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Once- vs. Twice-Weekly Carfilzomib in NDMM
Introduction
In the last two decades, several novel agents of various classes have been developed and approved to treat multi- ple myeloma (MM), resulting in improved overall survival (OS) for both transplant-eligible and -ineligible patients.1 Among new agents, the immunomodulatory drugs (IMiD) thalidomide and lenalidomide, and the proteasome inhibitor (PI) bortezomib, have been included in the initial treatment for newly diagnosed (ND) MM patients. Bortezomib, a first-generation PI, proved to be a very effec- tive anti-MM agent. It was initially approved for the relapse setting and then approved for upfront therapy. Despite the efficacy of bortezomib, its long-term adminis- tration is limited by the emergence of peripheral neuropa- thy, which was reported in 4-13% of patients (grade 3-4).2,3
Carfilzomib, a second-generation PI, showed significant activity among patients with relapsed and/or refractory (RR) MM and was approved by US Food and Drug Administration and the European Medicines Agency in combination with dexamethasone or lenalidomide-dex- amethasone (Rd) for the treatment of RRMM patients. Given the efficacy displayed by carfilzomib in the relapse setting, several trials tested carfilzomib as part of upfront therapy for NDMM patients, either with Rd (KRd) or with alkylating agents, such as melphalan-prednisone (KMP) or cyclophosphamide-dexamethasone (KCyd).4-7
Carfilzomib is currently approved with the twice-week- ly schedule at a dose of 27 mg/m2 over a 2-10-minute (min) infusion period when administered alone or in com- bination with lenalidomide and dexamethasone, or at a dose of 56 mg/m2 over a 30-min infusion period when given in combination with dexamethasone (Kd).
Table 1. Patients' characteristics.
Age, median (range) ≥75 years
Sex, female
Serum creatinine, mg/dL, median (range)
ISS
1 2 3
FISH Standard risk High risk Missing
Frailty Score
Fit
Intermediate fitness Frail
LDH, [UI/mol] median (range)
Missing
Nonetheless, other doses (up to 70 mg/m2) and schedules (once weekly) have been shown to be promising.
The current twice-weekly schedule may not be very convenient for patients (particularly for elderly patients with limited access to hospital facilities), affecting their quality of life and treatment compliance. In order to improve the convenience of the carfilzomib schedule, pre- liminary studies tested higher doses of carfilzomib admin- istered in a once-weekly schedule. The phase Ib/II CHAMPION-1 study tested different doses of once-week- ly carfilzomib in RRMM patients to define its maximum tolerated dose (MTD) combined with dexamethasone.8 The MTD of once-weekly carfilzomib proved to be 70 mg/m2 over a 30-min infusion period, displaying good effi- cacy and tolerability. Based on these results, a phase III study (ARROW) was initiated to compare twice-weekly carfilzomib at the dose of 27 mg/m2 with once-weekly carfilzomib at the dose of 70 mg/m2.9 Among 578 RRMM patients, once-weekly carfilzomib improved the overall response rate (ORR; 62.9% vs. 40.8%) and prolonged median progression-free survival (PFS) as compared to twice-weekly carfilzomib (median PFS, 11.2 vs. 7.6 months), with a similar rate of grade 3-4 adverse events (68% vs. 62%). A major limitation of the ARROW study was the low dose (27 mg/m2) of carfilzomib in the twice- weekly arm as compared to the 70 mg/m2 dose adopted in the once-weekly arm. This low dose was determined according to the carfilzomib approval at the time of study design.
We previously published data from two phase I/II (IST- CAR-561) and phase II (IST-CAR-506) studies investigat- ing once-weekly (70 mg/m2) and twice-weekly (36 mg/m2) carfilzomib combined with cyclophosphamide and dex-
All patients N=121
72 (55-86) 31 (26%) 68 (56%) 0.90 (0.46-3.7)
40 (33%) 38 (31%) 43 (36%)
57 (47%) 37 (31%) 27 (22%)
67 (55%) 40 (33%) 14 (12%) 296 (81-768) 20 (17%)
IST-CAR-561 Once-weekly N=63
72 (60-85) 14 (22%) 37 (59%) 0.82 (0.5-3.7)
24 (38%) 19 (30%) 20 (32%)
24 (38%) 19 (30%) 20 (32%)
37 (59%) 22 (35%)
4 (6%) 306 (100-768) 2 (3%)
IST-CAR-506 P Twice-weekly
N=58
71 (55-86) 0.67 17 (29%) 0.41 31 (53%) 0.59
1.00 (0.46-2.92) 0.06
16 (28%) 0.46 19 (33%)
23 (40%)
33 (57%) 0.4 18 (31%)
7 (12%)
30 (52%) 0.19 18 (31%)
10 (17%)
278 (81-654) 0.35
18 (31%)
N: number; IQR: interquartile range; LDH: lactate dehydrogenase; ISS: International Staging System; FISH: fluorescence in situ hybridization.
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