For relapsed/refractory multiple myeloma (MM) patients treated with the anti-CD38 monoclonal antibody daratumumab, management of infusion-related reactions (IRRs) required temporary slowing or stopping of infusion, suggesting that the drug has a favorable safety profile in this patient population.
The results were presented at the 2015 ASH Meeting on Hematologic Malignancies by 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.
In an earlier phase 1/2 study, daratumumab demonstrated single-agent activity in relapsed/refractory MM patients and mild and serious infusion-related reactions were generally rare. Similar safety and efficacy findings were reported in the phase 2 SIRIUS study. In the current analysis, Dr. Voorhees and co-authors examined IRR incidence and management in the open-label, international, multicenter phase 2 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 2, another 65 patients were enrolled into the 16 mg/kg group.
The current analysis included data from 106 patients in the 16 mg/kg group and 18 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 medication, 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.
In the case of IRR, 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)|