The Weekly Infusion of Bortezomib Reduces Peripheral Neuropathy.

Peripheral neuropathy (PN) is a non-hematologic side effect frequently reported in elderly patients treated with bortezomib-melphalan-prednisone (VMP). To address this issue, both bortezomib-melphalan-prednisone-thalidomide (VMPT) and VMP dosing regimens were changed; and bortezomib schedule was modified from twice weekly to weekly administration.

To determine incidence and risk factors of bortezomib-associated PN in twice weekly or weekly bortezomib infusion schedules.

Patients (N=511) older than 65 years were randomly assigned to receive VMPT followed by maintenance with bortezomib and thalidomide or VMP. Initially, patients were treated with nine 6-week cycles of VMPT (induction: bortezomib 1.3 mg/m² days 1,4,8,11,22,25,29,32 in cycles 1-4 and days 1,8,22,29 in cycles 5-9; melphalan 9 mg/m² days 1-4; prednisone 60 mg/m² days 1-4 and thalidomide 50 mg days 1-42; maintenance: bortezomib 1.3 mg/m² every 15 days and thalidomide 50 mg/day as maintenance) or VMP (bortezomib, melphalan and prednisone at the same doses and schedules previously described without maintenance). In March 2007, the protocol was amended: both VMPT and VMP induction schedules were changed to nine 5-week cycles and bortezomib schedule was modified to weekly administration (1.3 mg/m² days 1,8,15,22 in cycles 1-9). Baseline grade ≥ 2 PN was an exclusion criteria.

254 VMPT patients and 257 VMP patients were evaluated in intention-to-treat: 141 patients received twice weekly infusion of bortezomib and 370 once weekly. The overall incidence of PN was 37% in the VMPT patients and 27% in the VMP patients (p=0.01) while the grade ≥ 3 was quite similar (8% and 5%. p=0.19). When VMPT and VMP groups were combined, the incidence of PN was significantly higher in patients who received twice weekly infusion of bortezomib: the incidence of all grade PN was 45% in the twice weekly group and 27% in the once weekly group (p=0.0002), including a grade ≥ 3 PN incidence of 16% and 3% (p<0.0001), respectively (table 1). In multivariate analysis, the weekly infusion of bortezomib was the only predictive factor of lower incidence of PN (p<0.0001) whereas low-dose thalidomide did not affect PN rate (p=0.16). The weekly infusion of bortezomib significantly reduced discontinuation rate and bortezomib dose reduction (table 1). The weekly infusion of bortezomib slightly reduced the CR rate (p=0.07), but did not affect progression-free survival (p=0.31) and overall survival (p=0.44) (table 1).

The weekly infusion of bortezomib significantly decreased incidence of PN, discontinuation rate and dose-reduction rate without significant reduction of PFS. The addition of low-dose thalidomide to VMP did not increase the incidence of grade 3-4 PN. An update of these data and correlation between PN and clinical outcome will be presented at the meeting.

Bringhen:Celgene: Honoraria; Janssen-Cilag: Honoraria. Boccadoro:Janssen-Cilag: Research Funding, consultancy and advisory committees; Celgene: Research Funding, consultancy and advisory committees; Pharmion: Research Funding, consultancy and advisory committees. Palumbo:Janssen-Cilag: Honoraria; Celgene: Honoraria.