title: Overall survival of patients with relapsed multiple myeloma treated with panobinostat or placebo plus bortezomib and dexamethasone (the PANORAMA 1 trial): a randomised, placebo-controlled, phase 3 trial.
abstract: BACKGROUND
  Panobinostat plus bortezomib and dexamethasone significantly increased median progression-free survival compared with placebo plus bortezomib and dexamethasone in the phase 3 PANORAMA 1 trial. Here, we present the final overall survival analysis for this trial.
  
  
  METHODS
  PANORAMA 1 is a randomised, placebo-controlled, double-blind, phase 3 trial of patients with relapsed or relapsed and refractory multiple myeloma with one to three previous treatments. Patients were randomly assigned (1:1) to receive panobinostat (20 mg orally) or placebo, with bortezomib (1·3 mg/m2intravenously) and dexamethasone (20 mg orally), over two distinct treatment phases. In treatment phase 1 (eight 3-week cycles), patients received: panobinostat or placebo on days 1, 3, 5, 8, 10, and 12; bortezomib on days 1, 4, 8, and 11; and dexamethasone on days 1, 2, 4, 5, 8, 9, 11, and 12. During treatment phase 2 (four 6-week cycles with a 2 weeks on, 1 week off schedule), panobinostat or placebo was given three times a week, bortezomib was administered once a week, and dexamethasone was given on the days of and following bortezomib administration. The primary endpoint was progression-free survival; overall survival was a key secondary endpoint. This study is registered at ClinicalTrials.gov, NCT01023308.
  
  
  RESULTS
  Between Jan 21, 2010, and Feb 29, 2012, 768 patients were enrolled into the study and randomly assigned to receive either panobinostat (n=387) or placebo (n=381), plus bortezomib and dexamethasone. At data cutoff (June 29, 2015), 415 patients had died. Median overall survival was 40·3 months (95% CI 35·0-44·8) in those who received panobinostat, bortezomib, and dexamethasone versus 35·8 months (29·0-40·6) in those who received placebo, bortezomib, and dexamethasone (hazard ratio [HR] 0·94, 95% CI 0·78-1·14; p=0·54). Of patients who had received at least two previous regimens including bortezomib and an immunomodulatory drug, median overall survival was 25·5 months (95% CI 19·6-34·3) in 73 patients who received panobinostat, bortezomib, and dexamethasone versus 19·5 months (14·1-32·5) in 74 who received placebo (HR 1·01, 95% CI 0·68-1·50).
  
  
  CONCLUSIONS
  The overall survival benefit with panobinostat over placebo with bortezomib and dexamethasone was modest. However, optimisation of the regimen could potentially prolong treatment duration and improve patients' outcomes, although further trials will be required to confirm this.
  
  
  BACKGROUND
  Novartis Pharmaceuticals.
authors.affiliation: Clínica Universidad de Navarra, CIMA, IDISNA, Pamplona, Spain. Electronic address: sanmiguel@unav.es.
authors.forename: Jesús F
authors.initials: JF
authors.lastname: San-Miguel
authors.affiliation: Irmandade da Santa Casa de Misericordia de São Paulo, São Paulo, Brazil.
authors.forename: Vania T M
authors.initials: VT
authors.lastname: Hungria
authors.affiliation: Seoul National University Hospital, Seoul, South Korea.
authors.forename: Sung-Soo
authors.initials: SS
authors.lastname: Yoon
authors.affiliation: Ankara University School of Medicine, Ankara, Turkey.
authors.forename: Meral
authors.initials: M
authors.lastname: Beksac
authors.affiliation: National and Kapodistrian University of Athens, Athens, Greece.
authors.forename: Meletios A
authors.initials: MA
authors.lastname: Dimopoulos
authors.affiliation: Alexandria University, Alexandria, Egypt.
authors.forename: Ashraf
authors.initials: A
authors.lastname: Elghandour
authors.affiliation: Medical University of Warsaw, Warsaw, Poland.
authors.forename: Wieslaw W
authors.initials: WW
authors.lastname: Jedrzejczak
authors.affiliation: University of Kiel, Kiel, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Günther
authors.affiliation: King Chulalongkorn Memorial Hospital and Chulalongkorn University, Bangkok, Thailand.
authors.forename: Thanyaphong N
authors.initials: TN
authors.lastname: Nakorn
authors.affiliation: Siriraj Hospital, Bangkok, Thailand.
authors.forename: Noppadol
authors.initials: N
authors.lastname: Siritanaratkul
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Schlossman
authors.affiliation: Shanghai Changzheng Hospital, Shanghai, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Hou
authors.affiliation: University Hospital of Nantes, Nantes, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Moreau
authors.affiliation: Winship Cancer Institute of Emory University, Atlanta, GA, USA.
authors.forename: Sagar
authors.initials: S
authors.lastname: Lonial
authors.affiliation: Gachon University Gil Medical Center, Incheon, South Korea.
authors.forename: Jae H
authors.initials: JH
authors.lastname: Lee
authors.affiliation: University Hospital Würzburg, Würzburg, Germany.
authors.forename: Hermann
authors.initials: H
authors.lastname: Einsele
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Monika
authors.initials: M
authors.lastname: Sopala
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Bourras-Rezki
authors.initials: BR
authors.lastname: Bengoudifa
authors.affiliation: Novartis Pharma SAS, Rueil-Malmaison, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Binlich
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: Paul G
authors.initials: PG
authors.lastname: Richardson
mesh_terms: D000203:Activities of Daily Living / Q000145:classification; D000328:Adult; D000367:Age Factors; D000368:Aged; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000494:pharmacology* / Q000627:therapeutic use*; D044466:Asian People / Q000208:ethnology; D001247:Asthenia / Q000139:chemically induced; D001772:Blood Cell Count / Q000706:statistics & numerical data; D000069286:Bortezomib / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D002869:Chromosome Aberrations / Q000187:drug effects / Q000706:statistics & numerical data; D003404:Creatinine / Q000097:blood; D003907:Dexamethasone / Q000009:adverse effects* / Q000494:pharmacology* / Q000627:therapeutic use*; D003967:Diarrhea / Q000139:chemically induced; D018450:Disease Progression; D018572:Disease-Free Survival; D004311:Double-Blind Method; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D005843:Geography / Q000706:statistics & numerical data; D018380:Hematopoietic Stem Cell Transplantation / Q000706:statistics & numerical data; D006801:Humans; D006877:Hydroxamic Acids / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D007155:Immunologic Factors / Q000627:therapeutic use; D007211:Indoles / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000150:complications / Q000188:drug therapy* / Q000208:ethnology / Q000401:mortality*; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000401:mortality*; D009367:Neoplasm Staging; D000077767:Panobinostat; D010352:Patient Dropouts / Q000706:statistics & numerical data*; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced; D011788:Quality of Life; D051437:Renal Insufficiency / Q000150:complications; D012737:Sex Factors; D013256:Steroids / Q000627:therapeutic use; D016019:Survival Analysis; D013921:Thrombocytopenia / Q000139:chemically induced; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D018906:Antineoplastic Agents, Alkylating; D006877:Hydroxamic Acids; D007155:Immunologic Factors; D007211:Indoles; D013256:Steroids; D000069286:Bortezomib; D003907:Dexamethasone; D000077767:Panobinostat; D003404:Creatinine