title: Feasibility of fludarabine added to VAD during induction therapy in multiple myeloma: a randomised phase II-study.
abstract: Multiple myeloma (MM) is considered to be an essentially incurable haematological malignant disease, probably because of the existence of resistant clonal precursor cell with self-renewal capacity. Recent data have indicated that the myeloma cell hierarchy includes circulating clonal memory B cells, which differ considerably from the classical end-stage plasma cells, infiltrating the bone marrow. The pathophysiological significance of these cells is unknown, but hypothetically they may serve as 'sleeping' myeloma stem cells responsible for and 'feeding' post-treatment relapse and progression. The present study evaluates the toxicity and feasibility of fludarabine, added to the VAD-induction regimen in MM, and investigates the effect on the myeloma cell hierarchy. Nineteen patients were randomised to receive either four cycles of VAD (n = 9) or two cycles of VAD, followed by two cycles of VAD combined with 5 days fludarabine 25 mg/m2/day i.v. (n = 10). Toxicity evaluation showed more profound neutropenia in the fludarabine-treated patients and two infectious episodes in each study arm: three were fever of unknown origin while one, in the fludarabine-arm, was a local skin infection at the insertion site of the central venous line. Nine of the fludarabine-treated patients responded to treatment (two complete remission, seven partial remission), compared with five responders (all PR) in the control-arm. The effects on the blood circulating myeloma compartments identified an increased reduction of CD19+ B cells and myeloma plasma cells in the fludarabine-arm. In conclusion, adding fludarabine to VAD induction in multiple myeloma is feasible and may be clinically effective by reducing the myeloma clone.
authors.affiliation: Department of Haematology at Huddinge University Hospital and Karolinska Hospital, Karolinska Institutet, Stockholm, Sweden. bo.bjorkstrand@medhs.ki.se
authors.forename: Bo
authors.initials: B
authors.lastname: Björkstrand
authors.forename: Thomas
authors.initials: T
authors.lastname: Rasmussen
authors.forename: Kari
authors.initials: K
authors.lastname: Remes
authors.forename: Astrid
authors.initials: A
authors.lastname: Gruber
authors.forename: Tarja-Terttu
authors.initials: TT
authors.lastname: Pelliniemi
authors.forename: Hans E
authors.initials: HE
authors.lastname: Johnsen
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D001402:B-Lymphocytes / Q000187:drug effects / Q000473:pathology; D002999:Clone Cells / Q000187:drug effects / Q000473:pathology; D003561:Cytarabine / Q000008:administration & dosage; D003907:Dexamethasone / Q000008:administration & dosage; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy*; D009360:Neoplastic Cells, Circulating / Q000187:drug effects; D012074:Remission Induction; D014740:Vidarabine / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000633:toxicity; D014750:Vincristine / Q000008:administration & dosage
chemical_list: D003561:Cytarabine; D014750:Vincristine; D003907:Dexamethasone; D014740:Vidarabine; C024352:fludarabine