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Phase II CARTHADEX Study in NDMM
ited numbers, the negative impact of high-risk cytogenet- ics was not abrogated by carfilzomib.21 At the same time, overall risk status, based on cytogenetics and ISS stage, was not significantly associated with response. However, high-risk patients and patients with a higher R-ISS score had a significantly worse PFS. Median PFS and OS for all patients were 58 months and 83 months, respectively. These data show that treatment with KTd is effective as front-line treatment of transplant eligible patients with NDMM. Also, this regimen had no effect on stem cell mobilization and collection, with the exception of two patients in whom stem cell collection failed. Several phase
II trials have investigated treatment with carfilzomib in NDMM using different regimens.12-15 For example, in the CYKLONE trial, cyclophosphamide was added to the KTd regimen; this showed a comparable ORR of 91% and a PFS at 24 months of 76%. In this study, MTD was 20/36 mg/m2.13 In comparison, in the Carthadex trial, dose levels of 45 mg/m2 and 56 mg/m2 were well tolerated without additional toxicity compared to dose levels 27 mg/m2 and 36 mg/m2. The number of patients going off treatment due to excessive toxicity was low: 9 out of 111 patients (8%). Our data show that efficacy and safety are comparable at dose levels 36 mg/m2 and upward. Main grade 3/4 non-
AB
C
Logrank P=0.70
D
Logrank P=0.23 Logrank P=0.56
Figure 3. Kaplan-Meier curves overall survival (OS). (A) OS in all 111 patients. (B) OS per dose level. (C) OS according to risk status. (D) OS according to Revised-
International Staging System.
Table 4. Cardiac adverse events between dose levels.
20/27 mg/m2, n=50 20/36 mg/m2, n=20 20/45 mg/m2, n=21 20/56 mg/m2, n=20
Cardiac toxicity, n (%) Grade 1/2 Grade 3/4 Grade 1/2 Grade 3/4 Grade 1/2 Grade 3/4 Grade 1/2 Grade 3/4
Acutecoronarysyndrome 0(0) 0(0) 1(5) 0(0) 0(0) 0(0) 0(0) 0(0)
Atrialflutter Atrialfibrillation Anginapectoris Congestiveheartfailure Dyspnea
Palpitations
Pericardialfluid
1(2) 0(0) 0(0) 0(0) 0(0) 0(0) 0(0) 0(0) 1(2) 0(0) 0(0) 0(0) 0(0) 0(0) 0(0) 0(0) 3(6) 0(0) 1(5) 0(0) 2(10) 1(5) 1(5) 0(0) 1(2) 2(4) 1(5) 0(0) 0(0) 0(0) 0(0) 1(5) 0(0) 1(2) 0(0) 0(0) 0(0) 0(0) 0(0) 0(0) 1(2) 0(0) 1(5) 0(0) 1(5) 0(0) 0(0) 0(0) 0(0) 0(0) 0(0) 0(0) 0(0) 0(0) 1(5) 0(0)
Totalofcardiacevents 7(14) 3(6) 4(20) 0(0) 3(14) (5) 1(5) 1(5)
n: number.
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