In a phase I/II trial reported in The New England Journal of Medicine, Lokhorst et al found that the CD38-targeting human IgG1κ monoclonal antibody daratumumab had an acceptable safety profile and produced durable responses in relapsed multiple myeloma.
In the dose-escalation phase, 32 patients received daratumumab at doses of 0.005 to 24 mg/kg via intravenous infusion. In the dose-expansion phase, 30 patients received daratumumab 8 mg/kg and 42 received 16 mg/kg once weekly for eight doses, twice monthly for eight doses, and monthly for up to 24 months.
Patients in the dose-expansion phase had a median time from diagnosis of 5.7 years and had received a median of four prior treatments; 76% had received autologous stem cell transplantation, and 79% had disease refractory to the last therapy received, including 64% refractory to proteasome inhibitors and immunomodulatory agents and 64% refractory to bortezomib (Velcade) and lenalidomide (Revlimid).
No maximum tolerated dose was identified in the dose-escalation phase. In the dose-expansion phase, no dose-dependent adverse events were observed. Infusion-related reactions of any grade occurred in 71% of patients in the two dose cohorts, with a grade 3 reaction observed in 1%. No patient discontinued treatment due to infusion-related reactions. The majority of reactions occurred during the first infusion (67% of patients in the 8-mg/kg cohort and 71% in the 16-mg/kg cohort).
The most common adverse events of any grade other than infusion-related reactions were fatigue (42%), allergic rhinitis (31%), and pyrexia (28%). Grade 3 or 4 adverse events were reported in 53% of patients in the 8-mg/kg cohort and 26% of those in the 16-mg/kg cohort, with the most common overall being pneumonia (7%) and thrombocytopenia (6%).
Overall response rates were 10% in the 8-mg/kg cohort (all partial responses) and 36% in the 16-mg/kg cohort (including two complete responses). In patients in the higher-dose cohort with response, median time to response was 0.9 months, and time to best response was 1.8 months. Median duration of response was 6.9 months in the lower-dose cohort and not reached in the higher-dose cohort, with 65% of responders in this cohort being progression-free at 12 months. Median progression-free survival in this cohort was 5.6 months.
The investigators concluded: “Daratumumab monotherapy had a favorable safety profile and encouraging efficacy in patients with heavily pretreated and refractory myeloma.”
Henk M. Lokhorst, MD, PhD, of VU University Medical Center, Amsterdam, the Netherlands, is the corresponding author of The New England Journal of Medicine article.
The study was funded by Janssen Research and Development and Genmab. For full disclosures of the study authors, visit www.nejm.org.
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