Improved Myeloma Targeting by Combination of the Human Anti-CD38 Antibody Daratumumab with Lenalidomide and Bortezomib

Abstract 3030

Although multiple myeloma (MM) is considered an incurable malignancy of antibody-producing clonal plasma cells, over the past decade significant progress has been made in MM treatment by the availability of novel immunomodulating agents such as lenalidomide (LEN) and bortezomib (BORT). We are currently exploring the possibility to further improve MM therapy by combining LEN and BORT with novel agents, such as daratumumab (DARA), a human antibody directed against CD38 which mediates MM cell lysis via ADCC (antibody dependent cellular cytotoxicity), CDC (complement dependent cytotoxicity) and apoptosis. Our initial in vitro work show significantly improved MM cell killing by combined DARA with LEN treatment. We now investigated whether further improvement of this combination therapy is possible by addition of BORT. In ex vivo assays, which allow us to address killing directly in BM-MNC isolated from MM patients, we demonstrate that the DARA+LEN+BORT combination significantly exceeds the effectiveness of LEN+BORT treatment (P<0.001). Remarkably, triple therapy was also very effective, even when there was little or no response against LEN+BORT (P=0.0001). In other assays we further mimicked the in vivo conditions by incubating BM-MNC not only with LEN, BORT and DARA for 48 hours but also by adding complement. Addition of complement resulted in substantial enhancement of DARA-mediated MM tumor cell killing. This killing could not be further improved by addition of LEN and BORT. In conclusion, we demonstrate that addition of DARA to a LEN+BORT treatment regime increases overall clearance of MM cells ex vivo, suggesting that patients, even when not responding to LEN+BORT treatment, might benefit from a DARA+LEN+BORT combination therapy.