Phase III Trial of Carfilmozib (Kyprolis) in Multiple Myeloma Meets Primary Endpoint
Treatment extends progression-fee survival
A pivotal phase III study of carfilzomib (Kyprolis, Amgen/Onyx Pharmaceuticals) in patients with relapsed multiple myeloma has met its primary endpoint of progression-free survival (PFS).
Patients treated with carfilzomib for injection in combination with lenalidomide (Revlimid, Celgene) and low-dose dexamethasone lived significantly longer without their disease worsening compared with patients treated with lenalidomide and low-dose dexamethasone alone (median survival: 26.3 months vs. 17.6 months, respectively; hazard ratio = 0.690; P < 0.0001). While the data for overall survival (OS), a secondary endpoint, are not yet mature, the analysis showed a trend in favor of dexamethasone that did not reach statistical significance.
The results will be submitted for presentation at the upcoming 56th annual meeting of the American Society of Hematology later this year.
In the U.S., the new data may support the conversion of accelerated approval of Krypolis (carfilzomib) to full approval and may expand the current indication. In July 2012, the FDA granted accelerated approval to Kyprolis for the treatment of patients with multiple myeloma who have received at least two prior therapies, including bortezomib and an immunomodulatory agent, and who have demonstrated disease progression on or within 60 days of completion of the last therapy. Approval was based on the response rate. Clinical benefit, such as improvement in survival or symptoms, has not been verified.
The ASPIRE (CArfilzomib, Lenalidomide, and DexamethaSone Versus Lenalidomide and Dexamethasone for the Treatment of PatIents With Relapsed Multiple MyEloma) trial evaluated carfilzomib in combination with lenalidomide and low-dose dexamethasone compared with lenalidomide and low-dose dexamethasone in patients with relapsed multiple myeloma after treatment with one to three prior regimens. The study’s primary endpoint was PFS, defined as the time from treatment initiation to disease progression or death. Secondary endpoints included OS, the overall response rate, the duration of response, the disease control rate, health-related quality of life, and safety.
Patients were randomly assigned to receive carfilzomib (20 mg/m2 on days 1 and 2 of cycle 1 only, and then 27 mg/m2 subsequently), in addition to a standard dosing schedule of lenalidomide (25 mg per day for 21 days on and 7 days off) and low-dose dexamethasone (40 mg per week in 4-week cycles) compared with lenalidomide and low-dose dexamethasone alone. The study involved 792 patients in North America, Europe, and Israel.
In previous phase II trials, death occurred in 37 (7%) of 526 patients with relapsed and/or refractory multiple myeloma who received carfilzomib monotherapy. The most common causes of death, other than disease progression, were cardiac (five patients), end-organ failure (four patients), and infection (four patients). Important warnings and precautions include cardiac arrest, congestive heart failure, myocardial ischemia, pulmonary hypertension, pulmonary complications, infusion reactions, tumor lysis syndrome, thrombocytopenia, hepatic toxicity, and embryo-fetal toxicity.
Death due to cardiac arrest has occurred within a day of carfilzomib administration. Patients with New York Heart Association Class III and IV heart failure, myocardial infarction in the preceding 6 months, and conduction abnormalities uncontrolled by medications were not eligible for the clinical trials of carfilzomib. These patients may be at greater risk for cardiac complications.
Dyspnea occurred in 35% of patients enrolled in clinical trials. Grade-3 dyspnea was experienced by 5% of patients, and no grade-4 events were reported.
Multiple myeloma — the second most common hematologic cancer — results from an abnormality of plasma cells, usually in the bone marrow. In the U.S., approximately 70,000 people have the disease, and approximately 24,000 new cases are diagnosed annually.
Source: Amgen; August 4, 2014.