Page 154 - 2019_08-Haematologica-web

S. Bringhen et al.
twice-weekly carfilzomib, respectively. Similarly, the rates of infections leading to drug discontinuation were similar during induction (2 and 3) and maintenance (1 and 0) between the once- versus twice-weekly groups.
Overall, the incidence of treatment-related grade 3-5 AE was similar in the once-weekly and the twice-weekly carfilzomib groups, both in terms of hematologic (24% vs. 30%; P=0.82) and non-hematologic (38% vs. 41%; P= 0.83) AE. The most frequent non-hematologic grade ≥3 AE were infections [5 (8%) in the once-weekly group vs. 3 (5%) in the twice-weekly group], respiratory [4 (6%) vs. 1 (2%)], cardiac [4 (6%) vs. 5 (9%)] and hypertension [4 (6%) vs. 2 (4%)]. The incidence of treatment-related grade 3-5 AE during carfilzomib maintenance was low, with comparable rates of hematologic (0% vs. 5%) and non- hematologic (21% vs. 23%) AE in the once-weekly and the twice-weekly groups. The most frequent ≥3 AE was hypertension [4 (9%) vs. none]. All AE are reported in Table 2.
Discussion
In this pooled analysis of two phase I/II studies compar- ing two alternative schedules of carfilzomib, transplant- ineligible NDMM patients who received once-weekly carfilzomib at the dose of 70 mg/m2 showed similar response rates as compared to patients treated with twice- weekly carfilzomib at the dose of 36 mg/m2. Moreover, the analysis did not report differences in terms of PFS, PFS- 2, and OS. Administering high-dose carfilzomib (70 mg/m2) in a once-weekly schedule did not impair the safe- ty profile of the KCyd combination in comparison with a lower (36 mg/m2) twice-weekly schedule.
To date, two doses of twice-weekly carfilzomib, 27 mg/m2 and 56 mg/m2, have been approved for the treat- ment of RRMM patients, based on the results of the phase III ASPIRE and ENDEAVOR trials. In the ASPIRE study, carfilzomib was tested at the dose of 27 mg/m2.13 However, a higher dose of carfilzomib (36 mg/m2) had been investigated in combination with lenalidomide and dexamethasone, and was shown to be safe and effective for NDMM patients.4,14-16 In the ENDEAVOR trial, which compared Kd versus bortezomib-dexamethasone (Vd), carfilzomib was administered at the dose of 56 mg/m2.17,18
Despite the great results yielded by the introduction of carfilzomib, treatment compliance and quality of life of young active patients, as well as those of elderly patients with reduced mobility, are compromised by the need for frequent visits to the outpatient clinic for carfilzomib dos- ing. From this point of view, a shift from the current twice-weekly to a once-weekly dosing schedule would decrease by 50% patient visits to health care facilities, with a subsequent improvement in quality of life and a reduction in drug and health care costs. For these purpos- es, higher doses of carfilzomib, administered once-week- ly, were tested in the relapse setting in a phase Ib/II study and in a subsequent phase III study.6-9 Once-weekly carfil- zomib yielded a higher ORR as compared to twice-week- ly carfilzomib, resulting in prolonged median PFS (11.2 vs. 7.6 months) without significantly increasing the rate of AE or the risk of treatment discontinuation due to AE. However, the major limitation of the ARROW study was the low dose adopted for the twice-weekly arm, which was chosen by the investigators because it was the
approved dose at the time of trial design. Indeed, higher doses of carfilzomib (up to 36 mg/m2 when given in com- bination and 70 mg/m2 alone) have been safely delivered both in upfront and relapse settings.5,8,14-20
To our knowledge, this is the first analysis to compare two different schedules and doses of carfilzomib (70 mg/m2 once-weekly vs. 36 mg/m2 twice-weekly) as induc- tion and maintenance therapies for elderly, transplant-inel- igible NDMM patients.
In the ITT analysis, we observed no significant differ- ences in 3-year PFS (47% vs. 49%), PFS-2 (62% vs. 70%) and OS (70% vs. 72%) in patients receiving once- versus twice-weekly carfilzomib. The risks of dose reduction or treatment discontinuation were equal between the two groups. Of note, delivering 70 mg/m2 of carfilzomib in a single dose did not increase the risk of grade 3-5 hemato- logic (24% vs. 30%; P=0.82) and non-hematologic (38% vs. 41%; P=0.83) AE, as compared to a twice-weekly administration of 36 mg/m2 of carfilzomib. Importantly, no new cardiovascular safety risks were identified with once-weekly carfilzomib treatment at the 70 mg/m2 dose.
The aim of continuous treatment is to prolong PFS and OS among NDMM patients without negatively affecting their quality of life. For this purpose, we compared once- versus twice-weekly maintenance with carfilzomib. Among patients who received carfilzomib maintenance, we did not observe any significant differences in terms of 3-year PFS_m (47% vs. 51%), PFS-2_m (65% vs. 74%), and OS_m (72% vs. 73%) between the once-weekly and twice-weekly schedules. Continuous treatment with sin- gle-agent carfilzomib was well tolerated and grade 3-5 AE were infrequent in both groups, although patients in the once-weekly arm were at higher risk of developing grade 3-5 hypertension (9% vs. 0%) as compared to patients in the twice-weekly group.
As previously reported, carfilzomib is able to at least partially abrogate the unfavorable prognostic significance of high-risk FISH cytogenetic abnormalities.21 In this trial, we observed no difference between standard and high- risk FISH patients in terms of 3-year PFS (52% vs. 43%) and OS (78% vs. 73%), with a greater reduction in the risk of progression or death for high-risk FISH patients (as compared to standard-risk FISH patients) in the once- weekly (HR: 1.17) than in the twice-weekly (HR: 0.52) carfilzomib schedule. These results compared favorably with those observed in the ARROW trial.9 However, due to the high frequency of patients with unknown cytoge- netic risk and the small number of patients, these results should be interpreted with caution and this evidence must be confirmed by further studies.
The major limitation of our analysis was the non-ran- domized design of the two phase I/II studies. Indeed, the study populations were slightly different (e.g. frailty sta- tus, FISH data availability), but the most important inclu- sion and exclusion criteria, as well as the treatment schema, were identical. Furthermore, the reproducibility of the results in the community setting was limited both by the lower percentage of older patients (≥75 years) as compared to other studies (such as the FIRST and the ALCYONE), and by the fact that patients included in this analysis were treated in the context of clinical trials in a limited number of selected, experienced centers. With this limitation, our results should be interpreted with caution, even though they should be considered as the basis of future randomized trials.
1646
haematologica | 2019; 104(8)