Antigen escape as a shared mechanism of resistance to BCMA-directed therapies in multiple myeloma

Abstract

B-cell maturation antigen (BCMA)-targeting therapeutics have dramatically improved outcomes in relapsed/refractory multiple myeloma (RRMM). However, whether the mechanisms of resistance between these therapies are shared and how the identification of such mechanisms before therapy initiation could refine clinical decision-making remains undefined. We analyzed outcomes for 72 RRMM patients treated with teclistamab, a CD3 × BCMA bispecific antibody, 42% (30/72) of whom had prior BCMA-directed therapy exposure. Malignant plasma cell BCMA expression was present in all BCMA therapy-naïve patients. Prior therapy-mediated loss of plasma cell BCMA expression before teclistamab treatment, measured by immunohistochemistry, was observed in 3 patients, none of whom responded to teclistamab, and 1 of whom also did not respond to ciltacabtagene autoleucel. Whole exome sequencing of tumor DNA from 1 patient revealed biallelic loss of TNFRSF17 following treatment with belantamab mafodotin. Low-to-undetectable peripheral blood soluble BCMA levels correlated with the absence of BCMA expression by bone marrow plasma cells. Thus, although rare, loss of BCMA expression following TNFRSF17 gene deletions can occur following any BCMA-directed therapy and prevents response to subsequent anti-BCMA-directed treatments, underscoring the importance of verifying the presence of a target antigen.

Graphical abstract

Figure 1.

Therapy–triggered loss of plasma cell BCMA expression. Biopsy samples from 3 patients before initial anti-BCMA therapy (left, BCMA-naïve) are shown in contrast to biopsy samples after initial anti-BCMA therapy and prior to teclistamab treatment (right, Pre-Tec failure). (A) Patient 1 following belantamab mafoditin (bela) and cilta-cel treatment. (B) Patient 2 following cilta-cel treatment. (C) Patient 3 following belantamab treatment.

Figure 2.

TNFRSF17 deletion after belantamab treatment. (A) CNV analysis of bulk WES data from patient 1 following relapse from belantamab treatment demonstrates loss of both copies of TNFRSF17. This is consistent with the emergence of a plasma cell clone with biallelic loss of TNFRSF17 (supplemental Figure 1) and explains the lack of BCMA expression seen in patient 1. (B) Integrative genomic viewer (IGV) snapshot showing the genomic deletion beginning at ∼12 Mb on chromosome 16 and covering the entire TNFRSF17 locus. CNV, copy number variant.

Figure 3.

sBCMA levels parallel BM plasma cell BCMA expression. sBCMA levels from peripheral blood plasma at relevant timepoints show that low plasma sBCMA reflects the loss of plasma cell BCMA expression when assessed relative to the method of disease burden measurement used for each patient. (A) Patient 1 showed undetectable sBCMA before treatment with teclistamab (Tec). (B) Patient 2 showed undetectable sBCMA while in a CR to BCMA-directed CAR T-cell therapy, which remained low following relapse. (C) Patient 3 showed a disproportionate drop in sBCMA relative to serum monoclonal protein while in a PR to belantamab mafodotin (Bela), which preceded eventual BCMA-negative relapse. CR, complete response; PC, plasma cell; PR, partial response.