TY - JOUR
TI - Carfilzomib-induced endothelial dysfunction, recovery of proteasome activity, and prediction of cardiovascular complications: a prospective study
AU - Kastritis, E.
AU - Laina, A.
AU - Georgiopoulos, G.
AU - Gavriatopoulou, M.
AU - Papanagnou, E.-D.
AU - Eleutherakis-Papaiakovou, E.
AU - Fotiou, D.
AU - Kanellias, N.
AU - Dialoupi, I.
AU - Makris, N.
AU - Manios, E.
AU - Migkou, M.
AU - Roussou, M.
AU - Kotsopoulou, M.
AU - Stellos, K.
AU - Terpos, E.
AU - Trougakos, I.P.
AU - Stamatelopoulos, K.
AU - Dimopoulos, M.A.
JO - Leukemia Research
PY - 2021
VL - 35
TODO - 5
SP - 1418-1427
PB - Springer Nature BV
SN - 0145-2126
TODO - 10.1038/s41375-021-01141-4
TODO - carfilzomib;  proteasome;  antineoplastic agent;  carfilzomib;  dexamethasone;  oligopeptide;  proteasome, adult;  aged;  Article;  cancer immunotherapy;  cardiotoxicity;  clinical article;  endothelial dysfunction;  enzyme activity;  female;  flow-mediated dilation test;  human;  male;  multiple cycle treatment;  prediction;  priority journal;  prospective study;  survival rate;  cardiovascular system;  clinical trial;  drug effect;  middle aged;  multiple myeloma;  vascular disease;  vascular endothelium, Aged;  Antineoplastic Combined Chemotherapy Protocols;  Cardiovascular System;  Dexamethasone;  Endothelium, Vascular;  Female;  Humans;  Male;  Middle Aged;  Multiple Myeloma;  Oligopeptides;  Prospective Studies;  Proteasome Endopeptidase Complex;  Vascular Diseases
TODO - 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. © 2021, The Author(s), under exclusive licence to Springer Nature Limited part of Springer Nature.
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