MEETING NEWS
Safety Profile of Daratumumab in Relapsed/Refractory
Multiple Myeloma Patients
For relapsed/refractory multiple myeloma (MM) patients
treated with the anti-CD38 monoclonal antibody daratumumab, as with other monoclonal antibody therapies,
management of infusion-related reactions (IRRs) requires
temporary slowing or stopping of infusion.
Peter M. Voorhees, MD, from the Division of Hematology/Oncology at Lineberger Comprehensive Cancer Center at the University of
North Carolina in Chapel Hill, North Carolina, examined IRR incidence and management in the open-label, international, multicenter
phase II SIRIUS study at the 2015 ASH Meeting on Hematologic
Malignancies.
In an earlier phase
I/II study, daratumumab demonstrated
single-agent activity
in relapsed/refractory MM patients, in
which infusion-related
reactions were generally
rare. Similar safety and
efficacy findings were
reported in the phase II
SIRIUS study.
To determine the optimal dose and schedule of daratumumab,
part 1 of the SIRIUS trial randomized 34 patients to daratumumab 8
mg/kg every four weeks or daratumumab 16 mg/kg for eight weeks,
then every two weeks for 16 weeks. An additional 25 patients were
then enrolled in part 1 into the 16 mg/kg cohort. In part II, another
65 patients were enrolled in the 16 mg/kg group.
The analysis included data from 106 patients in the 16 mg/kg
group and 18 patients from the 8 mg/kg group. All patients were
treated with the pre-infusion medications as prescribed; all but
three of the patients in the 16 mg/kg group received post-infusion
medications. All patients had received three or more prior lines of
therapy, including a proteasome inhibitor and an immunomodulatory agent, or were double-refractory to both a proteasome inhibitor
and an immunomodulatory agent.
IRRs were defined as investigator-reported events such as cough,
hypersensitivity reactions, and cytokine release syndrome. To
manage IRRs, patients received pre-infusion medications, including methylprednisone, acetaminophen, and diphenhydramine.
Corticosteroid post-infusion medication (20 mg methylprednisone
or equivalent) was given on the two days following daratumumab
infusions to prevent delayed IRRs.
Daratumumab was initiated in 1,000 mL at 50 mL/hour. If the
patient experience no IRR or hypersensitivity, the rate increased to
200 mL/hour at 50/mL per hour intervals. Second and subsequent
infusions began at 50 mL/hour and 100 mL/hour, respectively, and
escalated to 200 mL/hour.
If IRRs occurred, infusions were temporarily interrupted or slowed.
IRRs with
daratumumab
were predominantly of grade
1 or 2 severity.
Rates of IRRs were similar between the 16 mg/kg and 8 mg/
kg groups: 43 percent and 44 percent, respectively. In terms of the
timing of IRRs:
• 87 percent and 82 percent of IRRs occurred during the first
infusion in the 16 mg/kg and 8 mg/kg groups, respectively
• 4 percent and 19 percent occurred during the second infusion
• 9 percent and 0 percent occurred during all subsequent
infusions
Median time to onset of IRR was 90 minutes (range = 1-514
minutes) after the start of infusion, and the median duration of infusion was 7.0 hours (range = 2-24 hours), 4.2 hours (range = 2-9
hours), and 3.4 hours (range = 1-7 hours) during the first, second,
and all subsequent infusions, respectively.
“IRRs were most likely to occur during the first or second
infusion, were predominantly of grade 1 or 2 severity, and did not
recur at a higher grade with subsequent infusions,” Dr. Voorhees
and co-authors observed. The most frequently reported IRRs are
listed in the TABLE.
TABLE. Infusion-Related Reactions Reported in Two or More
Patients
Adverse Event, n (%)
Congestion
16 mg/kg (N=106),
any grade
8 mg/kg (N=18),
any grade
13 (12.3)
1 (5.6)
Chills
6 (5.7)
5 (27.8)
Cough
6 (5.7)
3 (16.7)
Throat irritation
7 (6.6)
0
Dyspnea
6 (5.7)
1 (5.6)
Vomiting
6 (5.7)
1 (5.6)
Nausea
5 (4.7)
0
Bronchospasm
4 (3.8)
0
Infusion rates were decreased for 10 percent and 17 percent of
patients in the 16 mg/kg and 8 mg/kg groups, respectively.
Three patients were unable to finish an infusion due to an IRR
but went on to receive subsequent daratumumab infusions. The
remaining patients who experienced an IRR continued full-dose
therapy with supportive treatment. No patient discontinued treatment due to an IRR.
Reference
Voorhees PM, Weiss B, Usmani S, et al. Management of infusion-related reactions
following daratumumab monotherapy in patients with ≥3 lines of prior therapy or double
refractory multiple myeloma (MM): 54767414MMY2002 (Sirius). Abstract #60. Presented
at the 2015 ASH Meeting on Hematologic Malignancies; September 19, 2015; Chicago, IL.
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