Daratumumab Plus Bortezomib, Lenalidomide, and Dexamethasone (VRd) Outperforms VRd Alone for Multiple Myeloma
First head-to-head comparison supports adding daratumumab to standard frontline regimen
LBA 1: Phase 3 Randomized Study of Daratumumab (DARA) + Bortezomib, Lenalidomide, and Dexamethasone (VRd) Versus Vrd Alone in Patients (Pts) with Newly Diagnosed Multiple Myeloma (NDMM) Who Are Eligible for Autologous Stem Cell Transplantation (ASCT): Primary Results of the Perseus Trial
(SAN DIEGO, Dec. 12, 2023) – Patients with newly diagnosed multiple myeloma (MM) who received daratumumab along with the standard care regimen of bortezomib, lenalidomide, and dexamethasone (VRd) showed significantly higher rates of survival without disease progression compared with those who received standard care alone in a phase III trial being reported during the 65th American Society of Hematology (ASH) Annual Meeting and Exposition.
At a median follow up of 47.5 months the estimated rate of progression-free survival (PFS), the trial’s primary endpoint, was significantly improved with D-VRd versus VRd. Patients who received daratumumab plus VRd (D-VRd) had an estimated four-year PFS rate of 84.3% compared with 67.7% among those receiving VRd alone, a difference of about 17%.
Multiple myeloma is a blood cancer that forms in a type of white blood cell called plasma cells, and affects the bone marrow. It is most common in older adults and about 40% of patients die within five years of their diagnosis. Relapses are common after initial treatment, underscoring the need for improved therapies.
“We were not surprised to see the difference with the addition of daratumumab, but we were very surprised by the magnitude of the difference between the two arms,” said Pieter Sonneveld, MD, PhD, professor of hematology at Erasmus MC Cancer Institute in Rotterdam, the Netherlands, the study’s lead author. “This difference is of major clinical significance to the patient in terms of their well-being and [remaining] disease-free.”
Daratumumab is a monoclonal antibody targeting a protein that is overexpressed in MM cells. It has previously been approved for use in patients who are ineligible for stem cell transplant or for cancers that relapse or do not respond to standard initial therapies. The new phase III trial is the first to test its use as part of frontline therapy for newly diagnosed MM in a head-to-head comparison with the current standard of care.
For the trial, researchers enrolled 709 patients newly diagnosed with MM across multiple European countries who were considered eligible for autologous stem cell transplantation, which is part of the standard treatment for MM. Patients received up to six cycles of VRd induction therapy in 28-day cycles, proceeded to a stem cell transplant if possible, and continued taking lenalidomide afterward as maintenance therapy. Patients who were randomized to receive D-VRd also received daratumumab via subcutaneous injections during both the induction and maintenance phases. Researchers noted that elements of the trial design, including the use of subcutaneous injections rather than daratumumab infusions and the administration of treatment in 28-day cycles rather than 21-day cycles, were intended to make the regimen gentler on patients and reduce the likelihood of adverse effects.
At the time of data cutoff, 613 participants had completed the induction/consolidation phase of treatment and patients had been followed for a median of just under four years. PFS was significantly higher in the D-VRd arm and subgroup analyses showed that this was consistent across all groups including those with more advanced and higher-risk forms of MM.
Of patients who received the D-VRd regimen, 87.9% saw a complete response or better, meaning that cancer was not detectable after the treatment, compared with 70.1% among those who received standard care. Patients in the D-VRd arm also had a significantly higher rate of minimal residual disease (MRD) negativity, another marker indicating the cancer has been eradicated, which was achieved in 75.2% of patients receiving D-VRd and 47.5% of those receiving VRd alone. The amount of follow-up time is not yet sufficient to compare trends in overall survival rates.
The rate of serious treatment-related adverse events was higher in the D-VRd arm with 57% of patients who received daratumumab experiencing such events compared with 49.3% among those receiving VRd alone. However, researchers noted that adverse events led to treatment discontinuation significantly less often in the D-VRd arm, and most adverse events were short term and temporary. The most common adverse events of grade three or higher were low white blood cell counts, low platelet counts, diarrhea, pneumonia, and fever.
Taken together, Dr. Sonneveld said that the results suggest that D-VRd outperforms VRd alone for frontline MM treatment with a manageable safety profile.
“With these results, [I expect] this treatment schedule will be the future standard for these patients,” he said.
A follow-on analysis will examine the longer-term outcomes of stopping daratumumab after two years of maintenance therapy in patients who achieve MRD negativity.
The study was funded by the European Myeloma Network with support from Janssen Pharmaceuticals.
Pieter Sonneveld, MD, PhD, of Erasmus MC Cancer Institute, will discuss this study in the Late-Breaking Abstracts Session on Tuesday, Dec. 12, 2023, at 9:00 a.m. Pacific time in Hall A (San Diego Convention Center).
The American Society of Hematology (ASH) (hematology.org) is the world’s largest professional society of hematologists dedicated to furthering the understanding, diagnosis, treatment, and prevention of disorders affecting the blood. For more than 60 years, the Society has led the development of hematology as a discipline by promoting research, patient care, education, training, and advocacy in hematology.
ASH’s flagship journal, Blood (bloodjournal.org) is the most cited peer-reviewed publication in the field, and Blood Advances (bloodadvances.org) is an open-access, online journal that publishes more peer-reviewed hematology research than any other academic journal worldwide. Two new journals will be joining the Blood Journals portfolio in 2024, Blood Neoplasia (bloodneoplasia.org) and Blood Vessels, Thrombosis & Hemostasis (bloodvth.org).