Daratumumab, a fully human IgG1k monoclonal antibody that targets CD38, has demonstrated promising activity as monotherapy in patients with relapsed/refractory multiple myeloma, resulting in the initiation of several phase III clinical trials.
First in-human studies showed that daratumumab was tolerable at doses ranging from 4 to 24 mg/kg with response rates reaching 42% in patients with multiple myeloma who were considered resistant to at least 2 other prior lines of therapy and were ineligible for stem cell transplant. Additionally, daratumumab demonstrated exciting single-agent activity in patients with relapsed or refractory multiple myeloma in results from a phase I extension study presented at the ASCO Annual Meeting.
The phase I extension study evaluated the safety and efficacy of alternate 8-mg/kg and 16-mg/kg dosing schedules of daratumumab for up to 24 months. The dosing levels tested were 8 mg/kg, with or without a 10-mg pre-dose, given weekly for the first 8 infusions. The second dose examined daratumumab at 16 mg/kg without a pre-dose with a 3-week washout between the first 2 doses followed by 7 weekly doses. Following this induction period, patients received daratumumab twice monthly for 16 weeks, followed by monthly dosing until either disease progression or occurrence of toxicity or for a maximum of 24 months. Infusion dilutions of 500 to 1,000 mL were tested to establish safety.
The 30 patients in the 8-mg/kg cohorts received a median of 5 prior lines of therapy compared with 4 lines in the 20 patients in the 16-mg/kg cohort. Sixty percent of patients in the 8-mg/kg group and 38% in the 16-mg/kg group were refractory to both bortezomib and lenalidomide. The median number of full infusions was 10.5 and 11.5 in the 8- and 16-mg/kg daratumumab groups, respectively.
The duration of the first daratumumab infusion was a median of 6.5 to 7.6 hours. Infusion times were a median of 3.4 hours by the third full infusion in each dosing group.
There was no dose-related increase in grade 3/4 adverse events. Forty percent in the 8-mg/kg group and 25% in the 16-mg/kg group experienced a serious adverse event. “Almost all of the adverse events were related to infections, which is not unusual in such a heavily pretreated patient population,” Henk Lokhorst, MD, PhD, Department of Hematology, University Medical Center Utrecht, the Netherlands, said at the ASCO Annual Meeting.
Four patients (13%) had grade 3/4 thrombocytopenia in the 8-mg/kg cohort. Two patients in the 16-mg/kg cohort experienced grade 3/4 lymphopenia. There were 3 serious cases of pneumonia at 8 mg/kg. Only mild (grade 1 and 2) infusion-related reactions (IRRs) were reported, with 50% in the 16-mg/kg group reporting IRRs compared with a range of 17% to 75% in the 8-mg/kg groups.
Dilution of daratumumab to 1,000 mL reduced the number of IRRs. The rates of IRR were 17% and 50% in the 8- and 16-mg/kg groups, respectively, when the first full infusion volume was 1,000 mL.
Using the modified IMWG criteria, the best change in response in paraprotein measured was “better and deeper” in the cohort treated with 16 mg/kg of daratumumab, Lokhorst said during his talk.
“Forty percent of the patients receiving 16 mg had a more than 50% reduction in paraprotein versus only 30% in the 8-mg group,” he said.
The preliminary overall response rate was 35% in the 16-mg/kg cohort, with 2 complete remissions, compared with 10% in the 8-mg/kg cohort. Bone marrow biopsy was performed before treatment, after end of treatment and at end of study. “All patients who achieved a PR or better at 16 mg/kg and who had bone marrow involvement [4 of 4 patients] cleared bone marrow plasma cells after daratumumab treatment,” said Lokhorst.
Estimates for the median progression-free survival (PFS) in the 16-mg/kg group is immature. “The current median PFS in the 16-mg/kg group is 23 weeks, which is also the longest follow-up of any patient in this cohort,” Lokhorst said. The median PFS in the 8-mg/kg group was 14.9 months.
Several phase III studies are exploring daratumumab as a treatment for patients with relapsed or refractory multiple myeloma. One study is exploring the drug with lenalidomide and dexamethasone compared with lenalidomide and dexamethasone alone. This study is currently recruiting patients. Another phase III study, which is not yet recruiting, is looking at daratumumab in combination with bortezomib and dexamethasone.
A third phase III study, not yet recruiting, is exploring daratumumab with bortezomib plus melphalan and prednisone in previously untreated patients with multiple myeloma. This study plans to enroll 700 patients.