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arms: four deaths with KRd (3 myocardial ischemia, 1 car- diac failure) and four with Rd (1 myocardial ischemia, 3 cardiac failures).
The findings of the ENDEAVOR study31 were similar to those of ASPIRE, with a 28% incidence of dyspnea of unspecified origin and 25% of hypertension in patients treated with Kd. In this study, there were five cardiac deaths with Kd and six with Vd. Patients in the Kd group showed a higher incidence of grade ≥3 CVAEs, including hypertension, cardiac failure and dyspnea, while the inci- dence of ischemic heart disease was similar in the two groups. Venous thromboembolism was more common with Kd than with Vd (deep vein thrombosis: 3.7% for all grades and 0.9% for grade ≥3 in Kd recipients versus 0.9% for all grades and 0.4% for grade ≥3 in Vd recipients; pul- monary embolism: 2.6% for all grades and 1.7% for grade ≥3 in Kd recipients versus 0.9% for all grades and 0.9% for grade ≥3 in Vd recipients). Of interest, a preplanned prospective ENDEAVOR substudy (ECHO study) was performed to evaluate changes from baseline in LVEF, right ventricular function and pulmonary artery systolic pres- sure via echocardiography.39 Patients with a LVEF ≥40% and no evidence of New York Heart Association class III or IV heart failure, symptomatic ischemia, uncontrolled arrhythmias or recent myocardial ischemia were enrolled. All patients (75 treated with Kd, 76 treated with Vd) were assessed using two-dimensional transthoracic echocardio- grams at baseline, every 12 weeks and at the end of treat- ment. Notable differences between the two treatment groups were that more patients in the Kd group were older than 75 years: 21.3% versus 14.5% in the Vd group) and more had a prior cardiac-related history (26.7% versus 14.5%, respectively). Patients in the Kd arm had a higher incidence of heart failure reported by the treating physi- cian (10.8% versus 4.1%, respectively). A history of cardiac disorders was associated with an elevated but not statisti- cally significant different risk of heart failure. Patients receiving carfilzomib had a higher incidence of hyperten- sion compared to those receiving bortezomib (20.3% ver- sus 8.1%, respectively). Twenty-three patients (15.2%) discontinued treatment because of adverse events; eight due to non-fatal cardiac-related adverse events (Kd: n=6 versus Vd: n=2). The primary endpoint was a reduction in LVEF by 24 weeks. The ECHO data were analyzed in a blinded fashion. Among all patients in both arms, only one (in the Vd group) had a significant reduction in LVEF within the first 24 weeks. Six patients (3 in each group) had significant LVEF reductions at some time during the study, with normal LVEF being recovered in all but one. Fourteen patients (Kd: n=8; Vd: n=6) had clinically mean- ingful changes in echocardiograms; 79% did not meet the echocardiographic criteria for decreased LVEF. More Kd than Vd recipients had clinical evidence of heart failure (n=4 versus n=0, respectively) or pulmonary hypertension (n=4 versus n=1, respectively) based on investigator assess- ment. Thus, heart failure and pulmonary hypertension occurred more frequently with Kd than with Vd, although a echocardiographically detectable significant decline in LVEF was low in both treatment arms and occurred with similar frequencies. The substudy found limited utility for serial screening with echocardiograms to mitigate cardiac risks for unselected patients receiving carfilzomib. Another subgroup analysis of the ENDEAVOR study, con- ducted in 109 Asian patients, showed a toxicity profile similar to that in the general population. In the carfilzomib
arm, hypertension was reported in 26.4% of patients, dys- pnea in 17.0%.44
The different incidence of cardiotoxicity in ENDEAVOR and ASPIRE can be explained by comparing both study designs. The first factor is the carfilzomib dose: there was a higher incidence of cardiotoxicity in the ENDEAVOR study, but carfilzomib doses were substantially higher (56 mg/m2 versus 27 mg/m2). The second issue is that nearly 20% of the patients enrolled in the ENDEAVOR trial had a creatinine clearance <50 mL/min (and 6% of them had a creatinine clearance <30 mL/min) and, therefore, had a higher cardiovascular risk, while in ASPIRE only 6.3% of patients had a creatinine clearance between 30 and 50 mL/min.45 Consequently, a side-by-side comparison of both trials is hampered by different patient eligibility cri- teria.
An integrated analysis of patients with advanced MM enrolled in four phase 2 studies showed that 73.6% of patients had a history of cardiovascular events, and 70% had baseline cardiac risks.38 Cardiac failure (including chronic heart failure, pulmonary edema, and decreased LVEF) occurred in 7.2% of patients. The overall mortality rate was the same in patients with or without cardiovas- cular risks at baseline. CVAEs occurred in 22.1% and 14.3% of patients had hypertension (mainly grade 1–2). Cardiac events leading to treatment discontinuation occurred in 4.4% of patients. Cardiac adverse events did not increase in later treatment cycles, suggesting that there was no cumulative toxicity. Among CVAEs, arrhythmias of any grade were observed in 13.3% of patients (grade ≥3 in 2.3%). Dyspnea was included in respiratory adverse events and appeared in 42.2% of patients (all grades) and was grade ≥3 in 4.9%.
Newly diagnosed multiple myeloma
Carfilzomib, alone or in combination with other drugs, has also been investigated in newly diagnosed MM patients in several ongoing and completed studies.46 Data derived from these trials are very useful, because they are not biased by possible cardiotoxic effects of previous lines of therapy. The incidence of any grade hypertension was 9-24.7% while that of grade ≥3 was 2-10%. The incidence of any grade dyspnea was 18.1-28.6% while that of grade ≥3 was 3.6-4.8%. The most frequent cardiovascular events were dyspnea and hypertension (Table 3) with no apparent correlation with carfilzomib doses, schedules or other drug associations.
The CLARION trial compared carfilzomib, melphalan, and prednisone (KMP) versus bortezomib, melphalan, and prednisone (VMP) in newly diagnosed MM patients ineli- gible for transplant.47,48 The incidence of grade ≥3 adverse events was 74.7% versus 76.2%, respectively. Adverse events of interest included cardiac failure (all grades: 10.8% versus 4.3%; grade ≥3: 8.2% versus 2.8%), dyspnea (all grades: 18.1% versus 8.5%; grade ≥3: 3.6% versus 0.6%), and hypertension (all grades: 24.7% versus 8.1%; grade ≥3: 10.1% versus 3.6%, respectively).
The CHAMPION-2 study evaluated carfilzomib with cyclophosphamide and dexamethasone (KCd).49 One patient in the 45 mg/m2 cohort died due to sudden cardiac arrest, whereas no deaths occurred in the 36 or 56 mg/m2 cohorts. The authors concluded that carfilzomib adminis- tered at a dose of 56 mg/m2 twice weekly in combination with cyclophosphamide and dexamethasone showed acceptable toxicity. Likewise, an integrated analysis of
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haematologica | 2018; 103(9)