Skip to main content

Advertisement

SpringerLink
Log in

Proteasome Inhibitor-Related Cardiotoxicity: Mechanisms, Diagnosis, and Management

  • Cardio-oncology (EH Yang, Section Editor)
  • Published:
Current Oncology Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Multiple myeloma is the second most common hematologic malignancy in the USA, with over 32,000 new cases and nearly 13,000 deaths expected in 2019. The past few decades in myeloma research have yielded significant advances, leading to the expansion of novel anti-myeloma agents. This review describes the incidence and mechanisms of cardiotoxicity for the FDA-approved proteasome inhibitors in myeloma and proposes strategies to assess and manage resultant cardiovascular adverse events.

Recent Findings

Proteasome inhibition precipitates protein aggregation and alters transcriptional activation of NF-κB targets which contributes to a pro-apoptotic signaling cascade in myeloma cells. Similar effects in cardiomyocytes and vascular smooth muscle endothelium, along with off-target downregulation of autophagy and signaling alterations of nitric oxide homeostasis, may be linked to observed cardiotoxic effects. There is preliminary evidence for cardioprotective potential for rutin, dexrazoxane, and apremilast that could have clinical applicability in the future.

Summary

Of the proteasome inhibitors used in clinical practice, carfilzomib is the most strongly associated with cardiotoxicity. Patients with anticipated carfilzomib treatment should undergo assessment and optimization of baseline cardiovascular risk, with close monitoring during treatment. Previous clinical trials were not specifically designed to assess proteasome inhibitor-related cardiotoxicity, creating a need for future studies to identify and risk stratify vulnerable individuals and to develop potential cardioprotective strategies in attenuating cardiac injury.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69(1):7–34.

    Article  Google Scholar 

  2. Rajkumar SV, Dimopoulos MA, Palumbo A, Blade J, Merlini G, Mateos MV, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014;15(12):e538–48.

    PubMed  Google Scholar 

  3. Yeh ET, Bickford CL. Cardiovascular complications of cancer therapy: incidence, pathogenesis, diagnosis, and management. J Am Coll Cardiol. 2009;53(24):2231–47.

    CAS  PubMed  Google Scholar 

  4. Sheppard RJ, Berger J, Sebag IA. Cardiotoxicity of cancer therapeutics: current issues in screening, prevention, and therapy. Front Pharmacol. 2013;4:19.

    PubMed  PubMed Central  Google Scholar 

  5. Palumbo A, Bringhen S, Ludwig H, Dimopoulos MA, Bladé J, Mateos MV, et al. Personalized therapy in multiple myeloma according to patient age and vulnerability: a report of the European Myeloma Network (EMN). Blood. 2011;118(17):4519–29.

    CAS  PubMed  Google Scholar 

  6. Kistler KD, et al. Cardiac event rates in patients with newly diagnosed and relapsed multiple myeloma in US clinical practice. Blood. 2012;120(21).

  7. Kyle RA, Gertz MA, Witzig TE, Lust JA, Lacy MQ, Dispenzieri A, et al. Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clin Proc. 2003;78(1):21–33.

    PubMed  Google Scholar 

  8. Gansevoort RT, Correa-Rotter R, Hemmelgarn BR, Jafar TH, Heerspink HJL, Mann JF, et al. Chronic kidney disease and cardiovascular risk: epidemiology, mechanisms, and prevention. Lancet. 2013;382(9889):339–52.

    PubMed  Google Scholar 

  9. Sarnak MJ, Tighiouart H, Manjunath G, MacLeod B, Griffith J, Salem D, et al. Anemia as a risk factor for cardiovascular disease in the Atherosclerosis Risk in Communities (ARIC) study. J Am Coll Cardiol. 2002;40(1):27–33.

    PubMed  Google Scholar 

  10. Mozos I. Mechanisms linking red blood cell disorders and cardiovascular diseases. Biomed Res Int. 2015;2015:682054.

    PubMed  PubMed Central  Google Scholar 

  11. Madan S, Dispenzieri A, Lacy MQ, Buadi F, Hayman SR, Zeldenrust SR, et al. Clinical features and treatment response of light chain (AL) amyloidosis diagnosed in patients with previous diagnosis of multiple myeloma. Mayo Clin Proc. 2010;85(3):232–8.

    PubMed  PubMed Central  Google Scholar 

  12. Liu PP, Smyth D. Wild-type transthyretin amyloid cardiomyopathy: a missed cause of heart failure with preserved ejection fraction with evolving treatment implications. Circulation. 2016;133(3):245–7.

