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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 t he 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
TABLE 1.
refractory to the most recent
PI and IMiD
Patients were excluded from the
trial if they had received any antimyeloma 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
Overall Best Responses to Treatment
Stringent complete response
Complete response
Number of patients (%)
95% CI
3 (2.8%)
0.6-8.0
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
46 (43.4%)
33.8-53.4
18 (17%)
10.4-25.5
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
Not evaluable
6 (5.7%)
2.1-11.9
Stable disease
Progressive disease
24
ASH Clinical News
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 1 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 4.750.8)
• 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 nonhematologic 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.
REFERENCE
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.
August 2016