Adjusted Indirect Treatment Comparison of Progression-Free Survival with D-Rd and VRd Based on MAIA and SWOG S0777 Individual Patient-Level Data.

ABSTRACT

INTRODUCTION: Daratumumab plus lenalidomide and dexamethasone (D-Rd) and bortezomib plus lenalidomide and dexamethasone (VRd) are commonly used treatment combinations for transplant-ineligible (TIE) patients with newly diagnosed multiple myeloma (NDMM). D-Rd and VRd demonstrated superior efficacy relative to lenalidomide and dexamethasone (Rd) in the MAIA and SWOG S0777 trials, respectively, but have not been compared directly in a head-to-head trial. Naïve comparisons of efficacy across the two trials may be biased because MAIA enrolled only TIE patients (median age 73 years), whereas SWOG S0777 enrolled both TIE patients and transplant-eligible patients who chose to defer/refuse frontline stem cell transplantation (median age 63 years). The present study compared progression-free survival (PFS) in TIE patients with NDMM treated with D-Rd versus VRd based on an adjusted indirect treatment comparison (ITC) that leveraged individual patient-level data from MAIA and SWOG S0777. METHODS: Harmonized inclusion/exclusion criteria (including age ≥ 65 years as a proxy for transplant ineligibility) and propensity-score weighting were used to balance the trial populations on measured baseline characteristics. After differences in trial populations were adjusted for, an anchored ITC was performed wherein within-trial PFS hazard ratios (HRs) for D-Rd versus Rd and VRd versus Rd were estimated and used to make indirect inference about PFS for D-Rd versus VRd. RESULTS: PFS HRs were 0.52 (95% confidence interval [CI] 0.41-0.67) for D-Rd versus Rd based on MAIA data, 0.88 (95% CI 0.63-1.23) for VRd versus Rd based on SWOG S0777 data, and 0.59 (95% CI 0.39-0.90) for the Rd-anchored ITC of D-Rd versus VRd. Sensitivity and subgroup analyses produced results consistent with the primary results. CONCLUSION: This anchored ITC demonstrated a greater PFS benefit for D-Rd versus VRd in TIE patients with NDMM. In the absence of head-to-head trials comparing D-Rd and VRd, the present trial may help inform treatment selection in this patient population.

Multiple drug combinations can be used to treat patients with newly diagnosed multiple myeloma (NDMM) who are not eligible for a stem cell transplant. Two of these combinations­daratumumab plus lenalidomide and dexamethasone (D-Rd) and bortezomib plus lenalidomide and dexamethasone (VRd)­have each been studied in clinical trials (MAIA and SWOG S0777) against the combination of lenalidomide plus dexamethasone (Rd), but D-Rd and VRd have not been compared directly in a head-to-head clinical trial. Our study used data from the MAIA and SWOG S0777 trials to indirectly compare outcomes observed with D-Rd and VRd. For this indirect comparison between D-Rd and VRd, we first made adjustments to the patient populations of each trial to make them more similar to each other; this helped to make sure any differences we saw in treatment outcomes between D-Rd and VRd would not be because of differences in the characteristics of the patients who participated in the trials. After we made these adjustments to the patient populations of each trial, both D-Rd and VRd lowered the risk of disease progression or death compared with Rd alone. However, when indirectly compared in our study, D-Rd lowered the risk of disease progression or death by 41% compared with VRd. As data directly comparing treatment outcomes for D-Rd and VRd are not available, this indirect comparison can contribute to the information used to make treatment decisions for patients with NDMM who are not eligible for a stem cell transplant.