The resistec study: Dissecting immune correlates of resistance and response to teclistamab in real-world multiple myeloma

Abstract Introduction Although the introduction of proteasome inhibitors, immunomodulatory drugs (IMiDs), and anti-CD38 monoclonal antibodies has significantly improved Multiple myeloma (MM) patient survival, most individuals eventually relapse, with limited therapeutic options. Bispecific antibodies (BsAbs) that redirect T cells toward malignant plasma cells have revolutionized the therapeutic landscape for relapsed/refractory MM. These agents simultaneously bind a tumor-associated antigen, such as BCMA, and CD3 on T cells, thereby inducing targeted cytotoxicity. Among them, the FDA-approved anti-BCMA×CD3 BsAbs teclistamab and elranatamab have demonstrated high overall response rates in heavily pretreated patients. Despite significant clinical advances, many patients experience incomplete responses and resistance. Thus, there is a critical need to understand primary and acquired resistance. Increasing evidence suggests that the T cell immune landscape prior treatment influence BsAb efficacy. Yet, limited findings exist regarding prognostic value of other immune populations. Moreover, longitudinal analyses of how BsAb therapy modulates T cell phenotype and trafficking are still limited. Altogether, while BsAbs represent a major advance in MM therapy, key questions remain regarding their mechanisms of action and the determinants of clinical response and resistance. Methods: We analyzed longitudinal samples from the ResisTec trial (NCT05945524), a multicentric Intergroupe Francophone du Myélome (IFM) real-world study that enrolled 100 patients with RRMM treated with teclistamab. Bone marrow (BM) aspirates were collected at baseline and after 3 months and peripheral blood (PB) was collected every month. We performed single-cell RNA sequencing (scRNA-seq) on longitudinal samples collecting CD45⁺ immune cells and applied integrative bioinformatic pipelines to assess transcriptional and compositional changes across immune subsets. Immune remodeling patterns were correlated with treatment response and minimal residual disease (MRD) status after 3 months. Results were completed by forty markers' spectral flow cytometry. Results: By analyzing the frequencies of transcriptional clusters defining the baseline BM immune landscape, we identified a marked enrichment of myeloid-derived populations in patients with primary resistance to teclistamab. This shift occurred at the expense of T cells and specific NK cell subsets, suggesting an immunosuppressive environment unfavorable to T cell–redirected therapies. Interestingly, this lymphoid-to-myeloid skew mirrors immune remodeling we recently observed after first-line MM therapies in the “MIDAS” study. These findings raise the possibility that prior lines of treatment, while effective in inducing remission, may compromise adaptive immune function critical for the efficacy of subsequent immunotherapies. PB samples longitudinal analysis revealed that immune changes within the first month of treatment were more predictive of clinical response than baseline immune profiles. In non-responder patients, we observed a failure of cytotoxic CD8⁺ T cells to expand, accompanied by an incomplete contraction of Treg compartment, suggesting an early imbalance in effector versus suppressive immune responses. Notably, across all time points and locations, we did not detect canonical markers of T cell exhaustion in circulating T cells challenging the assumption that exhaustion is a dominant resistance mechanism in this context. Finally, clonal tracking of T cells that recirculate between PB and BM revealed that T cell clones expanded in the BM at baseline progressively accumulated in the blood during treatment, particularly in responder patients. This observation supports a model in which effective responses are associated with dynamic T cell mobilization and redistribution rather than static phenotypic signatures. Conclusions Response to teclistamab in multiple myeloma is associated with a favorable pre-existing lymphoid rich microenvironment in the BM, along with dynamic PB T cell remodeling marked by enhanced cytotoxic activity, reduced Treg frequencies, and clonal CD8⁺ T cell migration from BM to PB. These findings provide a rationale for predictive biomarkers and combinatorial strategies to overcome resistance.