The proteasome inhibitors (PIs), carfilzomib and bortezomib, are widely used to treat myeloma but head-to-head comparisons have produced conflicting results. We compared the activity of these PIs in combination with cyclophosphamide and dexamethasone (KCd vs VCd) in second line treatment using fixed duration therapy and evaluated the efficacy of carfilzomib maintenance. MUKfive was a phase II controlled, parallel group trial that randomised patients (2:1) to KCd (201) or VCd (99); responding patients on carfilzomib were randomised to maintenance carfilzomib (69) or no further treatment (72). Primary endpoints were (i) very good partial response (VGPR, non-inferiority, OR 0.8) at 24 weeks, and (ii) progression-free survival (PFS). More participants achieved ≥VGPR with carfilzomib compared to bortezomib (40.2% vs. 31.9%, OR=1.48, 90%CI:0.95,2.31; non-inferior), with a trend for particular benefit in adverse risk disease. KCd was associated with higher overall response (≥PR, 84.0% vs. 68.1%, OR=2.72, 90%CI:1.62,4.55, p=0.001). Neuropathy (grade ≥3 or ≥2 with pain) was more common with bortezomib (19.8% vs. 1.5%, p<0.0001), while grade ≥3 cardiac events and hypertension were only reported in the KCd arm (3.6% each). Median PFS in the KCd arm was 11.7 months vs. 10.2 months in the VCd arm (HR=0.95, 80% CI:0.77, 1.18). Carfilzomib maintenance was associated with longer PFS, median 11.9 months vs 5.6 months for no maintenance (HR 0.59, 80% CI 0.46-0.77, p=0.0086). When used as fixed duration therapy, KCd is at least as effective as VCd in first relapse, and carfilzomib is an effective maintenance agent. This trial is registered: ISRCTN 17354232.
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