Objectives: CANDOR, a randomized phase 3 study, showed significantly improved progression-free survival (PFS) and overall response rate (ORR) for twice-weekly carfilzomib, dexamethasone, and daratumumab (KdD) at 56 mg/m2 (TW KdD56) vs. carfilzomib and dexamethasone (Kd) in relapsed or refractory multiple myeloma (RRMM), with a 37% risk reduction in disease progression or death. The benefit of once-weekly carfilzomib (K) at 70 mg/m2 for the same triplet, KdD (OW KdD70), in RRMM was shown in the nonrandomized MMY1001 study. We performed robust cross-study comparisons to investigate how TW KdD56 compares with OW KdD70. Material and methods: For alignment, the primary analysis set for this comparison included individual data from CANDOR patients (pts) previously exposed to bortezomib and an immunomodulatory drug and all pts in MMY1001. The propensity score method allowed reliable cross-study comparison, controlling for baseline prespecified covariates such as age, creatinine clearance, performance status, prior treatment exposure/refractoriness, and time from initial diagnosis and relapse. Propensity score adjustment based on inverse probability of treatment weighting (IPTW) was implemented on efficacy endpoints, while safety was evaluated side by side. Results: The unadjusted and adjusted propensity score comparison of CANDOR and MMY1001 showed similar efficacy in terms of ORR and PFS in the TW KdD56 and OW KdD70 groups. Unadjusted ORR was 83.2% (95% confidence interval [CI]: 77.1–88.3) for TW and 81.2% (95% CI: 71.2–88.8) for OW; similarly, adjusted was 79.6% (95% CI: 71.2–87.9) for TW and 81.2% (95% CI: 72.9–89.5) for OW. Median PFS (OW/TW, in months) was not estimable (NE) in each group (unadjusted: NE (18.4-NE) for TW and 25.8 (19.4-NE) for OW; adjusted: NE (12.0-NE) for TW and 25.8 (19.4-NE) for OW). Adjusted hazard ratio for PFS (OW/TW) was 0.80 (95% CI: 0.49–1.32). As propensity score comparisons were for efficacy only, safety comparisons between CANDOR and MMY1001 included differing sample sizes and treatment duration. After a median follow-up of 16.8 and 23.5 months for TW and OW KdD regimens, respectively, treatment-emergent grade ≥3 adverse events (AEs) were reported in 84.3% (156/185) for TW and 82.4% (70/85) for OW. Treatment-emergent AEs leading to K discontinuation were reported by 21.1% (39) for TW and 18.8% (16) for OW. Treatment-emergent fatal AEs were reported in 10.8% (20) for TW and 3.5% (3) for OW. The safety of KdD56 and KdD70 was consistent with the known safety profiles of individual study treatments. Discussion: Similar efficacy in ORR was demonstrated with OW and TW KdD regimens, suggesting optimal control can be achieved through the provision of multiple treatment options. Some differences were observed between OW and TW KdD regimens for treatment-emergent AEs. Conclusion: OW KdD70 is an efficacious dosing option with a favorable benefit-risk profile, comparable with TW KdD56. The OW KdD70 dosing option represents a more convenient regimen that might encourage adherence and potentially lead to better outcomes for RRMM pts. Clinicaltrials.gov: NCT03158688.