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Editorials
pressure, left ventricular hypertrophy, and pulse wave velocity ≥9 m/s identified patients at higher risk of devel- oping CVAE during follow up. These findings indicated that careful monitoring, strict blood pressure control and identification of early symptoms suggestive of cardiac dysfunction, are crucial to ensure safe administration of Cfz.16–18
In newly diagnosed MM (NDMM), Cfz has been inves- tigated in several studies, and the updated results of the
Table 1. Carthadex-(KTd) results compared to selected other carfilzomib combinations in newly diagnosed multiple myeloma.
Carthadex trial of Cfz-thalidomide-dexamethasone (KTd) are now available. In this issue of the Journal, Wester et al. report on these findings.19 With longer medi- an follow up (58.7 months) of this multicenter phase II trial, impressive overall responses (ORR: 93%), with a high rate of CR (63% after consolidation) and substantial PFS and OS results (median: 58 and 83 months, respec- tively) were obtained.19 Cfz was escalated from 20/27 (n=50), to 20/36 (n=20), 20/45 (n=21) and 20/56 mg/m2
First author
Wester R, Haematologica 201919
Sonneveld P, Blood 201520
MIkhael JR, Br J Haematol 201521
Jackson, Blood (Suppl) 201822
Gay F,
Blood (Suppl.) 201823
Moreau P, Blood 201524
Bringhen S, Blood 201426
Bringhen S, Leukemia 201827
Facon T, Blood 201925
Study phase
II (#NTR2422) Follow-up report (median: 58.7 ms)
II (#NTR2422) Initial report (median: 23 ms)
Cyklone: I/II, median follow-up 17.5ms
III
III, median follow-up 20 ms
I/II
II, Median follow-up: 18ms
I/II, Median follow-up: 18ms
III, Clarion
# pts
111
91
64
526
474
68
58
63
955
Median age (range)
58 (29-66), Tx-eligible
58 (29-66), Tx-eligible
62.5 (27-82), Tx-eligible
61 (33-75) Tx-eligible
57 (52-62) Tx-eligible
72 (66-86), Tx-inelegible
71 (68-75), Tx-inelegible
72 (69-74), Tx-inelegible
72 (42-91), Tx-inelegible
CFz-dose
20/27 (n=50), 20/36 (n=20), 20/45 (n=21) 20/56 (n=20)
20/27 (n=50), 20/36 (n=20), 20/45 (n=21)
20->45
20/36
20/36
20, 27, 36, 45; MTD: 36
20->36 2x/w
45,56,70 ≥ 70 1x/w
KMP (n=478) 20≥36
VMP (n=477)
Combination treatment
CFz 20-> 56mg/m2 Thal: 200mg/d
Dex 40mg weekly, 4
induction C ->
ASCT->4 consolidation C
CFz 20-> 45mg/m2 Thal: 200mg/d Dex 40mg weekly
Cfz: 20->45mg/m2 1x/w Cyclo: 300mg/m2 d1,8,15, Thal 100mg d1-28,
Dex 40,g d1,8,15,22, MTD: 36, 9 C -> maint.
Cfz 36mg/m2 d1, 2, 8, 9, 15, 16
Cyclo: 500mg d1,8,15, Len 25mg d1-21
Dex 40mg d1,8,15,22,
KRd-ASCT-KRd vs. KRd12 vs. KCd- ASCT-KCd
Cfz: 20-45mg/m2 M 9mg/m2,
P 60mg/m2 d1-4, 9C
Cfz: 20->36mg/m2 Cyclo: 300mg/m2 d1,8,15, Dex 40,g d1,8,15,22, 9 C ≥ maint.
Cfz: 45->70mg/m2 1x/w Cyclo: 300mg/m2 d1,8,15, dex 40,g d1,8,15,22, 9 C ≥ maint.
Cfz: 20->36mg/m2 M 9mg/m2,
P 60mg/m2 d1-4, 9 C
V 1.3mg/m2 d1,4,8,11,22,25,29,32 ≥ d4,11,25,32, C5-9
ORR PFS OS
Notable FDA/EMA findings approval
Grade 3/4 AE: - Infections: 11% Respiratory: 8%
Skin: 9%, Vascular: 9% Cardiac 5%
Grade 3/4 AE: - Respiratory: 15%,
GI: 12%, Skin: 10%
G3/4 hypertension 6% - Cardiac events: 6%
Renal events: 5% Thromboembolic events: 5%, Dyspnea: 3%
All grade cardiac: 4% - All grade VTE: 12.5% Discont. 4.8%
G3/4 cardiac AE:3:2:4%, - Thrombosis: 1:2:2% Discont. 6:8:7%
Death in n=12: - PD (n=7),
infection (n=2)
cardiac failure (n=1) respiratory distress (n=1) urothelial ca (n=1)
AE 3-5: - cardiopulmonary: 7% Discontinuation: 14% Cfz-dose reductions: 21%
AE 3-5: - cardiopulmonary: 9%, Discontinuation: 22% Cfz-dose reductions: 9% 6ptsdied:2PD+AE(pulm. thromboembolism, resp. failure,pneumonia, sudden death)
Renal failure: 13.9 : 6.2% - Cardiac failure: 10.8 : 4.3% >G3 AE rates: 74.7 : 76.2% >G2 PNP: 2.5% : 35.1%
+
93%; CR: 18%
86%
91%
58 ms
36-ms-PFS: 72%
2y-PFS: 76%
≥VGPR: 36-ms-PFS:
83 ms
Not given
2y-OS: 96%
Not given
Not given
3y-OS: 80%
2y-OS: 87%
2y-OS: 81%
HR 1.08 (0.82-1.43)
82.3%
≥VGPR: 89:87:76%
90%
95%
89%
84.3%
78.8%
64.5%
Not given
Median: 21 ms
2y-PFS: 76%
2y-PFS: 53.2%
22.3
22.1
#: number, pts: patients; ND: newly diagnosed; RR: relapsed/refratory; MM: multiple myeloma; Cfz: carfilzomib; T: thalidomide;d: day; Dex: dexamethasone; M: melphalan; P: prednisone; v: borte- zomib; L: lenalidomide; ORR: overall response rate; PFS: progression free survival; OS: overall survival; AE: adverse events; pts: patients; ms: months; C: cycle; MTD: max.tolerated dose; maint: main- tenancetherapy;FDA:FoodandDrugAdminstration;CR:completeremission;GI:gastrointestinal;Tx:transplantation;VTE:venousthrombo-embolism;discontin.:discontinuation;PD:diseasepro- gression; ca: carcinoma; pulm.: pulmonary; resp: respiratory, HR: hazard risk.
haematologica | 2019; 104(11)
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