FLOW-MEDIATED DILATATION AND AORTIC BLOOD PRESSURE PREDICT CARDIOVASCULAR ADVERSE EVENTS DURING CARFILZOMIB TREATMENT: A PROSPECTIVE STUDY IN PATIENTS WITH RELAPSED/ REFRACTORY MULTIPLE MYELOMA.
Author(s): ,
Efstathios Kastritis
Affiliations:
Department of Clinical Therapeutics,National and Kapodistrian University of Athens,Athens,Greece;Department of Clinical Therapeutics,National and Kapodistrian University of Athens,Athens,Greece
,
Aggeliki Laina
Affiliations:
Department of Clinical Therapeutics,National and Kapodistrian University of Athens,Athens,Greece
,
Maria Gavriatopoulou
Affiliations:
Department of Clinical Therapeutics,National and Kapodistrian University of Athens,Athens,Greece
,
Georgios Georgiopoulos
Affiliations:
Department of Clinical Therapeutics,National and Kapodistrian University of Athens,Athens,Greece
,
Nikolaos Makris
Affiliations:
Department of Clinical Therapeutics,National and Kapodistrian University of Athens,Athens,Greece
,
Evangelos Eleutherakis-Papaiakovou
Affiliations:
Department of Clinical Therapeutics,National and Kapodistrian University of Athens,Athens,Greece
,
Despoina Fotiou
Affiliations:
Department of Clinical Therapeutics,National and Kapodistrian University of Athens,Athens,Greece
,
Nikolaos Kanellias
Affiliations:
Department of Clinical Therapeutics,National and Kapodistrian University of Athens,Athens,Greece
,
Ioanna Dialoupi
Affiliations:
Department of Clinical Therapeutics,National and Kapodistrian University of Athens,Athens,Greece
,
Efstathios Manios
Affiliations:
Department of Clinical Therapeutics,National and Kapodistrian University of Athens,Athens,Greece
,
Magdalini Migkou
Affiliations:
Department of Clinical Therapeutics,National and Kapodistrian University of Athens,Athens,Greece
,
Dimitrios C. Ziogas
Affiliations:
Department of Clinical Therapeutics,National and Kapodistrian University of Athens,Athens,Greece
,
Maria Roussou
Affiliations:
Department of Clinical Therapeutics,National and Kapodistrian University of Athens,Athens,Greece
,
Aristea-Maria Papanota
Affiliations:
Department of Clinical Therapeutics,National and Kapodistrian University of Athens,Athens,Greece
,
Eleni-Dimitra Papanagnou
Affiliations:
Department of Biology,National and Kapodistrian University of Athens,Athens,Greece
,
Maria Kotsopoulou
Affiliations:
Department of Hematology,Metaxa Hospital,Athens,Greece
,
Anastasia Pouli
Affiliations:
Department of Hematology,Aghios Savvas Cancer Hospital,Athens,Greece
,
Evangelos Terpos
Affiliations:
Department of Clinical Therapeutics,National and Kapodistrian University of Athens,Athens,Greece
,
Ioannis P. Trougakos
Affiliations:
Department of Biology,National and Kapodistrian University of Athens,Athens,Greece
,
Kimon Stamatelopoulos
Affiliations:
Department of Clinical Therapeutics,National and Kapodistrian University of Athens,Athens,Greece
Meletios A. Dimopoulos
Affiliations:
Department of Clinical Therapeutics,National and Kapodistrian University of Athens,Athens,Greece
EHA Library. Kastritis E. Jun 15, 2019; 267011; PS1394
Dr. Efstathios Kastritis
Dr. Efstathios Kastritis
Contributions
Abstract

Abstract: PS1394

Type: Poster Presentation

Presentation during EHA24: On Saturday, June 15, 2019 from 17:30 - 19:00

Location: Poster area

Background

Carfilzomib (CFZ) is a proteasome inhibitor associated with cardiovascular (CV) adverse events (AEs) such as hypertension (HTN), cardiac dysfunction and thrombotic events such as venous thromboemolism and thrombotic microangiopathy (TMA). Endothelial dysfunction is a major mediating mechanism in these complications and may be affected by proteasome inhibition caused by CFZ, but have not been explored in humans.

Aims
To assess whether indices of vascular dysfunction can provide prognostic information regarding the development of CV AEs in patients treated with carfilzomib

Methods

We prospectively evaluated markers of vascular function as potential predictors of CFZ-associated CV complications and assessed associations with CFZ-mediated inhibition of proteasome activity in 46 relapsed/refractory myeloma (MM) patients treated with Kd [CFZ 20/56 mg/m2 and dexamethasone](NCT03543579). At baseline and at pre-specified time-points during Kd therapy, cardiac echo and hemodynamic and vascular function parameters were non-invasively assessed [aortic blood pressure and arterial wave reflections using pulse wave analysis, aortic stiffness using pulse wave velocity and endothelial function using flow-mediated dilatation of the brachial artery (FMD)] while proteasome activity (PrA) was measured in peripheral blood mononuclear cells (PBMC). The incidence of CV events [hypertension, acute coronary syndrome (ACS) and heart failure(HF)] was defined as the primary end-point and of both CV events and extra-coronary thrombotic events (pulmonary embolism (PE) and TMA) was defined as the secondary end-point.

Results

Median follow up is 10 months. The prevalence of risk factors for CV toxicity was high (median 3 factors). CV AEs were recorded in 23 (50%) patients [HTN(Gr3/4): 29%, HF: 10%, ACS (Gr3): 4%, PA (Gr3): 2%, TMA: 10%]. Median time to first CV event was 1.87 months. Kd was discontinued in 3(6.25%) and dose was reduced in 2 patients (4.2%) due to cardiotoxicity; no CFZ dose reduction or discontinuation was needed for HTN.

Low FMD [adjusted HR=3.68] and high aortic systolic BP [adjusted HR=4.57] (but not peripheral systolic BP), were the strongest independent predictors of the primary end-point, even after adjustment for baseline risk factors. Low FMD (adjusted HR=4.01) was also an independent predictor the secondary end-point. Finally, increased baseline aortic, but not peripheral, SBP was the strongest independent predictor of grade ≥3 HTN events [adjusted HR=11.23] after adjustment for risk factors for CV toxicity.

FMD decreased acutely within 2 hours from 1st CFZ dose (from 5.2% to 3.6%, p=0.008), and partially recovered before and after 2nd CFZ infusion; the decrease was more pronounced among patients who had lower recovery rate of PBMC PrA 24hpost 1st CFZ (5.12%to 2.97%, p=0.002) but, was less pronounced in those who had higher PrA recovery rate (5.25% to 4.5%, p=0.197), indicating that PrA could be implicated in CFZ induced endothelial dysfunction.

Conclusion

Impaired FMD and increased aortic SBP at baseline were strong predictors of CV and extracoronary thrombotic AEs during CFZ therapy and could serve as clinical markers to identify patients at high risk for CFZ-associated CV toxicity.

Session topic: 14. Myeloma and other monoclonal gammopathies - Clinical

Keyword(s): Endothelial dysfunction, Proteasome inhibitor, Toxicity

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