Cardiovascular Complications Associated with Multiple Myeloma Therapies: Incidence, Pathophysiology, and Management
Purpose of Review
Multiple myeloma is a common hematologic malignancy characterized by recurrent relapsing disease course requiring use of various therapies. Over the past few decades, significant advancements in the treatment of myeloma have occurred including routine use of proteasome inhibitors and immunomodulatory drugs. These have effectively improved survival; however, some also have increased risk of cardiovascular toxicity. Here, we will review the incidence, pathophysiology, and management of cardiovascular complications associated with antimyeloma agents.
Cardiovascular complications associated with myeloma treatment are common. These cardiovascular complications include accelerated hypertension, ischemic heart disease, congestive heart failure, arrhythmia, pulmonary hypertension, venous thromboembolism, and arterial thromboembolism. Thromboprophylactic strategies during treatment with immunomodulatory agents and screening strategies to detect changes in myocardial function prior to the development of overt heart failure have occurred.
Cardiovascular complications associated with proteasome inhibitors and immunomodulatory drugs are an important component in supportive care of patients with myeloma. The incidence of cardiotoxicity is high, and, as such, early intervention and collaborative efforts between cardiologists and oncologists to mitigate and effectively manage these complications are imperative. Additional studies are needed to clarify the underlying pathophysiology and evaluate effective strategies for prevention and treatment.
KeywordsCardiovascular complication Multiple myeloma Cardiotoxicity Immunomodulatory drug Proteasome inhibitor Relapsed myeloma Thrombotic complication Venous thromboembolism Heart failure Thromboprophylaxis
Compliance with Ethical Standards
Conflict of Interest
The authors declare they have 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.
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- 6.Kistler KD, Kalman J, Sahni G, Murphy B, Werther W, Rajangam K, et al. 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;17:89–96.e3.CrossRefGoogle Scholar
- 10.Kistler KD, Rajangam K, Faich G, Lanes S. Event rates in patients with newly diagnosed and relapsed multiple myeloma in US clinical practice. 54th American Society of Hematology Annual Meeting. Atlanta, GA; 2012.Google Scholar
- 18.Laubach JP, Moslehi JJ, Francis SA, San Miguel JF, Sonneveld P, Orlowski RZ, et al. A retrospective analysis of 3954 patients in phase 2/3 trials of bortezomib for the treatment of multiple myeloma: towards providing a benchmark for the cardiac safety profile of proteasome inhibition in multiple myeloma. Br J Haematol. 2017;178:547–60.CrossRefGoogle Scholar
- 20.Zangari M, Fink L, Zhan F, Tricot G. Low venous thromboembolic risk with bortezomib in multiple myeloma and potential protective effect with thalidomide/lenalidomide-based therapy: review of data from phase 3 trials and studies of novel combination regimens. Clin Lymphoma Myeloma Leuk. 2011;11:228–36.CrossRefGoogle Scholar
- 22.Schwartz R, Davidson T. Pharmacology, pharmacokinetics, and practical applications of bortezomib. Oncology (Williston Park). 2004;18:14–21.Google Scholar
- 29.Dimopoulos MA, Moreau P, Palumbo A, Joshua D, Pour L, Hájek R, 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;17:27–38.CrossRefGoogle Scholar
- 35.Vij R, Siegel DS, Jagannath S, Jakubowiak AJ, Stewart AK, McDonagh K, et al. An open-label, single-arm, phase 2 study of single-agent carfilzomib in patients with relapsed and/or refractory multiple myeloma who have been previously treated with bortezomib. Br J Haematol. 2012;158:739–48.CrossRefGoogle Scholar
- 36.Papadopoulos KP, Siegel DS, Vesole DH, Lee P, Rosen ST, Zojwalla N, et al. Phase I study of 30-minute infusion of carfilzomib as single agent or in combination with low-dose dexamethasone in patients with relapsed and/or refractory multiple myeloma. J Clin Oncol. 2015;33:732–9.CrossRefGoogle Scholar
