{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T02:51:44Z","timestamp":1770173504516,"version":"3.49.0"},"reference-count":58,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T00:00:00Z","timestamp":1770076800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute of Health","award":["R01HL151659"],"award-info":[{"award-number":["R01HL151659"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background\/Objectives: Carfilzomib (CFZ) and bortezomib (BTZ) are proteasome inhibitors used as the first-line therapy for relapsed or refractory multiple myeloma (MM) but are associated with cardiovascular adverse events (CVAEs). This study aims to identify differentially methylated positions (DMPs) and regions (DMRs), and enriched pathways associated with CVAEs related to CFZ or BTZ-based treatment. Methods: Baseline germline DNA methylation profiles from 79 MM patients (49 on CFZ and 30 on BTZ) in the Prospective Study of Cardiac Events During Proteasome Inhibitor Therapy (PROTECT) were analyzed. Epigenome-wide analyses were performed within each group, followed by meta-analyses to identify signals common to CVAEs associated with both medicines. Results: Four DMPs were significantly associated with CFZ-CVAEs, including cg15144237 within ENSG00000224400 (p = 9.45 \u00d7 10\u221210), cg00927646 within TBX3 (p = 9.78 \u00d7 10\u22128), and cg10965131 within WDR86 (p = 1.00 \u00d7 10\u22127). One DMR was identified in the FAM166B region (p = 5.46 \u00d7 10\u22127). There was no evidence of any DMPs in BTZ-treated patients, however two DMPs and one DMR reached a suggestive level of significance (p &lt; 1.00 \u00d7 10\u22125): cg09666417 in DNAJC18 (p = 3.41 \u00d7 10\u22127) and cg12987761 in USP18 (p = 5.00 \u00d7 10\u22127), and a DMR mapped to the WDR86\/WDR86-AS1 region (p = 8.11 \u00d7 10\u22128). Meta-analysis did not find any significant DMPs, with the top CpG being cg17933807 in GNL2 (p = 7.38 \u00d7 10\u22125). Pathway enrichment analyses identified peroxisome, MAPK, Rap1, adherens junction, phospholipase D, autophagy, and aldosterone-related pathways to be implicated in CVAEs. Conclusions: Our study identified distinct DMPs, DMRs, and pathways enrichment associated with CVAE, suggesting epigenetic contributors to CVAEs and supporting the need for larger validation studies.<\/jats:p>","DOI":"10.3390\/cancers18030505","type":"journal-article","created":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T12:46:11Z","timestamp":1770122771000},"page":"505","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Epigenome-Wide Association Studies of Proteasome Inhibitor-Related Cardiotoxicity in Patients with Multiple Myeloma"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-5165-2190","authenticated-orcid":false,"given":"Raed Awadh","family":"Alshammari","sequence":"first","affiliation":[{"name":"Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics and Precision Medicine, College of Pharmacy, University of Florida, Gainesville, FL 32610-0486, USA"},{"name":"Department of Clinical Pharmacy, College of Pharmacy, University of Ha\u2019il, Ha\u2019il 55473, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samuel M.","family":"Rubinstein","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Hematology, University of North Carolina, Chapel Hill, NC 27514, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0281-3796","authenticated-orcid":false,"given":"Eric","family":"Farber-Eger","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lauren Lee","family":"Shaffer","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marwa","family":"Tantawy","sequence":"additional","affiliation":[{"name":"Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics and Precision Medicine, College of Pharmacy, University of Florida, Gainesville, FL 32610-0486, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mohammed E.","family":"Alomar","sequence":"additional","affiliation":[{"name":"Cardio-Oncology Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33216, USA"},{"name":"Division of Cardiovascular Sciences, Morsani College of Medicine, University of South Florida, Tampa, FL 33620, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Quinn S.","family":"Wells","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9458-0154","authenticated-orcid":false,"given":"Daniel","family":"Lenihan","sequence":"additional","affiliation":[{"name":"Cape Cardiology Group, Saint Francis Medical Center, Cape Girardeau, MO 63703, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert F.","family":"Cornell","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Hematology and Oncology, Vanderbilt University Medical Center, Nashville, TN 37232, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kenneth H.","family":"Shain","sequence":"additional","affiliation":[{"name":"Department of Malignant Hematology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33216, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4538-4733","authenticated-orcid":false,"given":"Rachid C.","family":"Baz","sequence":"additional","affiliation":[{"name":"Department of Malignant Hematology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33216, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8218-1620","authenticated-orcid":false,"given":"Yan","family":"Gong","sequence":"additional","affiliation":[{"name":"Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics and Precision Medicine, College of Pharmacy, University of Florida, Gainesville, FL 32610-0486, USA"},{"name":"Cardio-Oncology Working Group, University of Florida Health Cancer Institute, Gainesville, FL 32610, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1038\/s41572-024-00529-7","article-title":"Multiple myeloma","volume":"10","author":"Malard","year":"2024","journal-title":"Nat. Rev. Dis. 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