TNFRSF17 - руководство по геномическому профилированию с использованием альтернативных иммунотерапий на базе BCMA в множестве миеломы.

TO THE EDITOR:

B-cell maturation antigen (BCMA; TNFRSF17 ) is a key immunotherapy target in multiple myeloma (MM). Its plasma cell expression and survival role have enabled effective immunotherapeutic strategies. 1 , 2 Over the past decade, BCMA-directed approaches, including chimeric antigen receptor (CAR) T-cell therapies, bispecific T-cell engagers, and antibody–drug conjugates, have transformed the management of relapsed and refractory MM. 3 , 4 , 5 , 6 , 7 , 8 The activity of BCMA-directed bispecific antibodies was established in heavily pretreated MM through pivotal phase 1/2 trials supporting regulatory approval, including teclistamab (MajesTEC-1), 4 elranatamab (MagnetisMM-3), 7 and linvoseltamab (LINKER-MM1), which consistently reported overall response rates of 60% to 70%, with complete remission rates of 35% to 50% or higher and durable responses despite advanced disease.

However, some patients fail to respond or progress during treatment. Primary refractoriness or early progression is thought to be predominantly associated with extrinsic resistance mechanisms, including an immunosuppressive microenvironment that results in the exhaustion of effector CD8 + T cells. 9 In contrast, patients who initially respond to therapy and subsequently relapse more frequently exhibit tumor-intrinsic resistance mediated by antigen escape. This includes genetic alterations affecting TNFRSF17 , including focal or biallelic loss of the locus and structural changes that impair antibody or CAR binding. 10 , 11 , 12

Genomic sequencing of tumor plasma cells can identify tumor-intrinsic resistance mechanisms after BCMA-directed therapy. However, how such genomic findings can be used to inform real-world therapeutic decisions remains less well established. Importantly, the feasibility of this approach in routine clinical practice is critical for guiding the sequencing of BCMA-directed immunotherapies. Here, we report the use of targeted next-generation sequencing panel that enabled the identification of BCMA alterations, including mutations affecting the extracellular domain of BCMA, that informed treatment decisions in 5 patients with MM who developed clinical relapse after BCMA-directed therapy. These alterations were not detected at diagnosis and emerged after therapeutic exposure, consistent with treatment-driven clonal selection.

Targeted DNA sequencing of purified malignant plasma cells identified TNFRSF17 copy-number abnormalities, including heterozygous or homozygous deletions, and acquired BCMA coding single nucleotide variation. Details regarding plasma cell isolation, library preparation, and sequencing procedures are provided in the supplemental Methods . All procedures were conducted in accordance with the Declaration of Helsinki, and the study was approved by the institutional review board at Centre Hospitalier Universitaire of Lille.

The 5 patients included in this case series had received between 1 and 8 previous lines of therapy before exposure to BCMA-directed treatments. Of these, 2 patients were treated with teclistamab, 1 patient received elranatamab followed by idecabtagene vicleucel, 1 patient received idecabtagene vicleucel followed by linvoseltamab, and 1 patient was treated sequentially with linvoseltamab and elranatamab ( Table 1 ; supplemental Table 1 ). Treatment with BCMA-directed therapies resulted in clinical responses ranging from partial response to complete remission. None of the patients presented with extramedullary disease at diagnosis. All 5 patients had a routine practice genomic evaluation using an MM-targeted next-generation sequencing panel ( supplemental Table 2 ). All patients exhibited high-risk cytogenetic profiles according to the recent International Myeloma Working Group/International Myeloma Society criteria. 13 Specifically, 1 patient harbored a TP53 mutation in the absence of del(17p), 1 patient had del(17p), 2 patients had t(4;14) with 1q gain, and 1 patient exhibited the combination of t(4;14) and del(17p), together with a TP53 mutation ( Figure 1 ).

