Background: 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.
Patients and methods: We retrospectively evaluated the dose-response and dose-toxicity relationships in 114 unselected untreated MM patients intended for treatment with VMP with subcutaneous bortezomib.
Results: Sixty-two patients (54%) completed the 9 scheduled cycles. Median treatment duration was 48 weeks (range 1-57), cumulative bortezomib dose was 41.8 mg/m2 (2.6 – 67.6) and median dose intensity was 1.0 mg/m2 /week (0.2 – 2.6). Median progression-free survival (PFS) and overall survival (OS) for the full cohort were 86 weeks (95%CI 77-104) and 209 weeks (95% CI 157-259) respectively. Patients who progressed < 60 days after discontinuing bortezomib had received a significantly inferior mean cumulative dose, 34.6 mg/m2 than the remaining individuals, 45.5 (P=0.023). PFS was significantly improved for patients achieving a very good partial response (VGPR) or better (P=0.00007). Additional variables with a prognostic impact on PFS on univariate analysis included completion of the 9 scheduled cycles (P=0.00002), patients with at least 50 weeks of treatment (P=0.02) and patients receiving a cumulative dose of at least 49 mg/m2 (P=0.05). Achievement of a VGPR (HR 0.23; 95%CI 0.12-0.46; P=0.00002) and a cumulative dose of 49 mg/m2 (HR 0.46, 95%CI 0.27-0.78; P=0.003) 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.
Conclusions: 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.