Lenalidomide maintenance prolonged progression-free survival in multiple myeloma patients in three independent randomized clinical trials. Experts remain split, however, on whether the therapy should be considered a standard of care—and real safety concerns remain.
“Lenalidomide is a well-known and validated therapy in multiple myeloma and has significantly contributed to the improved survival of patients with this incurable disease,” said Joseph Mikhael MD, MEd, Vice Chair of Education for the Division of Hematology-Oncology at Mayo Clinic in Arizona and Associate Professor and Program Director of the Hematology-Oncology Fellowship Program. “The three current studies add further to the benefit of this drug, in patients who are both eligible and ineligible for autologous stem cell transplant.”
However, the trials, published in the May 10 issue of the New England Journal of Medicine, do not entirely settle the question of how best to use the drug, according to Mikhael, who was not involved in any of the studies.
“It is too early to consider lenalidomide maintenance as standard of care in all patients after transplant,” he said. “Although there was a survival advantage in the U.S. study, there was no survival advantage in the French study. Each patient should be considered individually as to whether or not they would benefit from this strategy.”
Other myeloma experts are less cautious, though, including Philip L. McCarthy, MD, who led the U.S.-based trial. “All of these studies show the same thing, a marked improvement in progression-free survival,” said McCarthy, Professor of Oncology and Director of the Blood and Marrow Transplant Program at Roswell Park Cancer Institute in Buffalo, NY. “And we did show an improvement in overall survival. I think that is obviously very attractive for the patients. So I do think it is ready to be standard of care.”
Progression Delay May Not Translate to Overall Survival
Two of the three trials tested lenalidomide maintenance in patients following transplant. In McCarthy's study (NEJM 2012;366:1770–1781), 460 patients were randomly assigned to lenalidomide versus placebo. To be eligible for the trial, patients had to be age 70 or younger and have at least stable disease 100 days after a stem cell transplant.
A planned interim analysis in 2009 showed a delay in disease progression with lenalidomide maintenance, and the trial was amended to allow patients in the placebo group to cross over to active drug at that time.
Now, with a median follow-up of 34 months, 37 percent of the patients initially assigned to lenalidomide have progressed compared with 58 percent initially assigned to placebo. The median time to progression in the two groups was 46 versus 27 months, respectively. Both measures had a statistically significant benefit for lenalidomide over placebo.
Moreover, the overall survival appears to be prolonged with lenalidomide maintenance in this trial. At the time of the current analysis, 15 percent of patients in the lenalidomide group had died as had 23 percent of patients in the placebo group, which was a statistically significant difference. The three-year survival in the two groups also suggest a benefit with active drug compared with placebo (88% vs. 80%).
Meanwhile, the France-based trial (NEJM 2012;366:1782–1791), led by Michel Attal, MD, from the Hematology Department at the Hôpital Purpan in Toulouse, also enrolled post-transplant patients. To be eligible, patients had to be younger than 65 and have nonprogressive disease after first-line transplant. Additionally, they had to be within six months of their transplant. The researchers randomly assigned 307 to lenalidomide and 307 to placebo; patients received treatment at one of 77 centers in France, Switzerland, and Belgium.
With a median follow-up of 30 months, 66 percent of the lenalidomide-treated patients remained progression-free, compared with 48 percent of the placebo-treated patients. Median progression-free survival was 41 months in the lenalidomide group and 23 months in the placebo group, which was a statistically significant difference. Moreover, the three-year progression-free survival also favored active therapy, compared with placebo (59% vs. 35%).
However, unlike the U.S. trial, the therapy did not appear to improve overall survival with three-year survival in the lenalidomide group at 80 percent compared with 84 percent in the placebo group.
“These two studies are interesting because one shows a survival benefit and the other does not,” said William Matsui, MD, Associate Professor of Oncology at Sidney Kimmel Comprehensive Cancer at Johns Hopkins University School of Medicine, who was not involved with the studies. “It is not like one group did things wrong and the other did them right. I think there are some subtleties of treatment that are different.”
He also points out that the follow-up is relatively short, with the majority of patients remaining alive in both studies. “We've seen this before in myeloma: If you wait long enough things don't always pan out. So who knows if you wait longer in both studies what would happen.”
Progression Delayed in Non-Transplant Patients
In the third study, led by Antonio Palumbo, MD, from the University of Turin's Myeloma Unit in Italy, researchers tested maintenance lenalidomide in patients age 65 and older who were not eligible for transplantation (NEJM 2012;366:1759–1769).
