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.
- 1Department of Hematology, Oncology and Stem Cell Transplantation, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.
- 2Clinic for Hematology and Medical Oncology, University Medical Center Goettingen, 37075 Goettingen, Germany.
Abstract
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.
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BibTeX
@article{greil2026vivo,
title = {{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.}},
author = {Christine Greil and Johannes Jung and Julia Felthaus and Dagmar Wider and Monika Engelhardt and Ralph Wäsch},
journal = {Cancers},
year = {2026},
month = sep,
doi = {10.3390/cancers18193093},
url = {https://europepmc.org/article/MED/42882787},
note = {CC BY},
}
RIS
TY - JOUR
TI - 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.
AU - Christine Greil
AU - Johannes Jung
AU - Julia Felthaus
AU - Dagmar Wider
AU - Monika Engelhardt
AU - Ralph Wäsch
PY - 2026
DA - 2026/09/23
JO - Cancers
DO - 10.3390/cancers18193093
UR - https://europepmc.org/article/MED/42882787
AB - 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.
SN - 2072-6694
ER -