Management of Infusion-Related Reactions Following Daratumumab Monotherapy in Patients with at Least 3 Lines of Prior Therapy or Double Refractory Multiple Myeloma (MM): 54767414MMY2002 (Sirius)

Introduction: Daratumumab (DARA), a human anti-CD38 IgG1κ monoclonal antibody, showed single agent activity in a phase 1/2 study of patients (pts) with relapsed or refractory (r/r) MM (Lokhorst HM. J Clin Oncol. 2014; 32(suppl): 8513). In this study infusion-related reactions (IRRs) were generally mild. The occurrence of serious adverse events (AEs) was rare with DARA monotherapy. Similar efficacy and safety findings were reported in a preliminary analysis of an ongoing phase 2 study (NCT01985126) of DARA monotherapy in MM pts who had received ≥3 prior lines of therapy, including a PI and IMiD, or were double refractory to a PI and IMiD (Lonial S. J Clin Oncol. 2015; 33(suppl): LBA8512). This analysis examined IRR incidence and management in this phase 2 study in r/r MM.

Methods: This open-label, 2-part, international, multicenter, phase 2 study was conducted to determine the optimal DARA dose and schedule. Thirty-four pts were randomized in part 1 to DARA 8 mg/kg q4w or DARA 16 mg/kg qw for 8 weeks, then q2w for 16 weeks, and q4w thereafter. An additional 25 pts were subsequently enrolled in part 1 into the 16-mg/kg cohort based on a pre-specified interim analysis. An additional 65 pts were then enrolled in the 16-mg/kg DARA group in part 2. IRRs were broadly defined to include investigator-reported events such as cough, hypersensitivity reactions, and cytokine release syndrome. To manage IRRs, pts received pre-infusion medication: methylprednisolone 100 mg (or equivalent) intravenously for the first 2 infusions and 60 mg thereafter; paracetamol (acetaminophen) 650-1000 mg orally; and diphenhydramine 25-50 mg (or equivalent). Corticosteroid post-infusion medication (20 mg methylprednisone or equivalent) was given on the 2 days following DARA infusions to prevent delayed IRRs. DARA infusion was initiated in 1,000 mL at 50 mL/hr. In the absence of IRRs/hypersensitivity, the rate increased hourly at 50-mL/hr intervals to 200 mL/hr. Second and subsequent infusions (in 500 mL) began at 50 and 100 mL/hr, respectively, and escalated to 200 mL/hr. Upon onset of IRRs, infusions were temporarily interrupted or slowed.

Results: Data from the DARA 16 mg/kg (n = 106) and 8 mg/kg (n = 18) treatment groups are presented. All pts received pre-infusion medication as prescribed, consisting of analgesics (100%), antihistamines (100%), and corticosteroids (100%). All pts received post-infusion corticosteroids except 3 pts in the 16 mg/kg group. IRRs occurred in 43% and 44% of pts in the 16 mg/kg and 8 mg/kg groups, respectively. Among pts receiving 16 mg/kg (8 mg/kg), 87% (82%) of IRRs were during the first infusion; 4% (19%) and 9% (0%) of IRRs occurred during the second and all subsequent infusions, respectively. The median (range) time to onset for IRRs was 90 (1-514) minutes after the start of infusion, and the median duration of infusion was 7.0 (2-24), 4.2 (2-9), and 3.4 (1-7) hours during the first, second, and all subsequent infusions, respectively. The most frequently reported IRRs appear in Table 1. Most IRRs were grade 1 or 2. Few pts reported grade 3 IRRs, which included bronchospasm (n = 2 at 16 mg/kg), and hypertension, anemia, and dyspnea (n = 1 each at 16 mg/kg), and chills and cytokine release syndrome (both in 1 pt at 8 mg/kg), and hypertension (n = 1 at 8 mg/kg). Infusion rates were decreased for 10% and 17% of pts in the 16 mg/kg and 8 mg/kg groups, respectively. Grade 4 IRRs were not reported, and no IRRs led to treatment discontinuation. Three pts were unable to finish an infusion due to an IRR but received subsequent DARA infusions; the remaining pts who experienced an IRR continued full-dose therapy with supportive treatment. Cytokine changes (IL-6, TNFα, IFNγ, and IL-1β) from baseline to 4 hours after the first DARA infusion were variable, but did not correlate with clinical response or IRRs.

Conclusions: DARA-related IRRs were manageable with temporary slowing or stopping of infusion. No pt discontinued treatment due to an IRR. 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. These results highlight the favorable safety profile of DARA in r/r MM pts.

Table 1. IRRs Reported in >2 Pts

	16 mg/kg	8 mg/kg
Adverse Event, n (%)	Any Grade	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