Dose intensity and treatment duration of bortezomib in transplant-ineligible newly diagnosed multiple myeloma.

Abstract

Bortezomib-related peripheral neuropathy (PN) affects a relevant proportion of multiple myeloma (MM) patients treated with melphalan, prednisone, and bortezomib (VMP). Empirical dose modifications have attempted to reduce toxicity without compromising efficacy. We retrospectively evaluated the dose-response and dose-toxicity relationships in 114 unselected untreated MM patients intended for treatment with VMP with subcutaneous bortezomib. Sixty-two patients (54%) completed the 9 scheduled cycles. Median treatment duration was 48weeks (range 1-57), cumulative bortezomib dose was 41.8mg/m2 (2.6-67.6) and median dose intensity was 1.0mg/m2 /wk (0.2-2.6). Median progression-free survival (PFS) and overall survival (OS) for the full cohort were 86weeks (95%CI 77-104) and 209weeks (95% CI 157-259) respectively. Patients who progressed <60days after discontinuing bortezomib had received a significantly inferior mean cumulative dose, 34.6mg/m2 than the remaining individuals, 45.5 (P=.023). PFS was significantly improved for patients achieving a very good partial response (VGPR) or better (P=.00007). Additional variables with a prognostic impact on PFS on univariate analysis included completion of the 9 scheduled cycles (P=.00002), patients with at least 50weeks of treatment (P=.02) and patients receiving a cumulative dose of at least 49mg/m2 (P=.05). Achievement of a VGPR (HR 0.23; 95%CI 0.12-0.46; P=.00002) and a cumulative dose of 49mg/m2 (HR 0.46, 95%CI 0.27-0.78; P=.003) were statistically independent prognostic factors for PFS. Toxicity-related treatment dose reductions occurred in 75 individuals (66%). PN was observed in 50 individuals (44.6%), grade 3 in 9 (8%). The only prognostic factor for emergence of PN in multivariate analysis was the presence of baseline PN. Biweekly full-dose treatment in the first cycles has a major impact in depth of response. Depth of response, cumulative bortezomib dose, and treatment duration had an impact in prolongation of PFS.