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.

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.

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.


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.

TABLE. Infusion-Related Reactions Reported in Two or More Patients
Adverse Event, n (%) 16 mg/kg (N=106), any grade 8 mg/kg (N=18), any grade
Congestion 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