Kyprolis Label Update Approved for Myeloma Treatment

The Food and Drug Administration (FDA) approved a supplemental new drug application that adds overall survival (OS) data from the phase 3 ENDEAVOR trial to the label for Kyprolis (carfilzomib) to treat patients with relapsed or refractory multiple myeloma.

Results from the primary ENDEAVOR OS analysis published in the Lancet Oncology showed that Kyprolis reduced the risk of death by 21 percent compared with Velcade (bortezomib) in patients with relapsed/refractory multiple myeloma.

Kyprolis in combination with dexamethasone extended OS by 7.6 months compared with Velcade and dexamethasone (47.6 vs 40 months). The OS benefit was consistent for both patients who received previous Velcade and those who did not.

"Overall survival is generally considered to be the gold standard of endpoints because it clearly demonstrates a drug's value in extending a patient's life" David M. Reese, M.D., senior vice president of Translational Sciences and Oncology at Amgen, said in a press release. "Blood cancer therapies approved by the FDA between 2003 and 2013 only improved overall survival by an average of 2.61 months. Kyprolis and dexamethasone improved overall survival by 7.6 months, underscoring that this regimen is a significant advancement and should be considered a standard of care for patients with relapsed or refractory multiple myeloma.”

Kyprolis is currently approved in combination with dexamethasone or with Revlimid (lenalidomide) plus dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma who have received one to three lines of therapy. The treatment is also approved as a monotherapy for relapsed/refractory myeloma patients who have received one or more lines of therapy.

Three-year follow-up data from ENDEAVOR showed that Kyprolis plus dexamethasone reduced the risk of death by 24 percent versus Velcade /dexamethasone, with a nine-month median OS benefit (47.8 vs 38.8 months). There were no new safety concerns with the longer follow-up.

From June 20, 2012, to June 30, 2014, 929 patients enrolled in ENDEAVOR, an open-label, randomized controlled study. Patients were randomly assigned to Kyprolis /dexamethasone (464 patients) or Velcade/dexamethasone (465 patients) and treated at 198 medical centers in 27 countries in Europe, North America, South America and the Asia-Pacific region.

Investigators administered Kyprolis at a starting dose of 20 mg/m² on days 1 and 2 of cycle 1. If tolerated, the dose was escalated to 56 mg/m² on day 8 of cycle 1. The 56 mg/m2 dose was then maintained on days 9, 15 and 16, and throughout subsequent cycles. Patients in the control arm received 1.3 mg/m² of Velcade. Most patients (75 percent) received Velcade subcutaneously.

The median age of patients enrolled in the trial was 65 years, and 93 percent had an ECOG performance status of 0 or 1 (about 50 percent ECOG 0), and about 20 percent of the patients had high cytogenetic risk by fluorescence in situ hybridization.

In a posthoc landmark analysis measuring OS from time of progression, investigators found that median OS was 21.5 months in both groups.

Adverse events observed in this updated analysis were consistent with those previously reported for ENDEAVOR. Investigators noted that rates of grade 2 or higher peripheral neuropathy were five-times higher in patients assigned to Velcade (35 percent vs 7 percent).

Median duration of treatment was 48.0 weeks (median, 12 cycles) in the Kyprolis arm versus 27 weeks (median, eight cycles) in the Velcade group. Median relative dose intensity was 91 percent for Kyprolis and 85 percent for Velcade.

Nearly all patients in both groups (99 percent) experienced any grade adverse events (AEs). The most common AEs (20 percent or higher) in the Kyprolis arm were anemia, diarrhea, pyrexia, dyspnea, fatigue, hypertension, cough, insomnia, upper respiratory tract infection, peripheral edema, nausea, bronchitis, asthenia, back pain, thrombocytopenia and headache.

Slightly more patients in the Kyprolis group experienced grade 3 or higher AEs (81 percent vs 71 percent). Frequent (at least 5 percent) grade 3 or higher AEs that occurred more often in the Kyprolis group included anemia (16 percent vs 10 percent in the Velcade arm), hypertension (15 percent vs 3 percent), dyspnea (6 percent vs 2 percent), and decreased lymphocyte count (6 percent vs 2 percent). Rates of pneumonia (9 percent) and thrombocytopenia (9 percent) were equal in both groups.

Twenty-seven patients (6 percent) in the Kyprolis arm experienced grade 3 or higher cardiac failure versus nine patients (2 percent) in the Velcade group. Six percent of patients assigned to Kyprolis and 3 percent of those assigned to Velcade experienced grade 3 or higher acute renal failure.