Cardiovascular Toxicity of Proteasome Inhibitors: Underlying Mechanisms and Management Strategies

Georgiopoulos, Georgios; Makris, Nikolaos; Laina, Ageliki; Theodorakakou, Foteini; Briasoulis, Αlexandros; Trougakos, Ioannis P.; Dimopoulos, Meletios-Athanasios; Kastritis, Efstathios; Stamatelopoulos, Kimon

doi:10.1016/j.jaccao.2022.12.005

Cited by 12 publications

(10 citation statements)

References 139 publications

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“…21,22 The coadministration of high-dose steroids sensitizes cells to IMiDs, further stimulating the release of thrombogenic proteins (e.g., tissue factor, von Willebrand factor, and factor VIII). 22,23 In contrast, bortezomiba first-in-class, dipeptidyl boronic acid-based, reversible PIhas been linked to a reduced thromboembolic risk. 23,24 Proposed mechanisms include plasminogen activator inhibitor-1 downregulation, thrombomodulin upregulation, and enhanced synthesis of nitric oxide (NO).…”

Section: Discussionmentioning

confidence: 99%

“…22,23 In contrast, bortezomiba first-in-class, dipeptidyl boronic acid-based, reversible PIhas been linked to a reduced thromboembolic risk. 23,24 Proposed mechanisms include plasminogen activator inhibitor-1 downregulation, thrombomodulin upregulation, and enhanced synthesis of nitric oxide (NO). [25][26][27] In a descriptive review of trials from 2006 to 2010, bortezomib-containing combinations led to VTE rates of only 1%-6%, whereas IMiD-based regimens (e.g., Rd, thalidomide/dexamethasone, and melphalan/prednisone/thalidomide) were associated with VTE rates of 2%-26%.…”

Section: Discussionmentioning

confidence: 99%

“…30 Shortly after carfilzomiba second-generation, epoxyketonebased, irreversible PIwas approved for RRMM, promising results with upfront combinations containing this drug began to emerge from NDMM trials. 23,31 In this scenario, the phase III ENDURANCE study compared KRd with VRda well-established first-line regimen for NDMMamong 1087 noncandidates for immediate ASCT. At a median follow-up of 9 months, there was no significant difference in median progression-free survival (PFS) between KRd and VRd (34.6 vs. 34.4 months; HR, 1.04; 95% CI, 0.83-1.31; p = .74) among standard/intermediate-risk patients.…”

Section: Discussionmentioning

confidence: 99%

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Thromboembolic risk of carfilzomib or bortezomib in combination with lenalidomide and dexamethasone for newly diagnosed multiple myeloma: A comparative systematic review and meta‐analysis

Costa,

Saravia

et al. 2024

American J Hematol

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Thrombosis represents a frequent and potentially severe complication in individuals diagnosed with multiple myeloma (MM). These events can be driven by both the disease as well as the therapies themselves. Overall, available evidence is inconclusive about the differential thrombogenicity of carfilzomib/lenalidomide/dexamethasone (KRd) and bortezomib/lenalidomide/dexamethasone (VRd). This meta‐analysis compares the risk for venous thromboembolism (VTE; including deep venous thrombosis and pulmonary embolism) and arterial thromboembolism (ATE; including myocardial infarction and ischemic stroke) with KRd versus VRd as primary therapy for newly diagnosed MM (NDMM). Out of 510 studies identified after deduplication, one randomized controlled trial and five retrospective cohort studies were included. We analyzed 2304 patients (VRd: 1380; KRd: 924) for VTE events and 2179 patients (VRd: 1316; KRd: 863) for ATE events. Lower rates of VTE were observed in the VRd group when compared with the KRd group (6.16% vs. 8.87%; odds ratio [OR], 0.53; 95% confidence interval [CI], 0.32–0.88; p = .01). Both treatment groups exhibited minimal ATE incidence, with no significant difference between them (0.91% vs. 1.16%; OR, 1.01; 95% CI, 0.24–4.20; p = .99). In view of potential biases from retrospective studies, heterogeneity of baseline population characteristics, and limited access to patient‐level data (e.g., VTE risk stratification and type of thromboprophylaxis regimen used) inherent to this meta‐analysis, additional research is warranted to further validate our findings and refine strategies for thrombosis prevention in MM.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Thromboembolic risk of carfilzomib or bortezomib in combination with lenalidomide and dexamethasone for newly diagnosed multiple myeloma: A comparative systematic review and meta‐analysis

Costa,

Saravia

et al. 2024

American J Hematol

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“…Carfilzomib has been associated with cardiotoxicity, including heart failure. 13 Despite this association, our institution has chosen carfilzomib as a first-line agent in treating AMR due to the r reported efficiency in DSA reduction, and its irreversible proteasome inhibition. 14,15 In our cohort, 60% of patients demonstrated graft dysfunction at the time of diagnosis of AMR; 5/6 of these patients were treated with carfilzomib, with graft recovery occurring in 3/5 patients.…”

