Comparative efficacy of ciltacabtagene autoleucel (cilta-cel) versus belantamab mafodotin (belamaf), bortezomib, and dexamethasone and versus belamaf, pomalidomide, and dexamethasone in patients with relapsed / refractory multiple myeloma (RRMM) previously treated with 1–3 prior lines of therapy using a matching-adjusted indirect comparison

Abstract

Abstract Introduction: The CARTITUDE-4 (NCT04181827) trial compared cilta-cel, a chimeric antigen receptor (CAR)-T cell treatment (tx) targeting B-cell maturation antigen (BCMA), with 2 standard-of-care regimens in patients (pts) with RRMM and 1–3 prior lines of therapy (LOT). Cilta-cel significantly improved overall survival (hazard ratio [HR] 0.55) and progression-free survival (PFS; HR 0.29). The DREAMM-7 (NCT04246047) and DREAMM-8 (NCT04484623) trials evaluated belamaf, an anti-BCMA antibody-drug conjugate (ADC), in combination with bortezomib and dexamethasone (BVd) and with pomalidomide and dexamethasone (BPd), respectively. Both trials demonstrated improved survival and response rates with belamaf in pts with ≥1 prior LOT. International Myeloma Working Group (IMWG) guidance for RRMM tx recommends using anti-BCMA T-cell redirecting therapy (TCRT), such as CAR-T (eg, cilta-cel), before anti-BCMA ADCs (eg, belamaf). As cilta-cel and belamaf have not been compared head to head, we conducted unanchored matching-adjusted indirect comparisons (MAICs) to estimate relative efficacies using CARTITUDE-4 study individual patient data (IPD) and published data from DREAMM-7 and DREAMM-8. Methods: Unanchored MAICs were performed using IPD from apheresed pts in the CARTITUDE-4 cilta-cel arm. Eligibility criteriafrom DREAMM-7 and DREAMM-8 were applied to the cilta-cel cohort. Further adjustments were made by weighting cilta-cel IPDto match reported baseline characteristics (including refractory status [for DREAMM-8], cytogenetic risk, International Staging System stage, and presence of extramedullary disease) from DREAMM-7 and DREAMM-8. Outcomes were compared using weighted IPD for cilta-cel and reported response rates and simulated IPD based on published Kaplan–Meier PFS curves for BVd and BPd. For each matched population, we compared PFS, ORR, and very good partial response or better (≥VGPR) and complete response or better (≥CR) rates. A weighted Cox proportional hazards model was used to estimate PFS HRs and 95% CIs. A weighted logistic regression analysis was used to derive relative response ratios (RRs) with 95% CIs to compare relative tx effects. Results: The MAICs included 208 apheresed pts from CARTITUDE-4 (cilta-cel), 243 pts from DREAMM-7 (BVd), and 155 pts from DREAMM-8 (BPd). To form comparable cohorts, we excluded cilta-cel pts who would not have been eligible for DREAMM-7 (n=87) or DREAMM-8 (n=55). Cilta-cel pts were most commonly excluded from the DREAMM-7 MAIC due to bortezomib refractoriness or anti-CD38 refractoriness (n=55 and n=50, respectively), and from the DREAMM-8 MAIC due to bortezomib refractoriness (n=55). After exclusions, 121 and 153 cilta-cel pts remained in the MAICs with BVd and BPd, respectively. After adjustment, cilta-cel was associated with significantly lower risk of progression or death compared with BVd (HR 0.46 [95% CI 0.28–0.75]; P=0.0020) and BPd (HR 0.61 [95% CI 0.39–0.96]; P=0.0320). ORR was significantly higher with cilta-cel vs BVd (92.9% vs 82.7%; RR 1.12 [95% CI 1.03–1.22]; P=0.0087) and vs BPd (89.3% vs 77.4%; RR 1.15 [95% CI 1.04–1.29]; P=0.0100). Rates of ≥VGPR and ≥CR were also higher with cilta-cel vs BVd (≥VGPR: 89.7% vs 65.8%; RR 1.36 [95% CI 1.21–1.53]; ≥CR: 86.0% vs 34.6%; RR 2.49 [95% CI 2.04–3.03]; both P<0.0001) and vs BPd (≥VGPR: 86.6% vs 63.9%; RR 1.36 [95% CI 1.18–1.56]; ≥CR: 81.8% vs 40.0%; RR 2.05 [95% CI 1.65–2.53]; both P<0.0001). Sensitivity analyses were consistent with the adjusted comparisons and showed statistically significant PFS and tx response benefits with cilta-cel vs BVd and BPd. Conclusions: These MAICs demonstrated superior PFS and response rates with cilta-cel compared with 2 belamaf-containing regimens (BVd and BPd). Results should be interpreted with caution as there were substantial differences in the pt populations of CARTITUDE-4 vs DREAMM-7 and DREAMM-8. However, adjusted cilta-cel cohort sizes remained large enough for robust comparisons that showed statistically significant differences across efficacy outcomes. Another limitation is the remaining potential unmeasured residual confounding differences. Nonetheless, these findings support IMWG guidance recommending anti-BCMA TCRTs prior to ADCs and provide valuable comparative evidence in the absence of head-to-head trials.