Studies Support Expanded Role for Lenalidomide in Treating Multiple Myeloma
Maintenance therapy with the drug lenalidomide (Revlimid) substantially lengthens the time patients with multiple myeloma live without their cancers progressing, according to the results of three randomized placebo-controlled clinical trials published May 10 in the New England Journal of Medicine. (See the table below for links to the study abstracts.) Overall survival was also improved in one of the trials, but according to several researchers, that conclusion is less definitive.
The results also showed that lenalidomide maintenance therapy carries an increased risk of second primary cancers. Largely in response to these findings, the Food and Drug Administration (FDA) last week issued an updated drug safety communication to warn physicians and patients about this increased risk.
Developing a second cancer is "a real risk, although it's small," according to Dr. Philip McCarthy of the Roswell Park Cancer Institute, who led one of the clinical trials, which was funded by NCI.
The risk of disease progression or death was greater for trial participants who received a placebo as maintenance therapy than for patients treated with lenalidomide, he added. "Physicians and patients will have to balance these [factors] out," he said. "For the vast majority of patients, though, I think it's reasonable to consider maintenance therapy with lenalidomide."
Slowing the Inevitable
In patients with multiple myeloma, standard treatment currently begins with induction therapy using two or more chemotherapy agents and, more recently, lenalidomide or bortezomib (Velcade), or both, in combination with a steroid. In patients who are younger than 65, this is often followed by an autologous stem cell transplant. (Because stem cell transplants can have significant side effects, their use is restricted in older or less-fit patients.)
—Dr. Keith Stockerl-Goldstein
Following these treatments, many patients' cancers will stabilize or go into partial or complete remission. But the disease invariably returns in nearly all patients, often within several years, noted Dr. Ola Landgren, head of the Multiple Myeloma Section in NCI's Center for Cancer Research.
Various maintenance treatments—used to solidify the response to induction therapy and delay cancer progression as long as possible—have been investigated. In several trials, for example, maintenance therapy with thalidomide was shown to improve progression-free and possibly overall survival. But long-term treatment with thalidomide can cause debilitating side effects, including severe peripheral neuropathy, explained Dr. Keith Stockerl-Goldstein of Washington University's Siteman Cancer Center in St. Louis.
"A large number of patients drop off of thalidomide because of the toxicity," he said, which has limited its clinical use. "The hope has been that, with less toxic drugs like lenalidomide and bortezomib, we could get the survival benefits without the side effects."
The NCI-funded trial conducted in the United States and a trial conducted in Europe led by French researchers, compared maintenance therapy with lenalidomide or a placebo in patients (younger than 71 and 65, respectively) who had undergone a stem cell transplant. Both arms of the European trial also included "consolidation" treatment with lenalidomide—a short course of the drug at a higher dose, prior to maintenance therapy.
The third trial, conducted in Europe, Australia, and Israel, tested lenalidomide maintenance therapy against a placebo in newly diagnosed patients aged 65 and older. Patients had received induction therapy and were not candidates for a stem cell transplant.
In all three trials, lenalidomide maintenance therapy substantially lengthened the time it took for the patients' cancers to progress. (See the table below.)
Progression-Free Survival in Three Trials of Lenalidomide Maintenance Therapy for Multiple Myeloma
|Trial||Stem Cell Transplant||Number of Patients Receiving Maintenance Therapy||Median Progression-Free Survival Results|
|United States||Yes||460||39 months|
|Europe||Yes||614||41 months||23 months|
|Europe, Australia, Israel||No||284||31 months||14 months|
* Data from 2009, when study was unblinded
** After median follow-up of 34 months, including patients who crossed over
The U.S. trial also showed an improvement in overall survival at 3 years (88 percent versus 80 percent), despite the fact that some patients in the placebo arm later switched to maintenance treatment with lenalidomide beginning in December 2009, when the trial was unblinded—meaning patients and their physicians were told which treatment the patients were receiving.
The unblinding occurred because an interim data analysis revealed the large difference in progression-free survival between the two groups. Patients receiving a placebo were then offered lenalidomide, and about two-thirds of the patients began taking the drug.
But this crossover "may make it difficult to see any improvement in the overall survival benefit over time," Dr. McCarthy said.
Second Cancers and Unanswered Questions
Although several side effects were more common in patients receiving lenalidomide, the most troubling was the development of a second primary cancer.
Studies have shown that multiple myeloma and its precursor condition, known as monoclonal gammopathy of undetermined significance, are independently associated with the development of a second primary cancer, namely acute myeloid leukemia, as well as myelodysplastic syndromes.
Numerous factors may influence the risk of a second cancer following multiple myeloma, Dr. Landgren noted. But the consistent finding in all three trials that more patients who received lenalidomide as a maintenance therapy developed a new primary cancer strongly implicates the drug. He agreed, however, that the observed excess risk, which was based on a small number of cases, is something that needs to be discussed with patients.
It "may be debatable" whether the trials' results establish a new standard of care for multiple myeloma, wrote Dr. Ashraf Badros of the University of Maryland Greenebaum Cancer Center in an accompanying editorial.
Dr. Stockerl-Goldstein agreed. Questions remain, he stressed, about the optimal duration of treatment, the lack of improved overall survival in the other two trials, and whether improved progression-free survival translates into better quality of life.
Such unknowns could also call into question the cost effectiveness of long-term treatment with lenalidomide, Dr. Badros wrote. A year of maintenance therapy could cost more than $160,000 for the drug alone, he calculated, not including lab tests, physician visits, and other costs.
In an effort to identify potential biomarkers that may indicate which patients are at greater risk of developing a second cancer following lenalidomide treatment or are most likely to benefit from maintenance therapy, Dr. Landgren and other NCI researchers have developed a program to analyze tumor samples from patients in the three trials. To increase the speed of this effort, Dr. Landgren said, the research team is also interested in analyzing samples from multiple myeloma patients not in clinical trials who develop second cancers.
Despite these unanswered questions, researchers are excited about the progress that has been made in this disease. After many years of no significant clinical advances in multiple myeloma, improved therapies have led to a threefold increase in survival over the last decade, Dr. Landgren noted.