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Cardiovascular & Hematological Disorders-Drug Targets

Author(s): W. Serra*, A. Fantin , C. Longo , G. Rabia , F. De Rosa, C. Plenteda , F. Re , E. Crisafulli and A. Chetta

DOI: 10.2174/1871529X19666181205100705

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Carfilzomib: A Tale of a Heartbreaking Moment: Case Report and Concise Review of the Literature

Page: [253 - 258] Pages: 6

  • * (Excluding Mailing and Handling)

Abstract

Background: Carfilzomib, a proteasome inhibitor, known as a therapeutical option for people who have already received one or more previous treatments for multiple myeloma, has well known cardiac and systemic adverse effects.

Objective: There is evidence supporting that adverse effects are dose dependent, yet there is no known patient phenotype characterized by worse associated consequences, nor are there widely accepted monitoring protocols.

Results: In this article we describe two patients with cardiovascular adverse events related to carfilzomib treatment and their clinical course. Our goal was to present two cases of daily practice, which highlighted the complexity of their management and led to underline how baseline evaluation and close follow-up with echocardiography and cardiac biomarkers, including natriuretic peptides, remain an important tool for the cardiotoxicity surveillance.

Conclusion: These reflections should lead to further studies in order to identify high risk patients for cardiovascular adverse event and clarify the real incidence of cardiotoxicity of this drug and adequate follow-up timing. Finally further research is needed to evaluate strategies for prevention and attenuation of cardiovascular complications of cancer therapy.

Keywords: Myocardium, carfilzomib, cardiotoxicity, heart failure, hypertension, multiple myeloma, echocardiography, proteasome.

