SIRIUS: Examining the Safety and Efficacy of Daratumumab in Heavily Pretreated Multiple Myeloma Patients

The anti-CD38 monoclonal antibody daratumumab led to an overall response rate (ORR) of 29 percent in patients with multiple myeloma (MM) who were refractory to treatment with proteasome inhibitors (PI) and immunomodulatory drugs (IMiD), according to a report from the SIRIUS trial published in The Lancet.

The SIRIUS trial, led by Sagar Lonial, MD, from the Winship Cancer Institute at Emory University in Atlanta, Georgia, is a two-part, open-label, multi-center, phase II study examining daratumumab in a heavily pretreated population of MM patients. All patients met the following inclusion criteria:

  • evidence of disease progression on or within 60 days of the last dose of the most recent previous MM treatment regimen
  • responded to at least one previous treatment regimen
  • received an alkylating agent alone or in combination with another MM treatment
  • received at least three previous lines of treatment (including a PI and an IMiD)
  • disease that was double refractory to the most recent PI and IMiD

Patients were excluded from the trial if they had received any anti-myeloma treatment within two weeks or autologous hematopoietic cell transplantation (AHCT) within 12 weeks of starting daratumumab.

The study, which included a dose-finding stage, is ongoing, and reports data from 106 patients who received intravenous daratumumab 16 mg/kg per week for eight weeks (cycles 1 and 2), then every two weeks for 16 weeks (cycles 3-6), and then every four weeks thereafter (cycle 7 and higher).

Eighty-five patients (80%) had undergone AHCT prior to treatment, and all patients received a median of five prior therapies (range = 2-14), including:

  • bortezomib (n=105; 99%)
  • carfilzomib (n=53; 50%)
  • lenalidomide (n=105; 99%)
  • pomalidomide (n=67; 63%)
  • thalidomide (n=47; 44%)

All patients were previously treated with dexamethasone, and most (n=87; 82%) received more than three prior lines of therapy and were “highly refractory,” according to the authors, with 97 percent (n=103) refractory to the last line of therapy prior to the study and 95 percent (n=101) refractory to the most recent PI and IMiD.

The median number of treatment cycles administered was four (range = 1-16 cycles), and 38 percent of patients (n=40) received six or more cycles of 16 mg/kg of daratumumab.

Over a median follow-up of 9.3 months (range = 0.5-14.4 months), 31 patients responded to daratumumab treatment, for an ORR of 29.2% (95% CI 20.8-38.9), including three patients with a stringent complete response (CR). See TABLE for details about patients’ responses.

The median time to first response to treatment was one month (range = 0.9-5.6 months), and responses improved over time in 25.8 percent of patients (n=8).

The median progression-free survival was 3.7 months (95% CI 2.8-4.6), while the median overall survival (OS) was not reached (95% CI 13.7 – not estimable). The 12-month OS was 64.8 percent (95% CI 8.6 – not estimable). Follow-up for more complete OS data is ongoing.

“Resistance to any previous therapy had no effect on the activity of daratumumab,” Dr. Lonial and colleagues wrote. Overall responses were noted in 29.7 percent of patients (n=30/101; 95% CI 21-39.6) who were refractory to both PIs and IMiDs, and in 26.8 percent of patients (n=20/70; 95% CI 18.4-40.6) who were refractory to at least three of the following agents: bortezomib, lenalidomide, carfilzomib, and pomalidomide.

Similar response rates were noted in patients:

  • with moderate renal impairment (n=11/42; 26.2%; 95% CI 13.9-42)
  • older than 75 years (n=4/12; 33.3%; 95% CI 9.9-65.1)
  • with extramedullary disease (n=3/14; 21.4%; 95% CI 4.7-50.8)
  • with high-risk baseline cytogenetic characteristics (n=4/20; 20%; 95% CI 5.7-43.7)

Among those treated with 16 mg/kg of daratumumab, the most common hematologic any-grade adverse events (AEs) included anemia (n=35; 33%), thrombocytopenia (n=27; 25%), and neutropenia (n=24; 23%). Grade ≥3 anemia (n=24; 32%) and thrombocytopenia (n=18; 24%) occurred more frequently in the 75 non-responders compared with the 31 patients who did respond (3% and 6%, respectively).

The most common non-hematologic AEs included fatigue (n=42; 40%) and nausea (n=31; 29%). Serious AEs occurred in 30 percent of patients (n=32), of whom 23 percent (n=24) had grade 3 or 4 serious AEs. Five patients discontinued daratumumab treatment due to AEs.

Twenty-nine percent (n=31) of patients treated with 16 mg/kg of daratumumab died during the study: 27 percent (n=29) of these deaths were related to progressive disease and 2 percent (n=2) were due to AEs. More responders than non-responders were alive at the time of analysis (94% [n=29/31] and 60% [n=45/75]).

“Based on deep and durable responses and a favorable safety profile, daratumumab 16 mg/kg seems suitable for [the] treatment of patients with MM,” the authors concluded. However, the study’s results are limited by the lack of a comparator arm, open label design, and relatively modest follow-up.


Lonial S, Weiss BM, Usmani SZ, et al. Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): an open-label, randomized, phase 2 trial. Lancet. 2016;387:1551-60.

TABLE. Overall Best Responses to Treatment  
  Number of patients (%) 95% CI
Stringent complete response 3 (2.8%) 0.6-8.0
Complete response 0 N/A
Very good partial response (VGPR) 10 (9.4%) 4.6-16.7
Partial response 18 (17%) 10.4-25.5
Minimal response 5 (4.7%) 1.5-10.7
Stable disease 46 (43.4%) 33.8-53.4
Progressive disease 18 (17%) 10.4-25.5
Not evaluable 6 (5.7%) 2.1-11.9
Overall response rate 31 (29.2%) 20.8-38.9
Clinical benefit rate 36 (34%) 25-43.8
VGPR or better 13 (12.3%) 6.7-20.1