Paper Details

ABSTRACT

Background: The ADVANCE trial (NCT04268498) is a randomized phase 2 study evaluating the addition of the anti-CD38 monoclonal antibody subcutaneous daratumumab (D) to Carfilzomib, Lenalidomide, and Dexamethasone (KRd) in newly diagnosed multiple myeloma (NDMM). A previous analysis reported that the primary endpoint of MRD-negativity at 10^-5 by NGS was significantly higher in the D-KRd arm compared to the KRd arm and no unexpected safety signals were observed (Landgren et al. JCO, 2025). The present analysis reports the updated progression-free survival (PFS) data.

Methods: 288 NDMM patients were randomly assigned 1:1 to receive 8 cycles (28-day cycles) of either D-KRd or KRd (D: 1800 mg SC, days 1, 8, 15, and 22 (C1-2), days 1 and 15 (C3-6), day 1 (C7-8); K: 20/56 mg/m² IV, days 1, 8, and 15; R: 25 mg days 1-21; d: 40/20 mg). Stem cell collection was encouraged after 4 cycles for eligible patients. After completion of cycle 8, patients were evaluated for MRD (ClonoSEQ). Autologous stem cell transplant was offered to MRD-positive patients (post C8). All patients transitioned to lenalidomide 10 mg maintenance (D1-21/28). Key eligibility included NDMM with ECOG PS 0-2 and adequate organ function, independent of transplant status. The study was monitored and approved by an independent data safety monitoring committee. PFS was defined as time from first randomization to progression or death from any cause, whichever occurred first. Time-to-event endpoints were analyzed using the Kaplan-Meier method and compared with the log-rank test. Adjusted hazard ratios and 95% confidence intervals (CI) were estimated in a multivariable Cox proportional-hazards regression model with the treatment as the primary explanatory variable, adjusted for International Staging System disease stage (I versus II versus III) and age.

Results:  The intention-to-treat analysis was comprised of 148 patients in the D-KRd arm and 140 patients in the KRd arm with a median observed follow-up duration of 22.3 months. PFS was analyzed at a prespecified 2-year time point. Two years after randomization, PFS favored D-KRd vs KRd (96% vs 90% 2-year PFS rates; log-rank P=0.023). In a Cox model adjusted for age and stage, the aHR was 0.35 (95% CI, 0.13-0.92; P=0.033). The treatment effect of PFS was generally consistent across the prespecified subgroups. Due to the relatively short follow-up, overall survival data are currently immature, and follow-up is ongoing.

Conclusions: The addition of subcutaneous daratumumab to KRd for 8 cycles of induction therapy, resulted in a significant PFS benefit. The present analysis of the ADVANCE trial supports the MRD negativity benefit reported previously. D-KRd induction represents a new standard of care for most NDMM patients receiving initial KRd-backbone therapy, independent of transplant eligibility.