Carfilzomib-induced endothelial dysfunction, recovery of proteasome activity, and prediction of cardiovascular complications: a prospective study.

Abstract

Carfilzomib (CFZ) improves survival in relapsed/refractory multiple myeloma but is associated with cardiovascular adverse events (CVAEs). We prospectively investigated the effect of CFZ on endothelial function and associations with CVAEs. Forty-eight patients treated with Kd (CFZ 20/56 mg/m2 and dexamethasone) underwent serial endothelial function evaluation, using brachial artery flow-mediated dilatation (FMD) and 26S proteasome activity (PrA) measurement in PBMCs; patients were followed until disease progression or cycle 6 for a median of 10 months. FMD and PrA decreased acutely after the first dose (p < 0.01) and FMD decreased at cycles 3 and 6 compared to baseline (p ≤ 0.05). FMD changes were associated with CFZ-induced PrA changes (p < 0.05) and lower PrA recovery during first cycle was associated with more prominent FMD decrease (p = 0.034 for group interaction). During treatment, 25 patients developed Grade ≥3 CVAEs. Low baseline FMD (HR 2.57 lowest vs. higher tertiles, 95% CI 1.081-6.1) was an independent predictor of CVAEs. During treatment, an acute FMD decrease >40% at the end of first cycle was also independently associated with CVAEs (HR = 3.91, 95% CI 1.29-11.83). Kd treatment impairs endothelial function which is associated with PrA inhibition and recovery. Both pre- and posttreatment FMD predicted CFZ-related CVAEs supporting its role as a possible cardiovascular toxicity biomarker.

• Authors: Efstathios Kastritis, Ageliki Laina, Georgios Georgiopoulos, Maria Gavriatopoulou, Eleni-Dimitra Papanagnou, Evangelos Eleutherakis-Papaiakovou, Despina Fotiou, Nikolaos Kanellias, Ioanna Dialoupi, Nikolaos Makris, Efstathios Manios, Magdalini Migkou, Maria Roussou, Maria Kotsopoulou, Konstantinos Stellos, Evangelos Terpos, Ioannis P Trougakos, Kimon Stamatelopoulos, Meletios A Dimopoulos
• Journal: Leukemia (Leukemia) Vol. 35 Issue 5 Pg. 1418-1427 (05 2021) ISSN: 1476-5551 [Electronic] England
• PMID: 33589757 (Publication Type: Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Oligopeptides
• carfilzomib
• Dexamethasone
• Proteasome Endopeptidase Complex

Topics

• Aged
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, therapeutic use)
• Cardiovascular System (drug effects)
• Dexamethasone (therapeutic use)
• Endothelium, Vascular (drug effects)
• Female
• Humans
• Male
• Middle Aged
• Multiple Myeloma (drug therapy)
• Oligopeptides (adverse effects, therapeutic use)
• Prospective Studies
• Proteasome Endopeptidase Complex (drug effects)
• Vascular Diseases (chemically induced)