Daratumumab Plus KRd May Be a New SOC Option in NDMM

Daratumumab plus KRd improved MRD-negativity and PFS vs KRd alone in patients with newly diagnosed multiple myeloma.

Adding daratumumab (D; Darzalex) to carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone (KRd) improved efficacy without compromising the known safety profile of all involved agents in the treatment of patients with newly diagnosed multiple myeloma, according to results from the phase 2 ADVANCE trial (NCT04268498) presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting.1

In the intention-to-treat population, the minimal residual disease (MRD) negativity of 10-5 assessed by next-generation sequencing (NGS) was met by 59% of patients in the group that received daratumumab plus KRd (DKRd) and 33% in the group who received KRd alone (OR, 2.9; 95% CI, 1.8-4.9; P <.0001).

When assessed by age, in patients younger than 60 years, the MRD negativity at 10-5 was 66% in the DKRd group vs 49% in the KRd group (P = .00571); in patients who were 60 years or older, the MRD negativity was 68% vs 42%, respectively (P = .00571). In those with high-risk disease, the MRD negativity was 59% with DKRd vs 41% with KRd alone (P = .170); in those with standard-risk disease, MRD negativity was 71% vs 43%, respectively (P = .00375).

At the median follow-up of 31.2 months, the median progression-free survival (PFS) rate was 92% in the DKRd group and 83% in the KRd group (P = .1400). Patients who received DKRd also experienced greater event-free survival (EFS) than those who received KRd alone (P = .0157).

“DKRd should be a new standard for newly diagnosed [patients with multiple myeloma] receiving initial KRd-backbone therapy, independent of transplant eligibility,” wrote presenting study author Carl Ola Landgren, MD, PhD, professor of medicine, chief of the Division of Myeloma in the Department of Medicine, and director of the Sylvester Myeloma Institute at the Miller School of Medicine, University of Miami, during the presentation.

A total of 306 patients with newly diagnosed multiple myeloma were randomly assigned, in a 1:1 ratio, to receive 8 cycles of either DKRd or KRd. Treatment consisted of 1800 mg of subcutaneous daratumumab for cycles 1 and 2 every week, and cycles 3 and 4 every 2 weeks; carfilzomib was given at 20 mg/m2 intravenously on day 1 and56 mg/m2 on days 8 and 15 during cycles 1 and for cycles 2 to 4, 56 mg/m2 on days 1, 8, and 15; lenalidomide was given at 25 mg by mouth on days 1 to 2; and dexamethasone was given at 40 mg intravenously or by mouth on days 1, 8, and 15. Patients then went on to a stem cell transplant.

After transplant, subcutaneous daratumumab was given at 1800 mg every 2 weeks for cycles 5 to 6 and every 4 weeks for cycles 7 to 8. Carfilzomib was given at 56 mg/m2 intravenously on days 1, 8, and 15; lenalidomide at 25 mg by mouth on days 1 to 21, and dexamethasone at 20 mg intravenously or by mouth on days 1, 8, and 15. Risk-adapted consolidation occurred where patients were determined to be MRD-positive or MRD-negative. If they were positive, they received an allogeneic stem cell transplant.

After transplant, patients received maintenance therapy with lenalidomide at 10 mg by mouth on days 1 to 21 until progression. Overall, twenty-four, 28 cycles were conducted.

It was noted that patients received minimal intravenous fluids, with 250 mg of intravenous saline given prior to carfilzomib doses on cycle 1 day 1, cycle 1 day 8, and cycle 1 day 15.

Eligible patients were 18 to 75 years old with newly diagnosed multiple myeloma and an ECOG performance status of 2 or less.

The median age was 60.8 years in the DKRd group and 60.7 years in the KRd group; 55.4% and 52.5% were male, respectively; 42.6% and 55.4% had an ECOG performance status of 0, and 60.8% and 65.5% were not Hispanic or Latino. Additionally, 60.8% and 63.3%, respectively, had International Staging Score stage I disease, and 36.5% and 30.9% had high-risk cytogenetics. The investigators noted that the 2 study arms were well-balanced.

The trial’s primary end point was the overall MRD negativity 10-5 via NGS using the ClonoSEQ assay after 8 cycles of combination therapy. Key secondary end points included PFS, EFS, overall survival, MRD negativity rate in peripheral blood, and safety.

Regarding safety, the most common any-grade adverse events (AEs) in the DKRd and the KRD groups were fatigue (50% vs 41%), diarrhea (45% vs 43%), rash macular-pap (32% vs 31%), insomnia (29% vs 29%), and upper respiratory infection (27% vs 34%); the most common grade 3/4 AEs were neutropenia (10% vs 16%), pneumonia (9% vs 5%), back pain (3% vs 6%), and anemia (6% vs 2%).

The most common serious AEs were pneumonia (9% vs 5%), acute kidney injury (3% vs 1%), pyrexia (2% vs 6%), and febrile neutropenia (2% vs 1%). It was noted that there were 2 deaths on the DKRd arm, both due to sepsis, and 1 death on the KRd arm due to progressive disease.

“The new investigator-initiated ADVANCE 2.0 clinical trial (bispecific BCMAxCD3 monoclonal antibody plus KRd or Rd) will open soon for the enrollment of [patients with newly diagnosed multiple myeloma],” Landgren concluded.

Reference

Landgren CO, Ye C, 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(suppl 16):7503. doi:10.1200/JCO.2025.43.16_suppl.750