The FDA has approved the supplemental new drug application for carfilzomib (Kyprolis, Amgen) for injection in combination with dexamethasone or with lenalidomide (Revlimid, Celgene) plus dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma who have received one to three lines of therapy. The FDA also approved carfilzomib as a single agent for the treatment of patients with relapsed or refractory multiple myeloma who have received one or more lines of therapy. This decision converts to full approval the initial accelerated approval that carfilzomib received in July 2012 as a single agent.
Proteasomes play an important role in cell function and growth by breaking down proteins that are damaged or no longer needed. Carfilzomib has been shown to block proteasomes, leading to an excessive build-up of proteins within cells. In some cells, carfilzomib can cause cell death, especially in myeloma cells because they are more likely to contain a higher amount of abnormal proteins. The irreversibility of carfilzomib’ binding has also been shown to offer a more sustained inhibition of the targeted enzymes.
The new indication for carfilzomib is the second in six months. In July 2015, the FDA approved another expanded indication for carfilzomib in combination with lenalidomide and dexamethasone (KRd) for the treatment of patients with multiple myeloma who have received one to three prior lines of therapy.
The FDA’s decision was based on results from the phase 3 ENDEAVOR (RandomizEd, OpeN Label, Phase 3 Study of Carfilzomib Plus DExAmethasone Vs BORtezomib Plus Dexamethasone in Patients With Relapsed Multiple Myeloma) trial, which evaluated carfilzomib in combination with low-dose dexamethasone (Kd) compared with bortezomib (Velcade, Millennium Pharmaceuticals) with low-dose dexamethasone (Vd) in 929 patients whose multiple myeloma had relapsed after at least one, but not more than three, prior therapeutic regimens. The study’s primary endpoint was progression-free survival (PFS), defined as the time from treatment initiation to disease progression or death.
Patients were treated with carfilzomib as a 30-minute infusion on days 1, 2, 8, 9, 15, and 16 of 28-day treatment cycles, along with low-dose dexamethasone (20 mg). For cycle 1 only, carfilzomib was administered at 20 mg/m2 on days 1 and 2, and, if tolerated, was followed by escalation to 56 mg/m2 from day 8. Patients who tolerated 56 mg/m2 in cycle 1 were kept at that 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 the regulatory approval of bortezomib. More than 75% of the patients in the control arm received bortezomib subcutaneously.
The study results showed that patients with relapsed multiple myeloma treated with Kd achieved 50% greater PFS of 18.7 months compared with 9.4 months among those receiving Vd (hazard ratio, 0.53; P < 0.0001), a current standard of care in relapsed multiple myeloma. The patients in this study were treated until disease progression. The most common adverse events in the carfilzomib arm included anemia, diarrhea, dyspnea, fatigue, insomnia, pyrexia, and thrombocytopenia.
Kd also demonstrated improvement over Vd for secondary endpoints, achieving a higher overall response rate (77% vs. 63%, respectively; P < 0.0001) and a lower rate of grade-2 or higher neuropathy events (6% vs. 32%).
Source: Amgen; January 21, 2016.
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