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S. Bringhen et al.
regardless of age. Five cardiovascular carfilzomib-related deaths were reported. No difference was observed in rela- tion to different carfilzomib doses and schedules.
A phase 1/2 study in newly diagnosed MM patients assessed carfilzomib, lenalidomide and weekly dexam- ethasone. During induction, grade 3/4 CVAEs included deep venous thrombosis/pulmonary embolism in 9% of cases. Grade 3/4 dyspnea was observed only during phase 1 and within the first three cycles.51 An updated follow-up in a subset of 23 elderly patients (≥65 years) was also per- formed:52 during induction, non-hematologic grade 3/4 adverse events (>10%) included thromboembolic events (13%). During maintenance, most adverse events were grade 1/2 and did not include CVAEs. This could be par- tially because patients reaching the maintenance phase have deeper and longer responses to therapy, and tolerate the treatment better.
In a multicenter, open-label phase 2 trial of KCd in eld- erly newly diagnosed MM patients, ineligible for autolo- gous SCT53, cardiac adverse events of any grade occurred during induction in 16% of patients and of grade ≥3 in 7% and included four cardiac events (heart failure, arrhyth- mia, myocardial ischemia and hypertension in one patient each) and stroke, acute pulmonary edema and pulmonary thromboembolism (also in one patient each). The safety profile was similar in the 15 patients >75 years who received one or more doses of KCd. As expected, no CVAEs occurred during maintenance. Seven patients died while on the study, one due to hypertension (related to carfilzomib) and another due to atrial fibrillation (deemed unrelated to carfilzomib).
A multicenter, open-label phase 1/2 trial determined the safety and efficacy of KCd in a weekly schedule in newly diagnosed patients aged ≥65 years who were ineligible for autologous SCT.54 Cardiopulmonary adverse events occurred in 9%. During induction, the incidence of CVAEs of any grade was 24%, while the incidence of CVAEs of grade 3–5 was 9%. Treatment-emergent serious adverse events occurred during induction in 26% of patients and included eight cardiac events (heart failure, pulmonary edema, sudden death and hypertension) and one pul- monary thromboembolism. During maintenance, any grade hypertension occurred in 15% of cases. Grade 3-5 non-hematologic adverse events were rare except for hypertension (10% of cases) and CVAEs (5%: 1 heart fail- ure and 1 myocardial ischemia). Treatment-emergent seri- ous adverse events occurred during maintenance in three patients and included heart failure and myocardial ischemia.
The FORTE trial compared KRd versus KCd in trans- plant-eligible patients with newly diagnosed MM.55 No significant differences were seen in rates of CVAEs (hyper- tension: 7% versus 6%, cardiac adverse events: 3% versus 5%), with the exception of venous thromboembolism/ pulmonary embolism (8% versus 2%). The slightly lower incidence of CVAEs, as compared to other studies, could be partially explained by the fact that newly diagnosed MM patients eligible for transplantation are fitter than those with relapsed or refractory MM and/or patients inel- igible for autologous SCT.
Real-life experience
Data derived from “real-life” experience with carfil- zomib unite more unselected patients than those treated within clinical trials, although they do not add much to
currently available knowledge (Table 4). The most robust data are derived from the study by Atrash et al., in 130 relapsed/refractory patients. In that study, 20% of patients had CVAEs. A history of cardiac events was present in 54% of patients.56 Fifteen (11.5%) were hospitalized for chronic heart failure, serious arrhythmias or pulmonary edema. Of four patients hospitalized for arrhythmia, two had cardiac arrests.
Conclusions
Melphalan, cyclophosphamide, and doxorubicin are fre- quently used in the treatment of MM, especially in the context of high-dose chemotherapy. Alkylating agents and anthracyclines are both characterized by the potential for cardiotoxicity. Cardiac function must be monitored care- fully in patients taking these drugs, particularly in the long-term, because of late onset toxicity. Electrocardiography and transthoracic echocardiography are useful for assessing cardiac function before high-dose melphalan and/or anthracycline-based treatment.
Immunomodulatory drugs, especially in combination with corticosteroids and chemotherapy, are associated with a high frequency of thromboembolic complications. Prophylaxis with cardio-aspirin, low molecular weight heparin or warfarin is mandatory. The choice of the most appropriate drug depends on the thrombotic risk. If the probability of venous thromboembolism/pulmonary embolism is high, low molecular weight heparin or war- farin should be preferred.
Cardiac adverse events are thought to be a class effect of proteasome inhibitors because they have been reported with bortezomib, carfilzomib and ixazomib; however, they appear to be more frequent with carfilzomib. A recent meta-analysis showed that the most frequent CVAEs during treatment with carfilzomib are hyperten- sion (all grades: 12.2%; grade ≥3: 4.3%), heart failure (all grades: 4.1%; grade ≥3: 2.5%) and ischemic heart disease (all grades: 1.8%; grade ≥3: 0.8%).8 The incidence of heart failure increases up to 20-25% in patients ≥75 years of age. Although true carfilzomib-induced cardiac failure is infre- quent and usually reversible, MM patients are typically elderly individuals and may frequently have cardiovascu- lar comorbidities, thereby increasing their risk of drug- related CVAEs.57 As found in the clinical trials described above, age is not the only risk factor for cardiovascular toxicity. Comorbidities, especially pre-existing hyperten- sion or cardiovascular diseases, carfilzomib dose, infusion time, and volume of hydration may increase the risk of CVAEs during carfilzomib treatment.43
However, carfilzomib has been shown to prolong both progression-free and overall survival in MM patients, and maximizing the benefit while reducing cardiovascular risks has become a priority in the management of these patients. At present, there are no strategies to prevent CVAEs that have been validated in prospective studies. The EMN expert panel suggests, based on clinical experi- ence, that cardiovascular risks should be assessed before starting carfilzomib and that measures to correct modifi- able risk factors, such as hypertension, high cholesterol levels, hyperglycemia, tobacco use, incorrect diet, should be started. Patients with cardiac risks may benefit from a cardiology review prior to receiving treatment and should be closely monitored for fluid overload. Patients receiving
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haematologica | 2018; 103(9)