The European Commission (EC) has approved a variation to the marketing authorization for Amgen's Kyprolis (carfilzomib) to include use in combination with dexamethasone alone for adult patients with multiple myeloma who have received at least one prior therapy. The extended indication marks the second approval for Kyprolis by the EC in less than a year.

"In the phase 3 head-to-head trial, Kyprolis in combination with dexamethasone doubled the time patients lived without their cancer progressing, as well as the rates of complete response compared to bortezomib and dexamethasone," said Sean E. Harper, M.D., executive vice president of research and development at Amgen. "Kyprolis-based regimens have now shown superiority over two former standard-of-care treatment options for relapsed multiple myeloma patients, reinforcing Kyprolis' place as a foundational therapy in this patient population."

The EC approved the extended indication for Kyprolis based on data from the phase 3 head-to-head ENDEAVOR trial in which patients with multiple myeloma treated with Kyprolis plus dexamethasone (Kd) achieved superior progression-free survival (PFS) of 18.7 months compared to 9.4 months in those receiving bortezomib plus dexamethasone (Vd) (HR=0.53; 95 percent CI: 0.44, 0.65; p <0.0001). Kd also demonstrated improvement over Vd for secondary endpoints, including rates of complete response or better, which were double in patients treated with Kd compared to those treated with Vd (12.5 percent vs. 6.2 percent, p <0.0001). The tolerability profile was similar in the two arms, however patients treated with Kd experienced a significantly lower rate of grade 2 or higher neuropathy events than those treated with Vd, a frequent dose-limiting toxicity in patients receiving bortezomib (6 percent [95 percent CI: 4, 8] vs. 32 percent [95 percent CI: 28, 36], respectively). The most common adverse reactions that occurred in greater than 20 percent of patients treated with Kyprolis were anemia, fatigue, diarrhea, thrombocytopenia, nausea, pyrexia, dyspnea, respiratory tract infection, cough and peripheral edema.

Kyprolis was first approved by the EC in November 2015 for use in combination with lenalidomide and dexamethasone for the treatment of adult patients with multiple myeloma who have received at least one prior therapy based on results of the ASPIRE study. Today's approval by the EC follows the U.S. Food and Drug Administration's approval of a supplemental New Drug Application based on the ENDEAVOR results in January 2016.

Multiple myeloma is an incurable blood cancer, characterized by a recurring pattern of remission and relapse. It is a rare and very aggressive disease that accounts for approximately one percent of all cancers worldwide. In Europe, approximately 39,000 patients are diagnosed with multiple myeloma each year and 24,000 patient deaths are reported on an annual basis.

The randomized ENDEAVOR (RandomizEd, OpeN Label, Phase 3 Study of Carfilzomib Plus DExamethAsone Vs Bortezomib Plus DexamethasOne in Patients With Relapsed Multiple Myeloma) trial of 929 patients evaluated Kyprolis in combination with low-dose dexamethasone, vs. bortezomib with low-dose dexamethasone in patients whose multiple myeloma has relapsed after at least one, but not more than three prior therapeutic regimens. The primary endpoint of the trial was PFS, defined as the time from treatment initiation to disease progression or death. In a clinical trial, measuring the PFS is one way to demonstrate how well a treatment works.

As stated above, Kyprolis with dexamethasone (Kd) was superior to bortezomib and dexamethasone (Vd) and demonstrated significantly longer PFS. Improvement in PFS in the Kd arm compared to the Vd arm was seen across key pre-specified subgroups, including bortezomib-naive patients, those with high- or standard-risk cytogenetics and with or without prior transplantation.

In terms of secondary endpoints, Kd achieved a higher overall response rate than Vd (76.9 percent vs. 62.6 percent; p <0.0001). In the Kyprolis and bortezomib groups, 54.3 percent and 28.6 percent of patients achieved a very good partial response or better (p <0.0001), respectively. Overall survival data are not yet mature and continue to be monitored.

Treatment discontinuation due to adverse events and on-study deaths were comparable between the two arms. A number of known adverse drug reactions were reported at a higher rate in the Kyprolis group compared with the bortezomib group, including any-grade dyspnea, hypertension, pyrexia, and cough as were any-grade cardiac failure (grouped term; 8 percent vs. 3 percent) and acute renal failure (grouped term; 8 percent vs. 5 percent).

Rates of grade 3 or higher adverse events were 73 percent in the Kyprolis group and 67 percent in the bortezomib group.7 Grade 3 or higher adverse events of interest in the Kyprolis and bortezomib groups included hypertension (preferred term; 9 percent vs. 3 percent), dyspnea (preferred term; 5 percent vs. 2 percent), cardiac failure (grouped term; 5 percent vs. 2 percent), acute renal failure (grouped term; 4 percent vs. 3 percent), ischemic heart disease (grouped term; 2 percent vs. 2 percent) and pulmonary hypertension (grouped term; 0.6 percent vs. 0.2 percent).

Patients received treatment until progression with Kyprolis as a 30-minute infusion on days 1, 2, 8, 9, 15 and 16 of a 28 day treatment cycle. Patients received low-dose dexamethasone (20 mg) orally or intravenously on days 1, 2, 8, 9, 15, 16, 22, and 23 of each treatment cycle. For Cycle 1 only, Kyprolis was administered at 20 mg/m2 on days 1 and 2, and if tolerated followed by escalation to 56 mg/m2 from day 8. Patients who tolerated 56 mg/m2 in Cycle 1 were kept at this dose for subsequent cycles. Patients who received bortezomib (1.3 mg/m2) with low-dose dexamethasone (20 mg) were administered bortezomib subcutaneously or intravenously at the discretion of the investigator and in accordance with regulatory approval of bortezomib. More than 75 percent of the patients in the control arm received bortezomib subcutaneously. This study was conducted at 235 sites worldwide.

Proteasomes play an important role in cell function and growth by breaking down proteins that are damaged or no longer needed. Kyprolis has been shown to block proteasomes, leading to an excessive build-up of proteins within cells. In some cells, Kyprolis can cause cell death, especially in myeloma cells because they are more likely to contain a higher amount of abnormal proteins.

Kyprolis is approved in the US for the following:

In combination with dexamethasone or with lenalidomide plus dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma who have received one to three lines of therapy.

As a single agent for the treatment of patients with relapsed or refractory multiple myeloma who have received one or more lines of therapy.

Kyprolis is also approved in Argentina, Israel, Kuwait, Mexico, Thailand, Colombia, Korea, Canada, Switzerland, Russia, Brazil and the European Union. Additional regulatory applications for Kyprolis are underway and have been submitted to health authorities worldwide.