title: Melphalan, prednisone, thalidomide and defibrotide in relapsed/refractory multiple myeloma: results of a multicenter phase I/II trial.
abstract: BACKGROUND
  Defibrotide is a novel orally bioavailable polydisperse oligonucleotide with anti-thrombotic and anti-adhesive effects. In SCID/NOD mice, defibrotide showed activity in human myeloma xenografts. This phase I/II study was conducted to identify the most appropriate dose of defibrotide in combination with melphalan, prednisone and thalidomide in patients with relapsed and relapsed/refractory multiple myeloma, and to determine its safety and tolerability as part of this regimen.
  
  
  METHODS
  This was a phase I/II, multicenter, dose-escalating, non-comparative, open label study. Oral melphalan was administered at a dose of 0.25 mg/kg on days 1-4, prednisone at a dose of 1.5 mg/kg also on days 1-4 and thalidomide at a dose of 50-100 mg/day continuously. Defibrotide was administered orally at three dose-levels: 2.4, 4.8 or 7.2 g on days 1-4 and 1.6, 3.2, or 4.8 g on days 5-35.
  
  
  RESULTS
  Twenty-four patients with relapsed/refractory multiple myeloma were enrolled. No dose-limiting toxicity was observed. In all patients, the complete response plus very good partial response rate was 9%, and the partial response rate was 43%. The 1-year progression-free survival and 1-year overall survival rates were 34% and 90%, respectively. The most frequent grade 3-4 adverse events included neutropenia, thrombocytopenia, anemia and fatigue. Deep vein thrombosis was reported in only one patient.
  
  
  CONCLUSIONS
  This combination of melphalan, prednisone and thalidomide together with defibrotide showed anti-tumor activity with a favorable tolerability. The maximum tolerated dose of defibrotide was identified as 7.2 g p.o. on days 1-4 followed by 4.8 g p.o. on days 5-35. Further trials are needed to confirm the role of this regimen and to evaluate the combination of defibrotide with new drugs.
authors.affiliation: Divisione, di Ematologia Dell'Università di Torino, Azienda Ospedaliera San, Giovanni Battista, Via Genova 3, 10126 Torino, Italy. appalumbo@yahoo.com
authors.forename: Antonio
authors.initials: A
authors.lastname: Palumbo
authors.forename: Alessandra
authors.initials: A
authors.lastname: Larocca
authors.forename: Mariella
authors.initials: M
authors.lastname: Genuardi
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Kotwica
authors.forename: Francesca
authors.initials: F
authors.lastname: Gay
authors.forename: Davide
authors.initials: D
authors.lastname: Rossi
authors.forename: Giulia
authors.initials: G
authors.lastname: Benevolo
authors.forename: Valeria
authors.initials: V
authors.lastname: Magarotto
authors.forename: Federica
authors.initials: F
authors.lastname: Cavallo
authors.forename: Sara
authors.initials: S
authors.lastname: Bringhen
authors.forename: Cecilia
authors.initials: C
authors.lastname: Rus
authors.forename: Luciano
authors.initials: L
authors.lastname: Masini
authors.forename: Massimo
authors.initials: M
authors.lastname: Iacobelli
authors.forename: Gianluca
authors.initials: G
authors.lastname: Gaidano
authors.forename: Constantine
authors.initials: C
authors.lastname: Mitsiades
authors.forename: Kenneth
authors.initials: K
authors.lastname: Anderson
authors.forename: Mario
authors.initials: M
authors.lastname: Boccadoro
authors.forename: Paul
authors.initials: P
authors.lastname: Richardson
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008558:Melphalan / Q000008:administration & dosage; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D011089:Polydeoxyribonucleotides / Q000008:administration & dosage; D011241:Prednisone / Q000008:administration & dosage; D016879:Salvage Therapy / Q000379:methods; D013792:Thalidomide / Q000008:administration & dosage; D016896:Treatment Outcome
chemical_list: D011089:Polydeoxyribonucleotides; C036901:defibrotide; D013792:Thalidomide; D008558:Melphalan; D011241:Prednisone