Table 1. Baseline characteristics and BCMA resistance mechanisms of the study patients Patient ID Sex Age, y Myeloma subtype HRCG at diagnosis EMD at diagnosis No. of previous lines of therapy (lines) Anti-BCMA therapy Best response to anti-BCMA Time to progression on anti-BCMA, mos Genetic alterations associated with BCMA resistance UPN 1 F 63 IgA Kappa Yes No 2L Linvoseltamab (3L) Elranatamab (5L) CR (3L) VGPR (5L) 15 (3L) 4 (3L) TNFRSF17 exon 1 c.37T>A : p.Y13N (VAF 90%) TNFRSF17 heterozygous deletion (3L), TNFRSF17 homozygous deletion (5L) UPN 2 M 63 IgG Kappa Yes No 3L Teclistamab VGPR 12 TNFRSF17 exon 1 c.89_90del : p.S30X (VAF 66%) TNFRSF17 exon 1 c.101_103del : p.P34del (VAF 17%) TNFRSF17 heterozygous deletion UPN 3 F 45 Light-chain λ Yes No 8L Elranatamab (9L) Ide-cel (12L) PR (9L) PR (12L) 7 (9L) 7 (12L) TNFRSF17 exon 1 c.109T>C : p.C37R (VAF 1%) UPN 4 M 60 IgG Kappa Yes No 2L Ide-cel (3L) Linvoseltamab (4L) CR (3L) VGPR (4L) 11 (3L) 9 (4L) TNFRSF17 exon 1 c.109T>C : p.C37R (VAF 4%) TNFRSF17 heterozygous deletion UPN 5 F 58 IgG Kappa Yes No 1L Teclistamab CR 13 TNFRSF17 exon 1 c.101_103del : p.P34del (VAF 46%) CR, complete remission; EMD, extramedullary disease; F, female; HRCG, high-risk cytogenetic; Ide-cel, idecabtagene vicleucel; Ig, immunoglobulin; L, line; M, male; VAF, variant allele frequency; PR, partial response; UPN, unique patient number; VGPR, very good partial response.

Baseline characteristics and BCMA resistance mechanisms of the study patients

CR, complete remission; EMD, extramedullary disease; F, female; HRCG, high-risk cytogenetic; Ide-cel, idecabtagene vicleucel; Ig, immunoglobulin; L, line; M, male; VAF, variant allele frequency; PR, partial response; UPN, unique patient number; VGPR, very good partial response.

Clonal trajectories and genomic mechanisms underlying resistance to BCMA-directed bispecific antibodies. (A-E) Representation of clonal evolution inferred from sequential genomic profiling in 5 representative patients (UPN 1-5). Each panel depicts the emergence and selection of resistant subclones under therapeutic pressure, highlighting recurrent alterations affecting TNFRSF17 (BCMA), as well as cooperating genomic events.

Targeted genomic profiling performed at relapse identified TNFRSF17 alterations ( Figure 1 ). These alterations included point mutations affecting the extracellular domain, focal monoallelic deletions, and in 1 case, complete biallelic loss of the TNFRSF17 locus. In patients with concomitant monoallelic deletion and acquired single nucleotide variation, these events were consistent with progressive impairment of BCMA under therapeutic pressure. By contrast, isolated heterozygous TNFRSF17 mutation must not be interpreted as complete antigen loss but may contribute to resistance through alteration of extracellular epitopes involved in therapeutic binding. The identified substitutions and indels clustered within exon 1 and involved residues Y13, S30, P34, and C37, all located in the extracellular domain and therefore directly relevant to antibody or CAR binding. In unique patient number (UPN) 2, 2 distinct alterations (p.S30X and p.P34del) were carried on separate sequencing reads. This finding is compatible with independent subclones, although a trans configuration within a shared subclone cannot be excluded without single-cell DNA sequencing. ( supplemental Figure 1 ).

These genomic results directly informed therapeutic decisions for 2 patients, supporting the clinical use of BCMA genomic sequencing at relapse ( supplemental Figure 2 ). UPN4 relapsed after idecabtagene vicleucel without a detectable BCMA alteration, supporting retreatment with a distinct BCMA-directed modality. This patient subsequently achieved a very good partial response with linvoseltamab, illustrating that the absence of tumor-intrinsic BCMA alteration can justify sequential BCMA targeting. In UPN1, the acquisition of a TNFRSF17 p.Y13N mutation after linvoseltamab exposure was particularly informative. This mutation has recently been functionally characterized, demonstrating preserved sensitivity to teclistamab and elranatamab. 14 Guided by these data, elranatamab was administered and induced a very good partial response lasting 4 months. Disease progression coincided with the emergence of a biallelic deletion of the TNFRSF17 locus, consistent with complete antigen loss and definitive escape from BCMA-targeted therapy.

