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Meta-Analysis
. 2017 Aug;178(4):547-560.
doi: 10.1111/bjh.14708. Epub 2017 May 3.

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

Jacob P Laubach  1 , Javid J Moslehi  2 , Sanjeev A Francis  3 , Jesús F San Miguel  4 , Pieter Sonneveld  5 , Robert Z Orlowski  6 , Philippe Moreau  7 , Laura Rosiñol  8 , Edward A Faber Jr  9 , Peter Voorhees  10 , Maria-Victoria Mateos  11 , Loreta Marquez  12 , Huaibao Feng  12 , Avinash Desai  13 , Helgi van de Velde  14 , Jennifer Elliott  14 , Hongliang Shi  14 , Edward Dow  15 , Nishith Jobanputra  14 , Dixie-Lee Esseltine  14 , Liviu Niculescu  14 , Kenneth C Anderson  1 , Sagar Lonial  16 , Paul G Richardson  1
Affiliations
Meta-Analysis

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

Jacob P Laubach et al. Br J Haematol. 2017 Aug.

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.

Keywords: bortezomib; cardiac; cardio-oncology; multiple myeloma.

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Figures

Fig 1.
Fig 1.
Time to first onset of CHF and dyspnoea in (A, B) VISTA (San Miguel et al, 2008), (C, D) the pooled transplant analysis and (E, F) APEX. HR shown for time to first onset of CHF or dyspnoea. Circles represent individual censored observations. APEX, Assessment of Proteasome Inhibition for Extending Remissions study;Btz, bortezomib; CHF, congestive heart failure; Dex, dexamethasone; HR, hazard ratio; MP, melphalan-prednisone; VISTA, VELCADE® as Initial Standard Therapy in Multiple Myeloma: Assessment with Melphalan and Prednisone study; VMP, bortezomib-melphalan-prednisone.
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