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Three-Drug Combination Benefits Some Patients with Relapsed Multiple Myeloma


Interim results from an international, randomized phase III trial suggest that the addition of a drug called carfilzomib (Kyprolis®) to a standard treatment improves outcomes for patients with multiple myeloma whose cancer has relapsed. Participants in the study who received carfilzomib plus lenalidomide (Revlimid®) and dexamethasone lived a median of 8.7 months longer without the disease getting worse than patients who received lenalidomide and dexamethasone alone.


New England Journal of Medicine, December 6, 2014 (See the journal abstract.)


Although survival rates have improved for patients with multiple myeloma, relapse is common, and new treatments are needed.

In 2012, the Food and Drug Administration approved carfilzomib for the treatment of multiple myeloma that had worsened during or after treatment with bortezomib (Velcade®) and immunomodulatory therapy. Carfilzomib, which is given intravenously, is a type of drug called a proteasome inhibitor.

Recent early-stage clinical trials have suggested that the addition of carfilzomib to a standard therapy for multiple myeloma—the combination of lenalidomide plus dexamethasone—may benefit some patients whose disease has relapsed or no longer responds to treatment. In the trials, the side effects of the three-drug combination were consistent with the known toxic effects of these agents.

The Study

In a phase III clinical trial, researchers randomly assigned 792 patients with relapsed multiple myeloma to receive carfilzomib plus lenalidomide and dexamethasone (carfilzomib group) or lenalidomide and dexamethasone alone (control group). The patients were from North America, Europe, and the Middle East.

Patients in each group received treatments in 28-day cycles until they withdrew consent, their disease progressed, or they experienced unacceptable toxic effects. Patients in the carfilzomib group continued to receive lenaolidomide and dexamethasone but stopped receiving carfilzomib after 18 cycles because data on the long-term safety of carfilzomib were not yet available when the study was initiated.

The study’s primary end point was progression-free survival. Secondary end points included overall survival, the rate of overall response (partial response or better), duration of response, health-related quality of life, and safety.

Keith Stewart, M.B., Ch.B., of the Mayo Clinic in Scottsdale, AZ, was the first author of the study, which was sponsored by the maker of carfilzomib, Onyx Pharmaceuticals.


Median progression-free survival was 26.3 months in the carfilzomib group, compared with 17.6 months in the control group.

The overall response rate—the percentage of patients whose cancers shrank or disappeared after treatment—was higher in the carfilzomib group than in the control group (87.1 percent versus 66.7 percent), including a complete response in 31.8 percent and 9.3 percent of patients in the two groups, respectively.

Patients in the carfilzomib group reported a number of common adverse events at a higher rate than did patients in the control group, including diarrhea, cough, fever, and hypertension. Adverse events of grade 3 or higher were reported in 83.7 percent and 80.7 percent of patients in the carfilzomab and control groups, respectively.

The duration of treatment was longer in the carfilzomib group than in the control group (median, 88 weeks versus 57 weeks). Serious adverse events, including cardiac events, were reported more frequently during the first 18 cycles of treatment than in later cycles.

Patients in the carfilzomib group remained in remission longer and reported superior health-related quality of life (according to the QLQ-C30 Global Health Status and Quality of Life scale) than those in the control group during the first 18 cycles of treatment.


The median overall survival had not been reached in either group at the time of publication, although there was a statistical trend favoring the carfilzomib group. Additional results beyond this interim analysis will be needed to assess overall survival.

As planned by the study designers, the trial did not collect data on the safety and efficacy of carfilzomib after 18 cycles.


The complete response rate among the carfilzomib group “is particularly encouraging because studies have shown an association between more robust responses and improved survival in patients with multiple myeloma,” the study authors wrote.

“Overall, I think this is a very important study,” said Mark Roschewski, M.D., of the Lymphoid Malignancies Branch in NCI’s Center for Cancer Research, who was not involved in the study. “We have enjoyed an onslaught of novel therapies in myeloma over the last 10 years, but the majority of clinical decisions are guided by phase II study results. The strength of the current study is the design as a randomized phase III controlled trial, which is needed to understand the best way to approach patients with multiple myeloma.”

The current study offered a true comparison of the efficacy with the toxicity in a similar patient population. “I was pleasantly surprised to see that the level of toxicity did not seem to be increased significantly, and the complete response rate was much higher with the three-drug regimen,” Dr. Roschewski pointed out. “In my opinion, a complete response rate of over 30 percent in a group of patients that had been previously treated with novel agents in most cases is quite impressive.”

Although it is unclear from the study results which patients benefit the most from the three-drug regimen and there was not a benefit with respect to overall survival, Dr. Roschewski concluded: “Given the favorable toxicity profile relative to the two-drug regimen, I think the three-drug regimen should be strongly considered in most patients.”

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