title: Weekly bortezomib in combination with temsirolimus in relapsed or relapsed and refractory multiple myeloma: a multicentre, phase 1/2, open-label, dose-escalation study.
abstract: BACKGROUND
  Multiple myeloma is the second most prevalent haematological malignancy and is incurable. Our aim was to assess the response and safety of the combination of temsirolimus (an mTOR inhibitor) and bortezomib in patients with relapsed or refractory multiple myeloma.
  
  
  METHODS
  We did an open-label, dose-escalation study in three centres in the USA. Patients were enrolled from June, 2007, to December, 2009. Eligible patients were aged 18 years or older with relapsed or relapsed and refractory multiple myeloma after one or more treatment (including lenalidomide, bortezomib, or thalidomide), with an Eastern Cooperative Oncology Group performance status of 0-2. Patients were assigned a dose level in the order of their entry into the study. Phase 1 was to assess the safety and establish the maximum tolerated dose (MTD) of the combination and phase 2 was to assess overall response rate at the MTD. Intravenous temsirolimus was given at 15 or 25 mg and intravenous bortezomib at 1·3 or 1·6 mg/m(2) once a week, with dose escalation until dose-limiting adverse events were recorded in two of the three people in the dose cohort. Use of steroids were not permitted. The primary endpoint was the proportion of patients with a partial response or better. Analyses were done on an intention-to-treat basis, with all patients who had been enrolled included. The study is registered with ClinicalTrials.gov, number NCT00483262.
  
  
  RESULTS
  20 patients were enrolled into the phase 1 study and 43 into phase 2. All patients were heavily pretreated (median five lines in the phase 1 cohort, and four lines in the phase 2 cohort). The MTD was determined to be 1·6 mg/m(2) bortezomib on days 1, 8, 15, and 22 in combination with 25 mg temsirolimus on days 1, 8, 15, 22, and 29, for a cycle of 35 days. In the phase 2 study, the proportion of patients with a partial response or better was 33% (14 of 43; 90% CI 21-47). Long-term follow-up of patients is ongoing. There were three deaths during treatment in the phase 1 and 2 studies: one patient died of septic shock in the phase 1 study; one patient died with H1N1 influenza infection and one died with cardiac amyloid and ventricular arrhythmia unrelated to treatment in the phase 2 study. In the phase 1 study, the most common treatment-related grade 3-4 adverse events were thrombocytopenia (13 patients), lymphopenia (ten), neutropenia (nine), leucopenia (seven), and anaemia (five). In the phase 2 study, the most common treatment-related grade 3-4 adverse events were thrombocytopenia (25 patients), lymphopenia (24), neutropenia (17), leucopenia (ten), anaemia (seven), and diarrhoea (five). Four patients in the phase 1 study had sensory peripheral neuropathy (grade 2 or less); in the phase 2 study, 11 had sensory peripheral neuropathy (all grade 2 or less) and seven motor peripheral neuropathy (one grade 3, six grade 2 or less).
  
  
  CONCLUSIONS
  mTOR inhibitors could have a role in combination with weekly bortezomib for the treatment of patients with relapsed and refractory multiple myeloma without the addition of steroids.
  
  
  BACKGROUND
  Millennium Inc, Pfizer Inc, Multiple Myeloma Research Foundation, and the Leukemia and Lymphoma Society.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. irene_ghobrial@dfci.harvard.edu
authors.forename: Irene M
authors.initials: IM
authors.lastname: Ghobrial
authors.forename: Edie
authors.initials: E
authors.lastname: Weller
authors.forename: Ravi
authors.initials: R
authors.lastname: Vij
authors.forename: Nikhil C
authors.initials: NC
authors.lastname: Munshi
authors.forename: Ranjit
authors.initials: R
authors.lastname: Banwait
authors.forename: Meghan
authors.initials: M
authors.lastname: Bagshaw
authors.forename: Robert
authors.initials: R
authors.lastname: Schlossman
authors.forename: Renee
authors.initials: R
authors.lastname: Leduc
authors.forename: Stacey
authors.initials: S
authors.lastname: Chuma
authors.forename: Janet
authors.initials: J
authors.lastname: Kunsman
authors.forename: Jacob
authors.initials: J
authors.lastname: Laubach
authors.forename: Andrzej J
authors.initials: AJ
authors.lastname: Jakubowiak
authors.forename: Patricia
authors.initials: P
authors.lastname: Maiso
authors.forename: Aldo
authors.initials: A
authors.lastname: Roccaro
authors.forename: Philippe
authors.initials: P
authors.lastname: Armand
authors.forename: Akari
authors.initials: A
authors.lastname: Dollard
authors.forename: Diane
authors.initials: D
authors.lastname: Warren
authors.forename: Brianna
authors.initials: B
authors.lastname: Harris
authors.forename: Tiffany
authors.initials: T
authors.lastname: Poon
authors.forename: Amy
authors.initials: A
authors.lastname: Sam
authors.forename: Scott
authors.initials: S
authors.lastname: Rodig
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Anderson
authors.forename: Paul G
authors.initials: PG
authors.lastname: Richardson
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001897:Boronic Acids / Q000008:administration & dosage*; D000069286:Bortezomib; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy; D011719:Pyrazines / Q000008:administration & dosage*; D012008:Recurrence; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives*
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D011719:Pyrazines; C401859:temsirolimus; D000069286:Bortezomib; D020123:Sirolimus