The team randomly assigned 459 patients to one of three treatments:
* melphalan–prednisone–lenalidomide induction plus lenalidomide maintenance (MPR-R);
* melphalan–prednisone–lenalidomide (MPR) plus placebo maintenance;
* melphalan–prednisone (MP) plus placebo maintenance.
With a median follow-up of 30 months, patients in the MPR-R group had significantly longer median progression-free survival at 31 months than patients in the MPR group at 14 months or in the MP group at 13 months. (The difference between the two placebo arms was not statistically significant.) The response rate was higher in the two arms that included lenalidomide in the induction regimen, compared with MP alone (MPR-R at 77%, MPR at 68%, versus MP at 50%).
Moreover, the researchers performed a prespecified landmark analysis to tease apart the benefit from inclusion of lenalidomide in the induction regimen and lenalidomide maintenance therapy. They found that median progression-free survival, measured from the start of maintenance treatment to progression, was 26 months in the MPR-R group compared with seven months in the MPR group.
Secondary Cancers Remain Real Concern
As with most cancer therapies, the benefits of maintenance lenalidomide come at a cost of unwanted adverse effects. In this case, the most serious treatment-associated adverse effect was secondary cancers, which were seen in all three studies.
Oddly, though, the types of secondary cancers seen were not consistent across the studies. The Palumbo group saw an increase in acute myeloid leukemia and myelodysplastic syndromes, as did McCarthy's team. By contrast, the Attal group saw several cases of Hodgkin's lymphoma and acute lymphoblastic leukemia.
“Everybody says that makes no sense based on what we are used to as causative agents for second cancers,” McCarthy said in an interview. “You usually don't expect B lymphoid cancers to develop or Hodgkin's lymphoma, whereas AML and MDS are not a surprise. [Attal's group doesn't] have a good explanation, and neither do I.”
McCarthy also points out that there was an increase in second solid tumors, which were spread “all over the place.” The reason for the increase is unknown. “It may be observation bias—i.e., more attention was paid to those patients still on study.”
Matsui agrees that the “weird smattering of solid tumors and weird clustering of lymphoid malignancies” is unlike what is typically seen with cytotoxic agents. He speculates that the pattern may be linked to some sort of immune system effect of the drug, as opposed to the genotoxic effects that are more commonly considered with traditional chemotherapeutics.
“We could probably be better about pinning it down and knowing who was at risk if we knew how lenalidomide worked,” he said.
The unusual pattern might be due, at least in part, to the underlying disease, according to both researchers. McCarthy notes that a Swedish registry study published in Blood last year showed that myeloma patients had an elevated risk for AML and MDS, as did patients with monoclonal gammopathy of unknown significance (M-GUS). “The latter group of patients would not have received chemotherapy,” he said. “Therefore I think there is something inherently wrong or abnormal about the bone marrow of somebody who has M-GUS, let alone multiple myeloma.
“We think something is wrong with the stem cell that predisposes these patients to a second cancer.”
Risk of Death
Despite the increased risk with lenalidomide of second cancers, all of the experts interviewed agree that the benefits likely outweigh the risks for many patients.
Said Mikhael: “The risks associated with this therapy are real—these include high cost and short-term toxicity, and the long-term risk of second cancers must also be considered. We also require more information in the long term about the risk of second cancers, but it must be placed in context of the proven benefit of this agent to delay progression of the disease.”
Similarly, Matsui says that more work needs to be done to understand which patients are at risk and how lenalidomide therapy is leading to secondary cancers. But in the meantime, physicians and patients need to weigh the risk of a second cancer and its impact on a patient's quality of life and health versus the likelihood of death from myeloma.
“Balancing all of the data, I think it would be a reasonable thing to screen patients for some things—colonoscopy, mammograms, for example—but if there are no tip-offs, then the question is how long do you do give maintenance?
The French trial's approach of giving it for two years and then stopping seems pretty reasonable. Does it decrease the risk of secondary cancer? It does provide a progression-free survival benefit. We don't know about overall survival. But without knowing, our job is still to do no harm.”
For McCarthy, the equation is even simpler: “The risk of dying from myeloma is much higher than the risk of getting a second cancer.”
Furthermore, he noted, some patients who enrolled in early trials with the drug have been taking it for seven or even 10 years now. “It is pretty well tolerated in the majority of patients, so I think it is not quite like taking a pill for blood pressure, but it is probably just one step removed.”