Upregulation of CD38 expression on multiple myeloma cells by novel HDAC6 inhibitors is a class effect and augments the efficacy of daratumumab

Multiple myeloma (MM) is incurable, so there is a significant unmet need for effective therapy for patients with relapsed or refractory disease. This situation has not changed despite the recent approval of the anti-CD38 antibody daratumumab, one of the most potent agents in MM treatment. The efficiency of daratumumab might be improved by combining it with synergistic anti-MM agents. We therefore investigated the potential of the histone deacetylase (HDAC) inhibitor ricolinostat to up-regulate CD38 on MM cells, thereby enhancing the performance of CD38-specific therapies. Using quantitative reverse transcription polymerase chain reaction and flow cytometry, we observed that ricolinostat significantly increases CD38 RNA levels and CD38 surface expression on MM cells. Super-resolution microscopy imaging of MM cells by direct stochastic optical reconstruction microscopy confirmed this rise with molecular resolution and revealed homogeneous distribution of CD38 molecules on the cell membrane. Particularly important is that combining ricolinostat with daratumumab induced enhanced lysis of MM cells. We also evaluated next-generation HDAC6 inhibitors (ACY-241, WT-161) and observed similar increase of CD38 levels suggesting that the upregulation of CD38 expression on MM cells by HDAC6 inhibitors is a class effect. This proof-of-concept illustrates the potential benefit of combining HDAC6 inhibitors and CD38-directed immunotherapy for MM treatment.This work was supported by the project “Center for Personalized Molecular Immunotherapy” funded within the EFRE-program of the European Union (Europäischer Fond für regionale Entwicklung); a grant from the German Ministry for Science and Education (BMBF, Bundesministerium für Bildung und Forschung, Grant # 13N14414). EG-G was supported by Instituto de Salud Carlos III (PFIS—FI12/00189). S Danhof was supported by the IZKF Würzburg (Interdisziplinäres Zentrum für Klinische Forschung), the MSNZ Würzburg (Mildred-Scheel-Nachwuchszentrum), and was a fellow of the Clinician Scientist Program of the Else-Kröner Forschungskolleg. MH was supported by Young Scholar Program of the Bavarian Academy of Sciences (Junges Kolleg, Bayerische Akademie der Wissenschaften)