Notably, complete biallelic loss of TNFRSF17 was observed at late relapse and coincided with the acquisition of additional cooperating alterations. At relapse, 3 distinct mutations affecting CYLD were identified, suggesting convergent activation of NFκB signaling pathways as an alternative survival mechanism in the context of BCMA loss. Beyond CYLD , other recurrent genomic events predicted to activate NFκB were observed, including biallelic deletion of TRAF3 (UPN 1) and a missense mutation in TRAF2 (UPN 3). This temporal association supports a model in which profound antigen escape, particularly biallelic BCMA deletion, is accompanied by reinforcement of prosurvival signaling, which may represent a therapeutic vulnerability in these tumor cells.

BCMA-targeted therapies have improved MM outcomes, but relapses still occur. 15 , 16 , 17 Our observations add to the growing evidence that such relapses may be associated with the acquisition of tumor-intrinsic genomic resistance mechanisms, including deletion of the TNFRSF17 locus and mutations affecting the extracellular domain of BCMA. 15 , 18 , 19 More importantly, beyond describing BCMA escape, this case series shows that targeted sequencing can guide treatment decisions and the sequencing of BCMA-directed immunotherapies in routine practice. Moreover, the therapeutic landscape of BCMA-directed agents includes bispecific antibodies and CAR T-cell therapies with distinct epitope recognition and binding properties. A recent study in hepta-refractory MM showed that BCMA status may predict benefit from BCMA retreatment, further supporting target reassessment of BCMA status before selecting a subsequent BCMA-directed therapy. 20 In vitro functional sensitivity data provide valuable insights into the biological consequences of specific BCMA alterations and may help to identify patients in whom sequential use of different BCMA-directed therapies remains a rational option.

In conclusion, our observations highlight the clinical value of TNFRSF17 sequencing in routine practice for guiding treatment decisions by capturing tumor-intrinsic genetic resistance that emerges under therapeutic pressure. These observations argue that BCMA sequencing should be considered at relapse after BCMA-directed therapy to refine treatment selection, avoid ineffective retreatment, and extend clinical benefit in patients who were heavily pretreated. Soluble BCMA levels were unavailable in this cohort, preventing the analysis of their correlation with TNFRSF17 genomic alterations and relapse dynamics. Future studies should integrate longitudinal soluble BCMA monitoring with genomic profiling to better characterize resistance to BCMA-directed therapies. Prospective studies combining longitudinal genomics with functional annotation will be essential to establish standardized strategies for resistance-guided treatment selection and optimize the use of BCMA-directed therapies across the disease course.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Acknowledgments

Acknowledgments: The Banque de Données des Hémopathies Lymphoïdes study is an academic, multicenter observational study. The authors acknowledge the support of Bristol Myers Squibb, AbbVie, and Sanofi. Linvoseltamab was provided by Regeneron Pharmaceuticals, Inc, which was not involved in the design, conduct, or analysis of this study.

Contribution: B.P. and S.M. designed the study and coordinated the sample and data collection within routine clinical practice; B.P., G.D., N.D., and C.P. performed molecular analysis; R.T., M.N., N.G., H.D., D.R., E.B., S.T., I.A., V.C., D.C., T.F., and S.M. provided clinical care and contributed to clinical data; A.C.-V. conducted library preparation and sequencing; H.L., P.N., and N.B. performed functional analysis in experimental models; and all authors reviewed and approved the final version of the manuscript.

Footnotes

The data that support the findings of this study are available from the corresponding author, Salomon Manier ( salomon.manier@chu-lille.fr ), on reasonable request.

The full-text version of this article contains a data supplement.

Supplementary Material

Supplemental Methods, Figures, Tables, and References

References

Associated Data

Supplementary Materials

Supplemental Methods, Figures, Tables, and References