Three phase III, double-blind, multicenter, randomized studies showed that lenalidomide (Revlimid) maintenance therapy for patients with multiple myeloma significantly improved progression-free survival or time to progression, the primary endpoints of the studies published in The New England Journal of Medicine.1-3
Newly Diagnosed Disease
Among newly diagnosed patients aged 65 years or older, melphalan, prednisone, and lenalidomide induction followed by lenalidomide maintenance (MPR-R) “significantly prolonged progression-free survival in patients with newly diagnosed multiple myeloma who were ineligible for transplantation, with the greatest benefit observed in patients 65 to 75 years of age.” These results reported by Antonio Palumbo, MD, of the University of Turin, Italy, and colleagues were culled from 82 centers in Europe, Australia, and Israel.1 The study was funded by Celgene.
Progression-free survival was significantly longer among the 152 patients receiving MPR-R (31 months) than among the 153 patients receiving melphalan, prednisone, and lenalidomide (MPR) or the 154 patients receiving melphalan plus prednisone (MP) followed by placebo MPR (14 months). Response rates were superior with MPR-R (77%) and MPR (68%) compared with MP (50%).
“In the present study, the major influence on progression-free survival was associated with lenalidomide maintenance therapy,” the researchers wrote. “A landmark analysis showed that lenalidomide maintenance reduced the rate of progression among all patients, regardless of age, by 66% as compared with placebo,” the authors reported. The median follow-up was 30 months. “Longer follow-up is required to evaluate an overall survival benefit,” the authors stated.
The most frequent adverse events during induction therapy were hematologic, with grade 4 neutropenia reported by 35% of the patients in the MPR-R group, 32% in the MPR group, and 8% in the MP group. The 3-year rate of second primary tumors was 7% with MPR-R and MPR and 3% with MP.
After Stem Cell Transplant
In two of the studies, lenalidomide was administered after autologous stem cell transplantation. Patients who began receiving lenalidomide maintenance therapy at day 100 after hematopoietic stem cell transplantation had significantly longer time to disease progression and significantly improved overall survival than those receiving placebo, but more toxicity and second cancers, according to a study reported by Philip L. McCarthy, MD, of Roswell Park Cancer Institute, Buffalo, New York, and other investigators.2 The study was conducted at multiple U.S. sites and funded by NCI.
More grade 3 or 4 hematologic adverse events and grade 3 nonhematologic events occurred in patients who received lenalidomide (P < .001 for both comparisons), the researchers reported. “Second primary cancers occurred in 18 patients who received lenalidomide (8%) and 6 patients who received placebo (3%).”
The 460 study participants were younger than 71 years of age and had stable disease or a marginal, partial, or complete response after stem-cell transplantation. After a median follow-up of 18 months, 44% of the patients in the placebo group had progressive disease or had died, compared to 20% in the lenalidomide group.
“The increase in time to progression led to early study unblinding, and despite the crossover, benefits with respect to progression and overall survival were seen in patients receiving lenalidomide maintenance therapy, especially those who had received lenalidomide-based induction therapy,” the authors reported.
The authors noted that the study reported by Attal et al (see below) did not show an overall survival benefit, which could be due to differences in induction and consolidation before transplantation, the use of lenalidomide consolidation in both groups after transplant, the use of two transplants in some patients, and the discontinuation of maintenance therapy.
Second Post-transplant Study
In the study by Michel Attal, MD, of the Hopital Purpan, Toulouse, and other investigators,3 lenalidomide maintenance after transplantation significantly prolonged progression-free and event-free survival compared to placebo, but 4 years after randomization, overall survival was similar in the two study groups.
“Our study was not designed to show an overall survival advantage, and the number of deaths is still low (25% rate of death),” the investigators noted. “The probability of surviving 4 years after randomization was high for both groups. This result might be related to the intensive strategy we used (reinforced induction, a second transplantation in patients who did not have a complete or very good partial response after the first transplantation, and consolidation) and to the activity of new agents that were used to treat relapses…. A longer follow-up is still required to assess the role of lenalidomide maintenance on overall survival.”
The French study, funded by the Programme Hospitalier de Recherche Clinique and others, involved 614 patients under age 65 with nonprogressive disease after first-line transplantation. Lenalidomide maintenance therapy improved median progression-free survival to 41 months vs 23 months with placebo. This benefit was seen across all subgroups.
“The incidence of second primary cancers was 3.1 per 100 patient-years in the lenalidomide group vs 1.2 per 100 patient-years in the placebo group (P = .002),” the authors noted. Median event-free survival was significantly improved with lenalidomide (40 vs 23 months; P < .001). Grade 3/4 peripheral neuropathy rates were similar in the two groups.
“Together with the findings reported by McCarthy et al, our data support the use of lenalidomide maintenance therapy after high-dose chemotherapy and autologous hematopoietic stem-cell transplantation in patients with myeloma, but the impressive benefits must be weighed against the increased risks,” the authors concluded.
Critical Questions
“These studies provide compelling evidence of improvement in progression-free survival; however, the results raise several critical questions,” according to an editorial accompanying the articles.4 These questions concern whether progression-free survival is the appropriate primary endpoint in maintenance if it doesn’t result in improved overall survival; whether lenalidomide maintenance therapy is safe, considering the adverse side effects and incidence of second cancers of 4%; and the cost, which can exceed $160,000 per year.
The editorial by Ashraf Z. Badros, MB, ChB, of the University of Maryland School of Medicine, Baltimore, also points out that pomalidomide and bortezomib (Velcade) are currently being tested in trials of maintenance therapy and both appear to have efficacy in the setting of resistance to lenalidomide. “As myeloma evolves from an ‘incurable’ cancer to a chronic disease, physicians are faced with the task of maximizing available treatments not only to improve survival but also to maintain their patients’ quality of life,” Dr. Badros said. ■
Disclosure: Dr. Palumbo has received honoraria for board membership, consultancy, and speakers bureau activities from Celgene and Janssen Cilag. Dr. McCarthy has received honoria for consultancy and speakers bureau activities from Celgene and Onyx. Dr. Attal has received grants from Celgene and serves on advisory boards for Celgene and Janssen. Dr. Badros has received research grants from Pfizer, AOI, Onyx, Bristol-Myers Squibb, BioInvent, Geron, and Lilly.
References
1. Palumbo A, Hajek R, Delforge M, et al: Continuous lenalidomide treatment for newly diagnosed multiple myeloma. N Engl J Med 366:1759-1769, 2012.
2. McCarthy PL, Kouros O, Hofmeister CC, et al: Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med 366:1770-1781, 2012.
3. Attal M, Lauwers-Cances V, Marit G, et al: Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. N Engl J Med 366:1782-1791, 2012.
4. Badros AZ: Lenalidomide in myeloma. N Engl J Med 366:1836-1838, 2012.
