A quadruplet regimen comprising an anti-CD38 monoclonal antibody daratumumab plus bortezomib, lenalidomide, and dexamethasone (D-VRd) as first-line treatment resulted in dramatically improved rates of measurable residual disease (MRD) negativity than the same regimen without daratumumab (VRd) in patients with newly diagnosed multiple myeloma (NDMM) who were ineligible or deemed to be unfit for a hematopoietic cell transplant.
The findings, from the CEPHEUS trial and published in Nature Medicine, offer evidence to support upfront treatment with a daratumumab-containing quadruplet in transplant-ineligible patients, researchers say.
“The CEPHEUS trial establishes a benchmark for the fit and intermediate-fit transplant ineligible or deferred patients for front-line therapy,” said Saad Usmani, MD, MBA, the primary author on the trial and chief of the myeloma service at Memorial Sloan Kettering Cancer Center in New York. He said the trial also makes the case that anti-CD38 monoclonal antibody-based induction regimens — followed by maintenance with lenalidomide plus daratumumab or lenalidomide alone — can be employed for the majority of patients with NDMM. He said the findings suggest this can produce better depth of response and progression-free survival (PFS) compared with triplet induction regimen bortezomib-lenalidomide-dexamethasone followed by lenalidomide-based maintenance.
Researchers enrolled 395 patients with transplant-ineligible or transplant-deferred NDMM between December 2018 and October 2019, with about half randomized to receive D-VRd and half to receive VRd.
At a median follow-up of 58.7 months, the overall MRD-negativity rate with a complete response (CR) or better was 60.9% for the D-VRd group compared with 39.4% for the VRd group (odds ratio = 2.37; 95% CI 1.58-3.55; p<0.0001). The treatment effect on these rates was generally consistent across the trial’s prespecified subgroups, including disease stage, ECOG performance status, and age group of below 70 or at least age 70, but was not the case for those at high cytogenetic risk.
Disease progression or death occurred in 63 of the patients receiving D-VRd and 91 of those receiving VRd, and D-VRd improved PFS compared with VRd, with a hazard ratio of 0.57.
Researchers found no adverse effects beyond the previously known risk profiles for the regimens.
The trial excluded patients determined to be frail, and a triplet regimen with daratumumab, lenalidomide, and dexamethasone is still preferred for frail patients, although a quadruplet might be used in certain subsets of frail patients, such as those with high-risk features that make them prone to early relapse, Dr. Usmani said.
Dr. Usmani said that even though transplant-deferred patients were included in the trial, in addition to patients who were transplant-ineligible, they did not account for most of the patients and noted that it was an older population overall.
“Transplant-deferred patients made up about 20% of the population randomized 1:1 to both arms of the study, but the median age of patient population on the study is greater than 70 years,” he said. “This median age is 10-plus years more than the median age reported for ‘transplant-eligible’ trials such as GRIFFIN, PERSEUS, GMMG-HD7, IsKIA” and others, he said.
Because many older patients with NDMM will not receive any subsequent therapy, choosing the right one at the start is crucial, the researchers said.
“The goal of therapy in NDMM is to pick therapies that give patients the best chance of achieving deep responses that translate to better survival outcomes,” Dr. Usmani said. “We always have to do so with safety, tolerability, and patients’ personal goals in mind. It has to be a well-informed care-team decision.”
Any conflicts of interest declared by the authors can be found in the original article.
Reference
Usmani SZ, Facon T, Hungria V, et al. Daratumumab plus bortezomib, lenalidomide and dexamethasone for transplant-ineligible or transplant-deferred newly diagnosed multiple myeloma: the randomized phase 3 CEPHEUS trial [published online ahead of print, 2025 Feb. 5]. Nat Med. doi: 10.1038/s41591-024-03485-7.
