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Cardiovascular safety in MM
newly diagnosed MM patients enrolled in three phase 1/2 studies evaluated CVAEs in patients treated with KCd.50 Any-grade cardiovascular events were reported in 42% of patients. The risk of CVAEs during treatment with carfil- zomib was significantly higher in patients ≥75 years old and the most important risk factor, regardless of age, was hypertension. Grade ≥3 adverse events occurred in 30% of patients. In patients <75 years, the most frequent grade ≥ 3 adverse events were hypertension (9%) and dyspnea
(10%). In patients ≥75 years, the most frequent grade ≥3 adverse events were hypertension and pulmonary edema (both: 13%). Thirty-four percent of patients who devel- oped CVAEs had hypertension at baseline or developed it during treatment compared with 14% of patients who did not have CVAEs. The risk of cardiotoxicity was lower dur- ing maintenance, with 22% of patients developing a car- diovascular event of any grade. The most frequent CVAE during maintenance was again hypertension (12%),
Table 3. Incidence of cardiovascular events in patients with newly diagnosed multiple myeloma treated with carfilzomib in phase 1, 2 and 3 studies.
Hypertension Cardiac Ischemic failure heart
disease
Dyspnea
Exertional dyspnea
DVT/PE
Arrhythmia
Aggregated cardiac failure
*
Studies
Phase 3 studies
CLARION47,48 KMP (n=474) VMP (n=470)
MYELOMA XI60 KCRd (n=526) CTd (n=1021) CRd (n=1021)
Phase 1/2 studies
Phase 1B CHAMPION 249 K dose: 36 mg/m2 (n=3), 45 mg/m2 (n=3), 56 mg/m2 (n=16)
CYKLONE61
KCTd(n=64) 9 6
Jakubowiak, 201251 KRd (n=53)
Phase 2 studies
All Grade All Grade All Grade All Grade All Grade All Grade All Grade All Grade grades ≥3 grades ≥3 grades ≥3 grades ≥3 grades ≥3 grades ≥3 grades ≥3 grades ≥3
24.7 10.1 10.8 8.2 8.1 3.6 4.3 2.8
3.0 2.1 18.1 3.6 1.9 1.3 8.5 0.6
28.6 4.7
20 3
0.5 1 0.3 0 10
2.5 1.3 1.2
4.8
4.8
38.1
4.8
Dytfeld, 201452
15
4
6 5
11 (DVT)4(DVT) 6(PE) 6(PE)
13
16 6
5.5 5.5
KRd ≥65 years (n=23)
Bringhen, 201453
KCd(n=58) 9222 7- 2242
Bringhen, 201754
wKCd (n=54)
Korde63
KRd (n=45 NDMM)
FORTE55
KRd (n=309) KCd (n=154)
11 0 6.6
3
3
5.5
3.7 4.4
3.7 24
1.8 1.8 0
1
0
K: carfilzomib; M: melphalan; P: prednisone;V: bortezomib; C: cyclophosphamide; d: dexamethasone;T: thalidomide; R: lenalidomide; w: weekly; DVT: deep vein thrombosis; PE: pulmonary embolism. *Aggregated cardiac failure includes heart failure, pulmonary edema, and myocardial infarction; NDMM: newly diagnosed multiple myeloma.
Table 4. Main studies conducted on real-life patients treated with carfilzomib-based regimens.
Study
Atrash56
Chari64
Rosenthal65 Dimopoulos66
Type of study
R
R
P P
N. of patients
130
498
62
60
Rate of pre-existing CV history
54%
84% of non-hospitalized; 92% of
hospitalized patients
20% baseline hypertension
28%
Rate of CVAE
11.5% hospitalized for heart failure
22% had ≥1 CVAE; 5% had ≥1 hospitalization for 8% had cardiac SAE; 32% had hypertension
11.6% had a CVAE
R: retrospective; P: prospective; N.: number; CV: cardiovascular; CVAE: cardiovascular adverse event(s); SAE: serious adverse event(s).
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