Patients with relapsed multiple myeloma had a 9-month improvement in progression-free survival (PFS) when they received the proteasome inhibitor carfilzomib (Kyprolis) in addition to standard therapy, a randomized trial showed.

The addition of carfilzomib to lenalidomide (Revlimid) and dexamethasone was associated with a median PFS of 26.3 months compared with 17.6 months for lenalidomide and dexamethasone. Median overall survival (OS) has yet to be reached in either group, but preliminary data suggest an advantage for the carfilzomib group, reported A. Keith Stewart, MB ChB, of the Mayo Clinic in Scottsdale, Ariz., at the American Society of Hematology (ASH) meeting.

“The primary endpoint of progression-free survival was met, with an unprecedented median time of 26 months,” Stewart said during an ASH press briefing. “There was a trend toward an overall survival benefit, but that has not yet been confirmed.”

In response to a question about his use of the term “unprecedented,” Stewart said, “In this same population of patients - patients who have relapsed one, two, or three times - the best result ever reported before with any combination chemotherapy was about 19 months.”

The results were published simultaneously in the New England Journal of Medicine. Although therapeutic advancements have substantially improved survival in myeloma, relapse remains an ongoing risk, necessitating continued evaluation of new and novel therapeutic approaches. The combination of lenalidomide and high-dose dexamethasone received FDA approval for relapsed multiple myeloma after phase III trials demonstrated superiority to dexamethasone alone, including a median PFS of 11.1 months. Carfilzomib has an approved indication as monotherapy for relapsed myeloma. Preliminary clinical trials showed that the combination of carfilzomib, lenalidomide, and weekly dexamethasone was active in relapsed myeloma and had a side-effect profile consistent with the drugs’ known toxicity. The results set the stage for the randomized phase III ASPIRE trial. Patients with relapsed myeloma and a treatment history of no more than three prior regimens were eligible for the trial. Prior treatment with bortezomib (Velcade) or with lenalidomide-dexamethasone combination therapy did not automatically disqualify patients. Investigators in North America, Europe, and the Middle East randomized 792 patients to receive lenalidomide and dexamethasone alone or in combination with carfilzomib. The trial had a primary endpoint of PFS, and secondary endpoints consisted of OS, overall response rate, duration of response, health-related quality of life, and safety. The trial ended early after an interim analysis showed that the carfilzomib arm had met the primary endpoint. At the data cutoff, 29.8% of the carfilzomib group and 21.7% of the control group remained on therapy. The 8.7-month difference in median PFS translated into a 31% reduction in the hazard for disease progression or death for the carfilzomib arm versus the control arm (HR 0.69, 95% CI 0.57-0.83, P=0.0001). The estimated 24-month OS was 73.3% for the carfilzomib group and 65.0% for the control group, although the difference did not meet the prespecified level of statistical significance (P=0.018 versus P=0.005). At the interim analysis, about 60% of the events required for survival analysis had occurred, Stewart added. Final survival data are expected in 2015. The three-drug regimen demonstrated superiority for overall response rate (87.1% versus 66.7%, P<0.001), complete response or better (31.8% versus 9.3%, P<0.001), stringent complete response (14.1% versus 4.3%), and health-related quality of life (P<0.001). The mean time to response was 1.6 months for the carfilzomib group and 2.3 months for the control group, and the median duration of response was 28.6 and 21.2 months, respectively. The median duration of treatment was 88 weeks in the carfilzomib arm and 57 weeks in the control group. The most common reason for stopping treatment was disease progression (39.8% for carfilzomib and 50.1% for control). Fewer than 1% of patients in either group withdrew because of adverse events. Adverse events (any grade) that occurred more often (absolute difference ≥5%) were hypokalemia, cough, upper respiratory tract infection, diarrhea, pyrexia, hypertension, thrombocytopenia, nasopharyngitis, and muscle spasms. Grade ≥3 adverse events occurred in 83.7% of carfilzomib-treated patients and 80.7% of the control group. Rates of serious adverse events were 59.7% and 53.7%, respectively. Grade ≥3 adverse events of special interest did not differ significantly between groups, including dyspnea, cardiac failure, ischemic heart disease, hypertension, and renal failure. The findings were among those from several studies discussed during the press briefing, including some preliminary clinical evaluations that presenters enthusiastically described as "blockbusters." Briefing moderator Brad Kahl, MD, of the University of Wisconsin in Madison, acknowledged that the agents and regimens will eventually have an impact on clinical practice but urged caution in the absence of data from larger, more advanced trials. In contrast, Kahl said the carfilzomib results "will establish a new standard of care for this outpatient population. I am confident that is a true statement."