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Potential of new BCMA-targeting therapies in overcoming resistance in multiple myeloma

Manraj Singh Sra1, Shaji Kumar1

  • 1Division of Hematology, Mayo Clinic, Rochester, MN, USA.

Expert Opinion on Biological Therapy
|July 11, 2026
PubMed
Abstract

Insights

Resistance to B-cell maturation antigen (BCMA)-targeted therapies in multiple myeloma is complex. Strategies to overcome resistance, including multi-antigen targeting, are crucial for improving patient outcomes.

Area of Science:

  • Oncology
  • Immunotherapy
  • Hematology

Background:

  • B-cell maturation antigen (BCMA) is a key therapeutic target in multiple myeloma.
  • Approved BCMA-directed therapies include CAR-T cells, bispecific T-cell engagers, and antibody-drug conjugates for relapsed/refractory disease.

Purpose of the Study:

  • To review the current landscape of BCMA-directed therapies.
  • To outline mechanisms of resistance to these therapies.
  • To discuss strategies for overcoming resistance.

Main Methods:

  • Literature review summarizing BCMA-directed therapies.
  • Analysis of resistance mechanisms across different treatment modalities.
  • Discussion of emerging strategies to improve treatment efficacy.

Main Results:

  • Resistance to BCMA-targeted therapies is multifactorial and modality-specific.
  • Antigen-related escape (e.g., TNFRSF17 loss, BCMA shedding) dominates resistance to bispecifics.
  • T-cell dysfunction drives relapse after CAR-T therapy.
  • Tumor-intrinsic factors like genomic complexity and plasma cell identity escape predict primary refractoriness.

Conclusions:

  • Understanding resistance mechanisms is critical for optimizing BCMA-directed therapies.
  • Multi-antigen targeting and combination therapies show promise for overcoming resistance.
  • Future strategies should address both tumor-intrinsic and immune-related resistance pathways.
Keywords:
BCMAMultiple myelomaciltacabtagene autoleucelidecabtagene vicleucelteclistamab

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