Daratumumab (Genmab) is a human IgG1 CD38 monoclonal antibody developed for the treatment of multiple myeloma.
In pre-clinical studies, daratumumab induced multiple myeloma cell death through complement mediated and antibody dependent cellular cytotoxicity (DeWeers M. J Immunol. 2011;186:1840-1848). This prompted an international phase 1/2 study in patients with relapsed and refractory multiple myeloma with no established therapeutic options remaining.
The phase 1 portion of the daratumumab study was presented at the ASH Annual Meeting and Exposition in 2012 (Plesner T. Blood. 2012;120:Abstract 73). Once-weekly doses up to 24 mg/kg were tolerated, and this was the maximum planned dose. Prednisolone or methylprednisolone was permitted up to a dose equivalent of 27 mg of dexamethasone per week to prevent infusion-related events.
Significant adverse events reported included one patient with grade 3 anemia and grade 4 thrombocytopenia at a dose level of 0.1 mg/kg. Two patients experienced bronchospasm at the 2 mg/kg and 24 mg/kg dose level. Grade 3 AST elevation occurred in one patient at 1 mg/kg dose level. Cytokine release syndrome grade 2 was reported in one patient at 0.1 mg/kg dose level. Infusion-related events were minimized with utilization of corticosteroid premedication at dose levels at or above 4 mg/kg. Based on the data from 32 patients presented, daratumumab seemed to be well tolerated.
The most interesting finding in this study was that daratumumab exhibited significant single-agent activity in relapsed and refractory multiple myeloma patients. This has not been demonstrated with other monoclonal antibody therapies in development for multiple myeloma treatment. At doses greater than or equal to 4 mg/kg, eight of 12 patients had minor response or better. By IMWG criteria, four patients (13%) achieved partial response or better.
Daratumumab combination therapy trials are moving forward. Relapsed and refractory multiple myeloma studies with lenalidomide (Revlimid, Celgene), dexamethasone and daratumumab — as well as bortezomib (Velcade, Millennium Pharmaceuticals), dexamethasone and daratumumab — are in early stages of recruitment. In addition, the CD38 target provides potential therapeutic options in other hematologic malignancies.
Notably, the FDA on May 1 granted daratumumab a breakthrough therapy designation. This will guide and speed the process of approval for use in multiple myeloma.
Jason Valent, MD
Associate staff physician
Department of Hematologic Oncology and Blood Disorders
Cleveland Clinic Taussig Cancer Institute
Disclosures: Valent reports no relevant financial disclosures.