title: Pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone alone for patients with relapsed and refractory multiple myeloma (MM-003): a randomised, open-label, phase 3 trial.
abstract: BACKGROUND
  Few effective treatments exist for patients with refractory or relapsed and refractory multiple myeloma not responding to treatment with bortezomib and lenalidomide. Pomalidomide alone has shown limited efficacy in patients with relapsed multiple myeloma, but synergistic effects have been noted when combined with dexamethasone. We compared the efficacy and safety of pomalidomide plus low-dose dexamethasone with high-dose dexamethasone alone in these patients.
  
  
  METHODS
  This multicentre, open-label, randomised phase 3 trial was undertaken in Australia, Canada, Europe, Russia, and the USA. Patients were eligible if they had been diagnosed with refractory or relapsed and refractory multiple myeloma, and had failed at least two previous treatments of bortezomib and lenalidomide. They were assigned in a 2:1 ratio with a validated interactive voice and internet response system to either 28 day cycles of pomalidomide (4 mg/day on days 1-21, orally) plus low-dose dexamethasone (40 mg/day on days 1, 8, 15, and 22, orally) or high-dose dexamethasone (40 mg/day on days 1-4, 9-12, and 17-20, orally) until disease progression or unacceptable toxicity. Stratification factors were age (≤75 years vs >75 years), disease population (refractory vs relapsed and refractory vs bortezomib intolerant), and number of previous treatments (two vs more than two). The primary endpoint was progression-free survival (PFS). Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01311687, and with EudraCT, number 2010-019820-30.
  
  
  RESULTS
  The accrual for the study has been completed and the analyses are presented. 302 patients were randomly assigned to receive pomalidomide plus low-dose dexamethasone and 153 high-dose dexamethasone. After a median follow-up of 10·0 months (IQR 7·2-13·2), median PFS with pomalidomide plus low-dose dexamethasone was 4·0 months (95% CI 3·6-4·7) versus 1·9 months (1·9-2·2) with high-dose dexamethasone (hazard ratio 0·48 [95% CI 0·39-0·60]; p<0·0001). The most common grade 3-4 haematological adverse events in the pomalidomide plus low-dose dexamethasone and high-dose dexamethasone groups were neutropenia (143 [48%] of 300 vs 24 [16%] of 150, respectively), anaemia (99 [33%] vs 55 [37%], respectively), and thrombocytopenia (67 [22%] vs 39 [26%], respectively). Grade 3-4 non-haematological adverse events in the pomalidomide plus low-dose dexamethasone and high-dose dexamethasone groups included pneumonia (38 [13%] vs 12 [8%], respectively), bone pain (21 [7%] vs seven [5%], respectively), and fatigue (16 [5%] vs nine [6%], respectively). There were 11 (4%) treatment-related adverse events leading to death in the pomalidomide plus low-dose dexamethasone group and seven (5%) in the high-dose dexamethasone group.
  
  
  CONCLUSIONS
  Pomalidomide plus low-dose dexamethasone, an oral regimen, could be considered a new treatment option in patients with refractory or relapsed and refractory multiple myeloma.
  
  
  BACKGROUND
  Celgene Corporation.
authors.affiliation: Hospital e Instituto Biosanitario de Salamanca (IBSAL), Universidad de Salamanca (IBMCC/CSIC), Salamanca, Spain; Clinica Universidad de Navarra, Pamplona, Spain. Electronic address: sanmiguel@unav.es.
authors.forename: Jesus San
authors.initials: JS
authors.lastname: Miguel
authors.affiliation: University Hospital Tübingen, Tübingen, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Weisel
authors.affiliation: University Hospital Hotel-Dieu, Nantes, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Moreau
authors.affiliation: Mayo Clinic, Rochester, MN, USA.
authors.forename: Martha
authors.initials: M
authors.lastname: Lacy
authors.affiliation: Vancouver General Hospital, Vancouver, BC, Canada.
authors.forename: Kevin
authors.initials: K
authors.lastname: Song
authors.affiliation: University Hospital Leuven, Leuven, Belgium.
authors.forename: Michel
authors.initials: M
authors.lastname: Delforge
authors.affiliation: Centre Hospitalier Lyon Sud/Hospices Civils de Lyon, Pierre-Bénite, France.
authors.forename: Lionel
authors.initials: L
authors.lastname: Karlin
authors.affiliation: University Hospital, Heidelberg, Germany.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Goldschmidt
authors.affiliation: Centre Hospitalier de la Côte Basque, Bayonne, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Banos
authors.affiliation: Institut Catala d'Oncologia, Hospital Germans Trias i Pujol, Barcelona, Spain.
authors.forename: Albert
authors.initials: A
authors.lastname: Oriol
authors.affiliation: Hospital Universitario La Princesa, Madrid, Spain.
authors.forename: Adrian
authors.initials: A
authors.lastname: Alegre
authors.affiliation: Princess Margaret Hospital, Toronto, ON, Canada.
authors.forename: Christine
authors.initials: C
authors.lastname: Chen
authors.affiliation: Institute of Hematology Seràgnoli, S Orsola's University Hospital, Bologna, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Cavo
authors.affiliation: Université Pierre et Marie Curie, Paris VI, Hôpital Saint Antoine, Paris, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Garderet
authors.affiliation: GUZ Moscow City Clinical Hospital S P Botkin, Moscow, Russia.
authors.forename: Valentina
authors.initials: V
authors.lastname: Ivanova
authors.affiliation: Hospital Universitario 12 de Octubre, Madrid, Spain.
authors.forename: Joaquin
authors.initials: J
authors.lastname: Martinez-Lopez
authors.affiliation: University of Alberta, Edmonton, AB, Canada.
authors.forename: Andrew
authors.initials: A
authors.lastname: Belch
authors.affiliation: University of Turin, Turin, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Palumbo
authors.affiliation: King's College Hospital, London, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Schey
authors.affiliation: Erasmus Medical Center, Rotterdam, Netherlands.
authors.forename: Pieter
authors.initials: P
authors.lastname: Sonneveld
authors.affiliation: Celgene Corporation, Summit, NJ, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Yu
authors.affiliation: Celgene Corporation, Summit, NJ, USA.
authors.forename: Lars
authors.initials: L
authors.lastname: Sternas
authors.affiliation: Celgene Corporation, Summit, NJ, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Jacques
authors.affiliation: Celgene Corporation, Summit, NJ, USA.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Zaki
authors.affiliation: Alexandra Hospital, Athens, Greece.
authors.forename: Meletios
authors.initials: M
authors.lastname: Dimopoulos
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D003907:Dexamethasone / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D009367:Neoplasm Staging; D011379:Prognosis; D016879:Salvage Therapy; D015996:Survival Rate; D013792:Thalidomide / Q000008:administration & dosage / Q000031:analogs & derivatives
chemical_list: D013792:Thalidomide; D003907:Dexamethasone; C467566:pomalidomide