Risk Factors for Cardiac Toxicities Associated with Proteasome Inhibitor Chemotherapy during Treatment of Multiple Myeloma
Authors: Chen John H. , Lenihan Daniel J. , Phillips Sharon E. , Jagasia Madan H. , Goodman Stacey A. , Kassim Adetola A. , Lacy Shelton L. , McDonagh Kevin T. , Moslehi Javid J. , Sethi Tarsheen K. , Slosky David A. , Ukaegbu Oluchi C. , Cornell Robert F. 
Published: October 2019

Abstract
Introduction
Proteasome inhibitors (PI) bortezomib (B) and carfilzomib (C) are cornerstone therapies for multiple myeloma (MM). An increased incidence of PI-induced cardiac adverse events (CAEs) has been reported in patients receiving C. However, risk factors for cardiac toxicity in this population remain unclear. Our objective is to evaluate the incidence of CAEs associated with C compared with B and identify risk factors for developing events.
Patients and Method
This was a retrospective analysis of 96 consecutive patients treated for MM at Vanderbilt University from 2011 to 2014 who received B (n=44) and/or C (n=52). Patients in the C group had been previously treated with B, whereas patients in the B group did not have exposure to C. No patients studied were included in both cohorts. We evaluated the clinical features and frequency of CAEs (grade II-IV heart failure, acute coronary syndrome, left ventricular dysfunction, atrial fibrillation/flutter, thromboembolism, systemic hypertension, pulmonary hypertension, orthostatic hypotension, or sudden cardiac death). To identify factors that predisposed patients to CAEs, we analyzed duration of PI therapy, 10-year atherosclerotic cardiovascular disease (ASCVD) risk (calculated risk of myocardial infarction or stroke), gender, use of antithrombotic (antiplatelet/anticoagulant) and antihypertensive medications, prior history of cardiac events, and disease cytogenetic profile. Patients with a prior history of cardiac events were followed by a cardio-oncologist during the course of treatment.
Results
Table 1 shows patient characteristics. Twenty-five patients experienced CAEs (B, 13% (n=12); C, 25% (n=13)). Cumulative incidence (CI) of CAEs was not significantly different in patients on C compared with B (log-rank test P = 0.41) (Figure 1). Heart failure was the most common type of CAE (Table 2). CAEs occurred after a median of 90 days (range, 4-456) with C and 63.5 days (range, 5-336) with B. By univariate analysis, more patients in the C group were prior smokers, underwent stem cell transplantation and had more prior lines of therapy. More patients in the B group used antithrombotic and ACE inhibitor agents. There were no other significant differences in the use of antihypertensive, antiarrhythmic, and lipid-lowering medications between cohorts.
Multivariate analysis showed that male gender (HR 5.3, 95% CI 1.5-18.0, P = 0.007) was an independent risk factor for developing CAEs. Patients taking antithrombotic agents had a lower risk of CAE compared with those not on these therapies (HR 0.1, 95% CI 0.04-0.54, P = 0.004). While ASCVD risk was not predictive of CAEs, patients with a prior history of cardiac events who were followed by a cardio-oncologist experienced fewer CAEs (HR 0.2, 95% CI 0.05-0.72, P = 0.014). Longer duration of PI use resulted in decreasing risk of CAE (HR 0.8, 95% CI 0.7-0.9, P = 0.010). There were no interactions between these outcomes.
Conclusions
In this series, the incidence of CAEs associated with C did not differ significantly from that of B. We found that events occurred early in therapy. Male gender was an independent risk factor for CAEs. Use of antithrombotic therapy was associated with significantly reduced risk of CAEs. These data suggest that patients may benefit from antithrombotic therapy and follow-up by a cardio-oncologist while on PI therapy, particularly if there is a prior history of cardiac events.
Table 1. Bortezomib % (n=44) Carfilzomib % (n=52) P-value ASCVD Risk 0.43 0-10% 46 50 10-20% 29 36 >20% 26 14 Male Gender 57 71 0.82 Median Age, y 61 (38-91) 60 (36-86) 0.20 Past Smoker 26 51 0.02 Type II Diabetes 11 17 0.41 Hyperlipidemia 27 27 0.97 Kidney Disease 9 12 0.70 Prior History of Cardiac Event 59 60 0.96 Median Duration on Bortezomib, d 229 203 0.67 Median Duration on Carfilzomib, d 87.5 ACE Inhibitor Use 32 13 0.03 Antithrombotic Use 48 23 0.01 ISS Stage 0.72 III 34 25 FISH Risk 0.13 Standard/Intermediate 93 85 High 7 15 Median Prior Lines of Therapy 0 (0-4) 2 (0-8) <0.001 Stem Cell Transplant 45 65 0.05
Table 2. Cardiac adverse events Bortezomib Carfilzomib P-value Total Cardiac Adverse Events* 19 17 0.08 Heart Failure 9 6 Acute Coronary Syndrome 1 2 Left Ventricular Dysfunction 0 1 Atrial Fibrillation/Flutter 2 2 Thromboembolism 2 2 Systemic Hypertension 3 3 Pulmonary Hypertension 0 1 Orthostatic Hypotension 2 0 Sudden Cardiac Death 0 0 *Some patients had multiple events
Figure 1. Cumulative incidence of cardiac adverse events Figure 1. Cumulative incidence of cardiac adverse events

Disclosures
No relevant conflicts of interest to declare.