Preclinical Evidence for the Therapeutic Potential of CD38-Targeted Immuno-Chemotherapy in Multiple Myeloma Patients Refractory to Lenalidomide and Bortezomib
Abstract
Purpose: Novel therapeutic agents have significantly improved the survival of patients with multiple myeloma. Nonetheless, the prognosis of patients with multiple myeloma who become refractory to the novel agents lenalidomide and bortezomib is very poor, indicating the urgent need for new therapeutic options for these patients. The human CD38 monoclonal antibody daratumumab is being evaluated as a novel therapy for multiple myeloma. Prompted with the encouraging results of ongoing clinical phase I/II trials, we now addressed the potential value of daratumumab alone or in combination with lenalidomide or bortezomib for the treatment of lenalidomide- and bortezomib-refractory patients. Experimental Design: In ex vivo assays, mainly evaluating antibody-dependent cell-mediated cytotoxicity, and in an in vivo xenograft mouse model, we evaluated daratumumab alone or in combination with lenalidomide or bortezomib as a potential therapy for lenalidomide- and bortezomib-refractory multiple myeloma patients. Results: Daratumumab induced significant lysis of lenalidomide/bortezomib-resistant multiple myeloma cell lines and of primary multiple myeloma cells in the bone marrow mononuclear cells derived from lenalidomide- and/or bortezomib-refractory patients. In these assays, lenalidomide but not bortezomib, synergistically enhanced daratumumab-mediated multiple myeloma lysis through activation of natural killer cells. Finally, in an in vivo xenograft model, only the combination of daratumumab with lenalidomide effectively reduced the tumorigenic growth of primary multiple myeloma cells from a lenalidomide- and bortezomib-refractory patient. Conclusions: Our results provide the first preclinical evidence for the benefit of daratumumab plus lenalidomide combination for lenalidomide- and bortezomib-refractory patients. Clin Cancer Res; 21(12); 2802–10. ©2014 AACR. See related commentary by Laubach and Richardson, p. 2660
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Daratumumab induces cell death through CDC, ADCC, ADCP, and regulation of CD38 enzyme activity.
“Daratumumab is an IgG1 monoclonal antibody that targeting CD38 and induces cell death through complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and regulation of CD38 enzyme activity [157, 158].”
From Multiple myeloma: signaling pathways and targeted therapy (2024) · cites this paper as [157]
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- Authors
- Nijhof, I. S., Groen, R. W. J., Noort, W. A., van Kessel, B., de Jong-Korlaar, R., Bakker, J., van Bueren, J. J. L., Parren, P. W. H. I., Lokhorst, H. M., van de Donk, N. W. C. J., Martens, A. C. M., & Mutis, T.
- Affiliations
- University Medical Center Utrecht (NL)
- 1Department of Clinical Chemistry and Hematology, University Medical Center Utrecht, Utrecht, the Netherlands.
- 3Department of Hematology, VU University Medical Center, Amsterdam, the Netherlands.
- Genmab (Netherlands) (NL)
- 5Genmab, Utrecht, the Netherlands.
- University of Southern Denmark (DK)
- 2Department of Hematology, University Medical Center Utrecht, Utrecht, the Netherlands.
- Corresponding author
- Mutis, Tuna
- Venue
- Clinical Cancer Research
- Published
- 2015-06-14
- Volume
- 21
- Issue
- 12
- Pages
- 2802-2810
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- OpenAlex
- W2010232494
- Cited by
- 151
- References
- 34
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 3 · 2023: 14 · 2022: 12 · 2021: 20 · 2020: 20 · 2019: 16 · 2018: 19 · 2017: 13 · 2016: 16 · 2015: 14
- FWCI
- 10.17
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- University of Southern Denmark Research Portal (University of Southern Denmark) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Topics
- Health Sciences › Medicine › Hematology › Multiple Myeloma Research and Treatments
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Keywords
- multiple myeloma, CD38, daratumumab, lenalidomide, bortezomib, drug resistance, combination therapy, antibody-dependent cellular cytotoxicity, natural killer cells, xenograft models, immunotherapy
- MeSH terms
- Bortezomib, Lenalidomide, Adult, Aged, Animals, Antibody-Dependent Cell Cytotoxicity, Disease Models, Animal, Drug Evaluation, Preclinical, Drug Synergism, Female, Humans, Immunotherapy, Killer Cells, Natural, Lymphocyte Activation, Male, Middle Aged, Multiple Myeloma, Thalidomide, Xenograft Model Antitumor Assays, Cell Line, Tumor, Mice, ADP-ribosyl Cyclase 1, Molecular Targeted Therapy
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