Elsevier

Journal of Cardiac Failure

Volume 21, Issue 2, February 2015, Pages 138-144
Journal of Cardiac Failure

Clinical Investigation
Patterns of Cardiac Toxicity Associated With Irreversible Proteasome Inhibition in the Treatment of Multiple Myeloma

https://doi.org/10.1016/j.cardfail.2014.11.008Get rights and content

Highlights

  • Case series of cardiotoxicity with carfilzomib, a proteasome inhibitor for myeloma.

  • There was a common clinical syndrome of dyspnea with LV systolic dysfunction.

  • Presentations ranged from exertional dyspnea to acute decompensated heart failure.

  • Cardiac function often improves with stopping the drug and initiating HF therapies.

Abstract

Carfilzomib is a novel irreversible proteasome inhibitor (PI) used with increasing frequency to treat patients with relapsed and/or refractory multiple myeloma (RRMM). This agent is an effective treatment for this challenging population, but proteasome inhibition has the potential of significant cardiac toxicity via the accumulation of intracellular protein aggregates. Although large clinical trials have not suggested an excess of heart failure with PI therapy, nonhuman animal studies and case reports in humans with the PI bortezomib have suggested otherwise. We describe the clinical presentation and management of 6 patients with RRMM who experienced significant cardiac toxicity associated with carfilzomib treatment. A common clinical syndrome of dyspnea associated with left ventricular systolic and/or diastolic dysfunction was identified. These abnormalities were largely reversible with prompt cessation of PI therapy and initiation of traditional heart failure treatments. Safe readministration of carfilzomib with dose modification was possible in some cases.

Section snippets

Patient 1

A 59-year-old Haitian woman with hypertension was treated for IgG kappa multiple myeloma for ∼10 years with the use of combinations of dexamethasone, melphalan, thalidomide, lenalidomide, and bortezomib. In February 2013 she started carfilzomib and dexamethasone for RRMM. A baseline 2-dimensional transthoracic echocardiogram (2D-echo) showed normal left ventricular (LV) systolic function (Table 1). Three months later, she presented with New York Heart Association (NYHA) functional class III HF

Discussion

Cardiovascular toxicity is a significant concern with carfilzomib, but it remains poorly understood. Initial trials and pooled safety data suggested an incidence of HF of ∼7%, but more recent reports note a higher incidence of up to 11% with higher drug doses.19 Cases of HF have been observed across multiple tumor types,20 and dyspnea is one of the most commonly reported symptoms but usually with few clinical details to interpret etiology. In the present case series, we describe a spectrum of

Study Limitations

Several limitations of this case series are noted. We were not able to define the overall incidence of cardiac dysfunction with this agent; that is better accomplished through prospective cohort studies or retrospective analyses of large clinical trial databases. During the time period in which these cases occurred, there were 25 patients treated with carfilzomib at Vanderbilt and 20 patients treated at Penn resulting in crude incidence rates of cardiac toxicity of 12% and 15%, respectively.

Conclusion

This case series highlights the potential risk of substantial cardiac toxicity in patients with RRMM being treated with carfilzomib. Our findings suggest that all patients should have a comprehensive cardiovascular evaluation before initiating PI therapy, and the development of new dyspnea during therapy warrants expedient evaluation for cardiotoxicity. There is a common clinical syndrome of dyspnea with LV systolic and diastolic dysfunction, although there is a wide range in the severity of

Disclosures

Dr Lenihan is a consultant for Onyx Pharmaceuticals, which manufactures carfilzomib. The other authors report no other relevant conflicts of interest regarding this manuscript.

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