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

Leukemia volume 35, pages 1418–1427 (2021)Cite this article

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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.

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Fig. 1: Flow chart and timeline of the study.
Fig. 2: FMD and PrA were decreased and intercorrelated 2 h after first CFZ dose administration.
Fig. 3: Longitudinal FMD changes across prespecified pre-infusion timepoints during Kd treatment.
Fig. 4: Kaplan-Meier survival curves for the probability of CVAEs.

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Acknowledgements

We thank Mrs Marina Karakitsou for performing all vascular studies of this work.

Funding

AL has received funding from the Hellenic Foundation for Research and Innovation (HFRI) and the General Secretariat for Research and Technology (GSRT), under grant agreement No. [1285]. This study was also supported by institutional funding to EK, IPT, KS, and MAD.

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Author notes

  1. These authors contributed equally: Efstathios Kastritis, Ageliki Laina, Georgios Georgiopoulos

  2. These authors jointly supervised this work: Ioannis P. Trougakos, Kimon Stamatelopoulos, Meletios A. Dimopoulos

Authors and Affiliations

  1. Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece

    Efstathios Kastritis, Ageliki Laina, Georgios Georgiopoulos, Maria Gavriatopoulou, Evangelos Eleutherakis-Papaiakovou, Despina Fotiou, Nikolaos Kanellias, Ioanna Dialoupi, Nikolaos Makris, Efstathios Manios, Magdalini Migkou, Maria Roussou, Maria Kotsopoulou, Konstantinos Stellos, Evangelos Terpos, Kimon Stamatelopoulos & Meletios A. Dimopoulos

  2. Department of Cell Biology and Biophysics, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece

    Eleni-Dimitra Papanagnou & Ioannis P. Trougakos

  3. Biosciences Institute, Vascular Biology and Medicine Theme, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, United Kingdom

    Konstantinos Stellos & Kimon Stamatelopoulos

Authors
  1. Efstathios Kastritis
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Contributions

EK, K.Stamatelopoulos, IPT, and MAD designed research, analyzed, and interpreted data. AL, MG, NM, E-DP, EM, ET, and K.Stellos performed research. IPT and E-DP contributed vital new reagents or analytical tools and assayed proteasome activity. EE-P, DF, NK, ID, MK, MR, and MM collected data. GG and K.Stamatelopoulos performed statistical analysis. EK, K.Stamatelopoulos, IPT, AL, and GG wrote the manuscript.

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Correspondence to Efstathios Kastritis or Kimon Stamatelopoulos.

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Conflict of interest

AMGEN financially supported part of the study as an investigator-initiated study (NCT03543579). EK reports honoraria from Amgen, Genesis Pharma, Takeda, Janssen and Prothena as well as research funding from Amgen and Janssen. KS received fees for being on the regional advisory board for Bayer. ET reports honoraria from Amgen, Celgene, Takeda, Novartis, Roche, Janssen, Bristol-Myers Squibb, and GlaxoSmithKline; consulting or advisory role at Takeda, Novartis, Janssen, Amgen, and Celgene; research funding from Amgen and Janssen; and travel, accommodations and expenses from Amgen, Janssen, Genesis Pharma, and Takeda. KS reports research funding and honoraria from Amgen. IPT reports research funding from Amgen. MAD reports honoraria from Amgen, Novartis, Celgene, Takeda, Janssen, and Bristol-Myers Squibb; consulting or advisory role at Amgen, Janssen, Takeda, and Celgene; research funding from Janssen and Amgen; and travel, accommodations, and expenses from Janssen. The rest of the authors report no conflicts.

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Kastritis, E., Laina, A., Georgiopoulos, G. et al. Carfilzomib-induced endothelial dysfunction, recovery of proteasome activity, and prediction of cardiovascular complications: a prospective study. Leukemia 35, 1418–1427 (2021). https://doi.org/10.1038/s41375-021-01141-4

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