O12.01 Increased teclistamab dosing interval improves clonotypic diversity and reduces infection risk in multiple myeloma

Background Bispecific antibodies are among the most effective treatments for relapsed/refractory (RRMM) multiple myeloma. However, most approved agents, including teclistamab, were developed with short dosing intervals and indefinite treatment duration. In view of the rapid and deep responses in most patients, the rationale for continuous dose-dense therapy is limited. Concurrently, infectious complications remain a major challenge, requiring treatment breaks and leading to fatal outcomes. In clinical practice, dose interval extension, from weekly to biweekly or monthly, has become increasingly common.Still, the immunological impact of extended interval dosing remains poorly understood. To address this, we conducted a multiomics study comparing immune effects of weekly (q1w), biweekly (q2w), and monthly (q4w) teclistamab dosing.Material and methods We biobanked peripheral blood mononuclear cells (PBMCs, n=87) from 30 RRMM patients who switched from q1w (n=34) to q2w (n=12) and/or q4w (n=33) teclistamab dosing. As a control, 8 baseline samples were also collected prior to treatment initiation.To characterize immune changes across dosing intervals, we performed single-cell multimodal sequencing (scRNA/CITE/TCR; n=28 (16 patients)) and 14-color flow cytometry (n=68). Additionally, we conducted in vitro cytotoxicity assays using MM.1S target cells and patient-derived T cells (n=20) across varying effector-to-target ratios.Results We first evaluated infection rates across treatment schedules dosing after 12 months and observed a significantly lower incidence of infections with better progression-free survival in patients receiving q4w compared to q1w.Next, from flow cytometry analysis, we observed elevated leukocytes count along with a higher number of T cells in the q4w samples compared to the q1w samples. ScRNA/CITE-seq analysis of T cells showed no significant differences in exhaustion signature across dosing schedules, a finding that was confirmed by flow cytometry. Furthermore, we detected increased frequencies of naïve T cells and central memory T cells, consistent with partial T-cell recovery during longer treatment-free intervals. From in vitro cytotoxicity assays, no significant differences in killing capacity were observed between T cells from patients on q1w, q2w or q4w dosing schedules.scTCR sequencing revealed pronounced T-cell receptor clonotypic diversity in q4w compared to q1w samples. Mapping TCR sequences to known viral epitopes exhibited a restricted antiviral repertoire in q1w samples. In contrast, q4w samples showed significantly broader viral TCR diversity, potentially contributing to the lower infection rate observed in this group. Lastly, we applied a tumor reactivity score (Kehl et al., Blood, 2025). From which, MM-reactive T cells markedly appeared to be increased from baseline to q1w dosing as expected, followed by a modest, non-significant decline with q2w and q4w intervals.Conclusion Our data support an initial dose-dense treatment phase to expand tumor-reactive T cells, followed by extended dosing intervals in responders to promote immune recovery, restore T-cell diversity, and reduce infections, while maintaining anti-myeloma activity. Nazia Afrin: None; Florian Eisele: Sobi, AbbVie; Emilia Stanojkovska: None; Mara John: None; Hanna Fischer: None; Moutaz Helal: None; Carolin Köchel: None; Niklas Kehl: None; Christine Riedhammer: Takeda; Sofie-Katrin Kadel: Jannsen; Julia Mersi: None; Torsten Steinbrunn: None; Johannes M. Waldschmidt: None; Sabrina Kraus: None; Johannes Duell: Novartis, Gilead/Kite, BMS, Janssen, Abbvie, Beigene; K. Martin Kortüm: BMS, Menarini, Novartis, Pfizer, GSK, J&J, AbbVie; Mirco Friedrich: None; Hermann Einsele: Janssen, Bristol-Myers Squibb; Angela Riedel: None; Leo Rasche: Janssen, Bristol-Myers Squibb