title: Perifosine plus bortezomib and dexamethasone in patients with relapsed/refractory multiple myeloma previously treated with bortezomib: results of a multicenter phase I/II trial.
abstract: OBJECTIVE
  Novel agents have improved patient outcome in relapsed or relapsed/refractory multiple myeloma (MM). Preclinical data show that the novel signal transduction modulator, perifosine, enhances the cytotoxicity of dexamethasone and bortezomib. Clinical data suggest that perifosine in combination with dexamethasone has activity in relapsed or relapsed/refractory MM.
  
  
  METHODS
  In a phase I/II study, perifosine in combination with bortezomib with or without dexamethasone was prospectively evaluated in 84 patients with relapsed or relapsed/refractory MM. All were heavily pretreated and bortezomib exposed; 73% were refractory to bortezomib, and 51% were refractory to bortezomib and dexamethasone. The dose selected for the phase II study was perifosine 50 mg/d plus bortezomib 1.3 mg/m(2), with the addition of low-dose dexamethasone at 20 mg if progression occurred on perifosine plus bortezomib alone.
  
  
  RESULTS
  An overall response rate (ORR; defined as minimal response or better) of 41% was demonstrated with this combination in 73 evaluable patients, including an ORR of 65% in bortezomib-relapsed patients and 32% in bortezomib-refractory patients. Therapy was generally well tolerated; toxicities, including gastrointestinal adverse effects and fatigue, proved manageable. No treatment-related mortality was seen. Median progression-free survival was 6.4 months, with a median overall survival of 25 months (22.5 months in bortezomib-refractory patients).
  
  
  CONCLUSIONS
  Perifosine-bortezomib ± dexamethasone demonstrated encouraging activity in heavily pretreated bortezomib-exposed patients with advanced MM. A phase III trial is underway comparing perifosine-bortezomib plus dexamethasone with bortezomib-dexamethasone in patients with relapsed/refractory MM previously treated with bortezomib.
authors: Dana-Farber Cancer Institute, 44 Binney St, Dana 1B02, Boston, MA 02115, USA. paul_richardson@dfci.harvard.edu
authors: Paul G
authors: PG
authors: Richardson
authors: Jeff
authors: J
authors: Wolf
authors: Andrzej
authors: A
authors: Jakubowiak
authors: Jeff
authors: J
authors: Zonder
authors: Sagar
authors: S
authors: Lonial
authors: David
authors: D
authors: Irwin
authors: John
authors: J
authors: Densmore
authors: Amrita
authors: A
authors: Krishnan
authors: Noopur
authors: N
authors: Raje
authors: Michael
authors: M
authors: Bar
authors: Tom
authors: T
authors: Martin
authors: Robert
authors: R
authors: Schlossman
authors: Irene M
authors: IM
authors: Ghobrial
authors: Nikhil
authors: N
authors: Munshi
authors: Jacob
authors: J
authors: Laubach
authors: Jeff
authors: J
authors: Allerton
authors: Teru
authors: T
authors: Hideshima
authors: Kathleen
authors: K
authors: Colson
authors: Enrique
authors: E
authors: Poradosu
authors: Lesa
authors: L
authors: Gardner
authors: Peter
authors: P
authors: Sportelli
authors: Kenneth C
authors: KC
authors: Anderson
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001897:Boronic Acids / Q000008:administration & dosage; D000069286:Bortezomib; D003907:Dexamethasone / Q000008:administration & dosage / Q000627:therapeutic use*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000401:mortality; D010767:Phosphorylcholine / Q000008:administration & dosage / Q000031:analogs & derivatives; D011719:Pyrazines / Q000008:administration & dosage; D012008:Recurrence
chemical_list: D001897:Boronic Acids; D011719:Pyrazines; D010767:Phosphorylcholine; C105905:perifosine; D000069286:Bortezomib; D003907:Dexamethasone