Longitudinal changes in echocardiographic variables and endothelial function to predict cardiovascular toxicities in patients with multiple myeloma receiving carfilzomib.

Abstract

e20012 Background: Carfilzomib (CFZ) is a second-generation proteasome inhibitor with activity in multiple myeloma (MM) that is associated with cardiotoxicity and dyspnea. The pathophysiology and risk factors for developing these toxicities are not well described. We are conducting a prospective observational study (NCT04827563) of longitudinal changes in cardiovascular and endothelial function among MM patients receiving CFZ. We hypothesize that baseline and longitudinal variations in cardiovascular and endothelial function correlate with development of cardiotoxicity and dyspnea in MM patients receiving CFZ. Methods: Patients with MM receiving first-time CFZ therapy are prospectively enrolled and undergo the following study procedures prior to CFZ initiation and then every 2 weeks for the first 6 weeks of CFZ therapy (C1D1, C1D15, C2D1, C2D15): 24-hour ambulatory blood pressure monitoring, echocardiography, pulse wave velocity, and EndoPAT endothelial function assessment. Patient-reported outcomes are also collected. Cardiovascular adverse events (CVAEs) and dyspnea are assessed at all timepoints, as well as at 3 and 6 months after enrollment, by CTCAE v5.0 and are adjudicated by a cardio-oncologist. Patients with endothelial dysfunction will be defined as reactive hyperemia index (RHI) <1.67 via EndoPAT. Baseline variables were analyzed with unpaired t-tests and longitudinal variables were analyzed by one-way repeated measures ANOVA. Results: Ten patients have completed 6 months of follow-up. Demographic data is summarized in the table. Four patients (40%) developed dyspnea, 2 with grade 1 and 2 with grade 3 at maximum, with most patients developing dyspnea by C1D15. Two patients had ongoing grade 1 dyspnea at follow-up. Four patients (40%) developed grade 3 or higher CVAEs, most of which were grade 3 hypertension and/or grade 3 HFpEF. Baseline left ventricular mass was significantly higher in patients who developed dyspnea compared to those who did not (p=0.040). EndoPAT values were significantly different between C1D1 and C1D15 in those with CVAEs (2.28 vs 1.74, p=0.0223). NTproBNP values were also significantly different between C1D1 and C1D15 in those with dyspnea (74.5 vs 129.3, p=0.006). Conclusions: MM patients that developed dyspnea during treatment with CFZ had a higher baseline LV mass and were more likely to develop increases in NTproBNP despite preserved ejection fraction, consistent with HFpEF. This group also had a greater change in EndoPAT values suggesting that short-term alterations in endothelial function may have a role in the development of dyspnea in those who may have the anatomic substrate for HFpEF. Clinical trial information: NCT04827563 . [Table: see text]