    PubMed  Google Scholar 

  13. Heckmann MB, Doroudgar S, Katus HA, Lehmann LH et al. Cardiovascular adverse events in multiple myeloma patients. J Thorac Dis. 2018; 10(Suppl 35): p. S4296–S4305.

  14. Demo SD, Kirk CJ, Aujay MA, Buchholz TJ, Dajee M, Ho MN, et al. Antitumor activity of PR-171, a novel irreversible inhibitor of the proteasome. Cancer Res. 2007;67(13):6383–91.

    CAS  PubMed  Google Scholar 

  15. Patel MB, Majetschak M. Distribution and interrelationship of ubiquitin proteasome pathway component activities and ubiquitin pools in various porcine tissues. Physiol Res. 2007;56(3):341–50.

    CAS  PubMed  Google Scholar 

  16. Obeng EA, Carlson LM, Gutman DM, Harrington WJ Jr, Lee KP, Boise LH. Proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma cells. Blood. 2006;107(12):4907–16.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Willis MS, Patterson C. Proteotoxicity and cardiac dysfunction – Alzheimer’s disease of the heart? N Engl J Med. 2013;368(5):455–64.

    CAS  PubMed  Google Scholar 

  18. Hasinoff BB, Patel D, Wu X. Molecular mechanisms of the cardiotoxicity of the proteasomal-targeted drugs bortezomib and carfilzomib. Cardiovasc Toxicol. 2017;17(3):237–50.

    CAS  PubMed  Google Scholar 

  19. Tannous P, Zhu H, Nemchenko A, Berry JM, Johnstone JL, Shelton JM, et al. Intracellular protein aggregation is a proximal trigger of cardiomyocyte autophagy. Circulation. 2008;117(24):3070–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Sanbe A, Osinska H, Saffitz JE, Glabe CG, Kayed R, Maloyan A, et al. Desmin-related cardiomyopathy in transgenic mice: a cardiac amyloidosis. Proc Natl Acad Sci U S A. 2004;101(27):10132–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Predmore JM, Wang P, Davis F, Bartolone S, Westfall MV, Dyke DB, et al. Ubiquitin proteasome dysfunction in human hypertrophic and dilated cardiomyopathies. Circulation. 2010;121(8):997–1004.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Barac YD, Emrich F, Krutzwakd-Josefson E, Schrepfer S, Sampaio LC, Willerson JT, et al. The ubiquitin-proteasome system: a potential therapeutic target for heart failure. J Heart Lung Transplant. 2017;36(7):708–14.

    PubMed  Google Scholar 

  23. Chauhan D, Hideshima T, Mitsiades C, Richardson P, Anderson KC. Proteasome inhibitor therapy in multiple myeloma. Mol Cancer Ther. 2005;4(4):686–92.

    CAS  PubMed  Google Scholar 

  24. Li ZW, Chen H, Campbell RA, Bonavida B, Berenson JR. NF-κB in the pathogenesis and treatment of multiple myeloma. Curr Opin Hematol. 2008;15(4):391–9.

    CAS  PubMed  Google Scholar 

  25. Hideshima T, Ikeda H, Chauhan D, Okawa Y, Raje N, Podar K, et al. Bortezomib induces canonical nuclear factor-kappaB activation in multiple myeloma cells. Blood. 2009;114(5):1046–52.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Frangogiannis NG, Smith CW, Entman ML. The inflammatory response in myocardial infarction. Cardiovasc Res. 2002;53(1):31–47.

    CAS  PubMed  Google Scholar 

  27. Kaiser RA, Bueno OF, Lips DJ, Doevendans PA, Jones F, Kimball TF, et al. Targeted inhibition of p38 mitogen-activated protein kinase antagonizes cardiac injury and cell death following ischemia-reperfusion in vivo. J Biol Chem. 2004;279(15):15524–30.

    CAS  PubMed  Google Scholar 

  28. Li RC, et al. PKCepsilon modulates NF-kappaB and AP-1 via mitogen-activated protein kinases in adult rabbit cardiomyocytes. Am J Physiol Heart Circ Physiol. 2000;279(4):H1679–89.

    CAS  PubMed  Google Scholar 

  29. Gordon JW, Shaw JA, Kirshenbaum LA. Multiple facets of NF-kappaB in the heart: to be or not to NF-kappaB. Circ Res. 2011;108(9):1122–32.

