title: Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): an open-label, randomised, phase 2 trial.
abstract: BACKGROUND
  New treatment options are needed for patients with multiple myeloma that is refractory to proteasome inhibitors and immunomodulatory drugs. We assessed daratumumab, a novel CD38-targeted monoclonal antibody, in patients with refractory multiple myeloma.
  
  
  METHODS
  In this open-label, multicentre, phase 2 trial done in Canada, Spain, and the USA, patients (age ≥18 years) with multiple myeloma who were previously treated with at least three lines of therapy (including proteasome inhibitors and immunomodulatory drugs), or were refractory to both proteasome inhibitors and immunomodulatory drugs, were randomly allocated in a 1:1 ratio to receive intravenous daratumumab 8 mg/kg or 16 mg/kg in part 1 stage 1 of the study, to decide the dose for further assessment in part 2. Patients received 8 mg/kg every 4 weeks, or 16 mg/kg per week for 8 weeks (cycles 1 and 2), then every 2 weeks for 16 weeks (cycles 3-6), and then every 4 weeks thereafter (cycle 7 and higher). The allocation schedule was computer-generated and randomisation, with permuted blocks, was done centrally with an interactive web response system. In part 1 stage 2 and part 2, patients received 16 mg/kg dosed as in part 1 stage 1. The primary endpoint was overall response rate (partial response [PR] + very good PR + complete response [CR] + stringent CR). All patients who received at least one dose of daratumumab were included in the analysis. The trial is registered with ClinicalTrials.gov, number NCT01985126.
  
  
  RESULTS
  The study is ongoing. In part 1 stage 1 of the study, 18 patients were randomly allocated to the 8 mg/kg group and 16 to the 16 mg/kg group. Findings are reported for the 106 patients who received daratumumab 16 mg/kg in parts 1 and 2. Patients received a median of five previous lines of therapy (range 2-14). 85 (80%) patients had previously received autologous stem cell transplantation, 101 (95%) were refractory to the most recent proteasome inhibitors and immunomodulatory drugs used, and 103 (97%) were refractory to the last line of therapy. Overall responses were noted in 31 patients (29.2%, 95% CI 20.8-38.9)-three (2.8%, 0.6-8.0) had a stringent CR, ten (9.4%, 4.6-16.7) had a very good PR, and 18 (17.0%, 10.4-25.5) had a PR. The median time to first response was 1.0 month (range 0.9-5.6). Median duration of response was 7.4 months (95% CI 5.5-not estimable) and progression-free survival was 3.7 months (95% CI 2.8-4.6). The 12-month overall survival was 64.8% (95% CI 51.2-75.5) and, at a subsequent cutoff, median overall survival was 17.5 months (95% CI 13.7-not estimable). Daratumumab was well tolerated; fatigue (42 [40%] patients) and anaemia (35 [33%]) of any grade were the most common adverse events. No drug-related adverse events led to treatment discontinuation.
  
  
  CONCLUSIONS
  Daratumumab monotherapy showed encouraging efficacy in heavily pretreated and refractory patients with multiple myeloma, with a favourable safety profile in this population of patients.
  
