title: Phase Ib study of panobinostat and bortezomib in relapsed or relapsed and refractory multiple myeloma.
abstract: OBJECTIVE
  Despite advancements, prognosis for patients with relapsed/refractory multiple myeloma (MM) is poor, and novel therapies are needed. Panobinostat is a potent deacetylase inhibitor that elicits synergistic effects on MM cells in combination with bortezomib. This phase Ib study sought to determine the maximum-tolerated dose (MTD) of panobinostat plus bortezomib in patients with relapsed or relapsed and refractory MM.
  
  
  METHODS
  In the dose-escalation phase (n = 47), panobinostat was administered orally thrice weekly every week in combination with bortezomib (21-day cycles). After MTD determination, patients were evaluated in an expansion phase (n = 15) that incorporated a 1-week treatment holiday of panobinostat, with dexamethasone added in cycle 2. Additional assessments included safety, pharmacokinetics, and efficacy per International Myeloma Working Group criteria.
  
  
  RESULTS
  The MTD was established at panobinostat 20 mg plus bortezomib 1.3 mg/m(2). Grade 3 or 4 adverse events (AEs) included thrombocytopenia (85.1%), neutropenia (63.8%), and asthenia (29.8%) in the escalation phase, and thrombocytopenia (66.7%), neutropenia (46.7%), and fatigue (20.0%) in the expansion phase. At MTD in the escalation phase, eight patients (47.1%) discontinued therapy as a result of AEs, whereas five patients (33.3%) discontinued treatment in the expansion phase. Expansion phase patients demonstrated greater median treatment duration. Overall response rate (ORR) was 73.3% in the expansion phase and 52.9% at the escalation phase MTD. Among bortezomib-refractory patients, the ORR was 26.3%, and 42.1% of patients had ≥ minimal response.
  
  
  CONCLUSIONS
  The MTD of panobinostat plus bortezomib was determined and demonstrated activity in patients with relapsed or relapsed/refractory MM, including bortezomib-refractory patients. A phase II/III clinical trial program (Panobinostat or Placebo With Bortezomib and Dexamethasone in Patients With Relapsed Multiple Myeloma [PANORAMA]) has been initiated.
authors.affiliation: Jesús F. San-Miguel and María Victoria Mateos, Servicio e Hematologia, Hospital Universitario de Salamanca, Instituto de Investigación Biomédica de Salamanca, Institut de Bilogia Molecular de Barcelona (Universidad de Salamanca-Spanish National Research Council), Salamanca; Joan Bladé, Hospital Clinic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; Paul G. Richardson and Kenneth C. Anderson, Dana-Farber Cancer Institute, Boston, MA; David Siegel, Hackensack University Medical Center, Hackensack; Kaushal K. Mishra and Song Mu, Novartis Pharmaceuticals Corporation, East Hanover, NJ; Andreas Günther, University of Kiel, Kiel; Orhan Sezer, Charité Universitätsmedizin Berlin, Berlin, Germany; Richard LeBlanc, Maisonneuve-Rosemont Hospital, Montreal, Quebec; Heather Sutherland, Vancouver General Hospital, Vancouver, British Columbia, Canada; and Monika Sopala and Priscille M. Bourquelot, Novartis Pharma AG, Basel, Switzerland.
authors.forename: Jesús F
authors.initials: JF
authors.lastname: San-Miguel
authors.forename: Paul G
authors.initials: PG
authors.lastname: Richardson
authors.forename: Andreas
authors.initials: A
authors.lastname: Günther
authors.forename: Orhan
authors.initials: O
authors.lastname: Sezer
authors.forename: David
authors.initials: D
authors.lastname: Siegel
authors.forename: Joan
authors.initials: J
authors.lastname: Bladé
authors.forename: Richard
authors.initials: R
authors.lastname: LeBlanc
authors.forename: Heather
authors.initials: H
authors.lastname: Sutherland
authors.forename: Monika
authors.initials: M
authors.lastname: Sopala
authors.forename: Kaushal K
authors.initials: KK
authors.lastname: Mishra
authors.forename: Song
authors.initials: S
authors.lastname: Mu
authors.forename: Priscille M
authors.initials: PM
authors.lastname: Bourquelot
authors.forename: María
authors.initials: M
authors.lastname: Victoria Mateos
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Anderson
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001897:Boronic Acids / Q000008:administration & dosage* / Q000009:adverse effects; D000069286:Bortezomib; D005260:Female; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D007211:Indoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy*; D000077767:Panobinostat; D011719:Pyrazines / Q000008:administration & dosage* / Q000009:adverse effects
chemical_list: D001897:Boronic Acids; D006877:Hydroxamic Acids; D007211:Indoles; D011719:Pyrazines; D000069286:Bortezomib; D000077767:Panobinostat