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R. Wester et al.
and two patients (10%) asked to discontinue treatment (Online Supplementary Table S2).
Discussion
Results of the first three dose levels of this phase II trial have been published before.11 In this paper, we discuss the results of four dose levels of carfilzomib. As reported above, treatment with KTd for induction and consolida- tion in transplant eligible patients with NDMM is safe, tolerable and effective. We included the additional cohort with the highest dose level of 56 mg/m2, based on the hypothesis that a higher dose level induces a higher response rate.12,16 Response after induction was high, with 65% of patients reaching at least VGPR, increasing to 86%
after consolidation therapy. CR rate after consolidation was high at 63%. Response (i.e. >CR) after consolidation at the three higher dose levels (20/36, 20/45, 20/56) was better than at the lowest dose level (20/27); however, the small sample size and the non-randomized design of the study preclude firm conclusions about superiority of the highest dose levels. In the ARROW trial, 478 patients with RRMM were randomized between treatment with carfil- zomib twice a week 27 mg/m2 or once weekly 70 mg/m2. PFS was higher with once weekly 70 mg/m2 than with twice weekly 27 mg/m2 (11.2 months vs. 7.6 months).20 These data and our data (based on response) suggest that a dose of at least 36 mg/m2 twice weekly (which equals 70 mg/m2 once weekly) would be the preferred dose.
An important remaining question relates to the efficacy of this regimen in high-risk patients. In this trial with lim-
Table 3. Response after consolidation therapy according to risk status and R-ISS.
Standard risk* High-risk* R-ISS 1 R-ISS 2 R-ISS 3 Total
Patients,n 46 43 26 65 10 111 sCR,n(%) 16(35) 9(21) 10(38) 19(29) 0(0) 33(30) ≥CR,n(%) 31(67) 25(58) 19(73) 37(57) 6(60) 70(63) ≥VGPR,n(%) 40(87) 36(84) 24(92) 54(83) 9(90) 96(86) ≥ PR, n (%) 44 (96) 38 (88) 26 (100) 58 (91) 10 (100) 104 (94)
*High-risk:t(4;14) and/or 17p- and/or add1q cytogenetic abnormalities and/or ISS stage 3 disease.Standard risk:the remaining patients with available cytogenetics and ISS stage. n: number; ISS: International Staging System; R-ISS: Revised International Staging System; sCR: stringent complete remission; CR: complete remission; VGPR: very good partial response; PR: partial response.
AB
C
Logrank P=0.94
D
Logrank P=0.006 Logrank P=0.04
Figure 2. Kaplan-Meier curves of progression-free survival (PFS). (A) PFS in all 111 patients. (B) PFS per dose level. (C) PFS according to risk status. (D) PFS according to Revised-International Staging System.
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