DKRd Induction Yields Superior MRD Negativity in NDMM, Regardless of Transplant
In the phase 2 ADVANCE trial (NCT04268498), frontline treatment with daratumumab-carfilzomib-lenalidomide-dexamethasone (DKRd) achieved significantly deeper minimal residual disease (MRD) responses compared to carfilzomib-lenalidomide-dexamethasone (KRd) in patients with newly diagnosed multiple myeloma (NDMM), regardless of transplant intent. The study enrolled 306 patients and was designed to evaluate MRD negativity at 10^⁻⁵ by next-generation sequencing (NGS) after 8 cycles of therapy as its primary endpoint.
Patients were randomized 1:1 to receive eight 28-day cycles of DKRd or KRd. Stem cell collection was recommended following cycle 4, but autologous transplant was reserved only for patients who remained MRD positive after 8 cycles. All patients transitioned to lenalidomide maintenance, with annual MRD assessment to monitor disease status over time. The study population was diverse, with a median age of 62 years (range 35-76), 23% Hispanic, 11% Black, and 35% with high-risk cytogenetics.
The addition of daratumumab yielded a notable improvement in MRD negativity rates: 59% of patients in the DKRd arm achieved MRD negativity at 10^⁻⁵, compared to 36% in the KRd group (adjusted odds ratio = 2.5; 95% CI, 1.5-4.2; P < .0007). These findings indicate a significant deepening of response with the four-drug combination.
While progression-free survival (PFS), event-free survival (EFS), and overall survival (OS) data remain immature at this stage, early trends favor DKRd. At a median follow-up of 32.7 months, progression events were slightly lower in the DKRd group (4% vs 5%), with 86% and 79% of patients progression-free and censored in the DKRd and KRd arms, respectively. Mortality was limited to one patient per arm.
Adverse events (AEs) were common across both treatment arms, with 98% of patients experiencing at least one AE. Hematologic toxicity was lower in the DKRd arm (15% vs 24%), and gastrointestinal events were slightly less frequent (68% vs 72%). However, DKRd was associated with a modest increase in infections (61% vs 53%).
Serious AEs that occurred in more than 1% of patients varied between the groups. Notably, pneumonia (3% vs 10%) and chest pain (0% vs 3%) were more frequent in the KRd group. Conversely, DKRd saw small incidences of events such as syncope, infusion reaction, and wound infection not seen in the KRd cohort. No new safety signals emerged, and toxicity remained within expected ranges.
The substantial improvement in MRD negativity without a corresponding increase in severe toxicity supports DKRd as a more effective frontline regimen for NDMM, regardless of transplant eligibility. These results are likely to influence payer decision-making in favor of broader access to daratumumab in combination regimens during initial therapy.
MRD negativity is increasingly accepted as a surrogate for long-term clinical benefit, and higher MRD rates achieved with DKRd provide compelling evidence for its use as a standard of care. The risk-benefit profile remains favorable, with manageable toxicity and no new safety concerns. Full PFS, EFS, and OS outcomes are pending and will be critical for long-term value assessment and coverage policy refinement.
Reference
Landgren CO, Ye JC, Hillengass J, et al. 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. J Clin Oncol. 2025;43:7503-7503. doi:10.1200/JCO.2025.43.16_suppl.7503