    CAS  PubMed  Google Scholar 

  30. Tang M, Li J, Huang W, Su H, Liang Q, Tian Z, et al. Proteasome functional insufficiency activates the calcineurin-NFAT pathway in cardiomyocytes and promotes maladaptive remodelling of stressed mouse hearts. Cardiovasc Res. 2010;88(3):424–33.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Herrmann J, Wohlert C, Saguner AM, Flores A, Nesbitt LL, Chade A, et al. Primary proteasome inhibition results in cardiac dysfunction. Eur J Heart Fail. 2013;15(6):614–23.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Nowis D, Mączewski M, Mackiewicz U, Kujawa M, Ratajska A, Wieckowski MR, et al. Cardiotoxicity of the anticancer therapeutic agent bortezomib. Am J Pathol. 2010;176(6):2658–68.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. •• Efentakis P, et al. Molecular mechanisms of carfilzomib-induced cardiotoxicity in mice and the emerging cardioprotective role of metformin. Blood. 2019;133(7):710–23 This paper suggests that carfilzomib induces cardiotoxicity in mice via activation of PP2A and disruption of downstream autophagy, suggesting that carfilzomib may have a distinct mechanism for cardiotoxicity aside from its direct effects on the proteasome.

    CAS  PubMed  Google Scholar 

  34. Rosenthal A, Luthi J, Behlolavek M. Carfilzomib and the cardiorenal system in myeloma: an endothelial effect? Blood Cancer J. 2016;6:e384.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. •• Cornell RF, et al. Prospective study of cardiac events during proteasome inhibitor therapy for relapsed multiple myeloma. J Clin Oncol. 2019:JCO.19.00231 This is the PROTECT trial, a prospective, observational study that followed patients treated with carfilzomib and bortezomib and monitored for CVAEs using cardiac biomarkers and echocardiography. Heart failure, hypertension, arrhythmia, ischemic heart disease, and pulmonary hypertension were all reported with the carfilzomib-based regimen, but the majority of these cardiotoxic effects were transient and reversible. Of note, the rates of CVAEs were higher in this population than rates reported in clinical trials that enrolled healthy patients, possibly owing to the fact that patients in real-world practice have higher incidence of baseline cardiovascular comorbidities.

  36. Yui JC, van Keer J, Weiss BM, Waxman AJ, Palmer MB, D'Agati VD, et al. Proteasome inhibitor associated thrombotic microangiopathy. Am J Hematol. 2016;91(9):E348–52.

    CAS  PubMed  Google Scholar 

  37. Chen-Scarabelli C, Corsetti G, Pasini E, Dioguardi FS, Sahni G, Narula J, et al. Spasmogenic effects of the proteasome inhibitor carfilzomib on coronary resistance, vascular tone and reactivity. EBioMedicine. 2017;21:206–12.

    PubMed  PubMed Central  Google Scholar 

  38. Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature. 1980;288(5789):373–6.

    CAS  PubMed  Google Scholar 

  39. Palmer RM, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature. 1987;327(6122):524–6.

    CAS  PubMed  Google Scholar 

  40. Stangl K, Stangl V. The ubiquitin-proteasome pathway and endothelial (dys)function. Cardiovasc Res. 2010;85(2):281–90.

    CAS  PubMed  Google Scholar 

  41. Herrmann J, Saguner AM, Versari D, Peterson TE, Chade A, Olson M, et al. Chronic proteasome inhibition contributes to coronary atherosclerosis. Circ Res. 2007;101(9):865–74.

    CAS  PubMed  Google Scholar 

  42. Landmesser U, Dikalov S, Price SR, McCann L, Fukai T, Holland SM, et al. Oxidation of tetrahydrobiopterin leads to uncoupling of endothelial cell nitric oxide synthase in hypertension. J Clin Invest. 2003;111(8):1201–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Cosentino F, Luscher TF. Tetrahydrobiopterin and endothelial nitric oxide synthase activity. Cardiovasc Res. 1999;43(2):274–8.

    CAS  PubMed  Google Scholar 

  44. Suryavanshi SV, Kulkarni YA. NF-kappabeta: a potential target in the management of vascular complications of diabetes. Front Pharmacol. 2017;8:798.

    PubMed  PubMed Central  Google Scholar 

  45. Spur EM, Althof N, Respondek D, Klingel K, Heuser A, Overkleeft HS, et al. Inhibition of chymotryptic-like standard proteasome activity exacerbates doxorubicin-induced cytotoxicity in primary cardiomyocytes. Toxicology. 2016;353-354:34–47.

