title: Effect of cumulative bortezomib dose on survival in multiple myeloma patients receiving bortezomib-melphalan-prednisone in the phase III VISTA study.
abstract: This analysis, using data from the bortezomib-melphalan-prednisone (VMP) arm of the Phase III VISTA study, investigated whether increased cumulative bortezomib dose could improve overall survival (OS) in transplant-ineligible patients with previously untreated multiple myeloma. Median cumulative bortezomib dose received by the 340 patients was 39 mg/m(2); this was selected as the cut-off for defining the dose groups to be compared for OS. Patient characteristics were well balanced between dose groups except for age. OS was significantly longer in the higher (≥39 mg/m(2)) versus lower (<39 mg/m(2)) cumulative bortezomib dose group (median 66.3 vs. 46.2 months; hazard ratio (HR) 0.533, P < 0.0001; age-adjusted HR 0.561, P = 0.0002). To overcome confounding effects of early discontinuations/deaths, which were more common in the lower cumulative dose group (27 vs. 4% of patients discontinued due to adverse events (AEs) in the lower and higher cumulative dose groups, respectively), a landmark analysis was conducted at 180 days, eliminating patients who died or discontinued before this time from the analysis. OS from this landmark remained significantly longer in the higher dose group (median 60.4 vs. 50.3 months; HR 0.709, P = 0.0372). Thus, higher cumulative bortezomib dose, reflecting prolonged treatment duration and/or dose intensity, appears associated with improved OS. Approaches to achieve higher cumulative doses could include subcutaneous bortezomib administration, dose/schedule modifications, continuing therapy in responding patients, and proactive AE management.
authors.affiliation: Hospital Universitario Salamanca, Instituto Biosanitario De Salamanca (IBSAL), Spain.
authors.forename: María Victoria
authors.initials: MV
authors.lastname: Mateos
authors.forename: Paul G
authors.initials: PG
authors.lastname: Richardson
authors.forename: Meletios A
authors.initials: MA
authors.lastname: Dimopoulos
authors.forename: Antonio
authors.initials: A
authors.lastname: Palumbo
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Anderson
authors.forename: Hongliang
authors.initials: H
authors.lastname: Shi
authors.forename: Jennifer
authors.initials: J
authors.lastname: Elliott
authors.forename: Edward
authors.initials: E
authors.lastname: Dow
authors.forename: Helgi
authors.initials: H
authors.lastname: van de Velde
authors.forename: Liviu
authors.initials: L
authors.lastname: Niculescu
authors.forename: Jesús F
authors.initials: JF
authors.lastname: San Miguel
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use*; D001897:Boronic Acids / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use*; D000069286:Bortezomib; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008558:Melphalan / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000401:mortality*; D011241:Prednisone / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D011719:Pyrazines / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use*; D016019:Survival Analysis
chemical_list: D001897:Boronic Acids; D011719:Pyrazines; D000069286:Bortezomib; D008558:Melphalan; D011241:Prednisone