The combination of continuous lenalidomide and low-dose dexamethasone extends PFS and trends toward improving OS compared with the standard MPT in patients with transplant-ineligible newly diagnosed multiple myeloma.
Thierry Facon, MD
The combination of continuous lenalidomide and low-dose dexamethasone (continuous Rd) extends progression-free survival (PFS) and trends toward improving overall survival (OS) compared with the standard combination of melphalan, prednisone, and thalidomide (MPT) in patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM). Results from an international phase 3 study comparing the two regimens, known as FIRST (Frontline Investigation of Lenalidomide Plus Dexamethasone Versus Standard Thalidomide), were presented by Thierry Facon, MD, at the 55th Annual Meeting of the American Society of Hematology.
The favorable effect of continuous Rd on clinical outcomes establishes it as “a new standard of care,” said Facon, professor of Hematology, Service des Maladies du Sang, Hôpital Claude Huriez, and CHRU Lille in France. Continuous treatment had typically been reserved for patients who relapsed following 72 weeks of induction therapy, due to toxicities associated with long-term therapy.
Fixed durations of MPT and bortezomib-melphalan-prednisone are preferred regimens for patients with NDMM ineligible for stem cell transplant as recommended by the National Comprehensive Cancer Network, he noted.
In FIRST, 1623 patients who were ≥65 years old or otherwise ineligible for autologous stem cell transplantation were randomized to one of three treatment arms: continuous Rd until disease progression; Rd for 18 28-day cycles (Rd18) for 72 weeks; or MPT for up to 12 42-day cycles for 72 weeks.
The median age of patients enrolled was 73 years; 35% of patients were ≥75 years old, and 41% of patients had International Staging System stage 3 disease.
Of the 535 patients enrolled in the continuous Rd arm, 121 (23%) were still on treatment assignment after a median follow-up of 37 months. “More patients allocated to lenalidomide-containing arms completed 72 weeks of treatment compared with patients allocated to MPT,” Facon said. Two hundred eight patients (39%) in the continuous Rd arm were treated for more than 2 years. Eleven percent withdrew from continuous Rd due to adverse events, compared with 13% randomized to Rd18 and 14% randomized to MPT.
The trial met its primary endpoint, demonstrating a 28% improvement in PFS with continuous Rd compared with MPT (hazard ratio [HR]=0.72; P = .00006). Three-year PFS was 42% in patients randomized to continuous Rd, 23% in those randomized to Rd18, and 23% in those randomized to MPT. “At this time point [3 years], we had an approximate 1-year difference in the PFS curves,” he said.
Median PFS was 25.5 months in the continuous Rd arm, 20.7 months in the Rd18 arm, and 21.2 months in the MPT arm.
A preplanned interim analysis of OS demonstrated a 22% reduction in risk of death in favor of continuous Rd versus MPT (HR=0.78, P = .01685), although the prespecified boundary (P<.0096) was not crossed. Four-year OS rates were 59.4% in the continuous Rd arm, 55.7% in the Rd18 arm, and 51.4% in the MPT arm.
Safety profiles were similar between treatment regimens, but patients treated with continuous Rd showed fewer secondary hematologic malignancies than those treated with MPT, Facon said. Hematologic malignancies occurred in 0.4% of patients assigned to continuous Rd compared with 2.2% assigned to MPT; the overall incidence of solid tumors was identical (2.8%).
Relevant grade 3/4 adverse events in the continuous Rd arm versus the MPT arm were as follows: neutropenia (28% vs 45%), thrombocytopenia (8% vs 11%), febrile neutropenia (1% vs 3%), infection (29% vs 17%), neuropathy (5% vs 15%), and deep vein thrombosis (5% vs 3%).
Facon T, Dimopoulos MA, Dispenzieri A, et al. Initial Phase 3 Results Of The First (Frontline Investigation Of Lenalidomide + Dexamethasone Versus Standard Thalidomide) Trial (MM-020/IFM 07 01) In Newly Diagnosed Multiple Myeloma Patients Ineligible For Stem Cell Transplantation. Presented at: The 55th ASH Annual Meeting; December 7-10, 2013; New Orleans, LA. Abstract 2.