Graphical Abstract

[1]
Sant, M.; Allemani, C.; Tereanu, C.; De Angelis, R.; Capocaccia, R.; Visser, O.; Marcos-Gragera, R.; Maynadié, M.; Simonetti, A.; Lutz, J.M.; Berrino, F. and the HAEMACARE Working Group. Incidence of hematologic malignancies in Europe by morphologic subtype: Results of the HAEMACARE project. Blood, 2010, 116, 3724-3734.
[2]
Savarese, G.; Lars, H.L. Global public health burden of heart failure. Card. Fail. Rev., 2017, 3(1), 7-11.
[3]
Jain, D.; Ahmad, T.; Cairo, M.; Aronow, W. Cardiotoxicity of cancer chemotherapy: Identification, prevention and treatment. Ann. Transl. Med., 2017, 5(17), 348.
[4]
McGowan, J.V.; Chung, R.; Maulik, A.; Piotrowska, I.; Walker, J.M.; Yellon, D.M. Anthracycline chemotherapy and cardiotoxicity. Cardiovasc. Drugs Ther., 2017, 31(1), 63-75.
[5]
Kristinsson, S.Y.; Anderson, W.F.; Landgren, O. Improved long-term survival in multiple myeloma up to the age of 80 years. Leukemia, 2014, 28(6), 1346-1348.
[6]
Kistler, K.D.; Kalman, J.; Sahni, G.; Murphy, B.; Werther, W.; Rajangam, K.; Chari, A. Incidence and risk of cardiac events in patients with previously treated multiple myeloma versus matched patients without multiple myeloma: An observational, retrospective, cohort study. Clin. Lymphoma Myeloma Leuk., 2017, 17(2), 89-96.e3.
[7]
Mark, T.M.; Yadlapati, S.; Neglyad, L.; Bourke, J.; Jayabalan, D.; Rossi, A.C.; Pearse, R.N.; Perry, A.; Pekle, K.; Pogonowski, K.; Tegnestam, L.; Huang, X.; Di Liberto, M.; Ely, S.; Coleman, M.; Chen-Kiang, S.; Niesvizky, R. High-dose carfilzomib and dexamethasone as first-line treatment in symptomatic multiple myeloma. Blood, 2015, 126(23), 4258.
[8]
Koulaouzidis, G.; Lyon, A.R. Proteasome inhibitors as a potential cause of heart failure. Heart Fail. Clin., 2017, 13(2), 289-295.
[9]
Tjionas, H.; Gupta, A.K. Heart failure secondary to carfilzomib-induced heart block in multiple myeloma patients. J. Oncol. Pharm. Pract., 2017, 23(2), 152-156.
[10]
Chari, A.; Hajje, D. Case series discussion of cardiac and vascular events following carfilzomib treatment: Possible mechanism, screening, and monitoring. BMC Cancer, 2014, 14, 915.
[11]
Chari, A.; Aggarwal, S.K.; Mezzi, K.; Wang, K.; Kim, C.; Zhu, S.; Braunlin, M.; Werther, W.; Mikhae, J. Cardiac events in real-world multiplemyeloma patients treated with carfilzomib: A retrospective claims database analysis. Blood, 2016, 128(22), 3319.
[12]
Waxman, A.J.; Clasen, S.; Hwang, W.T.; Garfall, A.; Vogl, D.T.; Carver, J.; O’Quinn, R.; Cohen, A.D.; Stadtmauer, E.A.; Ky, B.; Weiss, B.M. Carfilzomib-associated cardiovascular adverse events: A systematic review and meta-analysis. JAMA Oncol., 2017, 4(3)e174519
[13]
Jain, T.; Narayanasamy, H.; Mikhael, J. Reversible cardiotoxicity associated with carfilzomib use in patients with multiple myeloma. Blood, 2016, 128(22), 2126.
[14]
Grandin, E.W.; Ky, B.; Cornell, R.F.; Carver, J.; Lenihan, D.J. Patterns of cardiac toxicity associated with irreversible proteasome inhibition in the treatment of multiple myeloma. J. Card. Fail., 2015, 21(2), 138-144.
[15]
Tjionas, H.; Gupta, A.K. Heart failure secondary to carfilzomib-induced heart block in multiple myeloma patients. J. Oncol. Pharm. Pract., 2017, 23(2), 152-156.
[16]
Stewart, A.K.; Rajkumar, S.V.; Dimopoulos, M.A.; Masszi, T.; Špička, I.; Oriol, A.; Hájek, R.; Rosiñol, L.; Siegel, D.S.; Mihaylov, G.G.; Goranova-Marinova, V.; Rajnics, P.; Suvorov, A.; Niesvizky, R.; Jakubowiak, A.J.; San-Miguel, J.F.; Ludwig, H.; Wang, M.; Maisnar, V.; Minarik, J.; Bensinger, W.I.; Mateos, M.V.; Ben-Yehuda, D.; Kukreti, V.; Zojwalla, N.; Tonda, M.E.; Yang, X.; Xing, B.; Moreau, P.; Palumbo, A. ASPIRE Investigators. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N. Engl. J. Med., 2015, 372(2), 142-152.
[17]
Hájek, R.; Masszi, T.; Petrucci, M.T.; Palumbo, A.; Rosiñol, L.; Nagler, A.; Yong, K.L.; Oriol, A.; Minarik, J.; Pour, L.; Dimopoulos, M.A.; Maisnar, V.; Rossi, D.; Kasparu, H.; Van Droogenbroeck, J.; Yehuda, D.B.; Hardan, I.; Jenner, M.; Calbecka, M.; Dávid, M.; Ludwig, H. A randomized phase III study of carfilzomib vs low-dose corticosteroids with optional cyclophosphamide in relapsed and refractory multiple myeloma (FOCUS). Leukemia, 2017, 31(1), 107-114.
[18]
