Characterization of Cardiovascular Adverse Events and B-Type Natriuretic Peptide Levels in Patients with Multiple Myeloma Who Are Treated with Carfilzomib
Authors: Quach Hang , Nguyen Khue Minh , Ku Matthew , Bazargan Ali , Filshie Robin J , Tam Constantine S. , Demosthenous Lisa Catherine , Prior David 
Published: October 2019

Abstract
Background
Carfilzomib (K), a second generation proteasome inhibitor that is approved for patients (pts) with relapsed refractory multiple myeloma (RRMM) is associated with increased cardiovascular (CV) adverse effects (AE), in particular hypertension (HTN), dyspnea and cardiac failure (CCF), based on the ENDEAVOR (Dimopoulos, MA. et al. Lancet 2016) and ASPIRE studies (Stewart, K.et al. NEJM 2015). The clinical characteristic and underlying mechanism of K induced CVAE have been poorly elucidated, and the limited published data on the utility of cardiac enzymes as biomarkers have not been revealing. We conducted a retrospective single centre review of K-treated pts who have undergone systemic serial cardiovascular and cardiac enzyme assessment, to profile the nature of CVAE and patterns in cardiac enzymes that might have predictive utility in K-induced CVAE.
Method:
Between January 2016 to June 2018, all pts who were treated with K (D1,2,8,9,15,16 in a 28 day cycle)-based regimen for RRMM at St.Vincent's Hospital Melbourne underwent systematic cardiovascular assessment including documentation of baseline cardiac risk factors (RF) and transthoracic echo (TTE). Serial troponin, creatinine kinase (CK) and B-type Natriuretic Peptide (BNP) were performed at baseline (C1D1 or 2), mid cycle (D8 or 9) and end of treatment (D16) of every cycle. Repeat TTE was done at physicians' discretion. Systematic documentations of CVAEs (graded according to CTCAEv5) were retrieved from medical records. The incidence and severity of CVAE was collated and correlated with serial cardiac enzyme levels, the association of which was tested using Student's t-test.
Results
76 pts (67% male; median age 66(46-86) years) with RRMM who received a median of 6 cycles (1-26) of K-based treatment were included in this analysis. At baseline, 16 pts (21%) had at least 1 CVRF including HTN, history of ischaemic heart disease, hyperlipidaemia, diabetes or smoking. The incidence of HTN prior to treatment was 39%. On treatment, the incidence of HTN was 85% (28% grade≥3). 17% of pts required the addition of antihypertensive medications and 11% had K dose reduction due to HTN. K-related dyspnea occurred in 53% of pts (28% grade≥3), 52% of who required K dose reduction/interruption. CCF occurred in 14.5% (grade≥3, 13%) that all necessitated K interruption/dose reduction. 69 pts had baseline TTE that showed a median RVSP (right ventricular systolic pressure) of 32mmHg (range 20-48). On treatment, 38 pts had repeat TTE, mainly driven by dyspnea with a median RVSP of 41(20-93mmHg). Of the 18 pts with grade≥3 dyspnea who had repeat TTE, 83% had RSVP ≥39mmHg and 33% had RVSP≥50mmHg, compared to 70% with RSVP ≥39mmHg and 10% RVSP≥50mmHg in the group with grade 1-2 dyspnea. Troponin_I and CK level did not change significantly throughout K-treatment. However BNP level rose and fell within each cycle, typically with peaks at mid cycle (D9 and D16) and troughs at the beginning of a new cycle (D1 or 2). 87.1% of pts had at least one elevated BNP (>100ng/L) with a median maximal level of 300ng/L (range 114-2320ng/L). There was a significant difference in the incidence of grade ≥3 CVAEs (mainly HTN) in pts whose mid cycle BNPs (D9 or 16) were elevated in ≥50% of measurements during the first 4 cycles of K compared to the rest (65.5% vs. 25.0%, p=0.0084). In pts with dyspnea, persistent rise in mid cycle BNPs that does not normalise prior to next treatment cycle trended towards an increased incidence of raised RVSP of ≥39mmHg (21.7% vs. 7.9%, p=0.0543).
Conclusion.
The incidence of CVAEs in pts treated with K is higher in the real-world setting compared to that reported in the Endeavor and ASPIRE studies. Dyspnea is frequent, the degree of which correlates with the degree of raised RVSP, thus indicating pulmonary hypertension as a contributor to dyspnea in the setting of K treatment. BNP level typically peaks during mid cycle and troughs at the beginning of next cycle, indicating a temporal relationship to K infusions. In pts with dyspnea, the association of persistent rise in mid-cycle BNP (rather than troponin or CK) with raised RVSP and HTN perhaps indicate transient endothelial dysfunction as the mechanism for K-induced CVAE rather than myocyte injury.

Disclosures
Quach: Amgen: Consultancy, Research Funding; Sanofi Genzyme: Research Funding; Janssen Cilag: Consultancy; Celgene: Consultancy, Research Funding. Tam:Roche: Honoraria; AbbVie: Honoraria, Research Funding; Pharmacyclics: Honoraria, Travel funding; Beigene: Honoraria, Other: Travel funding; Pharmacyclics: Honoraria; Gilead: Honoraria; Janssen: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Beigene: Honoraria, Other: Travel funding; Gilead: Honoraria; Roche: Honoraria.