Page 23 - 2018_09-Mondo

Cardiovascular safety in MM
the global population is aging, the prevalence of both MM and cardiovascular disease is expected to increase in the near future.5,6
Cardiovascular disease in MM may derive from factors unrelated to the disease (age, diabetes, dyslipidemia, obe- sity, history of cardiovascular diseases), or those related to the myeloma (cardiac AL-amyloidosis, hyperviscosity, high-output failure, arteriovenous shunting, anemia, renal dysfunction) and/or be related to the treatment of the dis- ease [anthracyclines, corticosteroids, alkylating agents, immunomodulatory drugs, proteasome inhibitors, high- dose conditioning and autologous/allogeneic stem cell transplantation (SCT)].7 Of interest, the incidence of car- diovascular disease has been described to be higher in patients with MM (60.1%) than in non-MM patients (54.5%)7 and a recent review and meta-analysis of patients enrolled in clinical trials with carfilzomib showed that the incidence of all grade and grades ≥3 cardiovascular adverse events (CVAEs) was 18.1% and 8.2%, respectively.8 Although carfilzomib is one of the most cardiotoxic and, at the same time, effective novel agents used in MM treat- ment, it is not the only anti-myeloma drug characterized by a high risk of CVAEs. Moreover, it is difficult to esti- mate the actual incidence of chemotherapy-induced car- diovascular diseases, because current data about drug- induced cardiotoxicity were generated in clinical trials, from which patients with severe cardiovascular comor- bidities were excluded. However, in real-life clinical prac- tice, MM patients may indeed suffer from cardiovascular disease, have cardiovascular risk factors, and/or may have already received several cardiotoxic drugs. Physicians managing patients with MM are, therefore, obliged to carefully balance expected drug efficacy with toxicity. This review is published as a consensus paper by the European Hematology Association (EHA), the European Myeloma Network (EMN) and the Italian Society of Arterial Hypertension (SIIA), and it aims to describe CVAEs related to anti-myeloma treatment, especially novel agents and the proteasome inhibitor carfilzomib. Furthermore, the paper intends to be a starting point for future debates on how to manage CVAEs appropriately. At present, studies to validate recommendations on pre- vention and management of CVAEs during MM treatment are lacking, and overcoming this lacuna is particularly rel- evant. Besides focusing on toxicity issues, this review also aims to provide a more complete overview of MM treat- ments by clarifying the efficacy and outcome advantages associated with such treatments. Of note, this paper is not only a review of the current literature, but it is also the result of a thorough discussion involving a panel of EMN clinical experts in MM and cardiology experts.
Cardiovascular toxicity of multiple myeloma treatment
Antineoplastic therapy is frequently complicated by the onset of CVAEs, which in turn may increase treatment- related morbidity and mortality.9 Cardiovascular disease or events are among the most frequent adverse events dur- ing chemotherapy, leading to the concept of cardiotoxici- ty, which may be due to the direct effects of antineoplastic treatment on the structure and function of the heart or may accelerate the onset of cardiovascular disease in high-
risk patients with predisposing cardiovascular risks.10 Cardiovascular complications of antineoplastic therapy may be acute, subacute or chronic and can be classified depending on the type of damage,11 the organ structure or function targeted by the damage,10 or the drug responsible for the damage.12 Depending on the damage, two types of cardiotoxicity have been described: type I and type II. In type I cardiotoxicity, mostly associated with traditional anticancer therapies, there is irreversible destruction of myocytes, leading to congestive heart failure. Type II car- diotoxicity may involve a reversible loss of cardiac con- tractility and is mainly caused by new targeted therapies, such as vascular endothelial growth factor inhibitors and
tyrosine kinase inhibitors.11
With regards to the organ structure or function that is
the target of the damage, the classification of cardiovascu- lar chemotherapy-induced complications recognizes myocardial dysfunction and heart failure, coronary artery disease and myocardial ischemia, arrhythmias, hyperten- sion, thromboembolic disease, peripheral vascular disease and stroke, pulmonary hypertension, valvular diseases and pericardial complications.12 In MM, drug-related car- diotoxicity may be caused by chemotherapeutic agents or by new targeted therapies, such as immunomodulatory drugs (thalidomide, lenalidomide, pomalidomide) and proteasome inhibitors (bortezomib, ixazomib, carfil- zomib).
Cardiovascular toxicity induced by chemotherapy
Myocardial dysfunction and heart failure are common side effects of chemotherapy and may appear early dur- ing antineoplastic treatment or years thereafter. The risk of heart failure is increased in elderly patients with car- diovascular risks. Anthracyclines and alkylating agents are associated with direct cytotoxic cardiac injury. Cardiac damage induced by anthracyclines involves myocyte cell membrane injury by oxygen free radicals and lipid peroxidation, leading to oxidative stress10 and reduced cardiac contractility. In <1% of patients the effects may be manifested acutely (as supraventricular arrhythmia, transient left ventricular dysfunction or elec- trocardiographic changes). More commonly, the manifes- tations occur early within the first year of treatment [decline in left ventricular ejection fraction (LVEF)] or late (chronic heart failure). Cardiotoxic effects are dose- dependent and increased in patients with pre-existing car- diovascular diseases and in elderly patients. Cardiotoxicity is amplified by combination treatment, such as with alkylating or antimicrotubule agents, immuno- and targeted drugs. Cyclophosphamide induces heart failure in 7-28% of cases,9 although mainly in rela- tion to high doses before autologous SCT. The mecha- nism of damage may be direct endothelial injury, extrava- sation of toxic metabolites with interstitial hemorrhage, edema and structural damage to cardiomyocytes. Anthracyclines and alkylating agents may induce arrhyth- mias through direct cardiotoxicity, cardiac ischemia or metabolic changes caused by the chemotherapy.13 Moreover, all cancers lead to a prothrombotic state, release of pro-angiogenic cytokines and drug-induced hepatotoxicity, which may contribute further to throm- boembolism. Thromboembolic risks are particularly high in patients with other predisposing factors, in those with disseminated tumors and in those with hematologic neo- plasms, in particular MM.14 Arterial thromboembolism is
haematologica | 2018; 103(9)
1423