Cardiovascular Toxicity of Carfilzomib: The Real-World Evidence Based on the Adverse Event Reporting System Database of the FDA, the United States

Abstract

Background: Carfilzomib, an effective proteasome inhibitor agent for the therapy of relapsed and refractory multiple myeloma, has been related to a significant number of cardiovascular events. However, patterns of cardiovascular complications associated with this agent remain poorly characterized in real-world settings.Objective: To gain further insight into the frequency, spectrum, clinical features, timing, and outcomes of carfilzomib-related cardiovascular toxicities.Methods: This disproportionality (case/non-case) study was conducted leveraging records from FAERS database from 2014 to 2019. Cardiovascular events were defined and broadly categorized eight entities using narrow version of the Standardized MedDRA Queries (SMQs). Reporting odds ratios (ROR) and information component (IC) were calculated to measure disproportionality. Additionally, statistical shrinkage was applied to reduce false-positive signals.Results: The final number of records involved was 28,479,963, with 3,370 records submitted for carfilzomib related cardiovascular events. Significant disproportionality association between carfilzomib administration and cardiovascular events was captured (IC025/ROR025 = 0.85/1.95) when exploring in the entire database. Upon further analysis, all eight broad categories of cardiovascular toxicities were disproportionately associated with carfilzomib with varying frequencies, time-to-onset, and severities. Cardiomyopathy-related complications (N = 1,301, 38.61%), embolic and thrombotic events (N = 821, 24.36%), and cardiac failure (N = 765, 22.70%) largely comprised the reported problems. Notably, the strongest signal was detected for cardiac failure (IC025/ROR025 = 1.33/2.59), followed by pulmonary hypertension (IC025/ROR025 = 1.19/2.34). Median onset time of cardiovascular events was 41days (Q1-Q3: 9-114 days), with the shortest median time being 16 days (Q1–Q3: 4–85 days) for ischemic heart disease, with the longest time being 68 days (Q1–Q3: 21–139 days) for embolic and thrombotic events. Torsade de pointes/QT prolongation was identified as a new complication (IC025/ROR025 = 0.33/1.29) and was particularly noteworthy for highest death proportion (44.11%).Conclusions: Treatment with carfilzomib can lead to severe and versatile cardiovascular events. Early and intensive monitoring is important, particularly in the first 3 months after carfilzomib initiation. Maximizing the benefit while reducing potential cardiovascular harms of carfilzomib should become a priority.

Carfilzomib’s Real-World Safety Outcomes in Korea: Target Trial Emulation Study Using Electronic Health Records

“…As the median number of treatment cycles of KRd was six, it is likely that the treatments were often discontinued in the early cycle (up to six cycles) due to the adverse events of KRd. In several other studies, including RCTs [ 9 , 14 , 15 , 18 , 19 ], most adverse events tended to occur after 15–150 days or at the completion of 3–6 cycles, showing a trend similar to the results of this study. Therefore, close monitoring of the early cycles of KRd administration is required.…”

“…Studies using RWD have also been conducted to determine the safety of carfilzomib in clinical settings. Observational studies were performed using US multicenter electronic medical records (EMR) [ 13 ], US insurance claims data (Medicare) [ 14 ], and the FDA Adverse Event Reporting System (FAERS) database [ 15 ]. These studies did not provide any other safety information regarding various organ systems.…”

Cardiovascular toxicity associated with angiogenesis inhibitors: A comprehensive pharmacovigilance analysis based on the FDA Adverse Event Reporting System database from 2014 to 2021

“…In addition, all PTs representing symptoms, signs, investigations, or diagnoses likely to be relevant can be grouped into meaningful categories using the Standardized MedDRA Queries (SMQs) to define a medical condition of interest. In this study, cardiovascular AEs were grouped into nine narrow categories of SMQs (cardiac arrhythmia, cardiac failure, cardiomyopathy, embolic and thrombotic events, hypertension, ischemic heart disease, noninfectious myocarditis/pericarditis, pulmonary hypertension, and torsade de pointes/QT prolongation) ( Table 1 ) (see Supplementary Tables S1–S9 ) ( 22 ).…”

Immune-related interstitial lung disease adverse event following immune checkpoint inhibitors and immune checkpoint inhibitors plus anti-VEGF antibody/chemotherapy: A real-world study from 2014 to 2022 based on FAERS databases

“…A speci c PT can be assigned to several high-level terms (HLTs), high-level group terms (HLGTs), and system organ classes (SOCs). Additionally, different PTs can also be grouped into meaningful broader categories according to Standardized MedDRA Queries (SMQs) to de ne a medical condition or area of interest (Zhai et al 2021). In this study, we used SMQs to capture interstitial lung disease.…”