    CAS  PubMed  Google Scholar 

  46. Tanaka K. The proteasome: overview of structure and functions. Proc Jpn Acad Ser B Phys Biol Sci. 2009;85(1):12–36.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Dick LR, Fleming PE. Building on bortezomib: second-generation proteasome inhibitors as anti-cancer therapy. Drug Discov Today. 2010;15(5–6):243–9.

    CAS  PubMed  Google Scholar 

  48. Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin DH, et al. Extended follow-up of a phase II trial in relapsed, refractory multiple myeloma: final time-to-event results from the SUMMIT trial. Cancer. 2006;106(6):1316–9.

    CAS  PubMed  Google Scholar 

  49. Jagannath S, Barlogie B, Berenson JR, Siegel DS, Irwin D, Richardson PG, et al. Updated survival analyses after prolonged follow-up of the phase 2, multicenter CREST study of bortezomib in relapsed or refractory multiple myeloma. Br J Haematol. 2008;143(4):537–40.

    PubMed  Google Scholar 

  50. Richardson PG, Sonneveld P, Schuster M, Irwin D, Stadtmauer E, Facon T, et al. Extended follow-up of a phase 3 trial in relapsed multiple myeloma: final time-to-event results of the APEX trial. Blood. 2007;110(10):3557–60.

    CAS  PubMed  Google Scholar 

  51. San Miguel JF, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M, et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med. 2008;359(9):906–17.

    CAS  PubMed  Google Scholar 

  52. Bockorny M, Chakravarty S, Schulman P, Bockorny B, Bona R. Severe heart failure after bortezomib treatment in a patient with multiple myeloma: a case report and review of the literature. Acta Haematol. 2012;128(4):244–7.

    PubMed  Google Scholar 

  53. Gupta A, Pandey A, Sethi S. Bortezomib-induced congestive cardiac failure in a patient with multiple myeloma. Cardiovasc Toxicol. 2012;12(2):184–7.

    PubMed  Google Scholar 

  54. Honton B, Despas F, Dumonteil N, Rouvellat C, Roussel M, Carrie D, et al. Bortezomib and heart failure: case-report and review of the French Pharmacovigilance database. Fundam Clin Pharmacol. 2014;28(3):349–52.

    CAS  PubMed  Google Scholar 

  55. Voortman J, Giaccone G. Severe reversible cardiac failure after bortezomib treatment combined with chemotherapy in a non-small cell lung cancer patient: a case report. BMC Cancer. 2006;6.

  56. Enrico O, Gabriele B, Nadia C, Sara G, Daniele V, Giulia C, et al. Unexpected cardiotoxicity in haematological bortezomib treated patients. Br J Haematol. 2007;138(3):396–7.

    PubMed  Google Scholar 

  57. Takamatsu H, Yamashita T, Kotani T, Sawazaki A, Okumura H, Nakao S. Ischemic heart disease associated with bortezomib treatment combined with dexamethasone in a patient with multiple myeloma. Int J Hematol. 2010;91(5):903–6.

    PubMed  Google Scholar 

  58. Dasanu CA. Complete heart block secondary to bortezomib use in multiple myeloma. J Oncol Pharm Pract. 2011;17(3):282–4.

    CAS  PubMed  Google Scholar 

  59. Reneau JC, Asante D, van Houten H, Sangaralingham LR, Buadi FK, Lerman A, et al. Cardiotoxicity risk with bortezomib versus lenalidomide for treatment of multiple myeloma: a propensity matched study of 1,790 patients. Am J Hematol. 2017;92(2):E15–7.

    CAS  PubMed  Google Scholar 

  60. Xiao Y, et al. Incidence and risk of cardiotoxicity associated with bortezomib in the treatment of cancer: a systematic review and meta-analysis. PLoS One. 2014;9(1).

  61. Laubach JP, San Miguel JF, Sonneveld P. Quantifying the risk of heart failure associated with proteasome inhibition: a retrospective analysis of heart failure reported in phase 2 and phase 3 studies of bortezomib in multiple myeloma [abstract]. Blood. 2013;122:3187.

    Google Scholar 

  62. Ruckrich T, et al. Characterization of the ubiquitin-proteasome system in bortezomib-adapted cells. Leukemia. 2009;23(6):1098–105.

