David S. Siegel, MD, PhD
The combination of carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone reduced the risk of death by 21% compared with lenalidomide and dexamethasone alone for patients with relapsed multiple myeloma following prior treatment with 1 to 3 regimens, according to the final analysis of the phase III ASPIRE trial.
The median overall survival (OS) with the carfilzomib combination was 48.3 months versus 40.4 months with lenalidomide/dexamethasone alone (HR, 0.79, 95% CI, 0.67-0.95). The OS benefit seen at the final analysis was consistent even in those who received prior treatment with the proteasome inhibitor bortezomib (Velcade). There was a 25% reduction in the risk of death with carfilzomib in those not treated with bortezomib versus a 16% reduction for those treated with the proteasome inhibitor.
A full analysis of the final ASPIRE trial data will be submitted for presentation at a future medical conference and for publication in a medical journal, according to Amgen, the developer of the carfilzomib. Moreover, the company noted that data from the final assessment of ASPIRE would be submitted to regulatory agencies for a potential label update.
"For multiple myeloma patients, the first relapse is usually the most devastating," ASPIRE investigator David S. Siegel, MD, PhD, chief of the Division of Multiple Myeloma at John Theurer Cancer Center, said in a statement. "These data clearly show that the addition of Kyprolis – for just 18 cycles – to lenalidomide and dexamethasone at relapse gave patients a significantly improved chance of survival. With these results, this Kyprolis regimen should be considered a new standard of care."
The open-label phase III study enrolled 792 patients at a median age of 64 years who had received a median of two prior treatment regimens. Patients were randomized 1:1 to receive the 3-drug carfilzomib regimen or lenalidomide plus low-dose dexamethasone alone. In both groups of the trial, 66% of patients had received prior bortezomib and 20% had prior lenalidomide.
Lenalidomide was administered at 25 mg on days 1 to 21 and dexamethasone was administered at 40 mg on days 1, 8, 15, and 22 of a 28-day cycle. Intravenous carfilzomib was administered on days 1, 2, 8, 9, 15, and 16 during cycles 1-12. On day 1 and 2 of the first cycle, carfilzomib was administered at 20 mg/m2 followed by 27 mg/m2 thereafter. Treatment with carfilzomib was not administered on days 8 and 9 during cycles 13-18 and was not administered beyond 18 cycles. However, median treatment exposure in the carfilzomib arm was 22 cycles.
At the 24-month interim analysis, which was published in the New England Journal of Medicine
, 73.3% of patients in the carfilzomib arm were alive versus 65% with the 2-drug regimen. The objective response rate was 87.4% versus 66.9% and the median duration of response was 28.6 months compared with 21.2 months with and without carfilzomib, respectively. Of patients who responded, the complete response rate was 17.7% with carfilzomib versus 5.1% without and the very good partial response rate was 70.4% with carfilzomib versus 40.7% in the control arm.
In addition to the ASPIRE trial, carfilzomib also showed an improvement in OS in the phase III ENDEAVOR study. In updated data presented in March 2017, at the 16th International Myeloma Workshop (IMW) in New Delhi, the median OS with carfilzomib plus dexamethasone was 47.6 months compared with 40.0 months for bortezomib and dexamethasone (HR, 0.79; 95% CI, 0.65-0.96).
"The ENDEAVOR study has already demonstrated that Kyprolis is the superior proteasome inhibitor versus Velcade," Sean E. Harper, MD, executive vice president of Research and Development at Amgen, the company developing carfilzomib, said in a statement. "This overall survival benefit from the ASPIRE trial further supports the importance of proteasome inhibition and duration of treatment with Kyprolis in the treatment of relapsed multiple myeloma."
The FDA expanded the approval for carfilzomib in July 2015 to include patients with relapsed multiple myeloma who received at least 1 to 3 prior lines of therapy, based on results from the phase III ASPIRE trial. Carfilzomib had previously received an accelerated approval in July 2012 as a treatment for patients with multiple myeloma following at least 2 therapies, including bortezomib and an immunomodulatory agent.
Stewart KA, Rajkumar VS, Dimopoulos MA, et al. Carfilzomib, Lenalidomide, and Dexamethasone for Relapsed Multiple Myeloma. N Engl J Med. 2015; 372:142-152.