An Ex Vivo 3D Co-Culture Model of the Bone Marrow Niche Better Predicts Clinically Relevant Epigenetic Target Modulation to Improve Immunotherapy in Multiple Myeloma

Background: In the last decade, treatment options for multiple myeloma have increased remarkably, including antibodies or CAR-T cells targeting myeloma surface markers with unprecedented efficacy. To enhance immunomodulation and clinical efficacy even more, the combination of these agents with other drugs is highly relevant. A significant association between CD38 expression on myeloma cells and the cytotoxicity of the anti-CD38 antibody daratumumab has been shown. All-trans retinoic acid, the pan-histone deacetylase inhibitor panobinostat, and the enhancer of the zeste homolog 2 inhibitor tazemetostat induce CD38 upregulation and can augment the anti-myeloma effect of daratumumab in conventional cell culture. However, translation into a clinical trial failed. Methods: To better predict in vivo drug effects preclinically, we used an ex vivo 3D model, allowing long-term propagation of myeloma cell lines and primary cells from 12 patients in co-culture with human stromal cells in a milieu that more closely resembles the physiological conditions in the bone marrow niche. Results: While epigenetic CD38 upregulation with different drugs leading to enhanced daratumumab efficacy was reproducible in conventional 2D culture, this effect was not confirmed in the optimized 3D model. Here, the epigenetic modification of CD38 expression and the impact on the cytotoxic effect of daratumumab seem to depend on the individual plasma cell and its interaction with the bone marrow microenvironment, which could be a plausible explanation for the lack of clinical efficacy of this combination treatment. Conclusions: Epigenetically induced CD38 upregulation to enhance the effect of anti-CD38 antibodies does not appear to be clinically relevant when using an optimized preclinical model.