Cardiovascular AEs and possible pathophysiological mechanisms

Cardiac events that have been observed in several studies include hypertension, congestive heart failure, and coronary artery disease. The exact underlying pathophysiological mechanism is unknown. Whether it is due to an endothelial effect, accumulation of misfolded proteins in cardiomyocytes, short infusion time, higher dosage of carfilzomib, or a combination of these possible mechanisms needs to be cleared up.

To investigate whether carfilzomib has a damaging effect on cardiac endothelial cells, Chen-Scarabelli et al administered carfilzomib to isolated rabbit hearts and aortae. They found that carfilzomib increased coronary perfusion pressure, resting vasoconstriction tone, and the spasmogenic effect of other different agents. Carfilzomib also reduced the vasodilating effect of acetylcholine, suggesting carfilzomib has an impaired vasodilating effect via an endothelium-dependent mechanism.40

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PIs induce cell death of MM cells due to accumulation of misfolded of unfolded proteins, leading to cytotoxic stress and apoptosis. Fu et al exposed rat neonatal cardiomyocytes to PIs (MG132, epoxomicin), leading to endoplasmic reticulum-initiated death of cardiomyocytes. This might also be one of the explanations for the use of PIs sometimes leading to cardiac failure.41 Another factor of importance might be the infusion time of and dosage of carfilzomib. In a single-center retrospective analysis of 130 patients treated with carfilzomib, 26 patients developed significant cardiac AEs, with 20 of 26 patients receiving the carfilzomib in 2- to 10-minute infusions.42

Land et al performed a retrospective analysis of patients receiving bortezomib and/or carfilzomib from 2010 until 2014, investigating the incidence of cardiac AEs. A total of 157 patients were included: 47 treated with bortezomib and 110 with carfilzomib. In sum, 17% reported cardiotoxicity: 9% in the bortezomib and 20% in the carfilzomib group. Baseline cardiac characteristics of value to predict cardiac AEs were not found. However, there was a significant increase in cardiac AEs in the group treated at ≥36 mg/m2 compared to <20 mg/m2 and 27 mg/m2. However, patients treated with a dose of 36 mg/m2 were more heavily pretreated MM patients.43

Is monitoring of cardiovascular parameters before and during treatment of any additive value? Dimopoulos et al investigated the possible cardiotoxic effects of carfilzomib in 60 patients by performing serial echocardiography: 12% of patients experienced a reduction in left ventricular ejection fraction, which increased in time from 5% at 3 months till 12% at 15 months, and 23.5% of patients with a previous cardiovascular disease had a decline in left ventricular ejection fraction compared to only 7% in patients without previous cardiovascular disease. There was no association between the dose of carfilzomib or the duration of infusion. Also, a transient decrease in kidney function was noticed, although 55% of patients with baseline estimated glomerular filtration rate <60 mL/min/1.73 m2 showed an improved renal function.44

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In a prospective study investigating 62 patients treated with carfilzomib (first-line treatment as well as RRMM treatment), blood pressure, N-terminal pro-brain natriuretic peptide, echocardiography, and kidney function were monitored. Cardiovascular events were infrequent, but more frequently seen in heavily pretreated patients and those with cardiovascular dysfunction at baseline.45 Even though the pathophysiological mechanisms of cardiovascular events during carfilzomib treatment are not completely unraveled, caution is clearly needed in cardiovascularly compromised patients when treatment with carfilzomib is started.

Toxicity in combination therapy

The ENDEAVOR study, combining carfilzomib and dexamethasone, and the ASPIRE study, adding lenalidomide to this combination, are the only completed phase III studies performed with carfilzomib. Table 2 shows an overview of the most common hematologic and nonhematologic AEs in these two studies. It is notable that grade III or higher hematologic AEs in the ENDEAVOR and ASPIRE studies were lower compared to the pooled analysis of the AEs of carfilzomib as a single agent.

(To view a larger version of Table 2, click here.)

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