The anti-CD38 monoclonal antibody daratumumab has demonstrated a “favorable safety profile” and “encouraging efficacy” in patients with relapsed/refractory multiple myeloma (MM), according to researchers.
Results of a phase 1/2 study suggested the drug was most effective at a dose of 16 mg/kg. At this dose, the overall response rate was 36%.
Most adverse events (AEs) were grade 1 or 2, although serious AEs did occur.
“As a single-agent therapy, daratumumab showed significant promise against difficult-to-treat disease in our patients with advanced myeloma who have few other therapeutic options,” said Paul G. Richardson, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts.
“Because it targets a key receptor and works through different mechanisms than other available agents, it clearly has merited comprehensive testing in larger clinical trials. Preliminary results from these studies have been very encouraging.”
Dr Richardson and his colleagues reported results of the phase 1/2 study in NEJM. The research was previously presented at the 18th Congress of the EHA in 2013. It was sponsored by Janssen Research and Development and Genmab.
Another phase 2 study of single-agent daratumumab in MM was recently presented at the 2015 ASCO Annual Meeting.
Patients and treatment
The current study enrolled patients with relapsed MM or relapsed MM that was refractory to 2 or more prior lines of therapy. The study consisted of 2 parts.
In part 1 (n=30), researchers administered daratumumab in 10 different dosing cohorts at doses ranging from 0.005 to 24 mg/kg of body weight.
In part 2 (n=72), patients received 2 different doses of daratumumab on varying schedules. In schedules A (n=16), B (n=8), and C (n=6), patients received daratumumab at 8 mg/kg in 8 once-weekly infusions and then in twice-monthly infusions for 16 weeks.
In schedules D (n=20) and E (n=22), patients received daratumumab at 16 mg/kg, and, after the first infusion, they had a 3-week washout period to allow for the collection of pharmacokinetic data. They then received weekly treatment for 7 weeks, followed by twice-monthly treatment for 14 weeks.
Safety
There was no maximum tolerated dose identified in part 1 of the study. Infusion-related AEs occurred in 20 patients (63%), serious AEs occurred in 12 patients (37%), and AEs leading to treatment discontinuation occurred in 5 patients (16%).
In part 2, 71% of patients had infusion-related AEs. The most common AEs among patients in both dosing cohorts (8 mg/kg and 16 mg/kg) were fatigue (42%), allergic rhinitis (31%), pyrexia (28%), diarrhea (21%), upper respiratory tract infection (21%), and dyspnea (19%). The most frequent hematologic AE was neutropenia (12%).
Grade 3/4 AEs occurred in 53% of patients in the 8 mg/kg cohort and 26% in the 16 mg/kg cohort. Grade 3/4 AEs that were reported in 2 or more patients included pneumonia (n=5), thrombocytopenia (n=4), neutropenia (n=2), leukopenia (n=2), anemia (n=2), and hyperglycemia (n=2).
Serious AEs occurred in 40% of patients in the 8 mg/kg cohort and 33% in the 16 mg/kg cohort. The most frequent serious AEs were infection-related events.
Efficacy
In part 1, there were no responses among patients who received daratumumab at 2 mg/kg or less (n=18), but responses did occur in patients treated at doses of 4 mg/kg or higher (n=12).
There were 4 partial responses—1 in the 4 mg/kg group, 1 in the 16 mg/kg group, and 2 in the 24 mg/kg group. And there were 3 minimal responses—2 in the 4 mg/kg group and 1 in the 8 mg/kg group.
Three patients had stable disease—1 each in the 8 mg/kg, 16 mg/kg, and 24 mg/kg groups. One patient progressed (16 mg/kg), and 1 was not evaluable (8 mg/kg).
In part 2, the overall response rate was 10% in the 8 mg/kg cohort (3/30) and 36% (15/42) in the 16 mg/kg cohort.
There were 2 complete responses (16 mg/kg), 2 very good partial responses (16 mg/kg), 14 partial responses (3 in the 8 mg/kg cohort and 11 in the 16 mg/kg), and 10 minimal responses (6 in the 8 mg/kg cohort and 4 in the 16 mg/kg cohort).
Thirty-six patients had stable disease (14 in the 8 mg/kg cohort and 22 in the 16 mg/kg cohort). Six patients progressed (all in the 8 mg/kg cohort), and 2 patients were not evaluable (1 in each cohort).
The estimated median progression-free survival was 2.4 months in the 8 mg/kg cohort and 5.6 months in the 16 mg/kg cohort. The overall survival rate at 12 months was 77% in both cohorts.