    CAS  PubMed  Google Scholar 

  63. Oerlemans R, Franke NE, Assaraf YG, Cloos J, van Zantwijk I, Berkers CR, et al. Molecular basis of bortezomib resistance: proteasome subunit beta5 (PSMB5) gene mutation and overexpression of PSMB5 protein. Blood. 2008;112(6):2489–99.

    CAS  PubMed  Google Scholar 

  64. Sanchez E, et al. Carfilzomib overcomes resistance to bortezomib in the human Lagk-1A Multiple myeloma xenograft model. Blood. 2014;124(21).

  65. Berenson JR, Hilger JD, Yellin O, Dichmann R, Patel-Donnelly D, Boccia RV, et al. Replacement of bortezomib with carfilzomib for multiple myeloma patients progressing from bortezomib combination therapy. Leukemia. 2014;28(7):1529–36.

    CAS  PubMed  Google Scholar 

  66. Parlati F, Lee SJ, Aujay M, Suzuki E, Levitsky K, Lorens JB, et al. Carfilzomib can induce tumor cell death through selective inhibition of the chymotrypsin-like activity of the proteasome. Blood. 2009;114(16):3439–47.

    CAS  PubMed  Google Scholar 

  67. Kuhn DJ, Chen Q, Voorhees PM, Strader JS, Shenk KD, Sun CM, et al. Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquitin-proteasome pathway, against preclinical models of multiple myeloma. Blood. 2007;110(9):3281–90.

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Arastu-Kapur S, Anderl JL, Kraus M, Parlati F, Shenk KD, Lee SJ, et al. Nonproteasomal targets of the proteasome inhibitors bortezomib and carfilzomib: a link to clinical adverse events. Clin Cancer Res. 2011;17(9):2734–43.

    CAS  PubMed  Google Scholar 

  69. Siegel D, Martin T, Nooka A. Integrated safety profile of single-agent carfilzomib: experience from 526 patients enrolled in 4 phase II clinical studies. Hematologica. 2013;98:1753–61.

    CAS  Google Scholar 

  70. Stewart AK, Rajkumar SV, Dimopoulos MA. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med. 2015;372:142–52.

    PubMed  Google Scholar 

  71. •• Siegel DS, et al. Improvement in overall survival with carfilzomib, lenalidomide, and dexamethasone in patients with relapsed or refractory multiple myeloma. J Clin Oncol. 2018;36(8):728–34 This paper includes updated final overall survival data and safety results, reaffirming that cases of CVAE were increased in the carfilzomib-treated group. The paper suggests proactive monitoring and treatment to help resolve these issues.

    CAS  PubMed  Google Scholar 

  72. Dimopoulos MA, Goldschmidt H, Niesvizky R, Joshua D, Chng WJ, Oriol A, et al. Carfilzomib or bortezomib in relapsed or refractory multiple myeloma (ENDEAVOR): an interim overall survival analysis of an open-label, randomised, phase 3 trial. Lancet Oncol. 2017;18(10):1327–37.

    CAS  PubMed  Google Scholar 

  73. •• Dimopoulos MA, et al. Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): a randomised, phase 3, open-label, multicentre study. Lancet Oncol. 2016;17(1):27–38 This paper describes outcomes of the phase III ENDEAVOR study, in which an expected increase incidence of hypertension, heart failure, and dyspnea was detected. Of note, the study excluded patients with LVEF< 40% or clinical symptoms of NYHA III/IV, recent MI, or symptoms of cardiac ischemia. The study only reported outcomes of clinically overt heart failure, biomarkers were not measured, and LV function changes were only measured and analyzed in a subpopulation of 151 patients.

    CAS  PubMed  Google Scholar 

  74. Atrash S, Tullos A, Panozzo S, Bhutani M, van Rhee F, Barlogie B, et al. Cardiac complications in relapsed and refractory multiple myeloma patients treated with carfilzomib. Blood Cancer J. 2015;5:e272.

    CAS  PubMed  PubMed Central  Google Scholar 

  75. •• Waxman AJ, et al. Carfilzomib-associated cardiovascular adverse events: a systematic review and meta-analysis. JAMA Oncol. 2018;4(3):e174519 This systematic review and meta-analysis of 24 prospective clinical trials found a large range of reported CVAEs from carfilzomib. CVAEs were especially significant at higher doses of the drug. The study concludes that from the 3 RCTs in the study including ASPIRE, ENDEAVOR, and FOCUS, the use of carfilzomib was associated with 2-fold increased risk of high-grade CVAEs.

