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Cardiovascular safety in MM
Table 1. Incidence (in %) of cardiovascular events in patients with relapsed/refractory multiple myeloma treated with carfilzomib in phase 2 and 3 stud- ies
Hypertension
Cardiac failure
Ischemic heart disease Dyspnea
Grade ≥3 4.3
1.8
Grade ≥3 3.8
1.8
<6 <3
2 1
Grade ≥3 All grades Grade ≥3 3.3 19.4 2.8
2.1 14.9 1.8
<2 28 5 <3 13 2
15 1 90
1.3
K: carfilzomib; R: lenalidomide; d: dexamethasone; V: bortezomib; CS: corticosteroids. #In the ASPIRE study, the category of cardiac failure included (in descending order of frequency) cardiac failure, congestive cardiac failure, pulmonary edema, hepatic congestion, cardiopulmonary failure, acute pulmonary edema, acute cardiac failure, and right ventricular failure.The category of ischemic heart disease included (in descending order of frequency) angina pectoris,myocardial infarction,acute myocardial infarction,an increased serum creatine kinase level, coronary artery disease, myocardial ischemia, coronary artery occlusion, an increased troponin level, an increased level of troponin T, an acute coronary syndrome, abnormal results on a cardiac stress test, cardiomyopathy stress, unstable angina, coronary-artery stenosis, an abnormal ST-T segment on electrocardiography, and an abnormal T wave on electrocardiog- raphy.§In the ENDEAVOR study,cardiac failure included (in descending order of frequency):cardiac failure,ejection fraction decreased,pulmonary edema,acute cardiac failure,conges- tive cardiac failure,acute pulmonary edema,acute left ventricular failure,chronic cardiac failure,cardiopulmonary failure,hepatojugular reflex,right ventricular failure,and left ventricular failure. Ischemic heart disease included (in descending order of frequency): angina pectoris, acute coronary syndrome, myocardial infarction, increased troponin T, coronary artery dis- ease,increasedtroponinI,acutemyocardialinfarction,myocardialischemia,andcardiomyopathystress.*Phase2studies38 =pooledanalysisofsafetydatafromfourphase2studies(PX- 171-003-A0,PX-171-003-A1,PX-171-004,and PX-171-005) in 526 patients with relapsed and refractory multiple myeloma treated with carfilzomib.Carfilzomib was administered intravenously on days 1,2,8,9,15,and 16 in 28-day cycles.The planned dose regimen was 20/27 mg/m2 (starting dose of 20 mg/m2 in cycle 1 escalating to 27 mg/m2 in cycle 2) for all studies except PX- 171-005 (15/20/27 mg/m2 in cycles 1-3 n=50).
Phase 3 studies ASPIRE37 #
KRd group (n=392)
Rd group (n=389) ENDEAVOR31 §
Kdgroup(n=463)
Vdgroup(n=456) FOCUS40
Carfilzomib group (n=157) CS±cyclophosphamide group (n=158)
Phase 2 studies38 *
Carfilzomib (n=526)
All grades
14.3 6.9
All grades
6.4 4.1
<9 <4
5 1
7.2
All grades
5.9 4.6
<3 <4
25 9 9 3
15 3 6 0
5.7 3.4
was reported as a CVAE, but its etiology (cardiac, pul- monary versus other causes) remained undetermined, so it could be classified as either a cardiovascular or pulmonary adverse event.
Ixazomib
ixazomib is an oral analog of bortezomib that reversibly inhibits the chymotrypsin-like site of the 20S proteasome, and is responsible for caspase-dependent induction of apop- tosis and inhibition of cell cycle in MM cells. Moreover, ixa- zomib inhibits the NFκB pathways in MM supporting cells, thus influencing cytokines important for MM cell growth and survival.20 Kumar et al. reported an incidence of grade ≥3 hypertension of 5% in treatment-naïve patients given ixazomib in combination with lenalidomide and dexam- ethasone (Rd).32 The TOURMALINE MM1 study group analyzed the safety and efficacy profile of ixazomib in a phase 3 trial in patients with relapsed, refractory or relapsed and refractory MM.33 Patients received ixazomib-Rd or placebo-Rd. The rates of serious adverse events were simi- lar in both groups (47% and 49%), as were death rates dur- ing the study (4% and 6%, respectively); grade 3 or higher adverse events occurred in 74% and 69% of cases, respec- tively. There were no differences in the incidence of heart failure (4% in each group), arrhythmias (16% and 15%), hypertension (6% and 5%) and myocardial ischemia (1% and 2%, respectively). At present, there is only one case report in which ixazomib was described as possibly respon- sible for cardiotoxicity with a mechanism similar to that observed with bortezomib (type I chemotherapy-induced cardiotoxicity).34
Carfilzomib
Relapsed or refractory multiple myeloma
This second-generation proteasome inhibitor is an irre- versible cell-permeable tetrapeptide epoxyketone, an ana-
log of epoxomicin.35 The irreversible binding leads to the activity of carfilzomib being more sustained than that of bortezomib, as new proteasome subunit synthesis and assembly are required for restoration of proteasome activ- ity.21 Carfilzomib has been demonstrated to be more spe- cific than bortezomib, and the irreversible carfilzomib binding may provide better inhibition of proteasome activity, which may overcome bortezomib-resistance.36 In a head to head study of carfilzomib versus standard treat- ments, bortezomib or lenalidomide, carfilzomib demon- strated superior efficacy and was associated with improved overall survival. Data regarding cardiac events in MM patients receiving carfilzomib are available from various phase 1, 2 and 3 studies, as well as retrospective and observational analyses, in both relapsed/refractory MM and newly diagnosed MM. Data regarding the dosing and treatment schedules of relevant studies are reported in Table 2. The most frequent adverse event was hyperten- sion. In randomized clinical trials, the relative risks of all- grade and grade ≥3 CVAEs were 1.8 and 2.2, respectively, for patients receiving carfilzomib compared with control patients. Carfilzomib doses of 45 mg/m2 or higher were associated with high-grade CVAEs.8
The incidence of hypertension in patients with relapsed/refractory MM being treated with carfilzomib was 14.3-25% for all grades and 3-9% for grade ≥3, the cumulative incidence of cardiac failure of any grade was 5- 9% and that of grade ≥3 was 2-6%. Corresponding cumu- lative values for ischemic heart disease were 3-5.9% and 1.3-3.3%. The incidence of dyspnea of any grade was 15- 19.4% while that of grade ≥3 was 1-5% (Table 1). The most frequent cardiovascular events were dyspnea and hypertension.31,37-43
Carfilzomib has been approved in Europe for the treat- ment of relapsed or refractory MM, in combination with Rd or dexamethasone, based on the randomized trials
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