  
  BACKGROUND
  Janssen Research & Development.
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA. Electronic address: sloni01@emory.edu.
authors.forename: Sagar
authors.initials: S
authors.lastname: Lonial
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Abramson Cancer Center and Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Brendan M
authors.initials: BM
authors.lastname: Weiss
authors.affiliation: Levine Cancer Institute/Carolinas Healthcare System, Charlotte, NC, USA.
authors.forename: Saad Z
authors.initials: SZ
authors.lastname: Usmani
authors.affiliation: Robert H Lurie Comprehensive Cancer Center, Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Seema
authors.initials: S
authors.lastname: Singhal
authors.affiliation: Tisch Cancer Institute, Mount Sinai School of Medicine, New York, NY, USA.
authors.forename: Ajai
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authors.lastname: Chari
authors.affiliation: Tom Baker Cancer Center, University of Calgary, Calgary, AB, Canada.
authors.forename: Nizar J
authors.initials: NJ
authors.lastname: Bahlis
authors.affiliation: Cross Cancer Institute, Edmonton, AB, Canada.
authors.forename: Andrew
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authors.affiliation: The Judy and Bernard Briskin Myeloma Center, City of Hope, Duarte, CA, USA.
authors.forename: Amrita
authors.initials: A
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authors.affiliation: Cedars-Sinai Outpatient Cancer Center at the Samuel Oschin Comprehensive Cancer Institute, Los Angeles, CA, USA.
authors.forename: Robert A
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authors.affiliation: University Hospital of Salamanca/Instituto de Investigación Biomédica de Salamanca, Salamanca, Spain.
authors.forename: Maria Victoria
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authors.affiliation: Perlmutter Cancer Center, NYU Langone Medical Center, New York, NY, USA.
authors.forename: Amitabha
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authors.affiliation: Department of Lymphoma and Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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authors.lastname: Orlowski
authors.affiliation: Leukemia/Bone Marrow Transplant Program, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Heather J
authors.initials: HJ
authors.lastname: Sutherland
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer, Hospital Clinic de Barcelona, Barcelona, Spain.
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authors.lastname: Bladé
authors.affiliation: Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA.
authors.forename: Emma C
authors.initials: EC
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authors.affiliation: Institut Català d'Oncologia, Institut Josep Carreras, Hospital Germans Trias i Pujol, Barcelona, Spain.
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authors.affiliation: Sarah Cannon Research Institute, Nashville, TN, USA.
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authors.affiliation: Rutgers Cancer Institute of New Jersey, Robert Wood Johnson Medical School, Rutgers, State University of New Jersey, New Brunswick, NJ, USA.
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authors.lastname: Gharibo
authors.affiliation: Norton Health Care, Louisville, KY, USA.
authors.forename: Don A
authors.initials: DA
authors.lastname: Stevens
authors.affiliation: Hôpital Maisonneuve-Rosemont, Montreal, QC, Canada.
authors.forename: Richard
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authors.lastname: LeBlanc
authors.affiliation: Royal Victoria Hospital, Montreal, QC, Canada.
authors.forename: Michael
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authors.lastname: Sebag
authors.affiliation: University of Wisconsin Medical School, Madison, WI, USA.
authors.forename: Natalie
authors.initials: N
authors.lastname: Callander
authors.affiliation: University of Chicago Medicine, Chicago, IL, USA.
authors.forename: Andrzej
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authors.lastname: Jakubowiak
authors.affiliation: Dalhousie University and Queen Elizabeth II Health Sciences Center, Halifax, NS, Canada.
authors.forename: Darrell
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authors.lastname: White
authors.affiliation: Hospital Dr Peset and Universidad Católica San Vicente Mártir, Valencia, Spain.
authors.forename: Javier
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authors.lastname: de la Rubia
authors.affiliation: Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: Paul G
authors.initials: PG
authors.lastname: Richardson
authors.affiliation: Genmab, Copenhagen, Denmark.
authors.forename: Steen
authors.initials: S
authors.lastname: Lisby
authors.affiliation: Janssen Research and Development, Raritan, NJ, USA.
authors.forename: Huaibao
authors.initials: H
authors.lastname: Feng
authors.affiliation: Janssen Research and Development, Spring House, PA, USA.
authors.forename: Clarissa M
authors.initials: CM
authors.lastname: Uhlar
authors.affiliation: Janssen Research and Development, Raritan, NJ, USA.
authors.forename: Imran
authors.initials: I
authors.lastname: Khan
authors.affiliation: Janssen Research and Development, Spring House, PA, USA.
authors.forename: Tahamtan
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authors.lastname: Ahmadi
authors.affiliation: Division of Hematology and Oncology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
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mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002170:Canada; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy*; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D013030:Spain; D016896:Treatment Outcome; D014481:United States
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; C556306:daratumumab