A recommendation has been made by the European Medicines Agency’s Committee for Medicinal Products for Human Use to add final overall survival data from the open-label phase III ASPIRE trial to the label for carfilzomib for the treatment of patients with relapsed/refractory multiple myeloma.
David M. Reese, MD
A recommendation has been made by the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) to add final overall survival (OS) data from the open-label phase III ASPIRE trial to the label for carfilzomib (Kyprolis) for the treatment of patients with relapsed/refractory multiple myeloma.
Combination carfilzomib, lenalidomide (Revlimid), plus dexamethasone in the ASPIRE trial reduced the risk of death by 21% compared to lenalidomide/dexamethasone alone for patients with relapsed multiple myeloma receiving 1 to 3 prior treatment regimens.1Median OS in the carfilzomib combination group was 48.3 months versus 40.4 months with lenalidomide/dexamethasone alone (HR, 0.79, 95% CI, 0.67-0.95; P = .0045).
At final analysis, there was an OS benefit found to be 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 compared with a 16% reduction for those treated with the proteasome inhibitor.
The CHMP previously recommended updating carfilzomib’s label with OS data from the phase III ENDEAVOR trial. This demonstrated a reduced risk of death by 21% with carfilzomib versus bortezomib in patients with relapsed/refractory multiple myeloma (median OS, 47.6 vs 40.0 months; HR, 0.791; 95% CI, 0.648-0.964; P = .01).2The positive CHMP opinion on the ASPIRE results will now be sent to the European Commission for a final regulatory decision.
"This latest positive CHMP opinion marks the second time Amgen will add overall survival data from a phase III study to the label, further validating the fundamental role of Kyprolis in treating patients with relapsed or refractory multiple myeloma," said David M. Reese, MD, senior vice president of Translational Sciences and Oncology at Amgen.
"This is a major step towards advancing KYPROLIS-based regimens as standard of care, and we look forward to the European Commission's decision later this year," Reese added.
The ASPIRE study enrolled 792 patients with a median age of 64 years who had received a median of 2 prior treatment regimens. Patients were randomized 1:1 to receive either the 3-drug carfilzomib regimen or lenalidomide plus a low-dose of dexamethasone alone. Overall, 66% of patients had received prior bortezomib, while 20% had a prior treatment of lenalidomide.
Patients in the lenalidomide group were given the agent 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 to 12. On day 1 and 2 of the first cycle, carfilzomib was administered at 20 mg/m2 followed by 27 mg/m2 thereafter. Carfilzomib treatment was not administered on days 8 and 9 during cycles 13 to 18, nor was it administered beyond 18 cycles. Median treatment exposure, however, in the carfilzomib group was 22 cycles.
Final analysis of this data confirmed findings showing that carfilzomib was associated with a median progression-free survival of of 26.1 months versus 16.6 months among patients who were given lenalidomide and dexamethasone alone (HR, 0.66; 95% CI, 0.55-0.78; P <.0001).
Median duration of therapy in the experimental arm was 72.0 weeks for carfilzomib, 85.0 weeks for lenalidomide, and 80.2 weeks for dexamethasone. In the control arm, patients received lenalidomide for a median duration of 56.7 weeks and dexamethasone for a median of 48.7.
There were also similar adverse event (AE) rates between the treatment groups, including all-grade AEs (98.0% in both groups), grade ≥3 AEs (87.0% with carfilzomib vs 83.0% for the control group), serious adverse events (65.6% vs 56.8%), discontinuation due to AEs (33.4% vs 30.1%), and grade 5 AEs (11.5% vs 10.5%).
Safety data showed that all-grade nonhematologic events were generally more common in the experimental arm for diarrhea (44.4% vs 37.3%), fatigue (33.4% vs 31.9%), cough (29.6% vs 18.0%), pyrexia (29.8% vs 21.6%), upper respiratory infections (30.1% vs 20.8%), hypokalemia (29.6% vs 14.9%), and muscle spasms (27.0% vs 21.1%). With respect to grade ≥3 adverse events, The only grade ≥3 AEs were hypokalemia in the carfilzomib arm (10.5%) which affected as many as 10% of patients in either group.
Hypertension (17.1% vs 8.7%) and venous thrombotic events (10.2% vs 6.2%) also occured more frequently with carfilzomib. Otherwise, The incidence of acute renal failure, cardiac failure, ischemic heart disease, and peripheral neuropathy was noted in a similar proportion of patients in both groups. The most common grade ≥3 special interest AE was hypertension (6.4% with carfilzomib). No other grade ≥3 special-interest event was noted in as many as 5% of the patients.