Dimopoulos, M.A.; Palumbo, A.; Joshua, D.; Pour, L.; Hájek, R.; Facon, T.; Ludwig, H.; Oriol, A.; Goldschmidt, H.; Rosiñol, L.; Straub, J.; Suvorov, A.; Araujo, C.; Rimashevskaya, E.; Pika, T.; Gaidano, G.; Weisel, K.; Goranova-Marinova, V.; Schwarer, A.; Minuk, L.; Masszi, T.; Karamanesht Offidani, M.; Hungria, V.; Spencer, A.; Orlowski, R.Z.; Gillenwater, H.H.; Mohamed, N.; Feng, S.; Chng, W.J. ENDEAVOR Investigators. Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): A randomised, phase 3, open-label, multicentre study. The Lancet Oncology., 2016, 17(1), 27-38.
[19]
Imam, F.; Al-Harbi, N.O.; Al-Harbia, M.M.; Korashy, H.M.; Ansari, M.A.; Sayed-Ahmed, M.M.; Nagi, M.N.; Iqbal, M.; Khalid Anwer, M.; Kazmi, I.; Afzal, M.; Bahashwan, S. Rutin attenuates carfilzomib-induced cardiotoxicity through inhibition of nf-κb, hypertrophic gene expression and oxidative stress. Cardiovasc. Toxicol., 2017, 17(1), 58-66.
[20]
Chen-Scarabelli, C.; Corsetti, G.; Pasini, E.; Dioguardi, F.S.; Sahni, G.; Narula, J.; Gavazzoni, M.; Patel, H.; Saravolatz, L.; Knight, R.; Raddino, R.; Scarabelli, T.M. Spasmogenic effects of the proteasome inhibitor carfilzomib on coronary resistance, vascular tone and reactivity. EBioMedicine, 2017, 21, 206-212.
[21]
Rosenthal, A.; Luthi, J.; Belohlavek, M.; Kortüm, K.M.; Mookadam, F.; Mayo, A.; Fonseca, R.; Bergsagel, P.L.; Reeder, C.B.; Mikhael, J.R.; Stewart, A.K. Carfilzomib and the cardiorenal system in myeloma: An endothelial effect? Blood Cancer J., 2016, 6e384
[22]
Hasinoff, B.B.; Patel, D.; Wu, X. Molecular mechanisms of the cardiotoxicity of the proteasomal-targeted drugs Bortezomib and Carfilzomib. Cardiovasc. Toxicol., 2017, 17(3), 237-250.
[23]
Russell, S.D.; Lyon, A.; Lenihan, D.J. Serial echocardiographic assessment of patients (PTS) with relapsed multiple myeloma (RMM) receiving carfilzomib and dexamethasone (KD) vs bortezomib and dexamethasone (VD): A substudy of the phase 3 endeavor trial (NCT01568866). Blood, 2015, 126(23), 4250.
[24]
Danhof, S.; Schreder, M.; Rasche, L.; Strifler, S.; Einsele, H.; Knop, S. ‘Real-life’ experience of preapproval carfilzomib-based therapy in myeloma - analysis of cardiac toxicity and predisposing factors. Eur. J. Haematol., 2016, 97(1), 25-32.
[25]
Wang, Z.; Yang, J.; Kirk, J.; Fang, Y.; Alsina, M.; Badros, A.; Papadopoulos, K.; Wong, A.; Woo, T.; Bomba, D.; Li, J.; Infante, J.P.K. metabolism, and drug-drug interaction of carfilzomib. Drug Metab. Dispos., 2013, 41(1), 230-237.
[26]
Bringhen, S.; De Wit, E.; Dimopoulos, M.A. New agents in multiple myeloma: an examination of safety profiles. Clin. Lymphoma Myeloma Leuk., 2017, 17(7), 391-407.e5.
[27]
Grandin, E.W.; Ky, B.; Cornell, R.F.; Carver, J.; Lenihan, D.J. Patterns of cardiac toxicity associated with irreversible proteasome inhibition in the treatment of multiple myeloma. J. Card. Fail., 2015, 21(2), 138-144.
[28]
Atrash, S.; Tullos, A.; Panozzo, S.; Bhutani, M.; Van Rhee, F.; Barlogie, B.; Usmani, S.Z. Cardiac complications in relapsed and refractory multiple myeloma patients treated with carfilzomib. Blood Cancer J., 2015, 5e272
[29]
Zamorano, J.L. Lancellotti, P.; Rodriguez Muñoz, D.; Aboyans, V.; Asteggiano, R.; Galderisi, M.; Habib, G.; Lenihan, D.J.; Lip, G.Y.H.; Lyon, A.R.; Lopez Fernandez, T.; Mohty, D.; Piepoli, M.F.; Tamargo, J.; Torbicki, A.; Suter, T.M. e Group., ESC Scientific Document. 2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines: The Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology. Eur. Heart J., 2016, 37(36), 2768-2801.
[30]
Chari, A.; Hajje, D. Case series discussion of cardiac and vascular events following carfilzomib treatment: possible mechanism, screening, and monitoring. BMC Cancer, 2014, 14, 915.
[31]
Harvey, R.D. Incidence and management of adverse events in patients with relapsed and/or refractory multiple myeloma receiving single-agent carfilzomib. Clin. Pharmacol., 2014, 6, 87-96.
[32]
Amgen. Kyprolis (carfilzomib) summary of product characteristics. (Accessed April 2018). [Online] . http://www.ema.europa.eu/docs/ it_IT/document_library/EPAR_-_Product_Information/human/ 003790/WC500197692.pdf (Accused)
[33]
Siegel, D.S. From clinical trials to clinical practice: single-agent carfilzomib adverse events and their management in patients with relapsed and/or refractory multiple myeloma. Ther. Adv. Hematol., 2013, 4(6), 354-365.