    PubMed  Google Scholar 

  76. •• Fakhri B, et al. Measuring cardiopulmonary complications of carfilzomib treatment and associated risk factors using the SEER-Medicare database. Cancer. 2019; This retrospective assessment of 635 patients treated with carfilzomib in the general population using the SEER database potentially provides a more realistic portrayal of CVAE risk attributed to carfilzomib in true clinical practice and reports 22% of patients who developed hypertension and 14% who developed heart failure.

  77. Chauhan D, Tian Z, Zhou B, Kuhn D, Orlowski R, Raje N, et al. In vitro and in vivo selective antitumor activity of a novel orally bioavailable proteasome inhibitor MLN9708 against multiple myeloma cells. Clin Cancer Res. 2011;17(16):5311–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Kupperman E, Lee EC, Cao Y, Bannerman B, Fitzgerald M, Berger A, et al. Evaluation of the proteasome inhibitor MLN9708 in preclinical models of human cancer. Cancer Res. 2010;70(5):1970–80.

    CAS  PubMed  Google Scholar 

  79. • Moreau P, et al. Oral ixazomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016;374(17):1621–34 This paper reports the result from the phase III TOURMALINE-MM1 trial which compared ixazomib in ILd regimen to Ld, without evidence that CVAEs differed significantly between the groups. However, the study excluded patients with clinical symptoms of arrhythmia, HTN, HF, unstable angina, or myocardial infarction in the preceding 6 months.

    CAS  PubMed  Google Scholar 

  80. Dispenzieri A, Kastritis E, Wechalekar AD, Schönland SO, Kim K, Sanchorawala V, et al. Primary results from the phase 3 tourmaline-AL1 trial of ixazomib-dexamethasone versus physician’s choice of therapy in patients (Pts) with relapsed/refractory primary systemic AL amyloidosis (RRAL). Blood. 2019;134:139–9.

  81. • Ghobrial IM, et al. A phase Ib/II study of oprozomib in patients with advanced multiple myeloma and Waldenstrom macroglobulinemia. Clin Cancer Res. 2019;25(16):4907–16 This paper reports the potential therapeutic activity of oprozomib in RRMM, without known cardiovascular side effects.

    PubMed  Google Scholar 

  82. • Hari P, et al. Oprozomib in patients with newly diagnosed multiple myeloma. Blood Cancer J. 2019;9(9):66 This paper reports the potential therapeutic activity of oprozomib in NDMM, without known cardiovascular side effects.

    PubMed  PubMed Central  Google Scholar 

  83. Harrison SJ, Mainwaring P, Price T, Millward MJ, Padrik P, Underhill CR, et al. Phase I clinical trial of marizomib (NPI-0052) in patients with advanced malignancies including multiple myeloma: study NPI-0052-102 final results. Clin Cancer Res. 2016;22(18):4559–66.

    CAS  PubMed  Google Scholar 

  84. Spencer A, Harrison S, Zonder J, Badros A, Laubach J, Bergin K, et al. A phase 1 clinical trial evaluating marizomib, pomalidomide and low-dose dexamethasone in relapsed and refractory multiple myeloma (NPI-0052-107): final study results. Br J Haematol. 2018;180(1):41–51.

    CAS  PubMed  Google Scholar 

  85. Infante JR, Mendelson DS, Burris HA III, Bendell JC, Tolcher AW, Gordon MS, et al. A first-in-human dose-escalation study of the oral proteasome inhibitor oprozomib in patients with advanced solid tumors. Investig New Drugs. 2016;34(2):216–24.

    CAS  Google Scholar 

  86. Badros AZ, Vij R, Martin T, Zonder JA, Kunkel L, Wang Z, et al. Carfilzomib in multiple myeloma patients with renal impairment: pharmacokinetics and safety. Leukemia. 2013;27(8):1707–14.

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Siegel DS, Martin T, Wang M, Vij R, Jakubowiak AJ, Lonial S, et al. A phase 2 study of single-agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma. Blood. 2012;120(14):2817–25.

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Jagannath, S., et al., Long-term treatment and tolerability of the novel proteasome inhibitor carfilzomib (CFZ) in patients with relapsed and/or refractory multiple myeloma (R/R MM). Blood (ASH Annual Meeting Abstracts), 2010. 116(21).

  89. 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.

    CAS  PubMed  Google Scholar 

  90. 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.

