IntroductionProteasome 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 MethodThis 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.ResultsTable 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.ConclusionsIn 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 1Bortezomib % (n=44)Carfilzomib % (n=52)P-valueASCVD Risk0.430-10%465010-20%2936>20%2614Male Gender57710.82Median Age, y61 (38-91)60 (36-86)0.20Past Smoker26510.02Type II Diabetes11170.41Hyperlipidemia27270.97Kidney Disease9120.70Prior History of Cardiac Event59600.96Median Duration on Bortezomib, d2292030.67Median Duration on Carfilzomib, d87.5ACE Inhibitor Use32130.03Antithrombotic Use48230.01ISS Stage0.72III3425FISH Risk0.13Standard/Intermediate9385High715Median Prior Lines of Therapy0 (0-4)2 (0-8)<0.001Stem Cell Transplant45650.05Table 2Cardiac adverse eventsBortezomibCarfilzomibP-valueTotal Cardiac Adverse Events*19170.08Heart Failure96Acute Coronary Syndrome12Left Ventricular Dysfunction01Atrial Fibrillation/Flutter22Thromboembolism22Systemic Hypertension33Pulmonary Hypertension01Orthostatic Hypotension20Sudden Cardiac Death00*Some patients had multiple events [Display omitted] DisclosuresNo relevant conflicts of interest to declare.