Abstract
Introduction: Cytogenetic abnormalities such as del(17p), t(4;14), and gain(1q), among others and particularly when co-occurring, are associated with high-risk disease and inferior outcomes in newly diagnosed multiple myeloma (NDMM). The randomized phase 2 ADVANCE study (NCT04268498) evaluated 8 cycles of carfilzomib, lenalidomide, and dexamethasone with or without daratumumab (DKRd vs. KRd) in NDMM, with minimal residual disease (MRD)-guided transplant and transition to lenalidomide maintenance. The primary endpoint of MRD negativity rate at 10-5 by next-generation sequencing (NGS) was significantly higher in patients receiving DKRd compared to those receiving only KRd (59% vs 33%, adjusted OR=2.9, 95% CI: 1.8-4.9; P<0.0001). Here, we present the pre-planned analysis of MRD negativity by cytogenetic subgroups.
Methods: NDMM patients were randomized 1:1 to receive 8 cycles of KRd with or without daratumumab. Stem cell collection was encouraged after 4 cycles. Following cycle 8, patients were assessed for minimal residual disease (MRD) by NGS (ClonoSEQ, Adaptive Biotechnologies, Seattle) evaluated at a sensitivity of 10-5. MRD-negative patients transitioned directly to lenalidomide maintenance, while MRD-positive patients were offered autologous stem cell transplant followed by lenalidomide maintenance. The primary endpoint was MRD negativity after 8 cycles. Cytogenetics were determined by fluorescence in situ hybridization performed locally. This analysis evaluated MRD response stratified by individual cytogenetic abnormality and treatment arm.
Results: At the second prespecified analysis (data cutoff 01/15/2025), 306 patients were randomized (DKRd n=153; KRd n=153). MRD negativity rates favored DKRd over KRd across multiple cytogenetic subgroups. Among patients with gain(1q), MRD negativity was 65% with DKRd and 41% with KRd, and was 68% vs 43% in patients without gain(1q) (OR 0.97, 95% CI: 0.27-3.49; P=0.959). For patients with t(4;14), MRD negativity was 62% with DKRd and 33% with KRd, and was 67% vs 43% in those without t(4;14) (OR 1.16, 95% CI: 0.08-17.6; P=0.916). In patients with t(11;14), which is not considered a high-risk cytogenetic abnormality, MRD negativity was 59% with DKRd and 20% with KRd, and was 68% vs 49% in those without t(11;14) (OR 2.58, 95% CI: 0.52-12.8; P=0.248). Additional cytogenetic subgroup analyses will be reported at the meeting. While comparisons did not reach statistical significance due to small subgroup sizes, DKRd consistently resulted in higher MRD negativity rates across cytogenetic strata. These data suggest that the addition of daratumumab provides added benefit across cytogenetic groups in NDMM.
Conclusions: In this pre-planned cytogenetic subgroup analysis of the ADVANCE trial, treatment with DKRd improved MRD negativity rates compared to KRd across a range of cytogenetic subgroups in NDMM. These findings suggest that the addition of daratumumab enhances depth of response regardless of underlying cytogenetic risk, supporting its use as a frontline regimen across cytogenetic subgroup populations.
