A randomized phase III study of carfilzomib vs low-dose corticosteroids with optional cyclophosphamide in relapsed and refractory multiple myeloma (FOCUS)

Abstract

This randomized, phase III, open-label, multicenter study compared carfilzomib monotherapy against low-dose corticosteroids and optional cyclophosphamide in relapsed and refractory multiple myeloma (RRMM). Relapsed and refractory multiple myeloma patients were randomized (1:1) to receive carfilzomib (10-min intravenous infusion; 20 mg/m2 on days 1 and 2 of cycle 1; 27 mg/m2 thereafter) or a control regimen of low-dose corticosteroids (84 mg of dexamethasone or equivalent corticosteroid) with optional cyclophosphamide (1400 mg) for 28-day cycles. The primary endpoint was overall survival (OS). Three-hundred and fifteen patients were randomized to carfilzomib (n=157) or control (n=158). Both groups had a median of five prior regimens. In the control group, 95% of patients received cyclophosphamide. Median OS was 10.2 (95% confidence interval (CI) 8.4–14.4) vs 10.0 months (95% CI 7.7–12.0) with carfilzomib vs control (hazard ratio=0.975; 95% CI 0.760–1.249; P=0.4172). Progression-free survival was similar between groups; overall response rate was higher with carfilzomib (19.1 vs 11.4%). The most common grade ⩾3 adverse events were anemia (25.5 vs 30.7%), thrombocytopenia (24.2 vs 22.2%) and neutropenia (7.6 vs 12.4%) with carfilzomib vs control. Median OS for single-agent carfilzomib was similar to that for an active doublet control regimen in heavily pretreated RRMM patients.

Phase 1/2 study of lenalidomide combined with low-dose cyclophosphamide and prednisone in lenalidomide-refractory multiple myeloma

“…37 However, another study showed that low-dose cyclophosphamide (50 mg daily) combined with steroids has markedly lower activity in lenalidomide-and bortezomib-exposed patients (63% of these patients were double-refractory to bortezomib and IMiDs), with at least PR in 11.4% of these patients and a median PFS and OS of only 3.3 months and 10.0 months, respectively. 38 This outcome is inferior to that observed with the REP regimen in doublerefractory MM patients and suggests clinical synergy between lenalidomide and low-dose cyclophosphamide.…”

“…32 Carfilzomib monotherapy induces at least PR in 19.1% of extensively pretreated patients with a median PFS of 3.7 months. 38 Daratumumab induces at least PR in 29% to 36% of patients with a median PFS of 3.7 to 5.6 months, 45,46 whereas elotuzumab 47 has no single-agent activity in this setting. The outcome of the REP regimen also compares favorably to the results of carfilzomib-or pomalidomide-based combinations in relapsed/refractory For personal use only.…”

Analysis of carfilzomib cardiovascular safety profile across relapsed and/or refractory multiple myeloma clinical trials

“…This CV safety analysis was based on phase 1/1b trials (PX-171-001, 18 26 (supplemental Figure 1). Eligibility criteria for phase 1 and 2 studies were presented previously.…”

A question of class: Treatment options for patients with relapsed and/or refractory multiple myeloma

“…Although monotherapy is not commonly used in patients with RRMM, it should be noted that bortezomib monotherapy has shown efficacy in the phase III APEX study (Table II) (Harrison et al, 2015;Richardson et al, 2005). However, carfilzomib monotherapy did not improve OS when compared with low-dose corticosteroid treatment (plus optional cyclophosphamide) in patients who had received ≥3 previous lines of therapy (Table 2) (Hajek et al, 2016). Currently there are no phase III trial data assessing the efficacy of ixazomib monotherapy.…”