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Phase II CARTHADEX Study in NDMM
zomib (0%, 5%, 10%, and 15%, respectively) and consist- ing mainly of pneumonia (Online Supplementary Table S1). Table 4 summarizes cardiac AE. Any grade cardiac AE were reported in 12% of patients after induction therapy (14% in carfilzomib 27mg/m2, 15% in carfilzomib 36 mg/m2, 19% in carfilzomib 45 mg/m2, and 5% in carfil- zomib 56 mg/m2). These cardiac events consisted mainly of grade 1/2 toxicity (11 of 15 events). Five (5%) grade 3 cardiac AE were reported: three at dose level 27 mg/m2, one at dose level 45 mg/m2, and one at dose level 56
mg/m2.
Any grade cardiac AE increased to 18% after consolida-
tion therapy with no reports of grade 4 AE at all four dose levels, (18% in carfilzomib 27 mg/m2, 15% in carfilzomib 36 mg/m2, 19% in carfilzomib 45 mg/m2, and 15% in carfilzomib 56 mg/m2). These cardiac events consisted mainly of grade 1/2 toxicity (14 of 19 events). Five (5%) grade 3 cardiac AE were reported.
Nine patients (8%) developed hypertension during treatment (carfilzomib 27 mg/m2, n=3; carfilzomib 36 mg/m2, n=3; carfilzomib 45 mg/m2, n=2; carfilzomib 56 mg/m2, n=1); four (4%) of them had grade 3 toxicity. Five (5%) patients needed antihypertensive treatment.
Seven patients (6%) had pre-existing PN grade 1/2 and two patients (2%) had pre-existing grade 3 PN. During induction and consolidation therapy, 52 patients (47%) developed PN. Grade ≥ 2 PN events occurred in 23 patients (20%) independently from carfilzomib dose; these events were clinically manageable (carfilzomib 27 mg/m2, n=11; carfilzomib 36 mg/m2, n=3; carfilzomib 45 mg/m2, n=6; carfilzomib 56 mg/m2 n=3). Only one patient (1%) reported grade 3 PN (carfilzomib 27 mg/m2).
At least one serious AE (SAE) was reported in 43% of patients. In cohort 1, an SAE was reported in 21 (42%) patients, in cohort 2 in 8 (40%) patients, in cohort 3 in 7 (33%) patients, and in cohort 4 in 12 (60%) patients.
As reported above, nine patients (8%) discontinued treatment due to excessive toxicity: six patients during induction therapy, and three patients during consolidation therapy. In cohort 1, four (8%) patients went off protocol due to AE: one (5%) patient in cohort 2 and four (20%) patients in cohort 4. Table 5 shows an analysis of treat-
ment adherence to protocol. During consolidation treat- ment, normal completion rate for carfilzomib and dexam- ethasone was similar to induction treatment whereas this was higher for thalidomide, probably due to the lower dose of thalidomide during consolidation treatment. A higher percentage of patients prematurely discontinued treatment at the highest dose level of carfilzomib (5 patients, 30%). Four patients (20%) had excessive toxicity
excessive toxicity
not eligible for consolidation excessive toxicity
Figure 1. Consort diagram. Cyclo: cyclophosphamide; G-CSF: granulocyte colony-stimulating factor; HD: high dose; SC: stem cell. Ktd: carfilzomib, thalido- mide and dexamethasone; n: number: HDM + ASCT: high-dose melphalan + autologous stem cell transplantation.
Table 2. Response after induction, after high-dose melphalan (HDM) and after consolidation therapy.
Dosing level carfilzomib 20/27 mg/m2 20/36 mg/m2 20/45 mg/m2 20/56 mg/m2
Patients, n 50 20 21 20
All patients
111
Response after induction, n (%)
sCR 4(8) 1(5) 0(0) 1(5) 6(5)
≥CR 8(16) 5(25) 3(14) ≥ VGPR 27 (54) 16 (80) 13 (62) ≥PR 45 (90) 20 (100) 20 (95)
Response after HDM, n (%)
sCR 5(10) 2(10) 3(14)
12(24) 7(35) 9(43)
4(20) 20(18) 16 (80) 72 (65) 18 (90) 103 (93)
1(5) 11(10) 6(30) 34(31)
≥CR
≥ VGPR ≥PR
32 (64) 46 (92)
17 (85) 20 (100)
19 (90) 20 (95)
18 (90) 18 (90)
4 (20) 13 (65) 18 (90) 18 (90)
86 (77) 104 (94)
33 (30) 70 (63) 96 (86) 104 (94)
Response after consolidation, n (%) sCR
17 (34) 28 (56) 40 (80) 46 (92)
4 (20) 15 (75) 18 (90) 20 (100)
8 (38) 14 (67) 20 (95) 20 (95)
≥CR
≥ VGPR
≥PR
n: number; sCR: stringent complete remission; CR: complete remission; VGPR: very good partial response; PR: partial response.
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