NEW YORK (Reuters Health) – Lenalidomide maintenance therapy can significantly extend the time to progression and progression-free survival in patients with multiple myeloma, according to three double-blind studies in the May 10 New England Journal of Medicine.
In each test, the results were so dramatic, the researchers prematurely revealed the drug assignments.
But only in one study did the drug extend overall survival. In addition, lenalidomide alone costs $163,381 per year for the typical patient who is taking it to keep myeloma from reappearing. The studies did not look to see if the quality of life was better for patients taking the drug.
“Whether these data establish a new standard of care for myeloma may be debatable,” Dr. Ashraf Badros of the University of Maryland School of Medicine said in a Journal editorial. Other drugs are being tested as maintenance therapy “as myeloma evolves from an ‘incurable’ cancer to a chronic disease.”
Lenalidomide, sold under the brand name Revlimid by New Jersey-based Celgene Corp, is derived from thalidomide, notorious for causing birth defects.
The first study compared three treatments: conventional therapy with melphalan and prednisone followed by placebo; a combination of melphalan, prednisone and lenalidomide followed by placebo; and the three-drug combination with lenalidomide maintenance. None of the 459 patients, all age 65 and older, were eligible for stem cell transplantation. Celgene paid for the study.
With lenalidomide maintenance, median progression-free survival was 31 months versus 14 months in the group where lenalidomide wasn’t used as maintenance therapy (P<0.0001) and 13 months in the group that got no lenalidomide at all.
The maintenance treatment only improved progression-free survival in volunteers age 65 to 75 (P=0.001), not in older patients. Grade 4 neutropenia appeared in at least 32% of patients receiving lenalidomide vs 8% of those just getting melphalan-prednisone.
Although the study, led by Dr. Antonio Palumbo of the University of Turin in Italy, was not designed to assess overall survival, the researchers looked at it anyway. The three-year overall survival rate was 70% with maintenance therapy, 66% with just melphalan and prednisone, and 62% with the melphalan-prednisone-lenalidomide combination.
The other two studies were done in patients who had received a stem cell transplant.
In one, Dr. Philip McCarthy of the Roswell Park Cancer Institute in Buffalo, New York, and his colleagues found that 20% of the 231 who received lenalidomide died or had disease progression, compared to 44% of the 229 who got placebo as their maintenance treatment (P<0.001).
Theirs was the only study to show an improvement in overall survival. After a median follow-up of 34 months, 15% of the lenalidomide patients and 23% of the placebo group had died (P=0.03).
“Over time we have seen a benefit, but it may wash out because the majority of patients crossed over the lenalidomide” once initial results showed a significant benefit to the drug,” Dr. McCarthy told Reuters Health.
The lenalidomide recipients were more likely to have high-grade side effects, however, and about 10% had to stop taking the drug. In addition, the rate of secondary primary cancers was more than double in the lenalidomide group.
“The median overall survival among patients who required therapy before 1996 was approximately three years,” Dr. McCarthy and his team wrote. “In the era of new agents and autologous hematopoietic stem-cell transplantation, the median overall survival after transplantation is close to eight years. In this study, 85% of patients in the lenalidomide group and 77% of patients in the placebo group were alive at a median follow-up of nearly three years.”
The third study involved 614 patients who received unusually aggressive treatment before they were put on either placebo or maintenance therapy of at least 10 mg of lenalidomide per day for the first three months after their transplant.
In that case, progression-free survival was 41 months with lenalidomide and 23 months with placebo and the rate of median event-free survival was almost identical (P<0.001).
But four years after randomization, Dr. Michel Attal of Purpan Hospital in Toulouse, France and colleagues found no difference in overall survival.
One big problem with lenalidomide maintenance therapy is its cost, said Dr. McCarthy.
“That’s the issue,” he said. “I just saw somebody today who’s been on maintenance therapy and the insurance company is starting to get unhappy about the fact that it costs so much money, and it’s going to start denying him after so many years of treatment. We’re going to have to face this issue more. It’s brutal.”
Yet overall, “these three studies show the usefulness of lenalidomide maintenance therapy for prolonging the time to disease progression in both patients who have undergone stem-cell transplantation and those who have not,” the McCarthy team concluded. “Longer follow-up and additional studies may clarify the different findings.
N Engl J Med 2012; 366:1759-1791.