New Standard-of-Care Emerges for Multiple Myeloma
Summary
- The ADVANCE clinical trial for newly diagnosed multiple myeloma compares a new four-drug combination treatment (DKRd) with a three-drug treatment (KRd).
- Treatment with DKRd resulted in a high response rate — 59% of patients were minimal residual disease negative, compared to 36% of patients treated with KRd.
- The findings will be presented by Sylvester researcher C. Ola Landgren, the study’s leader, at the meeting of the American Society of Clinical Oncology.
A new four-drug combination is highly effective and safe in patients with newly diagnosed multiple myeloma, according to data that will be presented at the annual meeting of the American Society of Clinical Oncology, held May 30 through June 3 in Chicago.
The data emerged from the ADVANCE clinical trial led by Sylvester Comprehensive Cancer Center, part of the University of Miami Miller School of Medicine.
The randomized, multi-center trial tests the effects of adding the targeted drug daratumumab to the standard three-part therapy regimen, called 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, M.D., Ph.D., who will present the findings.
From MANHATTAN to ADVANCE
The new clinical trial has its roots in the MANHATTAN trial, a smaller trial also led by Dr. Landgren. In that trial, newly diagnosed multiple myeloma patients were also treated with daratumumab added to KRd, a combination called DKRd.
The results of the MANHATTAN trial were “spectacular,” said Dr. Landgren. Sensitive methods to assess for minimal residual disease (MRD) showed that 71% of patients had no detectable disease after completing their treatment. That trial, however, was a single-arm study. All 41 patients received DKRd.
The ADVANCE trial goes further by directly comparing KRd to DKRd in a large, multi-center, randomized (1:1) clinical trial in the U.S. Half of the 306 patients in the ADVANCE trial were randomly assigned to treatment with KRd and half to DKRd.
The new results show that 59% of DKRd-treated patients were MRD-negative after eight cycles of treatment compared with 36% of KRd-treated patients.
Encouraging Long-Term ADVANCE Results
The longer-term durability of the response is an open question. However, the data so far are encouraging: at 32.7 months of follow-up, 86% of patients on DKRd showed progression-free survival, compared to 79% of patients on KRd.
Adding daratumumab to KRd did not add any significant toxicities, added Dr. Landgren, in part because of exclusion of patients with underlying cardiovascular disease or patients who were frail. Prior to study enrollment, all patients were screened and cleared by standard labs, a standard clinical exam and EKG and cardiac ECHO, 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 drug combination leverages a range of therapeutic targets and modalities. Carfilzomib (brand name Kyprolis) inhibits the protein-degrading machinery in cells, and Lenalidomide (Revlimid and other brand names) 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 develop resistance.
A New Standard of Multiple Myeloma Care
Newly diagnosed multiple myeloma patients at Sylvester and other cancer centers are already routinely receiving the four-drug DKRd combination.
“It has definitely changed my practice,” said Sylvester physician Dickran Kazandjian, M.D., professor in the Myeloma Division at the Miller School and lead co-PI on the ADVANCE study. “Your best shot at getting your best response is with the first treatment.”
Dr. Landgren’s research has changed clinical practice before. His studies helped lead to the adoption of carfilzomib as a less toxic substitute for bortezomib.
Dr. Landgren and his team may change clinical practice yet again. They are planning a new multiple myeloma trial that will test several drugs in combination with a bispecific T cell engager, a newer type of immunotherapy 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 case they need a transplant after completing treatment. But the patients who achieved MRD-negative status kept their stem cells in the -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
• Stony Brook Cancer Center
The National Cancer Institute estimates that 36,110 people in 2025 will be newly affected by multiple myeloma, the second most common blood cancer.
Tags: ASCO 2025, blood cancers, cancer research, clinical trials, Dr. C. Ola Landgren, Dr. Dickran Kazandjian, multiple myeloma, Sylvester Comprehensive Cancer Center