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<p>Immunotherapies targeting surface antigens have transformed the treatment landscape of multiple myeloma (MM), with GPRC5D emerging as a promising therapeutic target. Monoallelic loss of <i>GPRC5D</i> is frequently observed in newly diagnosed MM patients, and the incidence of acquired <i>GPRC5D</i> alterations increases following exposure to GPRC5D-directed therapies. However, the functional consequences of both baseline monoallelic and therapy-induced biallelic <i>GPRC5D</i> alterations remain poorly understood. In this study, we modeled monoallelic versus biallelic loss of <i>GPRC5D</i> to investigate their impact on MM cell biology and responsiveness to GPRC5D-targeted immunotherapies. Our results demonstrate that monoallelic <i>GPRC5D</i> loss in OPM-2 cells reduces surface expression of the antigen and confers resistance to GPRC5D-directed therapies. Complete loss of <i>GPRC5D</i> 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.</p><p></p>

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Loss of GPRC5D enhances the proliferative capacity and competitive fitness of myeloma upon anti-GPRC5D immunotherapy

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年3月31日

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  • Umair Munawar,
  • Johanna Thurner,
  • Silvia Nerreter,
  • Thomas Nerreter,
  • Alexander M. Leipold,
  • Seungbin Han,
  • Christina Verbruggen,
  • Elena Gerhard-Hartmann,
  • Cornelia Vogt,
  • Björn Grams,
  • Shilpa Kurian,
  • Emma Besant,
  • Sabine Roth,
  • Julia Weingart,
  • Patrick Eiring,
  • Marietta Truger,
  • Nazia Afrin,
  • Torsten Steinbrunn,
  • Yoko Tamamushi,
  • Xiang Zhou,
  • Nina Rein,
  • Johanna Lehmann,
  • Max Köppel,
  • Andreas Rosenwald,
  • Claudia Haferlach,
  • Michael Hudecek,
  • Antoine-Emmanuel Saliba,
  • Leo Rasche,
  • Markus Sauer,
  • Hermann Einsele,
  • Bernhard Kuster,
  • Johannes Waldschmidt,
  • K. Martin Kortüm

摘要

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.