Quantifying The Risk Of Heart Failure Associated With Proteasome Inhibition: A Retrospective Analysis Of Heart Failure Reported In Phase 2 and Phase 3 Studies Of Bortezomib (Btz) In Multiple Myeloma (MM)
Authors: Laubach Jacob P. , San Miguel Jesús F , Sonneveld Pieter , Orlowski Robert Z. , Moreau Philippe , Rosiñol Laura , Moslehi Javid J , Faber Edward A , Voorhees Peter M , Marquez Loreta , Desai Avinash , van de Velde Helgi , Elliott Jennifer , Shi Hongliang , Dow Edward , Jobanputra Nishith , Esseltine Dixie-Lee , Niculescu Liviu , Anderson Kenneth C. , Lonial Sagar , Richardson Paul G. 
Published: October 2019

Abstract

Background
Due to recent treatment advances, MM patients (pts) are living longer (Kumar et al, Blood 2008), underscoring the importance of patient quality of life and management of adverse events (AEs) related to MM therapy. MM pts are at risk of cardiac events due to age and disease-related factors, as well as cardiotoxicity from treatments including anthracyclines, proteasome inhibitors (PIs), and high-dose therapy. Both of the US FDA-approved PIs, Btz and carfilzomib, have been associated with cardiac events in MM pts, with cardiac toxicity and cardiac adverse reactions included under ‘Warnings and Precautions’ in the respective US labels. The development of Btz, a reversible boronate peptide PI, involved numerous large, controlled clinical trials, providing a benchmark for the expected incidence of heart failure with PIs. Here, we report a retrospective analysis of the risk of heart failure associated with Btz in phase 2 and 3 MM studies leading to regulatory approvals in the US and EU.

Methods
Study databases were retrospectively analyzed for AEs of grade ≥3 heart failure. In the relapsed/refractory setting, the following studies were included: the phase 2 SUMMIT trial (Btz ± dexamethasone; Richardson et al, NEJM 2003), and the phase 3 APEX (Btz vs dexamethasone; Richardson et al, NEJM 2005), MMY-3001 (Btz + liposomal doxorubicin vs Btz; Orlowski et al, J Clin Oncol 2007), and MMY-3021 (subcutaneous [SC] vs intravenous [IV] Btz; Moreau et al, Lancet Oncol 2011) trials. In the upfront setting, the phase 3 VISTA trial (Btz-melphalan-prednisone [VMP] vs MP; San Miguel et al, NEJM 2008) in transplant-ineligible pts and a pooled analysis of three phase 3 trials (IFM 2005-01, HOVON-65/GMMG-HD4, PETHEMA GEM2005MENOS65) of Btz-based vs non-Btz-based induction (N=779 vs 776; Sonneveld et al, IMW 2013) in transplant-eligible pts were included. Cardiac exclusion criteria typically included NYHA class III/IV (≥II in MMY-3001), myocardial infarction within 6 mos, and ECG evidence of acute ischemia. Heart function tests (primarily ECG) were incorporated in study designs. Heart failure events were analyzed and re-coded for consistency across studies, using standardized MedDRA (v4.0, 8.0, 8.1, 9.0, 9.1, and 10.0) query preferred terms with grouping of clinically related events.

Results
2509 pts treated with Btz in the specified phase 2 and 3 trials and an additional 1445 pts treated with non-Btz-based therapies in the control arms of the phase 3 studies were included in this analysis. Pt characteristics and rates of grade ≥3 heart failure by study arm are shown in the table. Among all Btz-treated pts, the rate of grade ≥3 heart failure was 2.0%; the rate was 2.0% in newly diagnosed pts and 1.9% in relapsed and/or refractory pts. In the comparative studies (APEX, VISTA) and pooled pre-ASCT induction analysis, the overall rates across the Btz and non-Btz arms were 2.0% and 1.6%, respectively (p=0.41). Risk factors, including prior anthracycline exposure and history of cardiac complications, were balanced between Btz and non-Btz arms.

Conclusions
In this retrospective analysis of data from key phase 2 and 3 studies, Btz was associated with a low rate of grade ≥3 heart failure in both the newly diagnosed (2.0%) and relapsed and/or refractory (1.9%) settings. Importantly, across comparative studies, the rate was only marginally higher and not statistically different from the background rate in non-Btz comparator arms. Data from ongoing prospective and comparative studies are necessary to determine whether PIs – including Btz, carfilzomib, and PIs at earlier stages of clinical development – have different cardiotoxicity profiles.

Disclosures:
San Miguel: Millennium: The Takeda Oncology Company: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Onyx: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Sonneveld:Jansssen: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Onyx: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Orlowski:Bristol-Myers Squibb: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Millennium: The Takeda Oncology Company: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Onyx: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Resverlogix: Research Funding; Array Biopharma: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Merck: Membership on an entity’s Board of Directors or advisory committees. Moreau:Janssen: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Millennium: The Takeda Oncology Company: Membership on an entity’s Board of Directors or advisory committees; Onyx: Membership on an entity’s Board of Directors or advisory committees. Rosiñol:Janssen: Honoraria; Celgene: Honoraria. Moslehi:Alnylam: Consultancy; Novartis: Consultancy; Millennium: The Takeda Oncology Company: Consultancy; Forest Laboratories: Research Funding. Faber:Celgene: Consultancy, Honoraria; Millennium: The Takeda Oncology Company: Consultancy, Honoraria; Onyx: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria. Voorhees:Acetylon: Research Funding; Millennium: The Takeda Oncology Company: Research Funding; Merck: Research Funding; Janssen: Research Funding; Prolexys Pharmaceuticals: Research Funding; GlaxoSmithKline: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Abbott Laboratories: Consultancy. Marquez:Johnson & Johnson: Equity Ownership; Janssen: Employment. Desai:Janssen: Employment; Johnson & Johnson: Equity Ownership. van de Velde:Janssen: Employment; Johnson & Johnson: Equity Ownership. Elliott:Millennium: The Takeda Oncology Company: Employment. Shi:Millennium: The Takeda Oncology Company: Employment. Dow:Millennium: The Takeda Oncology Company: Employment. Jobanputra:Millennium: The Takeda Oncology Company: Employment. Esseltine:Millennium: The Takeda Oncology Company: Employment; The Takeda Pharmaceutical Company: Equity Ownership. Niculescu:Millennium: The Takeda Oncology Company: Employment. Anderson:Celgene: Consultancy; Onyx Pharmaceuticals: Consultancy; Sanofi-Aventis: Consultancy; Gilead: Consultancy; Acetylon Pharmaceuticals: Equity Ownership; Oncopep: Equity Ownership. Lonial:Merck: Consultancy; Onyx Pharmaceuticals: Consultancy; Bristol-Myers Squibb: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Millennium: The Takeda Oncology Company: Consultancy. Richardson:Millennium: The Takeda Oncology Company: Membership on an entity’s Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity’s Board of Directors or advisory committees; Celgene: Membership on an entity’s Board of Directors or advisory committees.