Once-weekly vs twice-weekly carfilzomib (K) dosing plus dexamethasone (d) in patients with relapsed and refractory multiple myeloma (RRMM): Results of the randomized phase 3 study A.R.R.O.W.

8000 Background: Twice-weekly K at 20/27 mg/m2 is approved for the treatment of RRMM. To develop a more convenient K regimen, once-weekly K plus d was assessed in the phase 1/2 CHAMPION-1 study, establishing a maximum tolerated dose of K 20/70 mg/m2 for RRMM pts. We present results from the pre-planned interim analysis of the phase 3 study A.R.R.O.W. comparing Kd once-weekly at 20/70 mg/m2 (once-weekly group) vs twice-weekly at 20/27 mg/m2 (twice-weekly group). Methods: Pts with 2–3 prior therapies and prior exposure to proteasome inhibitor and immunomodulatory agent were eligible. Pts were randomized 1:1 to receive either once- or twice-weekly K plus d. The once-weekly group received K (30-min IV) on days (D) 1, 8, and 15 of all cycles (20 mg/m2 on D1 [cycle 1]; 70 mg/m2 thereafter). The twice-weekly group received K (10-min IV) on D1, 2, 8, 9, 15, and 16 (20 mg/m2 on D1 and 2 during cycle 1 and 27 mg/m2 thereafter). All pts received d at 40 mg on D1, 8, 15 (all cycles), and 22 (cycle 1–9 only). Treatment was given in 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall response rate (ORR), overall survival, safety, and pharmacokinetics. Results: Baseline characteristics were generally balanced. Median PFS (once- vs twice-weekly) was 11.2 mo vs 7.6 mo (hazard ratio = 0.69; 1-sided P= 0.0014). ORR (once- vs twice-weekly) was 62.9% vs 40.8% (P< 0.0001); 7.1% vs 1.7% had a complete response or better. Grade ≥3 adverse events (AEs) occurred in 67.6% (once-weekly) and 61.7% (twice-weekly). Treatment-related grade 5 AEs occurred in 5 pts (2.1%) (once-weekly) and 2 pts (0.9%) (twice-weekly). The incidence of grade ≥3 hypertension and cardiac failure (once- vs twice-weekly) was 5.9% vs 5.5% and 2.9% vs 4.3%, respectively. Conclusions: Once-weekly Kd at 20/70 mg/m2 significantly improved PFS and ORR vs twice-weekly Kd at 20/27 mg/m2. The incidence of AEs was comparable between groups. No new safety risks were found in the once-weekly group. Overall, once-weekly Kd showed favorable benefit-risk profile with a convenient dosing regimen vs twice-weekly Kd. Clinical trial information: NCT02412878.