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S. Bringhen et al.
a rare event and may occur in patients receiving anthracy- clines. Venous thromboembolism is frequent, occurring in 15-20% of patients with MM.10 Anthracyclines and cyclophosphamide may also cause acute pericarditis,11 and high doses of alkylating agents have been associated with pulmonary veno-occlusive disease.10
Cardiovascular toxicity induced by new targeted therapies, such as immunomodulatory drugs
Immunomodulatory drugs may induce arrhythmias, such as bradycardia and atrioventricular block. The brady- cardia and heart block may be caused by the antineoplas- tic drugs themselves, age-related fibrosis or AL-amyloido- sis. Thalidomide is associated with sinus bradycardia in 5% of patients. Sinus bradycardia can lead to syncope and may require placement of a pacemaker.15 Immuno- modulatory drugs are characterized by an increased risk of thromboembolic events. The mechanisms underlying this phenomenon are direct damage to endothelial cells, increased platelet aggregation and higher von Willebrand factor serum levels. In the absence of thromboprophylax- is, the risk of venous thromboembolism is 1.3 and 4.1 per 100 patient-cycles in newly diagnosed patients receiving thalidomide alone and in combination with dexametha- sone, respectively. The corresponding risk at relapse is 0.4 and 0.8 per 100 patient-cycles and it increased to 6.7 in patients treated with thalidomide, dexamethasone and doxorubicin.16 In the absence of thromboprophylaxis, the risk of venous thromboembolism is 0.8 and 0.7 per 100 patient-cycles in newly diagnosed and relapsed patients, respectively, receiving lenalidomide and dexamethasone. Venous thromboembolism may be fatal if complicated by pulmonary embolism. Adequate prophylaxis, which is based on risk evaluation, is therefore mandatory. Risk fac- tors can be related to characteristics of the patient (age, obesity, history of venous thromboembolism, central- venous catheter, comorbidities – such as diabetes, infec- tions, cardiac diseases –, surgical procedures – including vertebroplasty and kyophoplasty –, and inherited throm- bophilia); related to the myeloma (diagnosis per se, hyper- viscosity) and related to therapy (high-dose dexametha- sone, doxorubicin, or multi-agent chemotherapy). Prophylaxis in low-risk patients (≤1 patient/myeloma- related risk factor) consists of aspirin 100 mg, unless con- traindicated. If more than one risk factor is present, low molecular weight heparin or full-dose warfarin should be used and continued for at least 4 months; subsequently, switching to aspirin may be an option.17,18 New oral anti- coagulants are increasingly being considered, although these drugs have not been systematically studied in myeloma yet. Specific recommendations cannot, there- fore, be made as yet.19 Recently, a pilot study with the novel oral anticoagulation agent apixaban was conducted to evaluate the feasibility of venous thrombo-prophylaxis in 104 patients with MM, during treatment with immunomodulatory drugs. Results were encouraging but further evaluation is needed.
Cardiovascular toxicity of proteasome inhibitors
The metabolism of cellular proteins has a pivotal role in regulating cell function and homeostasis. Intracellular pro- tein degradation is mainly regulated by the ubiquitin-pro- teasome pathway, which acts on proteins involved in cell cycle functions, apoptosis, transcription and DNA repair.20 Proteins are tagged by ubiquitin and recognized by the
26S proteasome complex, which degrades proteins into small peptides.21
If proteasome activity is altered, cells stop growing and undergo apoptosis at an increased rate because of an increasingly aberrant proteome.22 In several cancers, neo- plastic cells are more sensitive than untransformed cells to proteasome inhibition. Based on this evidence, protea- some inhibitors therefore represent a highly relevant ther- apeutic strategy in MM treatment.
The pathophysiology of the cardiotoxicity induced by proteasome inhibitors is not entirely clear. One mecha- nism could be the inhibition of sarcomeric protein turnover, resulting in myocyte death.23 Other hypotheses are increased apoptosis of endothelial progenitor cells, endothelial nitric oxide synthase dysfunction, functional/structural abnormalities of cardiomyocytes sec- ondary to protein accumulation due to impaired protein degradation, inhibition of physiological NFκB activity, potentiation of the effects of other cardiotoxic agents, sup- pression of the adaptive/cytoprotective activity of the ubiquitin-proteasome pathway in an underlying car- diomyopathy, myocardial scarring and fibrosis, endoplas- mic reticulum stress induction in cardiomyoblasts, dys- function of cardiac mitochondria, contractile left ventricu- lar dysfunction and/or increased smooth muscle cell apop- tosis causing atherosclerotic plaque instability.24-29
Bortezomib
Bortezomib is a dipeptide boronic acid that inhibits the proteolytic activity of the proteasome chymotrypsin-like site, via the formation of a reversible interaction at the 26S proteasome. With regards to bortezomib-related cardiotox- icity, the information leaflet for patients contains a warning concerning the possibility of acute development or exacer- bation of chronic heart failure and a new onset of decreased LVEF. There have also been isolated cases of QT-interval prolongation, but causality has not been established.30
The incidence of all grades of cardiac dysfunction in patients taking bortezomib shows marked variability from 2% to 17.9%, depending on the clinical trial.9,29 In the meta-analysis conducted by Xiao et al., the incidence of all grades and high-grade bortezomib-related cardiotoxicity was 3.8% and 2.3%, respectively.29 Of interest, borte- zomib does not seem to significantly increase the risk of all grades or high-grade cardiotoxicity, if compared with control medications. Nevertheless, the overall incidence of bortezomib-related cardiotoxicity of all grades was higher in MM patients (4.3%) than in non-MM patients.29 The main limitation of this meta-analysis was, however, that many cardiovascular comorbidities, as well as concomi- tant therapies, were unknown or unrecorded. Moreover, cardiotoxicity was misreported in many studies and the trials' treatment designs were very different, giving rises to heterogeneity of data regarding cardiovascular effects of bortezomib and a high probability of confounding effects secondary to other prior treatments or clinical conditions.
In the ENDEAVOR study, patients were randomized to receive carfilzomib and dexamethasone (Kd) or borte- zomib and dexamethasone (Vd).31 The patients’ median age was fairly low (65 years), with only about 15% of patients aged ≥75 years. The incidence of CVAEs with Vd treatment is summarized in Table 1. During treatment or within 30 days of receiving the last study-dose, 5% of patients in the Vd group died and cardiovascular events were the second cause of death. Interestingly, dyspnea
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haematologica | 2018; 103(9)