- 37.•Moreau P, Mateos MV, Berenson JR, et al. Once weekly versus twice weekly carfilzomib dosing in patients with relapsed and refractory multiple myeloma (A.R.R.O.W.): interim analysis results of a randomised, phase 3 study. Lancet Oncol. 2018;19:953–64. Only phase 3 randomized control trial evaluating dosing of carfilzomib for replased and refractory multiple myleoma. Early clinical trial data suggested bolus dose and infusion time may play a role in the development of proteasome inhibitor related cardiotoxicity. This trial showed that bolus and infusion methods likely have no effect in the development of cardiotoxicity. CrossRefGoogle Scholar
- 38.• Cornell RF, et al. Prospective study of cardiac events during proteasome inhibitor therapy for relapsed multiple myeloma. Blood. 2017;130:1855. Most recent prospective study to determine predictive markers and outcomes of cardiotoxicity associated with carfilzomib. Results showed that patients developed cardiotoxicity primarily within the first three months of therapy and it was associated with worse overall survivial. In addition, BNP and nt-BNP were shown to be predicitive markers of subsequent heart failure associated with treatment . Google Scholar
- 44.Shah C, Bishnoi R, Jain A, et al. Cardiotoxicity associated with carfilzomib: systematic review and meta-analysis. Leuk Lymphoma. 2018;1–13.Google Scholar
- 45.Russell SD, Lyon A, Lenihan DJ, Moreau P, Joshua D, Chng W-J, et al. Serial echocardiographic assessment of patients with relapsed multiple myleoma receiving carfilzomib and dexamethasone vs. bortezomib and dexamethasone: a substudy of the phase 3 endeavor trial. Blood. 2015;126:4250.Google Scholar
- 52.Gandhi AK, Kang J, Havens CG, Conklin T, Ning Y, Wu L, et al. Immunomodulatory agents lenalidomide and pomalidomide co-stimulate T cells by inducing degradation of T cell repressors Ikaros and Aiolos via modulation of the E3 ubiquitin ligase complex CRL4(CRBN.). Br J Haematol. 2014;164:811–21.CrossRefGoogle Scholar
- 55.Richardson P, Schlossman R, Jagannath S, Alsina M, Desikan R, Blood E, et al. Thalidomide for patients with relapsed multiple myeloma after high-dose chemotherapy and stem cell transplantation: results of an open-label multicenter phase 2 study of efficacy, toxicity, and biological activity. Mayo Clin Proc. 2004;79:875–82.CrossRefGoogle Scholar
- 60.Rajkumar SV, Jacobus S, Callander NS, Fonseca R, Vesole DH, Williams ME, et al. Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial. Lancet Oncol. 2010;11:29–37.CrossRefGoogle Scholar
- 62.• Dimopoulos MA, Dytfeld D, Grosicki S, et al. Elotuzumab plus pomalidomide and dexamethasone for multiple myeloma. N Engl J Med. 2018;379:1811–22. Recent trial evaluating novel combination therapy with elotuzumab and pomalidomide. Study protocol mandated the use of thromboprophylaxis with the IMiD therapy. Results showed that rates of VTE were <1% suggested that current strategies are effective. CrossRefGoogle Scholar
- 63.Miguel JS, Weisel K, Moreau P, Lacy M, Song K, Delforge M, et al. Pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone alone for patients with relapsed and refractory multiple myeloma (MM-003): a randomised, open-label, phase 3 trial. Lancet Oncol. 2013;14:1055–66.CrossRefGoogle Scholar
- 65.Lenalidomide: risk of thrombosis and thromboembolism.Google Scholar
- 68.Zangari M, Saghafifar F, Anaissie E, Badros A, Desikan R, Fassas A, et al. Activated protein C resistance in the absence of factor V Leiden mutation is a common finding in multiple myeloma and is associated with an increased risk of thrombotic complications. Blood Coagul Fibrinolysis. 2002;13:187–92.CrossRefGoogle Scholar
- 75.• Cornell RF, Goldhaber SZ, Englehardt BG, et al. Prospective study of apixaban for primary prevention of venous thromboembolism in patients with multiple myeloma receiving immunomodulatory therapy. Blood. 2018;132:1233. Pilot observational cohort study evaluating efficacy of direct anticoagulant, apixaban, for venous thromboembolism prophylaxis in patients receiving IMiDs. Interim analysis showed that this may be an effective strategy and is the only study to report these results. The study highlights the need for evaluationg the role of DOACs compared to warfarin and lovenox in prophylactic strategies. Google Scholar