Abstract
Multiple myeloma (MM) is the second most frequent hematologic cancer in the United States. Carfilzomib (CFZ), an irreversible proteasome inhibitor being used to treat relapsed and refractory MM, has been associated with cardiotoxicity, including heart failure. We hypothesized that a multi-omics approach integrating data from different omics would provide insights into the mechanisms of CFZ-related cardiovascular adverse events (CVAEs). Plasma samples were collected from 13 MM patients treated with CFZ (including 7 with CVAEs and 6 with no CVAEs) at the University of Florida Health Cancer Center. These samples were evaluated in global metabolomic profiling, global proteomic profiling, and microRNA (miRNA) profiling. Integrative pathway analysis was performed to identify genes and pathways differentially expressed between patients with and without CVAEs. The proteomics analysis identified the up-regulation of lactate dehydrogenase B (LDHB) [fold change (FC) = 8.2, p = 0.01] in patients who experienced CVAEs. The metabolomics analysis identified lower plasma abundance of pyruvate (FC = 0.16, p = 0.0004) and higher abundance of lactate (FC = 2.4, p = 0.0001) in patients with CVAEs. Differential expression analysis of miRNAs profiling identified mir-146b to be up-regulatein (FC = 14, p = 0.046) in patients with CVAE. Pathway analysis suggested that the pyruvate fermentation to lactate pathway is associated with CFZ-CVAEs. In this pilot multi-omics integrative analysis, we observed the down-regulation of pyruvate and up-regulation of LDHB among patients who experienced CVAEs, suggesting the importance of the pyruvate oxidation pathway associated with mitochondrial dysfunction. Validation and further investigation in a larger independent cohort are warranted to better understand the mechanisms of CFZ-CVAEs.
Highlights
Multiple myeloma (MM) is a malignant plasma cell disorder and is the second most frequent hematologic cancer in the United States [1]
Mitochondria is the active organelle the produces most reactive oxygen species (ROS) that leads to peroxidation of lipids and DNA damage in cardiomyocytes [21,22,23]
The pyruvate oxidation occurs after pyruvate is converted to acetyl-CoA in the mitochondria by the pyruvate dehydrogenase complex (PDC)
Summary
Multiple myeloma (MM) is a malignant plasma cell disorder and is the second most frequent hematologic cancer in the United States [1]. Proteasome inhibitors (PIs) are among the most important classes of drugs to treat newly diagnosed, relapsed, and refractory MM [2]. Three PIs, bortezomib (Velcade R ), carfilzomib (CFZ, Kyprolis R ), and ixazomib (Ninlaro R ), have been approved by the United States Food and Drug Administration (FDA) [5]. CFZ is a second-generation PI that irreversibly inhibits 20S proteasome and is FDA-approved to treat relapsed or refractory MM patients who have received one to three previous treatments for MM. MM patients treated with CFZ and dexamethasone had improved survival compared with those treated with bortezomib and dexamethasone [6, 7]
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