OBJECTIVES : Patients with multiple myeloma (MM) often have cardiovascular risk factors and/or established cardiovascular disease. Carfilzomib is approved for managing relapsed/refractory (RR) MM and may be associated with increased risk of cardiovascular adverse events (AEs). We leveraged machine learning to identify risk factors for developing cardiovascular AEs in patients with RRMM treated with carfilzomib.

METHODS : Retrospective data were pooled from carfilzomib phase 3 trials (ASPIRE, ARROW, FOCUS, ENDEAVOR). Variables analyzed included baseline patient demographics, vital signs, electrocardiogram results, laboratory values, and comorbidities. Topological data analysis (an analytic approach akin to dimensionality reduction and distinct from traditional multivariate modeling analysis) was used to reveal AE occurrence micropatterns. A decision algorithm accounting for both posterior and prior AE probability with respect to the variables was used to find clinically interpretable risk factors.

RESULTS : In the pooled population (n=1,484), grade ≥3 cardiovascular AEs of interest were cardiac failure (5.1%), ischemic heart disease (2.2%), and hypertension (9.2%). The modeling approach successfully grouped patients into high-risk %/low-risk % groups (cardiac failure: 31.1%/68.9%; ischemic heart disease: 38.5%/61.5%; hypertension: 32.1%/67.9%), with AE rates enriched in the high-risk group (cardiac failure AE rate was 4x higher in the high-risk than low-risk group [10.8% vs 2.4%]). Risk factors for grade ≥3 cardiac failure were baseline comorbidity of congestive heart failure, moderate-to-severe chronic kidney disease, mean QRS ≥120 msec, glucose ≥7.9 mmol/L, and Asian race; for grade ≥3 ischemic heart disease, risk factors were comorbidity of prior myocardial infarction, glucose ≥7.9 mmol/L, activated partial thromboplastin time ≤20 seconds and creatinine clearance ≤60 mL/min; for grade ≥3 hypertension, risk factors were systolic blood pressure ≥140 mmHg and Asian or African race.

CONCLUSIONS : Baseline risk factors identified for cardiovascular AEs were detectable by standard clinical assessment or laboratory tests. These findings may provide direction for future research into cardiovascular AE risk factors in carfilzomib-treated patients.