The SIRIUS phase II trial: daratumumab monotherapy in patients with treatment-refractory MM

In April 2016, the preliminary findings from the ongoing open-label, multi-center (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).

Treatment

• 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, the 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
• The 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

Conclusion

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.