Incidence and Management of Proteasome Inhibitor-Related Cardiotoxicity in Multiple Myeloma Patients at Memorial Sloan Kettering Cancer Center
Authors: Land Josiah , Afifi Salma , Adel Nelly G. , Devlin Sean , Arora Arshi , Lendvai Nikoletta , Landgren Ola 
Published: October 2019

Abstract
Introduction: Given that the rate of cardiovascular (CV) morbidity increases with age and the median age of patients with multiple myeloma (MM) is 65, CV complications can occur during MM treatment. The proteasome inhibitors (PIs), bortezomib and carfilzomib, may play a role in the development of treatment-related cardiotoxicity as suggested by phase 2 clinical studies and a phase 3 trial (Stewart AK et al. N Engl J Med 2015;372:142-52). Reported treatment-related cardiotoxicity includes hypertension, congestive heart failure (CHF), myocardial infarction, and cardiac arrest. The objectives of this study are to define the incidence of cardiotoxicity in MM patients treated with bortezomib and carfilzomib and to evaluate whether the dose and pre-existing cardiac history affects that incidence.
Study design and methods:Using the pharmacy database, we identified all MM patients treated at Memorial Sloan Kettering Cancer Center between 1/2010 to 10/2014 who were treated with bortezomib or carfilzomib in the second-line and relapsed refractory setting. Of note, all patients in the carfilzomib arm received prior bortezomib; thus, MM patients in the carfilzomib arm were more heavily pretreated and the two arms should be compared with caution. Data collected included: baseline demographics, baseline disease status, treatment given including dose and number of cycles, baseline cardiovascular comorbidities and medications, and pre- and post-treatment ejection fraction. Cardiotoxicity recorded was defined as grade 3 or more (requiring intervention) and included: hypertension, CHF, coronary artery disease, pulmonary hypertension, myocardial infarction, stroke, and/or arrhythmias. Descriptive statistics were used to analyze baseline demographics, including median and range for continuous variables and frequency and percentage for categorical variables. Fisher's exact test was used to assess the association between clinical and treatment characteristics and cardiotoxicity.
Results: 157 patients were eligible for analysis with 47 in the bortezomib arm and 110 in the carfilzomib arm. The overall incidence of cardiotoxicity across both arms was 17% with an incidence of 9% (n = 4) and 20% (n = 22) in the bortezomib and carfilzomib arms, respectively. The most common events reported were arrhythmias (n = 3) with bortezomib and CHF (n = 12) with carfilzomib. The incidence of CHF and cardiomyopathy was 4% and 19% in the bortezomib and the more heavily pretreated carfilzomib arms, respectively. Baseline cardiac comorbidities were not found to increase the risk of cardiotoxicity while on treatment with carfilzomib (p = 0.815); due to small numbers, we were unable to assess this aspect in the bortezomib arm. Based on a categorization of carfilzomib dose (≤20 mg/m2, 27 mg/m2, or ≥36 mg/m2) starting on cycle 2, there was a significant association between the dose level received and cardiotoxicity (p=0.003); patients treated at dose level ≥36 mg/m2 were most likely to have a cardiac-related event while on therapy. Patients receiving the higher doses were treated on a clinical trial (Lendvai et al. Blood 2014;124:899-906), and they were among the most heavily pretreated. Management of cardiac events with carfilzomib was largely supportive with all patients requiring pharmacological intervention, 64% (n= 14) requiring hospital admission, and 73% (n = 16) requiring treatment delays.
Conclusion: Grade 3 or more cardiotoxicity is a potential complication of treatment with PIs. However, there is no increased risk of CV deaths noted in our study. The results show a higher risk of cardiac toxicity in heavily pretreated MM patients receiving higher doses (≥36 mg/m2) of carfilzomib. The number of prior lines of therapy is a major factor when defining CV events in relation to a given therapy. Importantly, both carfilzomib and bortezomib are highly efficacious anti-myeloma drugs; CV risks should be assessed for individual patients and in relation to benefits.

Disclosures
Landgren: BMJ Publishing: Honoraria; Medscape: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Onyx: Honoraria; International Myeloma Foundation: Research Funding; Onyx: Research Funding; BMJ Publishing: Consultancy; Medscape: Consultancy; Bristol-Myers Squibb: Consultancy; Celgene: Consultancy; Onyx: Consultancy.