Phase III Trial of Lenalidomide Plus Dexamethasone in Newly Diagnosed Multiple Myeloma Patients Who Are Not Candidates for Stem Cell Transplantation
Study met primary endpoint of significant progression-free survival benefit compared with standard of care
Data from FIRST (Frontline Investigation of REVLIMID + Dexamethasone Versus Standard Thalidomide) (MM-020/IFM 07-01), an open-label phase III randomised study of continuous lenalidomide in combination with dexamethasone in patients newly diagnosed with multiple myeloma, who are not candidates for stem cell transplantation, have been published in the September 4 issue of the New England Journal of Medicine.
Initial findings, including that the trial had met its primary endpoint of progression-free survival (PFS), were reported during the Plenary session at the 55th American Society of Hematology (ASH) Annual Meeting in December 2013.
In the FIRST trial, 1,623 patients from 18 countries either ≥65 or < 65 years of age and ineligible for stem cell transplant were randomised 1:1:1 into three arms: lenalidomide plus low-dose dexamethasone in 28-day cycles until disease progression (continuous Rd); lenalidomide plus low-dose dexamethasone for 72 weeks (18 cycles, Rd18); or melphalan, prednisone and thalidomide in 42-day cycles for 72 weeks (12 cycles, MPT).
The primary endpoint was a comparison of progression-free survival for continuous Rd versus MPT.
The study findings
The findings, as published in the New England Journal of Medicine, demonstrated that at a median follow-up of 37 months among surviving patients, the median PFS was 25.5 months in continous Rd arm, 20.7 months in the arm Rd18 and 21.2 months in the MPT arm. This resulted in a 28% reduction in risk of progression or death for patients treated with continuous Rd compared with those treated with MPT (HR 0.72; p < 0.001) and a 30% reduction compared with Rd18 (HR 0.70; p < 0.001) in the study.
The pre-planned interim analysis of overall survival demonstrated a 22% reduction in risk of death for continuous Rd vs. MPT (HR 0.78; p = 0.02), although the difference did not cross the pre-specified superiority boundary (p < 0.0096). As of the time of the analysis (24 May, 2013), 121 of 535 (23%) patients in the continuous Rd arm were still on therapy.
Additional secondary endpoints showed response rates were also significantly better with continuous Rd (75%) and with Rd18 (73%) than with MPT (62%; p < 0.001 for both comparisons). More patients achieved a very good partial response or better in the continuous Rd (44%) or Rd18 arms (43%) compared with MPT (28%). Complete response rates were 15%, 14% and 9% for continuous Rd, Rd18 and MPT, respectively. Median duration of response was 35.0 months with continuous Rd compared with 22.3 months for MPT (HR 0.63; p < 0.001) and 22.1 months for Rd18 (HR 0.60; p < 0.001). Median time to disease progression was 32.5 months for patients receiving continuous Rd compared with 23.9 months (HR 0.68; p < 0.001) for MPT and 21.9 months (HR 0.62; p < 0.001) for Rd18.
Safety results showed that grade 3/4 adverse events that occurred in at least 8% of patients in the continuous Rd arm, Rd18 arm or MPT arm included neutropaenia (28%, 26%, 45%, respectively), anaemia (18%, 16%, 19%), thrombocytopenia (8%, 8%,11%), febrile neutropenia (1%, 3%, 3%), leukopenia (5%, 6%, 10%), infection (29%, 22%, 17%), pneumonia (8%, 8%, 6%), deep-vein thrombosis and/or pulmonary embolism (8%, 6%, 5%), asthenia (8%, 6%, 6%), fatigue (7%, 9%, 6%), and peripheral sensory neuropathy (1%, < 1%, 9%). Rates of grade 3/4 cardiac disorders for patients in the continuous Rd, Rd18 and MPT arms were 12%, 7% and 9%, respectively. The incidence of invasive second primary malignancies was 3% in patients in continous Rd arm, 6% in patients in Rd18 arm and 5% in those in the arm MPT; the overall incidence of solid tumours was identical in the continuous Rd and MPT arms (3%) and 5% in the Rd18 arm.
The authors concluded: “As compared with MPT, continuous lenalidomide-dexamethasone given until disease progression was associated with a significant improvement in progression-free survival, with an overall survival benefit at the interim analysis, among patients with newly diagnosed multiple myeloma who were ineligible for stem-cell transplantation.”
The study was funded by Intergroupe, Francophone du Myélome and Celgene.
Application for new indication
Based on the results of the FIRST study, the lenalidomide’s manufacturing company Celgene submitted lenalidomide in combination with dexamethasone for the treatment of newly diagnosed multiple myeloma patients with the European Medicines Agency in February 2014 and with the USA Food and Drug Administration in April 2014.
Currently, lenalidomide is approved in combination with dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior therapy in nearly 70 countries, encompassing Europe, the Americas, the Middle-East and Asia, and in combination with dexamethasone for the treatment of patients whose disease has progressed after one therapy in Australia and New Zealand.
Lenalidomide is also approved in the United States, Canada, Switzerland, Australia, New Zealand and several Latin American countries, as well as Malaysia and Israel, for transfusion-dependent anaemia due to low- or intermediate-1-risk MDS associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities and in Europe for the treatment of patients with transfusion-dependent anaemia due to low- or intermediate-1-risk myelodysplastic syndromes associated with an isolated deletion 5q cytogenetic abnormality when other therapeutic options are insufficient or inadequate.
In addition, lenalidomide is approved in the United States for the treatment of patients with mantle cell lymphoma whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib.