David M. Reese, MD
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended adding final overall survival (OS) data from the phase III ASPIRE trial to the label for carfilzomib (Kyprolis) for the treatment of patients with relapsed/refractory multiple myeloma.
In ASPIRE, the combination of carfilzomib, 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.1
The median 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; P
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.
The CHMP previously recommended updating carfilzomib’s label with OS data from the phase III ENDEAVOR trial, which showed that carfilzomib reduced the risk of death by 21% compared with 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
The 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," David M. Reese, MD, senior vice president of Translational Sciences and Oncology at Amgen, said in a statement. "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."
The open-label phase III ASPIRE 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 to 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 to 18 and was not administered beyond 18 cycles. However, median treatment exposure in the carfilzomib arm was 22 cycles
The final data analysis for ASPIRE also confirmed findings showing that carfilzomib was associated with a median progression-free survival of of 26.1 months compared with 16.6 months among patients who received lenalidomide and dexamethasone alone (HR, 0.66; 95% CI, 0.55-0.78; P
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.
Adverse event (AE) rates were similar 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, only hypokalemia in the carfilzomib arm (10.5%) 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%) occurred more often with carfilzomib. Otherwise, the incidence of acute renal failure, cardiac failure, ischemic heart disease, and peripheral neuropathy occurred 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 occurred in as many as 5% of patients.
- Stewart AK, Siegel D, Ludwig H, et al. Overall survival (OS) of patients with relapsed/refractory multiple myeloma (RRMM) treated with carfilzomib, lenalidomide, and dexamethasone (Krd) versus lenalidomide and dexamethasone (Rd): Final analysis from the randomized phase 3 ASPIRE trial. Presented at: American Society of Hematology 59th Annual meeting; December 9-12, 2017; Atlanta, GA. Abstract 743.
- Dimopoulos MA, Goldschmidt H, Niesvizky R, et al. Carfilzomib or bortezomib in relapsed or refractory multiple myeloma (ENDEAVOR): an interim overall survival analysis of an open-label, randomised, phase 3 trial [published online August 23, 2017]. Lancet Oncol. doi: 10.1016/ S1470-2045(17)30578-8.