    PubMed  PubMed Central  Google Scholar 

  91. Dimopoulos MA, Roussou M, Gavriatopoulou M, Psimenou E, Ziogas D, Eleutherakis-Papaiakovou E, et al. Cardiac and renal complications of carfilzomib in patients with multiple myeloma. Blood Adv. 2017;1(7):449–54.

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Grandin EW, Ky B, Cornell RF, Carver J, Lenihan DJ. Patterns of cardiac toxicity associated with irreversible proteasome inhibition in the treatment of multiple myeloma. J Card Fail. 2015;21:138–44.

    CAS  PubMed  Google Scholar 

  93. Chen JH, Lenihan DJ, Phillips SE, Harrell SL, Cornell RF. Cardiac events during treatment with proteasome inhibitor therapy for multiple myeloma. Cardio-Oncology. 2017;3(1):4.

    PubMed  PubMed Central  Google Scholar 

  94. Mikhael J. Management of carfilzomib-associated cardiac adverse events. Clin Lymphoma Myeloma Leuk. 2016;16(5):241–5.

    PubMed  Google Scholar 

  95. Harvey RD. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Yang EH, et al. Recurrent heart failure with preserved ejection fraction associated with carfilzomib administration for multiple myeloma. Cardio-Oncology. 2018;4(1).

  97. Atrash S, Tullos A, Panozzo S, Waheed S, van Rhee F, Restrepo A, et al. Retrospective analysis of cardiovascular (CV) events following compassionate use of carfilzomib (CFZ) in patients (Pts) with relapsed and refractory multiple myeloma (RRMM). J Clin Oncol. 2013;31(15):8595.

    Google Scholar 

  98. Onyx Pharmaceuticals, Inc. Kyprolis (carfilzomib). U.S. Food and Drug Administration website. https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202714lbl.pdf Revised July 2012. Accessed January 9, 2020.

  99. Jain T, Narayanasamy H, Mikhael J, Reeder CB, Bergsagel PL, Mayo A, et al. Systolic dysfunction associated with carfilzomib use in patients with multiple myeloma. Blood Cancer J. 2017;7(12):642.

    PubMed  PubMed Central  Google Scholar 

  100. • Imam F, et al. Rutin attenuates carfilzomib-induced cardiotoxicity through inhibition of NF-kappaB, hypertrophic gene expression and oxidative stress. Cardiovasc Toxicol. 2017;17(1):58–66 This paper reports that treatment with rutin reversed cardiotoxic changes induced by carfilzomib, with prevention of NF-κB activation and hypertrophic gene expression, attenuation of oxidative stress, and amelioration of histopathologic changes in rat hearts.

    CAS  PubMed  Google Scholar 

  101. Zhang S, et al. Cardiac protective effects of dexrazoxane on animal cardiotoxicity model induced by anthracycline combined with trastuzumab is associated with upregulation of calpain-2. Medicine (United States). 2015;94(4).

  102. • Al-Harbi NO. Carfilzomib-induced cardiotoxicity mitigated by dexrazoxane through inhibition of hypertrophic gene expression and oxidative stress in rats. Toxicol Mech Methods. 2016;26(3):189–95 This paper reports that treatment with topoisomerase-II inhibitor dexrazoxane reversed cardiotoxic changes induced by carfilzomib, with reduction of hypertrophic gene expression, attenuation of oxidative stress, and amelioration of histopathologic changes in rat hearts.

    CAS  PubMed  Google Scholar 

  103. • Imam F, et al. Apremilast reversed carfilzomib-induced cardiotoxicity through inhibition of oxidative stress, NF-kappaB and MAPK signaling in rats. Toxicol Mech Methods. 2016;26(9):700–8 This paper reports that treatment with PDE4 inhibitor apremilast reversed cardiotoxic changes induced by carfilzomib, including reversal of the increased NF-κB, ERK, and JNK mRNA expression as well as inflammatory markers such as TNF-α.

    CAS  PubMed  Google Scholar 

  104. Kuhn DJ, Hunsucker SA, Chen Q, Voorhees PM, Orlowski M, Orlowski RZ. Targeted inhibition of the immunoproteasome is a potent strategy against models of multiple myeloma that overcomes resistance to conventional drugs and nonspecific proteasome inhibitors. Blood. 2009;113(19):4667–76.

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Singh AV, Bandi M, Aujay MA, Kirk CJ, Hark DE, Raje N, et al. PR-924, a selective inhibitor of the immunoproteasome subunit LMP-7, blocks multiple myeloma cell growth both in vitro and in vivo. Br J Haematol. 2011;152(2):155–63.

