A new four-drug combination appears to be effective and safe in patients with newly diagnosed multiple myeloma, according to data from the ADVANCE clinical trial conducted by investigators at Sylvester Comprehensive Cancer Center, part of the University of Miami Miller School of Medicine. Presented at the 2025 ASCO Annual Meeting (Abstract 7503), the randomized, multicenter trial tested the effects of adding the targeted drug daratumumab to the standard three-part therapy regimen KRd (carfilzomib, lenalidomide, and dexamethasone).
“This study shows that daratumumab added to KRd is a new standard of care for those patients who had previously been candidates for just KRd,” said Sylvester Myeloma Institute Director and study head C. Ola Landgren, MD, PhD.
From MANHATTAN to ADVANCE
The new clinical trial has its roots in the MANHATTAN trial, a smaller trial also conducted by Dr. Landgren and colleagues. In that trial, patients newly diagnosed with multiple myeloma were also treated with daratumumab added to KRd.
The results of the MANHATTAN trial were “spectacular,” according to Dr. Landgren. Sensitive methods to assess for measurable residual disease (MRD) showed that 71% of patients had no detectable disease after completing their treatment. That trial, however, was a single-arm study in which all 41 patients received daratumumab plus KRd.
The ADVANCE trial goes further by directly comparing KRd with daratumumab plus KRd in a large, multicenter, randomized (1:1) clinical trial in the United States.
Improving Outcomes
Of the 306 patients in the ADVANCE trial, half were randomly assigned to eight 28-day cycles of treatment with KRd and half, to daratumumab plus KRd. After the eight cycles were completed, 59% of the patients given daratumumab plus KRd were MRD-negative compared with 36% of patients given KRd.
The longer-term durability of the response remains an open question. However, the data so far are encouraging: at 32.7 months of follow-up, progression-free survival in patients given daratumumab plus KRd was 86% compared with 79% in patients given KRd.
Dr. Landgren noted that adding daratumumab to KRd did not seem to add any significant toxicities, in part because patients with underlying cardiovascular disease or patients who were frail were excluded from the study. Prior to study enrollment, all patients were screened and cleared by standard labs, a standard clinical exam, and cardiac tests, per the study protocol.
“If you give it to the right patients, in the right way, it is an extremely safe and very effective therapy,” said Dr. Landgren.
The new four-drug combination leverages a range of therapeutic targets and modalities. Carfilzomib inhibits the protein-degrading machinery in cells, and lenalidomide stimulates immune activity against tumors, among other actions. Dexamethasone has effects on immunity and inflammation.
“These three drugs may shrink tumors enough to enable daratumumab to finish the job,” said Dr. Landgren. Daratumumab targets the CD38 protein on multiple myeloma cells and induces tumor cell death.
Tumors from patients in the trial are undergoing detailed molecular scrutiny. Questions include why tumors respond differently to the drug regimens, and why some patients develop resistance to treatment.
A New Standard of Care?
At Sylvester and other cancer centers, patients newly diagnosed with multiple myeloma are already routinely receiving the four-drug combination of daratumumab plus KRd. “It has definitely changed my practice,” said Sylvester physician Dickran Kazandjian, MD, lead co–principal investigator on the ADVANCE study. “Your best shot at getting your best response is with the first treatment.”
The ADVANCE trial also showcases a trend in which an increasing number of patients are forgoing up-front transplantation as a consequence of achieving MRD negativity with modern, effective combination therapy alone. Eligible patients in the study had stem cells collected after four cycles, in the event they might need a transplant after completing treatment. But the patients who achieved MRD-negative status kept their stem cells in a –80°C freezer and deferred their transplant. Instead, they moved straight to lenalidomide maintenance therapy, per the study protocol.
Drs. Landgren and Kazandjian credit the Sylvester clinical trial team for bringing the ADVANCE study to Sylvester locations throughout south Florida. Other institutions involved in the ADVANCE trial are MD Anderson Cancer Center, Memorial Sloan Kettering Cancer Center, Moffitt Cancer Center, Roswell Park Comprehensive Cancer Center, Huntsman Cancer Foundation, and Stony Brook Cancer Center.
Disclosure: This study was funded by the National Institutes of Health, Janssen, and Amgen. For full disclosures of the study authors, visit coi.asco.org.
