Proteasome Inhibitor-Related Cardiotoxicity: Mechanisms, Diagnosis, and Management

Abstract

Purpose of Review Multiple myeloma is the second most common hematologic malignancy in the USA, with over 32,000 new cases and nearly 13,000 deaths expected in 2019. The past few decades in myeloma research have yielded significant advances, leading to the expansion of novel anti-myeloma agents. This review describes the incidence and mechanisms of cardiotoxicity for the FDA-approved proteasome inhibitors in myeloma and proposes strategies to assess and manage resultant cardiovascular adverse events. Recent Findings Proteasome inhibition precipitates protein aggregation and alters transcriptional activation of NF-κB targets which contributes to a pro-apoptotic signaling cascade in myeloma cells. Similar effects in cardiomyocytes and vascular smooth muscle endothelium, along with off-target downregulation of autophagy and signaling alterations of nitric oxide homeostasis, may be linked to observed cardiotoxic effects. There is preliminary evidence for cardioprotective potential for rutin, dexrazoxane, and apremilast that could have clinical applicability in the future. Summary Of the proteasome inhibitors used in clinical practice, carfilzomib is the most strongly associated with cardiotoxicity. Patients with anticipated carfilzomib treatment should undergo assessment and optimization of baseline cardiovascular risk, with close monitoring during treatment. Previous clinical trials were not specifically designed to assess proteasome inhibitor-related cardiotoxicity, creating a need for future studies to identify and risk stratify vulnerable individuals and to develop potential cardioprotective strategies in attenuating cardiac injury.

Cardiovascular Toxicity of Carfilzomib: The Real-World Evidence Based on the Adverse Event Reporting System Database of the FDA, the United States

“…Fourth, despite several studies have noted that carfilzomib-associated toxicities occurred early (usually within two cycles), the time-to-onset of these events after administrating carfilzomib is still unclear ( 3 , 6 , 33 ). Our study partially fill the knowledge gap and provide useful information for future studies.…”

“…Carfilzomib has a more favorable safety profile than other PI agents and is used with increasing frequency in clinical practice to treat MM sufferers. However, of the PIs used, carfilzomib is the most strongly associated with cardiotoxicity ( 6 ). Although most cardiovascular complications are reversible, in some cases they may lead to life-threatening and even fatal complications ( 7 , 8 ).…”

A high-throughput screening identifies ZNF418 as a novel regulator of the ubiquitin-proteasome system and autophagy-lysosomal pathway

“…Our data, which define the protein’s impact on UPS and ALP function, may also explain its positive effects on cardiac hypertrophy and cancer, since for both diseases, inhibition of UPS activity and upregulation of ALP activity can be beneficial [ 38 , 47 , 48 , 54 ]. However, these data have to be taken cautiously, because others have shown that genetically-based enhancement of the proteasome activity is cardioprotective or inhibition of cardiac proteasomes is detrimental to the heart after myocardial ischemia/reperfusion injury or pressure overload in mice [ 27 , 55 , 56 ], and importantly, proteasome inhibitors such as bortezomib or carfilzomib can cause cardiotoxicity in humans with multiple myeloma [ 57 ].…”

Micro-CT for Biological and Biomedical Studies: A Comparison of Imaging Techniques

“…Multiple myeloma (MM) is a plasma cell disease, the second most common hematologic malignancy in the USA [ 93 ], and it is considered a treatable but generally incurable cancer type [ 94 ]. It is characterised by the uncontrolled growth of monoclonal plasma cells in bone marrow, resulting in the overproduction of fractions or non-functional intact immunoglobulins.…”