Dara-KRd Boosts MRD Negativity Rates in Newly Diagnosed Multiple Myeloma

Dara-KRd in Newly Diagnosed Multiple

Myeloma | Image Credit: © Motion Pics

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The addition of daratumumab (Darzalex) to carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone (Dara-KRd) improved rates of minimal residual disease (MRD) negativity vs KRd alone in patients with newly diagnosed multiple myeloma, independent of transplant eligibility, according to findings from the phase 2 ADVANCE trial (NCT04268498) presented at the 2025 ASCO Annual Meeting.1

In the intention-to-treat population, MRD negativity at a threshold of 10–5 assessed by next-generation sequencing (NGS) was met by 59% of patients in the group that received Dara-KRd and 33% of those in the group that received KRd alone (odds ratio, 2.9; 95% CI, 1.8-4.9; P < .0001).

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

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

“Dara-KRd should be a new standard for newly diagnosed [patients with multiple myeloma] receiving initial KRd backbone therapy, independent of transplant eligibility,” presenting study author Carl Ola Landgren, MD, PhD, said.

Landgren is a 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 at the University of Miami in Florida.

A total of 306 patients with newly diagnosed multiple myeloma were randomly assigned in a 1:1 ratio to receive 8 cycles of either Dara-KRd or KRd.

For the first 4 cycles, daratumumab was administered subcutaneously at 1800 mg weekly for cycles 1 and 2, and every 2 weeks for cycles 3 and 4.; carfilzomib was given at 20 mg/m2 intravenously (IV) on day 1 and 56 mg/m2 on days 8 and 15 during cycle 1, and at 56 mg/m2 on days 1, 8, and 15 for cycles 2 to 4; lenalidomide was given at 25 mg by mouth on days 1 to 21 of each cycle; and dexamethasone was given at 40 mg IV or by mouth on days 1, 8, and 15 of each cycle. After 4 cycles, patients were tested for MRD. Patients who were transplant eligible and MRD positive after 4 cycles were recommended to undergo autologous stem cell transplant. For patients who were MRD negative after 4 cycles, the protocol default was deferred transplant for patients with collected stem cells.

After stem cell harvest, patients received 4 additional cycles of therapy. Subcutaneous daratumumab was given at 1800 mg every 2 weeks for cycles 5 and 6 and every 4 weeks for cycles 7 and 8. Carfilzomib was given at 56 mg/m2 IV on days 1, 8, and 15 of each cycle; lenalidomide was given at 25 mg by mouth on days 1 to 21 of each cycle; and dexamethasone was administered at 20 mg IV or by mouth on days 1, 8, and 15 of each cycle. During the risk-adapted consolidation portion, patients were deemed MRD positive or MRD negative. MRD-positive patients then underwent allogeneic stem cell transplant. After 4 cycles, transplant-eligible patients underwent transplant.

After completion of the 8 cycles of induction therapy (with or without transplant), patients moved to maintenance therapy with lenalidomide at 10 mg by mouth on days 1 to 21 of each cycle until progression. The study protocol included 2 years of maintenance therapy, after which patients continued with standard-of-care maintenance.

Landgren noted that patients received minimal IV fluids, with 250 mg of IC saline given prior to carfilzomib doses on days 1, 8, and 15 of cycle 1.

Eligible patients were 18 to 75 years old with newly diagnosed multiple myeloma and an ECOG performance status of 0 to 2.

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

The trial’s primary end point was overall MRD negativity rate at 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 Dara-KRd and KRD groups, respectively, were fatigue (50% vs 41%), diarrhea (45% vs 43%), maculopapular rash (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%). Two deaths occurred on the Dara-KRd arm, both due to sepsis. One death occurred on the KRd arm due to progressive disease.

“The new investigator-initiated [phase 2] ADVANCE 2.0 clinical trial [(NCT06997081), which is evaluating a] bispecific BCMAxCD3-directed 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