Pomalidomide plus Low-Dose Dexamethasone Improves Survival for Patients with Multiple Myeloma
Summary
Results from a randomized phase III trial show that the combination of pomalidomide (Pomalyst®) and low-dose dexamethasone may benefit some patients with multiple myeloma that has worsened (progressed) despite other treatments. Patients who received the combination therapy lived longer without the disease progressing (progression-free survival) than patients who received high-dose dexamethasone alone. Overall survival was also improved in the group that received the combination therapy compared with the other group.
Source
Lancet Oncology, September 3, 2013 (See the journal abstract.)
Background
Patients with advanced multiple myeloma whose disease worsens after multiple lines of therapy have few treatment options and a poor prognosis. The median survival time for these patients is 9 months.
Previous studies have indicated that pomalidomide may be useful in patients with multiple myeloma that is not responding to other treatments. The drug, a capsule taken by mouth, belongs to a class of medications called immunomodulating agents. Pomalidomide does two things: first, it helps the bone marrow to produce normal blood cells, and second, it enhances the ability of immune cells to kill abnormal cells in the bone marrow.
On February 8, 2013, the Food and Drug Administration (FDA) granted accelerated approval to pomalidomide for the treatment of patients with multiple myeloma who received at least two prior therapies, including lenalidomide (Revlimid®) and bortezomib (Velcade®), and whose disease progressed within 60 days of completing the last therapy.
Several pomalidomide-based studies are under way, including a trial required by the FDA as a condition of accelerated approval for the drug. That randomized phase III clinical trial (CC-4047-MM-007) is comparing pomalidomide, bortezomib, and low-dose dexamethasone with bortezomib plus low-dose dexamethasone in patients with previously treated multiple myeloma.
The Study
The trial published in Lancet Oncology was designed to compare pomalidomide plus low-dose dexamethasone and high-dose dexamethasone, which was considered a standard treatment when the trial was launched. The researchers randomly assigned 302 patients to receive pomalidomide plus low-dose dexamethasone and 153 to receive high-dose dexamethasone. The participants—from Australia, Canada, Europe, Russia, and the United States—all had advanced multiple myeloma that was refractory or both relapsed and refractory. In all cases, the disease had progressed despite at least two prior treatments of bortezomib, lenalidomide, or both.
The primary endpoint of the open-label study was progression-free survival (PFS). The key secondary endpoint was overall survival. Other secondary endpoints included the overall response rate (the proportion of patients who achieved at least a partial response), time to progression, and quality of life. Celgene Corporation, the maker of pomalidomide, funded the clinical trial.
Results
After a median follow-up of 10.0 months, the researchers found, patients in the pomalidomide plus dexamethasone group had lived 4.0 months without the disease worsening, compared with just 1.9 months among the patients assigned to receive high-dose dexamethasone alone. In addition, patients in the pomalidomide group lived about 4.6 months longer than patients in the high-dose dexamethasone group (12.7 months versus 8.1 months). Furthermore, nearly one-third of the patients in the pomalidomide group (95 of 302 patients) had their tumors shrink or showed other signs of achieving a partial response.
Common side effects in both groups included neutropenia, anemia, and thrombocytopenia. In the pomalidomide group, the side effects were similar to those observed in other trials involving pomalidomide and were largely manageable; few patients discontinued treatment because of treatment-related adverse events. There were 11 treatment-related adverse events leading to death in the pomalidomide group and 7 in the high-dose dexamethasone group.
“Based on our results, pomalidomide plus low-dose dexamethasone could be a treatment option for patients with advanced refractory or relapsed and refractory multiple myeloma in whom treatment with bortezomib and lenalidomide has been unsuccessful,” lead author Jesus San Miguel, MD, of Universidad de Salamanca, Spain, and his colleagues concluded.
Limitations
A limitation of the study was its open-label design, the authors noted. In addition, some patients in the high-dose dexamethasone group “crossed over” and began to take the combination therapy before their disease had progressed, which may have affected the magnitude of the difference in overall survival between the treatment groups. Similarly, assessing PFS between the groups was a challenge, because many patients in the high-dose dexamethasone group “crossed over” and began to take the combination therapy after a benefit was evident.
Comment
“Based on these data, pomalidomide plus low-dose dexamethasone is an important new addition to the treatment armamentarium for patients with advanced refractory or relapsed and refractory multiple myeloma,” commented Ola Landgren, MD, PhD, chief of NCI’s Multiple Myeloma Section. “The anti-myeloma effect is substantial, and the side-effect profile for this regimen is very reasonable.”
The results of this trial are similar to those of early studies involving pomalidomide, noted Xavier Leleu, MD, PhD, of Hopital Huriez, CHRU, Lille, France, in an accompanying editorial.
A subsequent report will describe the effect of pomalidomide on quality of life, Dr. Leleu continued, “but it seems logical to assume that the oral availability of pomalidomide, rapid onset of response, increased depth of response and prolonged survival will improve the quality of life of patients with refractory or relapsed and refractory myeloma.”
Additional studies of the drug are under way and should help researchers learn how best to build on the current findings to benefit patients with this disease, he added. “Pomalidomide can be used in combination with almost all existing antimyeloma drugs because of its favorable safety profile.”