Soluble B-cell maturation antigen in lacrimal fluid as a potential biomarker and mediator of keratopathy in multiple myeloma

Haematologica. 2024 Nov 1;109(11):3670-3680. doi: 10.3324/haematol.2024.285205.

Abstract

Belantamab mafodotin (belantamab) is a first-in-class anti-B-cell maturation antigen (BCMA) antibody-drug conjugate approved for the treatment of triple-class refractory multiple myeloma. It provides a unique therapeutic option for patients ineligible for chimeric antigen receptor (CAR) T and bispecific antibody therapy, and/or patients progressing on anti-CD38 treatment where CAR T and bispecifics might be kept in reserve. Wider use of the drug can be challenged by its distinct ocular side effect profile, including corneal microcysts and keratopathy. While dose reduction has been the most effective way to reduce these toxicities, the underlying mechanism of this BCMA off-target effect remains to be characterized. In this study, we provide the first evidence for soluble BCMA (sBCMA) in lacrimal fluid and report on its correlation with tumor burden in myeloma patients. We confirm that corneal cells do not express BCMA, and show that sBCMA-belantamab complexes may rather be internalized by corneal epithelial cells through receptor-ligand independent pinocytosis. Using an hTcEpi corneal cell-line model, we show that the pinocytosis inhibitor EIPA significantly reduces belantamab-specific cell killing. As a proof of concept, we provide detailed patient profiles demonstrating that, after belantamab-induced cell killing, sBCMA is released into circulation, followed by a delayed increase of sBCMA in the tear fluid and subsequent onset of keratopathy. Based on the proposed mechanism, pinocytosis-induced keratopathy can be prevented by lowering the entry of sBCMA into the lacrimal fluid. Future therapeutic concepts may therefore consist of belantamab-free debulking therapy prior to belantamab consolidation and/or concomitant use of γ-secretase inhibition as currently evaluated for belantamab and nirogacestat in ongoing studies.

MeSH terms

  • Antibodies, Monoclonal, Humanized / therapeutic use
  • B-Cell Maturation Antigen* / metabolism
  • Biomarkers
  • Biomarkers, Tumor
  • Corneal Diseases / etiology
  • Corneal Diseases / metabolism
  • Corneal Diseases / pathology
  • Female
  • Humans
  • Male
  • Middle Aged
  • Multiple Myeloma* / metabolism
  • Multiple Myeloma* / therapy
  • Tears / metabolism

Substances

  • B-Cell Maturation Antigen
  • Biomarkers
  • belantamab mafodotin
  • Antibodies, Monoclonal, Humanized
  • TNFRSF17 protein, human
  • Biomarkers, Tumor

Grants and funding

Funding: JMW is supported by the Germany Ministry of Education and Research (BMBF) and Interdisziplinäres Zentrum für Klinische Forschung (IZKF) Würzburg. KMK is supported by Stifterverband. LR and KMK are supported by Mildred-Scheel-Nachwuchszentrum (MSNZ) Würzburg