Page 151 - 2019_08-Haematologica-web

Once- vs. Twice-Weekly Carfilzomib in NDMM
carfilzomib, the primary goals of this analysis were: (1) to com- pare PFS, PFS-2 and OS from the date of entry onto the trial in the intention-to-treat (ITT) population; (2) to compare PFS from start of maintenance therapy (PFS_m), PFS 2 from start of maintenance therapy (PFS-2_m) and overall survival from start of maintenance therapy (OS_m) in a population who completed the induction phase and started maintenance treatment. (Note that PFS-2 was calculated from the date of enrollment to the date of second relapse/progression or death or the date the patient was last known to be in remission.)
Secondary end points were responses, time to response, and safety of once- versus twice-weekly carfilzomib.
Responses were recorded at the beginning of every cycle, according to the International Myeloma Working Group (IMWG) criteria. All adverse events (AE) were assessed during each cycle and graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (version 4.0).10 Fluorescence in situ hybridization (FISH) was centrally assessed with a 10% cut-off for numerical aberrations and a 15% cut-off for IgH translocations; high-risk FISH was defined by the presence of at least one of the following chromosomal abnormalities: del(17p), t(4;14) or t(14;16).11 Frailty status was evaluated accord- ing to the IMWG Frailty Score.12
The intention-to-treat population consisted of all the enrolled patients and was the basis for the analysis of efficacy end points. Patients were analyzed according to initial treatment assignment. The safety population was defined as all the enrolled patients who received at least one dose of carfilzomib, cyclophosphamide or dexamethasone, and was the basis for the analysis of the safety end points.
Statistical analysis
Data from the two studies were pooled together and analyzed. Comparisons between different patient groups were investigated using Fisher exact test. Time to response was calculated from the start of treatment to the date of the first response [complete remis- sion (CR), partial remission (PR)]. PFS was calculated from the date of enrollment to the date of progression or death or the date the patient was last known to be in remission. PFS-2 was calculated from the date of enrollment to the date of second relapse/progres- sion or death or the date the patient was last known to be in remission. OS was calculated from the date of enrollment to the date of death or the date the patient was last known to be alive. PFS_m, PFS-2_m and OS_m were calculated from the date of the start of maintenance therapy. In order to account for potential con- founders, the comparison once- versus twice-weekly carfilzomib was adjusted for age, International Staging System (ISS), FISH, Frailty Score, and, in relation to the maintenance analysis, for response to induction therapy.
Time-to-event data were analyzed using the Kaplan-Meier method; survival curves were compared with the log-rank test. Results are presented as hazard ratios (HRs), 95% confidence intervals (95% CIs), and two-sided P-values. Data were censored on September 30th 2015 for the IST-CAR-506 study and on April 30th 2018 for the IST-CAR-561 study. Data were analyzed using R software (version 3.5.1).
Results
One hundred and twenty-one transplant-ineligible NDMM patients were analyzed: 63 from the IST-CAR-
Table 2. Grade 3-5 treatment-related adverse events during induction and maintenance therapy.
Grade 3-5 AE
At least 1 hematologic AE Anemia
Neutropenia Thrombocytopenia
At least 1 non-hematologic AE
Cardiac
- Heart failure
- Myocardial infarction
- Atrial fibrillation/flutter
- Sudden death Vascular
- Hypertension Gastrointestinal
Infection Nervous Respiratory
- Pulmonary edema Fatigue
Creatinine increase
At least 1 dose reduction for carfilzomib
Patients who discontinued carfilzomib due to AE
AE: adverse events.
IST-CAR-561 Once-weekly N=63 (%)
15 (24) 2 (3) 13 (21) 4 (6) 24 (38) 4 (6) 3 (5) 0
0
1 (2) 5 (8) 4 (6) 3 (5) 5 (8) 2 (3) 4 (6) 3 (5) 0
2 (3) 18 (29) 17 (27)
Overall
IST-CAR-506 Twice-weekly N=56 (%)
17 (30) 6 (11) 12 (21) 3 (5) 23 (41) 5 (9) 2 (4) 1 (2) 2 (4) 0
6 (11) 2 (4) 3 (5) 3 (5) 3 (5) 1 (2) 1 (2) 3 (5) 0
17 (30) 17 (30)
haematologica | 2019; 104(8)
1643