Case series discussion of cardiac and vascular events following carfilzomib treatment: possible mechanism, screening, and monitoring

Abstract

BackgroundCarfilzomib is a selective proteasome inhibitor approved in the United States in 2012 for the treatment of relapsed and refractory multiple myeloma. Although cardiopulmonary and vascular events have been reported infrequently, they can be potentially serious complications, and their incidence and pathophysiology following carfilzomib treatment remain poorly characterized in a real-world patient population.MethodsWe retrospectively reviewed the records of 67 patients with relapsed and/or refractory multiple myeloma treated at our institution.ResultsWe describe 12 patients who experienced cardiac or vascular-related adverse events subsequent to carfilzomib-based treatment (median age, 59 years [range, 49–77]). Nine patients had prior autologous stem cell transplant, and three had prior anthracycline exposure. Detailed case reports are provided for five representative patients: (1) systemic hypertension in a 65-year-old Caucasian female with a history of hypertension, hypothyroidism, and stage III chronic kidney disease; (2) pulmonary hypertension in a 72-year-old Caucasian male with a history of recurrent respiratory infections and chronic right lower extremity deep venous thrombosis; (3) acute renal insufficiency with increased blood pressure in a 50-year-old Caucasian male with a history of hypertension and stage IV chronic kidney disease; (4) heart failure in a 64-year-old African American female with a history of hypertension; and (5) dyspnea and lung disease in a 58-year-old Asian American male with a history significant for hepatitis B virus infection.ConclusionsWhile cardiac and vascular-related adverse events were reported in patients with relapsed and/or refractory multiple myeloma who were treated with carfilzomib, most patients had a history of the specific cardiac or vascular adverse event they exhibited and demonstrated an improvement or resolution in symptoms after the discontinuation of therapy. Appropriate screening and monitoring could potentially allow at-risk patients to benefit fully from treatment with carfilzomib.

Analysis of carfilzomib cardiovascular safety profile across relapsed and/or refractory multiple myeloma clinical trials

“…Careful clinical volume status assessment may be a useful measure to proactively manage patients at risk for developing heart failure. Increasing evidence suggests a possible effect of proteasome inhibition on vascular endothelium, [34][35][36][37] rather than cardiac myocytes. Therefore, vascular impact biomarkers should be investigated.…”

Proteasome inhibitors in cancer therapy

“…Whereas the rates of peripheral neuropathy are lower with carfilzomib, a few patients have developed cardiovascular complications, including hypertension and heart failure with decreased left ventricular ejection fraction 46 . Endothelial dysfunction has been proposed to occur after carfilzomib administration through inhibition of endothelial nitric oxide synthase activity 52 . An echocardiography assessment is recommended for all patients before starting carfilzomib treatment, though utility of this evaluation in predicting those at risk for cardiac events has not been proven, and additional studies are needed in this area.…”

Carfilzomib for the Treatment of Patients with Relapsed and/or Refractory Multiple Myeloma

“…Similarly, in the ENDEAVOR study, the incidence of hypertension was reported to be higher in the Kd group compared with the Vd group [60]. Intervention with antihypertensive medications and the cautious use of diuretics have been suggested as beneficial symptomatic management strategies in patients reporting hypertension after treatment with carfilzomib [72].…”

“…Cardiac events have been reported to be associated with proteasome inhibition and are hypothesized to be a class effect for these agents [71][72][73]. Cardiac failure was reported in 7% of patients in the Phase II studies, although it should also be noted that 74% of patients had a medical history of cardiovascular disease [64].…”