PFS Superior in Multiple Myeloma With Less Frequent, Higher Dose Carfilzomib

Sean E. Harper, MD

Sean E. Harper, MD

Progression-free survival (PFS) was extended by 3.6 months with higher-dose, once-weekly carfilzomib (Kyprolis) compared with a lower-dose, twice-weekly regimen in patients with relapsed/refractory multiple myeloma, according to according to phase III results from the ARROW trial.

In the trial, patients assigned to once-weekly carfilzomib at 70 mg/m²with dexamethasone had 3.6 months longer PFS compared with those assigned to a twice-weekly 27 mg/m²dose with dexamethasone (11.2 vs 7.6 months; hazard ratio [HR], 0.69; 95% CI, 0.54-0.88).

“Kyprolis has been demonstrated to be the most effective proteasome inhibitor available to patients with multiple myeloma,” Sean E. Harper, MD, executive vice president of Research and Development at Amgen, the manufacturer of carfilzomib, said in a press release. “We are encouraged by the efficacy and safety profile of Kyprolis and dexamethasone administered once-weekly in the ARROW study.”

ARROW is an open-label phase III trial comparing once-weekly versus twice-weekly carfilzomib. Eligible patients (N = 478) had undergone at least 2, but no more than 3, prior therapies for relapsed and refractory multiple myeloma including bortezomib (Velcade) and an IMiD.

Patients were randomly assigned to once-weekly carfilzomib (20 mg/m²on day 1 of cycle 1; 70 mg/m²on days 8 and 15 of cycle 1; and 70 mg/m²on days 1, 8, and 15 of subsequent cycles) or twice-weekly carfilzomib (20 mg/m²on days 1 and 2 of cycle 1; 27 mg/m²on days 8, 9, 15, and 16 of cycle 1; and 27 mg/m²on days 1, 2, 8, 9, 15, and 16 of subsequent cycles). Patients in both arms received 40 mg of dexamethasone.

The primary endpoint of the trial was PFS. Secondary endpoints included overall response rate, overall survival, and safety and tolerability.

The most frequently reported treatment-emergent adverse events (≥20%) in either treatment arm were anemia, diarrhea, fatigue, hypertension, insomnia, and pyrexia.

In July 2015, the FDA approved carfilzomib for use in combination with lenalidomide (Revlimid) and dexamethasone for the treatment of patients with relapsed/refractory multiple myeloma following 1 to 3 lines of therapy, based on based on results from the phase III ASPIRE trial.

This indication was expanded in January 2016 for use in combination with dexamethasone or with lenalidomide plus dexamethasone for patients with relapsed/refractory multiple myeloma following prior treatment with 1 to 3 lines of therapy, based on findings from the phase III ENDEAVOR trial.

The drug is also approved as a monotherapy for the treatment of patients with relapsed/refractory myeloma who have received 1 or more lines of therapy.

In August 2017, the FDA accepted a supplemental new drug application (sNDA) seeking to add overall survival (OS) data from the phase III ENDEAVOR trial to the label for carfilzomib for use in patients with relapsed or refractory multiple myeloma.

Results from ENDEAVOR trial published inThe Lancet Oncologyin August showed that carfilzomib reduced the risk of death by 21% compared with bortezomib.

Carfilzomib in combination with dexamethasone extended OS by 7.6 months compared with bortezomib and dexamethasone (47.6 vs 40 months; HR, 0.791; 95% CI, 0.648-0.964;P= .010). The OS benefit was consistent for both patients who received previous bortezomib (HR, 0.75) and those who did not (HR, 0.84).

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

Investigators administered carfilzomib at a starting dose of 20 mg/m²on 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 bortezomib. Most patients (75%) received bortezomib subcutaneously.

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

Reference:

Dimopoulos MA, Goldschmidt H, Niesvizky R, et al. Carfilzomib or bortezomib in relapsed or refractory multiple myeloma (ENDEAVOR): an interim overall survival analysis of an open-label, randomised, phase 3 trial [published online August 23, 2017].Lancet Oncol. doi: 10.1016/ S1470-2045(17)30578-8.