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FDA Expands Carfilzomib's Myeloma Approval

Jason M. Broderick @jasoncology
Published: Friday, Jul 24, 2015

Dr. Sean E. Harper

Sean E. Harper, MD

The FDA has broadened the approval of carfilzomib (Kyprolis) to include patients with relapsed multiple myeloma who have received at least one to three prior lines of therapy, based on results from the phase III ASPIRE trial.

Carfilzomib previously received an accelerated approval in July 2012 as a treatment for patients with multiple myeloma following at least two therapies, including bortezomib and an immunomodulatory agent. Along with the expanded indication, the FDA has granted a full approval to carfilzomib.

"The expanded indication of Kyprolis provides patients with relapsed multiple myeloma a new therapeutic option, helping to address a real unmet need for this common blood cancer," Sean E. Harper, MD, executive vice president of Research and Development at Amgen, said in a statement. "The approval of a second indication for Kyprolis in just three years demonstrates that it is becoming a critical component in the treatment of multiple myeloma, and underscores our commitment to advancing care for patients with this challenging disease."

In the pivotal ASPIRE trial, the combination of carfilzomib, lenalidomide, and low-dose dexamethasone reduced the risk of progression by 31% compared with lenalidomide and low-dose dexamethasone alone in patients with relapsed multiple myeloma. The median progression-free survival (PFS) with carfilzomib was 26.3 months compared with 17.6 months without the proteasome inhibitor (HR = 0.69; 95% CI, 0.57-0.83; P <.0001).

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.

In both arms, lenalidomide was administered at 25 mg on days 1-21 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, 73.3% of patients in the carfilzomib arm were alive versus 65% with the 2-drug regimen. The median overall survival was not yet reached with a trend favoring the carfilzomib arm (HR = 0.79; 95% CI, 0.63-0.99; P = .018).

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.

"The ability of this Kyprolis treatment regimen to produce deep and durable responses is critical towards extending the time patients live without their disease progressing," ASPIRE principal investigator A. Keith Stewart, MBChB, said in a statement. 

Treatment discontinuation due to an adverse event occurred in 15.2% of patients treated with carfilzomib compared with 17.4% with the 2-drug regimen.

The most common grade ≥3 hematologic adverse events with carfilzomib compared with the control arm were neutropenia (29.6% vs 26.5%), anemia (17.9% vs 17.2%), and thrombocytopenia (16.6% vs 12.3%). The most common grade ≥3 nonhematologic side effects were pneumonia (12.5% vs 10.5%), hypokalemia (9.4% vs 4.9%), and hypophosphatemia (8.4% vs 4.6%).

For the 3-drug regimen versus the 2-drug regimen, respectively, all-grade acute renal failure occurred in 8.4% of patients versus 7.2%, cardiac failure was seen in 6.4% of patients versus 4.1%, and ischemic heart disease was experienced by 5.9% of patients compared with 4.6%.

The initial approval of carfilzomib was based on data from a single-arm clinical trial that enrolled 266 patients with relapsed multiple myeloma who received at least two prior therapies. In this study, the ORR with carfilzomib was 22.9%.


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