Comparative Efficacy and Safety of Daratumumab in Combination with Bortezomib, Melphalan, and Prednisone (D-VMP) in Alcyone Versus Bortezomib, Melphalan, and Prednisone (VMP) in Vista in Newly Diagnosed Multiple Myeloma (NDMM) Patients Using Propensity Score Matching (PSM)

Introduction: VMP is a standard of care regimen for transplant-ineligible NDMM outside of the United States. The VISTA trial established the dosing schedule of bortezomib (V) in VMP to be administered IV twice weekly for four 6-week cycles, and then once weekly for five 6-week cycles (San-Miguel J, et al. N Engl J Med 2008. 359:906-917). To mitigate V-associated side effects (such as peripheral neuropathy) resulting from this intensive dosing schedule, subsequent trials utilized modified dosing schedules that reduced V-associated toxicity without sacrificing efficacy. Propensity score matching (PSM), which controls for differences in baseline covariates, have previously been used to compare outcomes for patients (pts) treated with modified VMP dosing schedules in previous trials and provided evidence of benefit for a lower-intensity V regimen vs VISTA VMP (Mateos MV, et al. Ann Hematol 2016. 95[12]:2033-2041). The phase 3 ALCYONE study of D-VMP vs VMP using a modified V dosing schedule in both arms significantly improved progression-free survival (PFS; HR 0.50 [95% CI, 0.38-0.65], P <0.001) and overall response rate (ORR; P <0.001) with D-VMP in transplant-ineligible pts with NDMM (Mateos MV, et al. N Engl J Med 2018. 378:518-528). To compare efficacy and safety of D-VMP in ALCYONE vs VISTA VMP, a PSM analysis was conducted with comparable follow-up (16.5 months for ALCYONE vs 16.3 months for VISTA).

Methods: This PSM analysis compared the D-VMP arm of ALCYONE vs the VMP arm of VISTA. In ALCYONE, pts in the D-VMP arm received up to nine 6-week cycles of VMP (V 1.3 mg/m² SC twice weekly [Cycle 1] and then weekly [Cycles 2-9]; M 9 mg/m² PO during Days 1-4 [Cycles 1-9]; P 60 mg/m² PO during Days 1-4 [Cycles 1-9]) and D 16 mg/kg IV QW for Cycle 1, Q3W for Cycles 2-9, and Q4W for Cycles 10+ (post VMP-treatment phase). In VISTA, pts in the VMP arm received up to nine 6-week cycles of VMP (V 1.3 mg/m² by IV twice weekly [Cycles 1-4] and then weekly [Cycles 5-9]; M 9 mg/m² PO on Days 1-4 [Cycles 1-9]; and P 60 mg/m² PO on Days 1-4 [Cycles 1-9]). Age, gender, renal function, International Staging System (ISS), type of MM (IgG, non-IgG), and ECOG performance score (converted from Karnofsky Performance Scores in VISTA) were identified as variables for matching.

Propensity scores were estimated by logistic regression, in which the treatment group was regressed on matching variables. Data from the two groups (ALCYONE D-VMP and VISTA VMP) were matched on the logit of the propensity score. A greedy algorithm was used, in which once a match was made, the match was not reconsidered. The standardized difference was determined to assess the similarity of baseline covariates between treatment groups before and after matching. Differences between groups were compared using log-rank tests for PFS and time to progression (TTP). ORR and adverse event rates were analyzed on the basis of Cochran-Mantel-Haenszel Chi-square test.

As disease progression for VISTA VMP was originally based on the EBMT criteria, PFS for VISTA VMP was re-defined based on IMWG criteria to allow for comparison with D-VMP.

Results: A total of 350 D-VMP pts in ALCYONE and 344 VMP pts in VISTA were randomized in their respective studies. Pts were matched (281 pairs) on renal function, ISS, type of MM, and ECOG performance scores. After matching, systematic differences between the 2 treatment groups were substantially reduced or eliminated.

After matching, median PFS for D-VMP was not reached (NR) vs 20.6 months for VISTA VMP, leading to an unadjusted HR of 0.52 (95% CI, 0.38-0.71; P <0.0001; Figure); the adjusted PFS HR was 0.50 (95% CI, 0.36-0.68; P <0.0001). Median TTP was NR vs 21.7 months (unadjusted HR, 0.43; 95% CI, 0.30-0.63; P <0.0001; adjusted HR, 0.42; 95% CI, 0.29-0.61; P <0.0001). Matched ORR was 90.8% for D-VMP vs 74.5% for VISTA VMP (P <0.0001). Rate of peripheral sensory neuropathy was significantly lower with D-VMP vs VISTA VMP (27.8% vs 44.5%; P <0.0001), in part due to the modified V dosing schedule and use of SC vs IV V (Moreau P, et al. Lancet Oncol 2011. 12:431-440).

Conclusions: This PSM analysis demonstrates that ALCYONE D-VMP significantly improves efficacy compared to VISTA VMP. As reflected in the HRs, the improvement of efficacy is similar as seen within the ALCYONE study comparing D-VMP vs VMP using a modified V dosing schedule in both arms. In addition, this analysis also shows that D-VMP is associated with a lower incidence of peripheral sensory neuropathy compared to VISTA VMP.

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