OS benefit, reducing the risk of death by 71% (OS hazard ratio [HR]: 0.29; 95% CI: 0.20-0.41) and showed significant PFS superiority, reducing the risk of disease progression or death by 67% (PFS HR: 0.33; 95% CI: 0.24-0.46) and by 74% (RW-PFS HR: 0.26; 95% CI: 0.19-0.35), whilst reducing the risk of progression, death or next treatment by 74% (TTNT HR: 0.26; 95% CI: 0.19-0.36). Cilta-cel demonstrated improved ORR (odds ratio [OR]: 3.60; 95% CI: 2.26-5.82), ≥VGPR (OR: 8.09; 95% CI: 5.16-12.89), and deep improvement of ≥CR (OR: 20.92; 95% CI: 12.57-36.02) vs. the comparator cohort. All results were statistically significant (p&lt;0.0001) and consistent across sensitivity analyses.
Conclusion:
In this analysis cilta-cel confirmed the superior efficacy compared to alternative treatments from this pooled comparator cohort across all efficacy outcomes, particularly overall survival, highlighting the potential for cilta-cel to be considered a new standard of care option for lenalidomide-refractory RRMM patients, who have received 1-3 prior LOTs, including an IMiD and a PI.