    CAS  PubMed  Google Scholar 

  106. Huber EM, Basler M, Schwab R, Heinemeyer W, Kirk CJ, Groettrup M, et al. Immuno- and constitutive proteasome crystal structures reveal differences in substrate and inhibitor specificity. Cell. 2012;148(4):727–38.

    CAS  PubMed  Google Scholar 

  107. Moreau P, Pylypenko H, Grosicki S, Karamanesht I, Leleu X, Grishunina M, et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol. 2011;12(5):431–40.

    PubMed  Google Scholar 

  108. • Hu B, et al. Efficacy and safety of subcutaneous versus intravenous bortezomib in multiple myeloma: a meta-analysis. Int J Clin Pharmacol Ther. 2017;55(4):329–38 This meta-analysis suggests that subcutaneous administration of bortezomib may reduce incidence of thrombocytopenia, renal, and urinary disorders related to the drug when compared to intravenous route of administration. This supports the theory that side effects of other proteasome inhibitors, including carfilzomib, may be abrogated by modifications in its route of delivery. This may explain how orally administered homologues of carfilzomib such as oprozomib have few cardiovascular side effects.

    PubMed  Google Scholar 

  109. Mateos MV, Oriol A, Martínez-López J, Gutiérrez N, Teruel AI, de Paz R, et al. Bortezomib, melphalan, and prednisone versus bortezomib, thalidomide, and prednisone as induction therapy followed by maintenance treatment with bortezomib and thalidomide versus bortezomib and prednisone in elderly patients with untreated multiple myeloma: a randomised trial. Lancet Oncol. 2010;11(10):934–41.

    CAS  PubMed  Google Scholar 

  110. Palumbo A, Bringhen S, Rossi D, Cavalli M, Larocca A, Ria R, et al. Bortezomib-melphalan-prednisone-thalidomide followed by maintenance with bortezomib-thalidomide compared with bortezomib-melphalan-prednisone for initial treatment of multiple myeloma: a randomized controlled trial. J Clin Oncol. 2010;28(34):5101–9.

    CAS  PubMed  Google Scholar 

  111. Bringhen S, Larocca A, Rossi D, Cavalli M, Genuardi M, Ria R, et al. Efficacy and safety of once-weekly bortezomib in multiple myeloma patients. Blood. 2010;116(23):4745–53.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medicine, Division of General Internal Medicine, Ronald Reagan-UCLA Medical Center, Los Angeles, CA, USA

    Perry Wu

  2. Department of Medicine, Division of Hematology/Oncology, Mayo Clinic, Rochester, MN, USA

    Ohad Oren & Morie A. Gertz

  3. Department of Medicine, UCLA Cardio-Oncology Program, Division of Cardiology, Ronald Reagan – UCLA Medical Center, University of California, 100 Medical Plaza, Suite 630, Los Angeles, CA, 90095, USA

    Eric H. Yang

Authors
  1. Perry Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ohad Oren
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Morie A. Gertz
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Eric H. Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Eric H. Yang.

Ethics declarations

Conflict of Interest

Perry Wu declares that he has no conflict of interest. Ohad Oren declares that he has no conflict of interest. Morie A. Gertz is supported by grants/research funding from Spectrum Pharmaceuticals, the Amyloidosis Foundation, the International Waldenstrom’s Macroglobulinemia Foundation, and the National Institutes of Health National Cancer Institute (SPORE MM SPORE 5P50 CA186781–04); has received compensation from Ionis/Akcea, Alnylam, Prothena, Celgene, Janssen, Spectrum Pharmaceuticals, Annexon Biosciences, Apellis, Amgen, Medscape, Physicians’ Education Resource, AbbVie (Data Safety Monitoring Board), and Research To Practice for service as a consultant; has received speaker’s honoraria from Teva, Johnson and Johnson, Medscape, and DAVA Oncology; has served on advisory boards for Pharmacyclics and Proclara Biosciences; has assisted in the development of educational materials for i3 Health; and has received royalties from Springer Publishing. Eric H. Yang declares that he has no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Cardio-oncology

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wu, P., Oren, O., Gertz, M.A. et al. Proteasome Inhibitor-Related Cardiotoxicity: Mechanisms, Diagnosis, and Management. Curr Oncol Rep 22, 66 (2020). https://doi.org/10.1007/s11912-020-00931-w

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11912-020-00931-w

Keywords

Search

Navigation