GPRC5D as a novel target for the treatment of multiple myeloma: a narrative review

  • Blood Cancer J. 2024 Feb 2;14(1):24. doi: 10.1038/s41408-023-00966-9.
Paula Rodriguez-Otero  1 ,  Niels W C J van de Donk  2 ,  Kodandaram Pillarisetti  3 ,  Ingrid Cornax  4 ,  Deeksha Vishwamitra  3 ,  Kathleen Gray  5 ,  Brandi Hilder  3 ,  Jaszianne Tolbert  3 ,  Thomas Renaud  6 ,  Tara Masterson  3 ,  Christoph Heuck  3 ,  Colleen Kane  3 ,  Raluca Verona  3 ,  Philippe Moreau  7 ,  Nizar Bahlis  8 ,  Ajai Chari  9
Affiliations
  • 1. Clínica Universidad de Navarra, CCUN, University of Navarra, Pamplona, Spain. [email protected].
  • 2. Amsterdam University Medical Center, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
  • 3. Janssen Research & Development, Spring House, PA, USA.
  • 4. Janssen Research & Development, La Jolla, CA, USA.
  • 5. Janssen Scientific Affairs, Horsham, PA, USA.
  • 6. Janssen Research & Development, Raritan, NJ, USA.
  • 7. University Hospital Hôtel-Dieu, Nantes, France.
  • 8. Arnie Charbonneau Cancer Research Institute, University of Calgary, Calgary, Alberta, Canada.
  • 9. Icahn School of Medicine at Mount Sinai, New York, NY, USA.
PMID: 38307865 DOI: 10.1038/s41408-023-00966-9
Abstract

Multiple myeloma is a genetically complex and heterogenous malignancy with a 5-year survival rate of approximately 60%. Despite advances in therapy, patients experience cycles of remission and relapse, with each successive line of therapy associated with poorer outcomes; therefore, therapies with different mechanisms of action against new myeloma antigens are needed. G protein-coupled receptor class C group 5 member D (GPRC5D) has emerged as a novel therapeutic target for the treatment of multiple myeloma. We review the biology and target validation of GPRC5D, and clinical data from early phase trials of GPRC5D-targeting bispecific antibodies, talquetamab and forimtamig, and chimeric antigen receptor T cell (CAR-T) therapies, MCARH109, OriCAR-017, and BMS-986393. In addition to adverse events (AEs) associated with T-cell-redirection therapies irrespective of target, a consistent pattern of dermatologic and oral AEs has been reported across several trials of GPRC5D-targeting bispecific antibodies, as well as rare cerebellar events with CAR-T therapy. Additional studies are needed to understand the underlying mechanisms involved in the development of skin- and oral-related toxicities. We review the strategies that have been used to manage these GPRC5D-related toxicities. Preliminary efficacy data showed overall response rates for GPRC5D-targeting T-cell-redirecting therapies were ≥64%; most responders achieved a very good partial response or better. Pharmacokinetics/pharmacodynamics showed that these therapies led to cytokine release and T-cell activation. In conclusion, results from early phase trials of GPRC5D-targeting T-cell-redirecting agents have shown promising efficacy and manageable safety profiles, including lower Infection rates compared with B-cell maturation antigen- and Fc receptor-like protein 5-targeting bispecific antibodies. Further clinical trials, including those investigating GPRC5D-targeting T-cell-redirecting agents in combination with Other anti-myeloma therapies and with different treatment modalities, may help to elucidate the future optimal treatment regimen and sequence for patients with multiple myeloma and improve survival outcomes. Video Summary.

Products