Carfilzomib‐associated cardiovascular adverse events in a non‐Caucasian cohort of patients with multiple myeloma: A real‐world experience

Mangla, Ankit; Paydary, Koosha; Liu, Jiaxiang; Mbachi, Chimezie; Yim, Barbara; Lad, Thomas E.

doi:10.1002/hon.2535

Cited by 7 publications

(11 citation statements)

References 8 publications

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“…Aconitine was previously reported to induce apoptosis in H9c2 cardiac cells (Gao et al, 2018). Therefore, our findings lend the credence to the notion that the modifications by CFZ or aconitine of I K(DR) amplitude or gating inherently in vascular smooth muscle and in heart cells is intimately linked to its action on variable forms of cardiovascular catastrophes (Iannaccone et al, 2018; Mangla et al, 2018; Efentakis et al, 2019).…”

Section: Discussionsupporting

confidence: 76%

“…Recent studies have recently demonstrated that CFZ might produce cardiovascular adverse events, although it evidently improves survival of patients suffering from multiple myeloma (Gavazzoni et al, 2018; Heckmann et al, 2018; Iannaccone et al, 2018; Mangla et al, 2018; Efentakis et al, 2019). For these reasons, we further evaluated whether addition of CFZ is able to exert any perturbations on I K(DR) inherently in A7r5 vascular smooth myocytes or H9c2 cardiac cells.…”

Section: Resultsmentioning

confidence: 99%

“…Recently, it has been demonstrated that administration of CFZ is able to affect adverse cardiovascular events (Gavazzoni et al, 2018; Heckmann et al, 2018; Iannaccone et al, 2018; Mangla et al, 2018; Efentakis et al, 2019). Protein quality control inside the cell, with which proteasome inhibitors mainly interfere, is thought to be an important part of the molecular machinery of cardiomyocytes, endothelial cells, and probably all other members of the cardiac environment (Heckmann et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

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High Effectiveness in Actions of Carfilzomib on Delayed-Rectifier K+ Current and on Spontaneous Action Potentials

Liu

Lee

et al. 2019

Front. Pharmacol.

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Carfilzomib (CFZ, Kyprolis®) is widely recognized as an irreversible inhibitor of proteasome activity; however, its actions on ion currents in electrically excitable cells are largely unresolved. The possible actions of CFZ on ionic currents and membrane potential in pituitary GH3, A7r5 vascular smooth muscle, and heart-derived H9c2 cells were extensively investigated in this study. The presence of CFZ suppressed the amplitude of delayed-rectifier K+ current (I K(DR)) in a time-, state-, and concentration-dependent manner in pituitary GH3 cells. Based on minimal reaction scheme, the value of dissociation constant for CFZ-induced open-channel block of I K(DR) in these cells was 0.33 µM, which is similar to the IC50 value (0.32 µM) used for its efficacy on inhibition of I K(DR) amplitude. Recovery from I K(DR) block by CFZ (0.3 µM and 1 µM) could be well fitted by single exponential with 447 and 645 ms, respectively. The M-type K+ current, another type of K+ current elicited by low-threshold potential, was slightly suppressed by CFZ (1 µM). Under current-clamp condition, addition of CFZ depolarized GH3 cells, broadened the duration of action potentials as well as raised the firing frequency. In A7r5 vascular smooth muscle cells or H9c2 cardiac cells, the CFZ-induced inhibition of I K(DR) remained efficacious. Therefore, our study led us to reflect that CFZ or other structurally similar compounds should somehow act on the activity of membrane KV channels through which they influence the functional activities in different types of electrically excitable cells such as endocrine, neuroendocrine cells, smooth muscle cells, or heart cells, if similar in vivo findings occur.

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Section: Discussionsupporting

confidence: 76%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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High Effectiveness in Actions of Carfilzomib on Delayed-Rectifier K+ Current and on Spontaneous Action Potentials

Liu

Lee

et al. 2019

Front. Pharmacol.

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“…Importantly, predictors of CVAEs have been lacking. 3,[15][16][17][18][19][20][21][22] This study, conducted with multicenter hematology and cardiology collaboration, prospectively demonstrates that monitoring patients receiving carfilzomib-based therapy with natriuretic peptides is highly predictive for development of CVAEs. Because a majority of CVAEs (86%) occurred within the first 3 months of therapy, measuring natriuretic peptides levels using either BNP or NTproBNP seems to provide clinical benefit.…”

Section: Discussionmentioning

confidence: 95%

Prospective Study of Cardiac Events During Proteasome Inhibitor Therapy for Relapsed Multiple Myeloma

