A retrospective analysis of 3954 patients in phase 2/3 trials of bortezomib for the treatment of multiple myeloma: towards providing a benchmark for the cardiac safety profile of proteasome inhibition in multiple myeloma

• Type of Material: Article
• Authors: Jacob P. Laubach, Dana-Farber Cancer Institute; Javid J. Moslehi, Vanderbilt University; Sanjeev A. Francis, Massachusetts General Hospital; Jesús F. San Miguel, Clinica Universidad de Navarra; Pieter Sonneveld, Erasmus Medical Centre; Robert Z. Orlowski, University of Texas M. D. Anderson Cancer Center; Philippe Moreau, University Hospital Nantes; Laura Rosinol, Hospital Clínic de Barcelona; Edward A. Faber, Oncology/Hematology Care, Cincinnati; Peter Voorhees, Levine Cancer Institute; Maria-Victoria Mateos, University of Salamanca; Loreta Marquez, Janssen Research & Development LLC; Huaibao Feng, Janssen Research & Development LLC; Avinash Desai, Janssen Global Services LLC; Helgi van de Velde, Millennium Pharmaceuticals Inc; Jennifer Elliott, Millennium Pharmaceuticals Inc; Hongliang Shi, Millennium Pharmaceuticals Inc; Edward Dow, Foundation Medicine, Inc.; Nishith Jobanputra, Millennium Pharmaceuticals Inc; Sagar Lonial, Emory University
• Language: English
• Date: 2017-08-01
• Publisher: Wiley: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2017 John Wiley & Sons Ltd
• Final Published Version (URL): http://dx.doi.org/10.1111/bjh.14708
• Title of Journal or Parent Work: British Journal of Haematology
• ISSN: 0007-1048
• Volume: 178
• Issue: 4
• Start Page: 547
• End Page: 560
• Grant/Funding Information: Millennium Pharmaceuticals Inc., and Janssen Global Services LLC
• Keywords: Science & Technology; HEART-FAILURE; bortezomib; INDUCTION TREATMENT; THERAPY; Hematology; Life Sciences & Biomedicine; multiple myeloma; STEM-CELL TRANSPLANTATION; cardiac; BLOCK SECONDARY; PLUS DEXAMETHASONE; cardio-oncology; DOSE DEXAMETHASONE; CARFILZOMIB; AL AMYLOIDOSIS; SYSTEM
• Research Categories: Health Sciences, Public Health; Health Sciences, Oncology; Health Sciences, Pharmacology

Abstract

This retrospective analysis aimed to establish the overall cardiac safety profile of bortezomib using patient-level data from one phase 2 and seven phase 3 studies in previously untreated and relapsed/refractory multiple myeloma (MM). Seven clinically relevant primary [congestive heart failure (CHF), arrhythmias, ischaemic heart disease (IHD), cardiac death] and secondary (hypertension, dyspnoea, oedema) cardiac endpoints were defined based on MedDRA v16.0 preferred terms. 2509 bortezomib-treated patients and 1445 patients in non-bortezomib-based control arms were included. The incidence of grade ≥3 CHF was 1·3–4·0% in studies in relapsed/refractory MM and 1·2–4·7% in previously untreated MM (2·0–7·6% all grades), with no significant differences between bortezomib- and non-bortezomib-based arms in comparative studies. Incidences of arrhythmias (1·3–5·9% grade ≥2; 0·6–4·1% grade ≥3), IHD (1·2–2·9% all grades; 0·4–2·7% grade ≥3) and cardiac death (0–1·4%) were low, with no differences between bortezomib-based and non-bortezomib-based arms. Higher rates of oedema (mostly grade 1/2) were seen in bortezomib-based versus non-bortezomib-based arms in one study and a pooled transplant study analysis. Logistic regression analyses of comparative studies showed no impact on cardiac risk with bortezomib-based versus non-bortezomib-based treatment. Bortezomib-based treatment was associated with low incidences of cardiac events.