Daratumumab Combo Yields Significantly Higher MRD Negativity in Multiple Myeloma

C. Ola Landgren, MD, PhD, and Noopur Raje, MD, discussed results from the ADVANCE trial of DKRd in patients with newly diagnosed multiple myeloma.

Results from the phase 2 ADVANCE trial (NCT04268498) assessing carfilzomib (Krypolis), lenalidomide (Revlimid), and dexamethasone with or without daratumumab (Darzalex; DKRd) were shared during the 2025 Lymphoma, Leukemia & Myeloma Congress. The patient population included those with newly diagnosed multiple myeloma.

C. Ola Landgren, MD, PhD, and Noopur Raje, MD, reviewed the results from the study, which revealed significantly higher minimal residual disease (MRD) negativity at 10-5 in the DKRd arm vs the KRd arm. The pair discussed the clinical significance of these results for the multiple myeloma field and their impact on first-line therapy for this patient population.

Landgren is a professor, chief of the Division of Myeloma in the Department of Medicine, director of the Sylvester Myeloma Institute, co-leader of the Translational and Clinical Oncology Program, and Paul J. DiMare Endowed Chair in Immunotherapy at the University of Miami Miller School of Medicine, and an editorial advisory board member of the journal ONCOLOGY. Raje is director of the Center for Multiple Myeloma at Massachusetts General Hospital.

The ADVANCE Trial

The trial enrolled 306 patients who were newly diagnosed with multiple myeloma and randomly assigned them 1:1 to receive 8 cycles of either DKRd (n = 148) or KRd (n = 139). For patients who were eligible, stem cell collection was encouraged after 4 cycles. After the completion of cycle 8, patients were evaluated for MRD. Post cycle 8, if patients were MRD-positive, transplant was recommended. If they were MRD-negative, it was deferred.

The median patient age was 60.8 years vs 60.7 years in the DKRd and KRd arms, respectively. A total of 55.4% vs 52.5% of patients were male, 42.6% vs 55.4% had an ECOG performance status of 0, and 60.8% vs 65.5% were not Hispanic or Latino. Additionally, 60.8% vs 63.3% had International Staging System stage 1 disease, and 36.5% vs 30.9% of patients were high-risk.

In the DKRd arm, 59% of patients were MRD-negative at 10-5 vs 33% in the KRd arm (OR, 2.9; 95% CI, 1.8-4.9; P <.0001). For patients who were high-risk, the MRD negativity in the DKRd arm was 59% vs 41% in the KRd arm (P = .170). Additionally, the rates for those who were standard risk were 71% vs 43% (P = .00375).

“Complete MRD negativity is, in my opinion, the new complete response. We have the tools. We should be using the tools, and we should be trying to get most of our patients into that MRD-negative state. Obviously, you can’t stop at that; you have to maintain that MRD negativity. We’re now talking about sustained MRD negativity, which is going to translate into even better progression-free survival [PFS] and overall survival [results], but MRD seems to be a good surrogate,” Raje said.

At 31.2 months of follow-up, the progression-free survival rate was 92% in the DKRd arm and 83% in the KRd arm (P = .1400). The P value for event-free survival was .0157, with the graph showing a clear benefit for DKRd vs KRd.

Landgren, who presented the ADVANCE results at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting, noted that while PFS was not yet mature, there was a trend for better results. This was substantiated by the fact that MRD negativity tends to be a strong predictor of PFS.

Based on these results, Raje is already using the quadruplet in her clinic at Massachusetts General Hospital for patients who are younger or fitter. In patients who are older or frailer, a quadruplet therapy is still used, but this includes daratumumab, lenalidomide, bortezomib, and dexamethasone, and it tends to be better tolerated.

Landgren agreed that DKRd is typically given to the same population, but based on the results from the ADVANCE trial, this should be applicable across the board.

“For younger, fitter patients, which is a very high proportion of the patients we see…. We would give DKRd to those patients, and it would be supported by the current NCCN guideline, if you claim that this is a high-risk disease population. The ADVANCE trial shows that this should be widely applicable across the board. I expect that the guideline will hopefully be updated to reflect this big, randomized trial,” Landgren said.

Raje also pointed to other trials like the phase 3 IMROZ (NCT03319667) and PERSEUS (NCT03710603) studies, which used bortezomib twice a week, when in the real world it was about once a week. She highlighted that the ADVANCE trial used carfilzomib once a week, which is what clinics are doing, and is much better tolerated. She also pointed out that the dosing schedule is a lot easier for patients to accommodate once a week rather than multiple times a week.

Safety Analysis

The safety profile remained consistent with previously reported data in the space. Serious adverse effects (AEs) included pneumonia (9% vs 5%), acute kidney injury (3% vs 1%), chest pain (2% vs 0%), febrile neutropenia (2% vs 1%), pyrexia (2% vs 6%), and embolism (2% vs 0%), between the DKRd and KRd arms, respectively. Two patients in the DKRd arm died from sepsis, and 1 patient in the KRd arm died from progressive disease.

Raje, who has had much experience with each drug in the quadruplet regimen, feels confident in how to manage AEs when they arise. She noted that with carfilzomib, there may be a slightly higher clot risk. Additionally, at her practice, carfilzomib is given slowly over 30 minutes, which helps to offset potential AEs. She also tries to reduce the amount of dexamethasone that’s given, which may be the reason for fewer events related to thrombosis.

Before enrollment on the trial, each patient was tested with an echocardiogram and an EKG. If they did have cardiovascular disease or events, they were not given a carfilzomib-based regimen. Intravenous fluid was also minimized.

“Daratumumab is one of the easiest drugs to give subcutaneously. It has been a game-changer, to be honest. There is a slightly increased risk of infection and a slightly increased risk of immunosuppression when you add daratumumab. We’ve been using it for so many years and have gotten accustomed to using it. With the DKRd regimen, the one thing we do see is more immunosuppression in the way of decreased immunoglobulins intermittently in patients who have repeated infections. Those are the ones whom I would consider using intravenous immunoglobulin [IVIG] for in this situation,” Raje said.

Landgren noted that using IVIG is a topic everyone has been discussing in 2025. In multiple myeloma, when bispecific antibodies are being used, most patients will experience hypogammaglobulinemia. Daratumumab was designed to kill abnormal plasma cells, but sometimes it kills the normal ones too, and it would not let his patients drop under 200 immunoglobulin G levels.

Moving Towards the Future

To close up the discussion, Landgren asked Raje where she believed the field was headed in 2026 and beyond. Raje noted that whatever tends to work in the relapsed/refractory setting will also work in the first-line. In the first-line setting, trials are underway, utilizing bispecific antibodies or CAR T-cell therapies, which may lead the autologous stem cell transplant window to shrink over time.

MRD as an end point is also being investigated, including how to use sustained MRD as a surrogate end point for PFS and overall survival. Raje noted that a prevalent discussion will be how to combine all of these.

“In the ADVANCE trial, is treatment forever? The biggest unmet need in multiple myeloma is: can we stop treatment? In my opinion, the first [patients] that we can stop treatment for are going to be standard risk patients. That’s the future. I’m very excited about all the immunotherapies, and I do think they’re going to be used up front,” Raje concluded.

For Landgren, the future of multiple myeloma will include more immunotherapies, small molecules, and chemotherapy-free regimens that will sustain MRD negativity and move towards a cure.

Reference

Landgren CO, Ye JC, Hillengrass 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.7503