Randomized, multi-center study of carfilzomib, lenalidomide, and dexamethasone (KRd) with or without daratumumab (D) in patients with newly diagnosed multiple myeloma (NDMM): The ADVANCE clinical trial.

Abstract

7503 Background: The use of modern combination therapy in NDMM patients delivers deep and durable treatment responses independent of transplant status. In the current ADVANCE study (NCT04268498), patients were randomly assigned to receive 8 cycles of carfilzomib-lenalidomide-dexamethasone with or without daratumumab (DKRd vs KRd). Transplants were offered to patients who were minimal residual disease (MRD) positive after 8 cycles. All patients transitioned to lenalidomide maintenance. Primary endpoint was MRD negativity 10^-5 by NGS after up to 8 cycles of combination therapy. Methods: 306 NDMM patients were randomly assigned 1:1 to receive 8 cycles (28-day cycles) of either DKRd 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). Transplant was reserved for MRD-positive patients (post C8). MRD-negative patients transitioned to lenalidomide 10 mg maintenance (D1-21/28). Sustained MRD status was monitored annually. 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. Results: At 2nd prespecified analysis (data cutoff 01/15/25) demographics and disease characteristics were well balanced and included: median age 62 y/o (range: 35-76), Hispanic: 23%, Black: 11%, ISS 2-3: 39%, ECOG PS 2: 6%, and high-risk cytogenetics: 35%. The primary endpoint of MRD negativity at 10^-5 by NGS was significantly higher in the DKRd arm compared to the KRd arm (59% vs 36%, adjusted OR=2.5, 95%CI: 1.5-4.2; P<0.0007). EFS, PFS and OS data are currently immature, however, at 32.7 months median follow-up, PFS events included one death in each arm, PD 4 vs 5%, and 86 vs 79% were progression-free and censored in the DKRd vs KRd arms, respectively. Overall, 98% had an adverse event (AE) with hematologic AEs occurring in 15 vs 24%; cardiac AEs: 13 vs 16%; gastrointestinal AEs: 68 vs 72%; infections: 61 vs 53%; acute kidney injury: 1 vs 4%; vascular disorders: 6 vs 2% with DKRd vs KRd, respectively. Serious AEs occurring in >1% included: febrile neutropenia: 2 vs 2%; pyrexia: 5 vs 2%; chest pain: 0 vs 3%; non-cardiac chest pain: 2 vs 0%; pneumonia: 3 vs 10%; sepsis: 2 vs 0%; COVID-19: 2 vs 0%; wound infection: 2 vs 0%; hip fracture: 2 vs 0%; infusion reaction: 2 vs 0%; back pain: 2 vs 0%; syncope: 2 vs 0%; acute kidney injury: 0 vs 3%; and dyspnea: 2 vs 0%, with DKRd vs KRd, respectively. Conclusions: In this large randomized, multicenter investigator-initiated trial for NDMM, treatment with DKRd (59%) compared to KRd (36%) showed a significant, 2.5-fold higher MRD negativity rate with no new safety concerns. Updated EFS, PFS and OS results will be presented at the meeting. Based on these results, DKRd should be a new standard for most NDMM patients receiving initial KRd-backbone therapy. Clinical trial information: NCT04268498 .

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