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    Cellular and T cell engager Immunotherapy

    (OA-11) Baseline and Longitudinal Immune and Inflammatory Correlates of Response to Bispecific Antibodies in Relapsed/Refractory Multiple Myeloma

    Wednesday, September 17, 2025
    11:40 - 11:50 East Coast USA Time
    Location: Room 718
    Introduction: Bispecific antibodies (BsAbs) are highly efficacious in relapsed refractory multiple myeloma (RRMM), but predictive biomarkers remain incompletely defined. High ferritin, an inflammatory marker, has been linked to worse outcomes in MM, including among CAR T cell recipients. Additionally, a low effector T cell to tumor ratio - potentially reflected by absolute lymphocyte count (ALC) - may impair BsAb-mediated cytotoxicity.

    Methods: We identified 325 RRMM patients treated with BsAbs at Mount Sinai to evaluate the prognostic impact of ferritin and ALC. Descriptive analyses summarized baseline characteristics and ferritin and ALC dynamics. Kaplan-Meier analysis was used to estimate survival. Group-based trajectory modeling identified patient clusters by ferritin and ALC trends. CITE-Seq was performed on bone marrow (BM) and peripheral blood (PB) samples of 45 patients, with associations analyzed via generalized linear models.

    Results:

    Median age was 68; 45.9% had high-risk cytogenetics and 22.8% extramedullary disease. Most had ≥5 prior therapies; 86.8% were triple-class and 46.2% penta-drug refractory. Nearly 49% received BCMA-targeted BsAbs; 44% talquetamab, 6.5% cevostamab, and 10% combinations with daratumumab and/or IMiDs. Elevated baseline ferritin ( >400ng/mL) was associated with lower overall response rate (ORR) (62.5% vs 74.8%, p=0.033), fewer ≥VGPR responses (43.3% vs 60.6%, p=0.005), shorter PFS (5.1 vs 16.3mos, p=0.00029), and reduced OS (13.87mos vs not reached, p< 0.0001). Ferritin trajectory analysis identified 3 groups: F1 (rising ferritin, PFS 1.87mos, ORR 40%); F2 (chronically high, PFS 14.6mos, ORR 71%); F3 (down-trending, PFS 25.47mos, ORR 87%). Low baseline ALC (≤0.9x10³/µL) was linked to shorter PFS (6.87 vs 22.17mos, p=0.00068), and trajectory analysis revealed 3 groups:  A1 (persistent lymphopenia, PFS 1.1mos, ORR 32%), A2 (stable ALC, PFS 6.47mos, ORR 67%), A3 (rising ALC, PFS 22.87mos, ORR 83%). Noteworthy, lymphopenia was associated with being triple-class refractory and previously receiving CAR T or cytotoxic therapy.

    CITE-Seq of BM revealed that higher ferritin was associated with higher granulocyte-macrophage progenitors (p=0.0006), classical monocytes (p=0.01), and plasmacytoid dendritic cells (p=0.02). In PB, high ferritin was positively associated with CD8CM (p=0.02) and CD8SCM (p=0.04) and negatively associated with CD8EM T cells (p=0.05). While F1 trend was driven by tumor burden, CITE-Seq of PB revealed that patients on the F2 trend had higher CD8CM T cells (p=0.02) and CD56Bright NK cells (p=0.04) and lower gd T cells (p=0.01) and mucosal-associated invariant T cells (p=0.02) compared to F3, suggesting a distinct immunologic basis.

    Conclusions: Elevated ferritin and low ALC correlate with worse outcomes in BsAb-treated RRMM patients, supporting their use as prognostic and dynamic risk markers. Immune profiling linked ferritin levels and trends to distinct cellular patterns, informing resistance biology and potential therapeutic targets.