Cardiotoxicity associated with carfilzomib: Systematic review and meta-analysis.

Abstract

e21674 Background: Carfilzomib (Carf)is a novel proteasome inhibitor (PI) that is approved for patients with relapsed multiple myeloma (RMM) who have failed ≥ 1 prior lines of therapy. The incidence and seriousness of Carf associated cardiotoxicity (CT) is not well defined. We hypothesize that CT is more frequent than that seen with other PIs. We performed systematic review of Carf literature with meta-analysis to determine its incidence and overall risk. Methods: Initial search of literature led to a total of 175 Carf related articles. However, we used 29 publicatons; phase I/II, phase II and phase III (n = 3) clinical trials in which Carf was used as monotherapy or in combination with other chemo agents. We excluded phase I studies and studies without CT data. Incidence rates and odds ratios (OR) were calculated with either fixed effect or random effect model based on the heterogeneity of included studies. Toxicity was reported according to CTCAE v4.0. Results: A total of 4560 patients with various hematological and solid malignancies were included. Incidence of all grades and high grades (≥ 3) CT (including arrhythmias, CHF with LVEF drop, and coronary syndrome) were 7.8% and 4.72%, respectively. When compared to control group taken from phase III clinical trials, the risk of developing CT due to Carf was significantly higher with OR of 1.90 and 2.03 (P < 0.01) for all grades and high grades, respectively. Moreover, incidence of CT was significantly higher in Carf combination therapy (9.85%) compared to Carf monotherapy (5.40%) (P = 0.01). Furthermore, incidence of high grade CT was 7.5% and 5% with and without concomitant immunomodulatory agent (IMiD), respectively (P = 0.004). There was no variation in the incidence of CT among newly diagnosed versus RMM (P = 0.6), and no Carf dose effect. Mortality rate associated with cardiotoxicity was 1.5%. Conclusions: Overall incidence of Carf related CT seems to be higher than that reported with other PIs. Although, the pathophysiology is poorly understood, this trend could potentially be secondary to irreversible nature of proteasome inhibition by Carf. There seems to be a significant increase in CT with combination of Carf and an IMiD. Prior therapies and higher Carf doses have no effect on CT incidence.

Measuring cardiopulmonary complications of carfilzomib treatment and associated risk factors using the SEER‐Medicare database

“…Older age, prior lines of therapy, and concurrent myeloma therapies were not found to be associated with the development of CAEs. 10 Similarly, age was not associated with an increased risk of CAEs in the current study population. Given the growing enthusiasm in the field to move carfilzomib to earlier lines of therapy [14][15][16] and the heterogeneous pattern of dosing in various clinical trials, an in-depth understanding of patient-related and dose-related risk factors is essential to guide future treatment strategies in selecting the right patient population and modifying the dose based on patient characteristics.…”

“…Based on the literature review, we examined age, sex, and common comorbidities, including diabetes, dyslipidemia, and chronic obstructive pulmonary disease (COPD), as independent variables to identify the risk factors associated with developing toxicities. [7][8][9][10][11] It is interesting to note that preexisting comorbidities with the same codes as the examined CAEs and PAEs could not be examined as risk factors because patients with these AEs were excluded. Among all the examined variables, COPD was found to be independently associated with the development of AEs.…”

“…The cumulative relative risk of all-grade CAEs was 1.8 compared with patients who were not exposed to carfilzomib. 10 Another analysis of a cohort of >2000 patients with recurrent and/or refractory multiple myeloma who were enrolled in phase 1 to 3 trials demonstrated CAEs of grade ≥3, including hypertension (6%), dyspnea (5%), and cardiac failure (4%). However, it was noted that these AEs rarely led to treatment discontinuation or death.…”

Efficacy and safety of carfilzomib in relapsed and/or refractory multiple myeloma: systematic review and meta-analysis of 14 trials

“…Our analysis shows that the most commonly reported adverse events were hematological with no significant difference between Carf and control group. Interestingly, ORs for developing cardiotoxicity ( P = 0.002) and HTN ( P < 0.0001) were significantly higher with Carf [ 43 ]. Cardiotoxicity of these novel agents is thought to be the result of modulation of endothelial nitric oxide synthase (eNOS) activity and nitric oxide (NO) levels by proteasome inhibition [ 34 ].…”

Carfilzomib induced cardiotoxicity in a multiple myeloma patient

“…In the latter case, triple therapy with immunomodulators, dexamethasone, and proteasome inhibitors (PI) such as carfilzomib is indicated. The function of carfilzomib is to irreversibly inhibit the protease activity of 20S proteasome, −which is responsible for inter-cellular protein degradation through the ubiquitin-proteasome-, and to disrupt cellular signaling pathways, leading the cell to apoptosis [2].…”