Relapsed/refractory patients

Results from the SIRIUS phase 2 trial assessing daratumumab monotherapy in patients with treatment-refractory MM

In April 2016, the preliminary findings from the ongoing open-label, multi-centre (Canada, Spain and USA) phase 2 trial for daratumumab (SIRIUS) were published in The Lancet. This trial, led by Sagar Lonial from the Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, USA, assessed the efficacy of a novel anti-CD138 targeted antibody as a monotherapy in patients with refractory Multiple Myeloma (MM).


  • Recruited patients had been previously treated with at least three lines of therapy, including proteasome inhibitors and immunomodulatory drugs
  • To establish correct dosing, patients were randomly assigned into two treatment groups, and administered intravenous daratumumab at 8mg/kg (18 patients) or 16mg/kg (16 patients)
  • Following the first interim analysis, a second cohort of 25 additional patients received 16mg/kg for 8 weeks
  • After the second interim analysis, an additional 65 patients were added, to give a total of 106 patients to be included in the final analysis
  • Primary endpoint assessed was overall response rate (ORR) (ORR= partial response (PR) and complete response (CR)

Key Findings

  • Findings are reported for 106 patients that received the 16mg/kg dosing
  • Patients had received a median of 5 previous lines of treatment (range 2-14):
    • 85% (80 patients) had received autologous stem cell transplants
    • 95% (101 patients) were refractory to the most recent proteasome inhibitors and immunomodulatory drugs used
    • 97% (103 patients) were refractory to the last line of therapy
  • ORRs were recorded 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
    • Eighteen (17.0%, 10.4-25.5) had a PR
  • Median time to first response = 1 month
  • Median duration of response = 7.4 months (95% CI 5.5-not estimable)
  • Median PFS = 3.7 months (95% CI 2.8-4.6).
  • The 12-month OS = 64.8% (95% CI 51.2-75.5)
  • At a subsequent cut-off, median OS = 17.5 months (95% CI 13.7-not estimable). 
  • Most common AE’s (all grades) were fatigue (42 patients, 40%) and anemia (35 patients, 35%) and therefore highly manageable
  • No patient discontinued due to AE’s


Daratumumab gave an ORR of 29% and was well tolerated at 16 mg/kg with a durable response. It therefore shows promise as a monotherapy in patients who are resistant to proteasome inhibitors and immunomodulatory drugs. Further studies to assess tolerability and efficacy in combination with other drug regimens are ongoing, and patients with early stage MM (at the time of going to press) were being recruited to phase 3 trials. Daratumumab was the first monoclonal antibody approved for treatment of MM and is currently approved for therapy, in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of treatment of patients with MM who have received at least one prior therapy.



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.


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, number NCT01985126.


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.


Daratumumab monotherapy showed encouraging efficacy in heavily pretreated and refractory patients with multiple myeloma, with a favourable safety profile in this population of patients.


Janssen Research & Development.

  1. Lonial S. et al. Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): an open-label, randomised, phase 2 trial. Lancet. 2016 Apr 9;387(10027):1551-60. DIO: 10.1016/S0140-6736(15)01120-4. Epub 2016 Jan 7.