Carfilzomib or bortezomib in combination with cyclophosphamide and dexamethasone followed by carfilzomib maintenance for patients with multiple myeloma after one prior therapy: results from a multicenter, phase II, randomized, controlled trial (MUK<i>five</i>)
Kwee L. Yong,
Samantha Hinsley,
Holger W. Auner,
Ceri Bygrave,
Martin F. Kaiser,
Karthik Ramasamy,
Ruth M. de Tute,
Debbie Sherratt,
Louise Flanagan,
Mamta Garg,
Stephen Hawkins,
Catherine Williams,
Jamie Cavenagh,
Neil K. Rabin,
James Croft,
Gareth Morgan,
Faith Davies,
Roger G. Owen,
Sarah R. Brown
Affiliations
Kwee L. Yong
Cancer Institute, University College London, London
Samantha Hinsley
Clinical Trials Research Unit, Leeds Institute of Clinical Trials Research, University of Leeds, Leeds
Holger W. Auner
Department of Immunology and Inflammation and The Hugh and Josseline Langmuir Centre for Myeloma Research, Imperial College London, London
Ceri Bygrave
Cardiff and Vale University Health Board, Cardiff
Martin F. Kaiser
The Institute of Cancer Research, London, UK and The Royal Marsden Hospital NHS Foundation Trust, London
Karthik Ramasamy
Department of Clinical Haematology, Oxford University Hospitals NHS Trust, Oxford
Ruth M. de Tute
Department of Clinical Haematology, Leeds Teaching Hospitals NHS Trust, Leeds
Debbie Sherratt
Clinical Trials Research Unit, Leeds Institute of Clinical Trials Research, University of Leeds, Leeds
Louise Flanagan
Clinical Trials Research Unit, Leeds Institute of Clinical Trials Research, University of Leeds, Leeds
Mamta Garg
Department of Haematology, University Hospitals of Leicester NHS Trust, Leicester
Stephen Hawkins
The Clatterbridge Cancer Centre, Liverpool
Catherine Williams
Centre for Clinical Haematology, Nottingham University Hospitals, Nottingham
Jamie Cavenagh
Department of Haematology, St Bartholomew's Hospital, London
Neil K. Rabin
Department of Haematology, University College Hospital, London
James Croft
The Institute of Cancer Research, London, UK and The Royal Marsden Hospital NHS Foundation Trust, London
Gareth Morgan
Perlmutter Cancer Center, NYU Langone Health, New York
Faith Davies
Perlmutter Cancer Center, NYU Langone Health, New York
Roger G. Owen
Haematological Malignancy Diagnostic Service (HMDS), St James's University Hospital, Leeds
Sarah R. Brown
Clinical Trials Research Unit, Leeds Institute of Clinical Trials Research, University of Leeds, Leeds
The proteasome inhibitors, carfilzomib and bortezomib, are widely used to treat myeloma but head-to-head comparisons have produced conflicting results. We compared the activity of these proteasome inhibitors 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 randomized patients (2:1) to KCd (n=201) or VCd (n=99); responding patients on carfilzomib were randomized to maintenance carfilzomib (n=69) or no further treatment (n=72). Primary endpoints were: (i) very good partial response (non-inferiority, odds ratio [OR] 0.8) at 24 weeks, and (ii) progression-free survival. More participants achieved a very good partial response or better with carfilzomib than with bortezomib (40.2% vs. 31.9%, OR=1.48, 90% confidence interval [CI]: 0.95, 2.31; non-inferior), with a trend for particular benefit in patients with adverse-risk disease. KCd was associated with higher overall response (partial response or better, 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). The median progression-free survival in the KCd arm was 11.7 months vs. 10.2 months in the VCd arm (hazard ratio [HR]=0.95, 80% CI: 0.77, 1.18). Carfilzomib maintenance was associated with longer progression-free survival, 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 in first relapase, KCd is at least as effective as VCd, and carfilzomib is an effective maintenance agent. This trial was registered with International Standard Randomised Controlled Trial Number (ISRCTN) identifier: ISRCTN17354232.
