Loss of GPRC5D enhances the proliferative capacity and competitive fitness of myeloma upon anti-GPRC5D immunotherapy
Immunotherapies targeting surface antigens have transformed the treatment landscape of multiple myeloma (MM), with GPRC5D emerging as a promising therapeutic target. Monoallelic loss of GPRC5D is frequently observed in newly diagnosed MM patients, and the incidence of acquired GPRC5D alterations increases following exposure to GPRC5D-directed therapies. However, the functional consequences of both baseline monoallelic and therapy-induced biallelic GPRC5D alterations remain poorly understood. In this study, we modeled monoallelic versus biallelic loss of GPRC5D to investigate their impact on MM cell biology and responsiveness to GPRC5D-targeted immunotherapies. Our results demonstrate that monoallelic GPRC5D loss in OPM-2 cells reduces surface expression of the antigen and confers resistance to GPRC5D-directed therapies. Complete loss of GPRC5D alters the transcriptional state of MM cells and promotes reprogramming of the phosphoproteomic circuitry ultimately resulting in a pro-proliferative chemokine environment. As a result, GPRC5D deficiency increases the basal proliferation rate of MM cells thereby providing a competitive advantage which may further be amplified by selecting these aggressive phenotypes during ongoing treatment with anti-GPRC5D immunotherapies.
Authors
- Alexander M. Leipold (ORCID: https://orcid.org/0000-0002-9471-3276)
- Marietta Truger (ORCID: https://orcid.org/0000-0002-2286-0656)
- Thomas Nerreter (ORCID: https://orcid.org/0000-0002-0493-1369)
- Max Köppel
- Umair Munawar (ORCID: https://orcid.org/0000-0001-9710-9923)
- Johanna Lehmann (ORCID: https://orcid.org/0000-0001-9010-5794)
- Leo Rasche (ORCID: https://orcid.org/0000-0002-9536-9649)
- Christina Verbruggen (ORCID: https://orcid.org/0009-0004-4162-2188)
- Silvia Nerreter (ORCID: https://orcid.org/0000-0001-5252-1519)
- Bernhard Küster (ORCID: https://orcid.org/0000-0002-9094-1677)
- Julia Weingart (ORCID: https://orcid.org/0000-0001-9302-6047)
- Patrick Eiring
- Nazia Afrin
- Seungbin Han (ORCID: https://orcid.org/0000-0003-1117-3102)
- Cornelia Vogt (ORCID: https://orcid.org/0000-0002-7749-4227)
- Sabine Roth (ORCID: https://orcid.org/0000-0002-4288-4751)
- Antoine‐Emmanuel Saliba (ORCID: https://orcid.org/0000-0001-8539-2784)
- Johannes M. Waldschmidt (ORCID: https://orcid.org/0000-0001-5340-1818)
- Shilpa Kurian
- Björn Grams
- Emma Besant
- Nina Rein
- A. Rosenwald
- T Steinbrunn
- Xiang Zhou
- Hermann Einsele
- Markus Sauer
- Claudia Haferlach
- Elena Gerhard-Hartmann
- Yoko Tamamushi
- Johanna Thurner
- Michael Hudecek
- K. Martin Kortüm
Institutions
- Harvard University (US)
- University of Würzburg (DE)
- Munich Leukemia Laboratory (Germany) (DE)
- Dana-Farber Cancer Institute (US)
- Helmholtz Centre for Infection Research (DE)
- Helmholtz Institute for RNA-based Infection Research (DE)
- Universitätsklinikum Würzburg (DE)
- Technical University of Munich (DE)
Publication Details
- Journal
- Leukemia
- Published
- 2026-03-31
- DOI
- https://doi.org/10.1038/s41375-026-02920-7
- Primary Topic
- Multiple Myeloma Research and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- European Commission
- Deutsche Forschungsgemeinschaft
- Bundesministerium für Bildung und Forschung
- Deutsche Krebshilfe
- Julius-Maximilians-Universität Würzburg