Cornell

Weiss

et al. 2019

JCO

143

111

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PURPOSE Cardiovascular adverse events (CVAEs) can occur during proteasome inhibitor (PI) therapy. We conducted a prospective, observational, multi-institutional study to define risk factors and outcomes in patients with multiple myeloma (MM) receiving PIs. PATIENTS AND METHODS Patients with relapsed MM initiating carfilzomib- or bortezomib-based therapy underwent baseline assessments and repeated assessments at regular intervals over 6 months, including cardiac biomarkers (troponin I or T, brain natriuretic peptide [BNP], and N-terminal proBNP), ECG, and echocardiography. Monitoring occurred over 18 months for development of CVAEs. RESULTS Of 95 patients enrolled, 65 received carfilzomib and 30 received bortezomib, with median 25 months of follow-up. Sixty-four CVAEs occurred, with 55% grade 3 or greater in severity. CVAEs occurred in 51% of patients treated with carfilzomib and 17% of those treated with bortezomib ( P = .002). Median time to first CVAE from treatment start was 31 days, and 86% occurred within the first 3 months. Patients receiving carfilzomib-based therapy with a baseline elevated BNP level higher than 100 pg/mL or N-terminal proBNP level higher than 125 pg/mL had increased risk for CVAE (odds ratio, 10.8; P < .001). Elevated natriuretic peptides occurring mid–first cycle of treatment with carfilzomib were associated with a substantially higher risk of CVAEs (odds ratio, 36.0; P < .001). Patients who experienced a CVAE had inferior progression-free survival (log-rank P = .01) and overall survival (log-rank P < .001). PI therapy was safely resumed in 89% of patients, although 41% required chemotherapy modifications. CONCLUSION CVAEs are common during PI therapy for relapsed MM, especially with carfilzomib, particularly within the first 3 months of therapy. CVAEs were associated with worse overall outcomes, but usually, discontinuation of therapy was not required. Natriuretic peptides were highly predictive of CVAEs; however, validation of this finding is necessary before uniform incorporation into the routine management of patients receiving carfilzomib.

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“…Left ventricular mass and pulse wave velocity are both independent predictors of CVAEs in the general population and specific subgroups [12,13,14,15]. Recent studies have suggested a correlation between left ventricular hypertrophy and the development of CVAEs during follow up in MM patients treated with the new proteasome inhibitor [16], but further analysis is required to define the potential predictive role of these parameters in this oncological population.…”

Section: Introductionmentioning

confidence: 99%

Cardiovascular Organ Damage and Blood Pressure Levels Predict Adverse Events in Multiple Myeloma Patients Undergoing Carfilzomib Therapy

Bruno¹,

Bringhen

Maffei³

et al. 2019

Cancers

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Carfilzomib is a second-generation proteasome inhibitor approved for the treatment of multiple myeloma (MM). It seems to determine cardiovascular toxicity, primarily arterial hypertension. No predictive factors for cardiovascular adverse events (CVAEs) are known in patients affected by multiple myeloma treated with carfilzomib. We evaluated the role of cardiovascular organ damage parameters to predict CVAEs in MM patients taking carfilzomib. Seventy patients affected by MM were prospectively enrolled. A comprehensive cardiovascular evaluation was performed before carfilzomib therapy; they underwent a transthoracic echocardiogram and the assessment of carotid-femoral pulse wave velocity. All the patients were followed up (FU) to determine the incidence of CVAEs. The mean age was 60.3 ± 8.2, and 51% were male. The median FU was 9.3 (4.3; 20.4) months. A proportion of 33% experienced CVAEs, 91% of them had uncontrolled hypertension, 4.5% acute coronary syndrome, and 4.5% cardiac arrhythmias. Subjects with CVAEs after carfilzomib treatment had significantly higher blood pressure values, left ventricular mass (98 ± 23 vs. 85 ± 17 g/m2, p = 0.01), and pulse wave velocity (8.5 ± 1.7 vs. 7.5 ± 1.6 m/s, p = 0.02) at baseline evaluation compared to the others. Furthermore, baseline uncontrolled blood pressure, left ventricular hypertrophy, and pulse wave velocity ≥ 9 m/s were able to identify patients at higher risk of developing CVAEs during FU. These preliminary findings indicate that blood pressure control, left ventricular mass, and pulse wave velocity may predict CVAEs in MM patients treated with carfilzomib.

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Carfilzomib‐associated cardiovascular adverse events in a non‐Caucasian cohort of patients with multiple myeloma: A real‐world experience

Cited by 7 publications

References 8 publications

High Effectiveness in Actions of Carfilzomib on Delayed-Rectifier K+ Current and on Spontaneous Action Potentials

High Effectiveness in Actions of Carfilzomib on Delayed-Rectifier K+ Current and on Spontaneous Action Potentials

Prospective Study of Cardiac Events During Proteasome Inhibitor Therapy for Relapsed Multiple Myeloma

Cardiovascular Organ Damage and Blood Pressure Levels Predict Adverse Events in Multiple Myeloma Patients Undergoing Carfilzomib Therapy

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