The Human CD38 Monoclonal Antibody Daratumumab Improves the Anti-Myeloma Effect of Lenalidomide with Dexamethasone in Vitro

Abstract 5106

Multiple myeloma (MM) represents an incurable malignancy of antibody-producing clonal plasma cells. Over the past decade significant progress has been made in MM treatment using novel immunomodulating agents such as lenalidomide (LEN) and bortezomib (BORT). Daratumumab (DARA) is a human CD38 antibody with broad spectrum killing activity. DARA mediates MM cell death via ADCC (antibody dependent cellular cytotoxicity), CDC (complement dependent cytotoxicity) and apoptosis. We are currently exploring the possibility to further improve MM therapy by combining novel MM therapeutics with DARA. Our initial in vitro work already showed significantly improved MM cell killing by combining DARA with LEN and BORT treatment, especially in patient samples which showed poor responses to the LEN-BORT combination. We now investigated whether DARA can also further improve therapy of lenalidomide or bortezomib in combination with corticosteroids. In ex vivo assays, which allow us to address MM cell lysis directly in BM-MNC isolated from MM patients, DARA significantly enhanced killing of MM cells that were treated with LEN or dexamethasone (DEX). Importantly, DARA was also able to enhance lysis of MM cells that were poor responders to the LEN-DEX combination. This suggests that patients might benefit from a DARA-LEN-DEX combination therapy. Experiments showing effects of DARA on killing of BORT-DEX treated cells are currently underway. The results of this study extend our previous results with LEN-BORT-DARA, showing that MM cells lysis is enhanced by DARA, especially in in samples from patients that are refractory or poorly responding to existing and novel emerging combination therapies. These results support the hypothesis that powerful and complementary effects may be achieved when DARA is combined with LEN and cortocosteroids in clinical MM studies.