One of the current standards of care for older patients with newly diagnosed multiple myeloma (NDMM) who are transplant ineligible is bortezomib, lenalidomide, and dexamethasone (VRd). However, the addition of the anti-CD38 monoclonal antibody isatuximab (ISA) has been shown to significantly reduce the risk of progression or death in this population, according to a study presented at the European Hematology Association (EHA) 2024 Congress.
“We have seen studies showing that younger transplant-eligible patients should receive four drugs for induction and sometimes for consolidation as well. This is now true for elderly patients below the age of 80 years,” said corresponding author Thierry Facon, MD, of Lille University Hospital in France. “This could trigger a new discussion. In the past, we referred to transplant- eligible versus transplant-ineligible, and now a new concept may emerge: quad-eligibility versus quad-ineligibility.”
In the global, prospective, randomized, open- label study IMROZ, Dr. Facon and colleagues analyzed the benefit of ISA-VRd over VRd alone. The study was the first to combine an anti-CD38 monoclonal antibody with VRd for older patients with NDMM who were transplant ineligible. In the study, 446 patients with a median age of 72 years and balanced characteristics were randomized to receive VRd (n=181) and ISA-VRd (n=265). The primary endpoint was progression-free survival (PFS), and key secondary endpoints were complete response (CR) or better, measurable residual disease (MRD)-negative CR, very good partial response or better, and overall survival (OS).
After a median follow-up of five years, ISA-VRd showed superior PFS, OS, and MRD negativity over VRd alone. Median PFS was not reached for ISA-VRd compared to 54 months for the VRd arm. The five-year PFS rates were 63% and 45% for ISA-VRd and VRd, respectively (hazard ratio [HR] = 0.59), representing a 40% reduction in the risk of progression or death. OS rates at five years were 66% for VRd compared to 72% for ISA-VRd (HR=0.77), representing a 22% reduction in the risk of death. MRD negativity in patients with CR in the ISA-VRd arm was 55.5% compared to 41% in the VRd arm; moreover, sustained MRD negativity for more than one year in the ISA-VRd arm was more than double (46.8% vs. 24.3%).
“The addition of isatuximab did not significantly affect safety,” Dr. Facon said. In the ISA-VRd arm, both grade 3 or higher adverse events (AEs) and grade 5 treatment-emergent adverse events were more frequent, but exposure-adjusted incidence rates were similar. Rates of serious AEs and AEs leading to discontinuations were similar between the two arms. Researchers attributed the greater number of AEs to longer exposure to ISA-VRd (53 months vs. 31 months). Both the safety and efficacy demonstrated in this study “will establish ISA-VRd as a new standard of care for elderly patients aged less than 80 years” Dr. Facon said.
Researchers cited the restriction of patient age to younger than 80 years as an appropriate limitation to the study.
“It is more challenging to give four drugs to patients over the age of 80, so we decided to remain on the safe side,” Dr. Facon said.
“ISA-VRd is a very effective regimen, which will delay relapse significantly,” Dr. Facon said. Still, “when prescribing four drugs to elderly patients, practicians must always balance the risk and the benefit. Patients must be managed carefully to achieve the best possible clinical outcome.”
Any conflicts of interest declared by the authors can be found in the original abstract.
Reference
Facon T, Dimopoulos MA, Leleu X, et al. Phase 3 study results of isatuximab, bortezomib, lenalidomide, and dexamethasone (ISA-VRd) versus VRd for transplant-ineligible patients with newly diagnosed multiple myeloma (IMROZ). Abstract S100. Presented at the European Hematology Association (EHA) 2024 Congress; June 15, 2024; Madrid, Spain.