How does resistance arise for immunotherapy in relapsed/refractory multiple myeloma?

Presented by

Dr Nizar Bahlis, University of Calgary, Canada

Conference

EMN2024

A total of 6 novel therapies are approved for relapsed/refractory multiple myeloma, including 2 CAR T-cell products (ide-cel and cilta-cel), 3 bispecific antibodies (teclistamab, elranatamab, and talquetamab), and 1 antibody-drug conjugate (belantamab mafodotin, now with conditional approval rescinded). Dr Nizar Bahlis (University of Calgary, Canada) presented mechanisms of resistance to CAR T-cell and bispecific antibody therapies.

“When we think about mechanisms of resistance in general, we can broadly classify them into 2 subgroups: immune-mediated or tumour intrinsic,” said Dr Bahlis. However, resistance can also be classified as primary resistance and acquired resistance. In the case of bispecific antibodies, “that’s very different because primary refractory resistance is characterised by disease burden and, to some extent, by T-cell exhaustion,” while acquired resistance is determined by immune escape due to BCMA or GPRC5D deletion mutations [1].

T cell and immune factors can lead to resistance to CAR T-cell therapy by several mechanisms either due to the CAR T-cell product itself (exhausted T cells, lowered CD4/CD8 ratio, decreased pharmacokinetics, and T-cell persistence, reduced population of T_SCM and T_CM cells), as well as expanded regulatory T cells in the CAR-T product, and myelosuppressive and dendritic cell factors [1]. For bispecific antibodies, resistance can occur due to an abundance of exhausted CD8+ T-cell clones at baseline and expansion of regulatory T cells in the tumour microenvironment [1]

Tumour intrinsic factors for CAR T-cell therapy resistance include high disease burden (ISS stage III, increase in bone marrow plasmacytosis, and increase in serum BCMA), presence of extramedullary disease, and high-risk cytogenetics. Another tumor intrinsic factor is antigenic drifting or functional loss which is rare for BCMA but common for GPRC5D. The same factors can apply to resistance to bispecific antibodies, but functional loss of BCMA is much more common [1].

In summary, mechanisms of resistance to immunotherapies can be characterised both by factors which are intrinsic to the product itself in the case of CAR T-cell therapies, as well as immune-mediated factors and tumour intrinsic factors (high disease burden, extramedullary disease, tumour mutations) for both CAR T-cell therapy and bispecific antibodies.

N Bahlis. Mechanisms of resistance to immunotherapy. Session VII: Immunotherapy. EMN 2024, 18–20 April, Turin, Italy.

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