Section: Discussionmentioning

confidence: 99%

“…Carfilzomib has been associated with cardiotoxicity, including heart failure 13 . Despite this association, our institution has chosen carfilzomib as a first‐line agent in treating AMR due to the r reported efficiency in DSA reduction, and its irreversible proteasome inhibition 14,15 .…”

Section: Discussionmentioning

confidence: 99%

Reduction of HLA donor specific antibodies in heart transplant patients treated with proteasome inhibitors for antibody mediated rejection

Horn,

Xu,

Dibridge

et al. 2023

Clinical Transplantation

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In this project, we describe proteasome inhibitor (PI) treatment of antibody‐mediated rejection (AMR) in heart transplantation (HTX). From January 2018 to September 2021, 10 patients were treated with PI for AMR: carfilzomib (CFZ) n = 8; bortezomib (BTZ) n = 2. Patients received 1–3 cycles of PI. All patients had ≥1 strong donor‐specific antibody (DSA) (mean fluorescence intensity [MFI] > 8000) in undiluted serum. Most DSAs (20/21) had HLA class II specificity. The MFI of strong DSAs had a median reduction of 56% (IQR = 13%–89%) in undiluted serum and 92% (IQR = 53%–95%) at 1:16 dilution. Seventeen DSAs in seven patients were reduced > 50% at 1:16 dilution after treatment. Four DSAs from three patients did not respond. DSA with MFI > 8000 at 1:16 dilution was less responsive to treatment. 60% (6/10) patients presented with graft dysfunction; 4/6 recovered ejection fraction > 40% after treatment. Pathologic AMR was resolved in 5/7 (71.4%) of patients within 1 year after treatment. 9/10 (90%) patients survived to 1 year after AMR diagnosis. Using PI in AMR resulted in significant DSA reduction with some resolution of graft dysfunction. Larger studies are needed to evaluate PI for AMR.

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Real-world incidence and risk factors of bortezomib-related cardiovascular adverse events in patients with multiple myeloma

Jang,

Jeong,

Heo

et al. 2024

Blood Res.

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Background Although most studies on the cardiovascular toxicity of proteasome inhibitors have focused on carfilzomib, the risk of cardiotoxicity associated with bortezomib remains controversial. This study aimed to evaluate the incidence and risk factors of cardiovascular adverse events (CVAEs) associated with bortezomib in patients with multiple myeloma in a real-world setting. Methods This cross-sectional study included patients who were treated with bortezomib at a tertiary hospital in South Korea. CVAEs, defined as hypertension, arrhythmia, heart failure, myocardial infarction, pulmonary arterial hypertension, angina, and venous thromboembolism, were detected using cardiac markers, ECG, echocardiography, medications, or documentation by clinicians. The patients were observed for at least 6 months and up to 2 years after starting bortezomib administration. Results Among the 395 patients, 20.8% experienced CVAEs of any grade, and 14.7% experienced severe adverse events. The median onset time for any CVAE was 101.5 days (IQR, 42–182 days), and new-onset/worsened hypertension was the most prevalent CVAE. The risk of CVAEs increased in patients with a body mass index lower than 18.5 (adjusted HR (aHR) 3.50, 95% confidence interval (CI) 1.05-11.72), light chain (1.80, 1.04-3.13), and IgD (4.63, 1.06-20.20) as the multiple myeloma subtype, baseline stroke (4.52, 1.59-12.80), and hypertension (1.99, 1.23-3.23). However, CVAEs did not significantly affect the 2-year overall survival and progression-free survival. Conclusion Approximately 15% of the Korean patients treated with bortezomib experienced severe CVAEs. Thus, patients, especially those with identified risk factors, should be closely monitored for CVAE symptoms during bortezomib treatment.

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Cardiovascular Toxicity of Proteasome Inhibitors: Underlying Mechanisms and Management Strategies

Cited by 12 publications

References 139 publications

Thromboembolic risk of carfilzomib or bortezomib in combination with lenalidomide and dexamethasone for newly diagnosed multiple myeloma: A comparative systematic review and meta‐analysis

Thromboembolic risk of carfilzomib or bortezomib in combination with lenalidomide and dexamethasone for newly diagnosed multiple myeloma: A comparative systematic review and meta‐analysis

Reduction of HLA donor specific antibodies in heart transplant patients treated with proteasome inhibitors for antibody mediated rejection

Real-world incidence and risk factors of bortezomib-related cardiovascular adverse events in patients with multiple myeloma

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