P176 | EFFECTOR/TARGET IMBALANCE AND HIGH DISEASE BURDEN IDENTIFY NON-RESPONDERS TO BISPECIFIC ANTIBODIES IN RELAPSED/REFRACTORY MYELOMA: PRELIMINARY FINDINGS

In relapsed/refractory multiple myeloma (RRMM), bispecific antibodies (BsAbs) have reshaped the therapeutic landscape, achieving unprecedented responses in triple-class exposed or refractory patients. However, up to 30–40% are primary refractory, highlighting the need for early predictors of non-response. We conducted a retrospective study to explore biomarkers associated with primary refractoriness to BsAbs in RRMM. The study was approved by the Ethics Committee of Palermo University Hospital (approval number 02/2022, codename: MMVision). We analyzed clinical and laboratory data from the first nine RRMM patients treated with BsAbs at our center. All were lenalidomide-refractory and had prior exposure to at least one proteasome inhibitor and one anti-CD38 monoclonal antibody. Six received teclistamab, two elranatamab, and one talquetamab. Three patients were classified as primary refractory, while six achieved at least a very good partial response (VGPR). We compared 20 laboratory parameters and 5 derived ratios (e.g., neutrophil-to-lymphocyte, lymphocyte-to-monocyte). Significant differences were found in ISS stage (p=0.0071), creatinine (p=0.0241), lymphocyte-to-monocyte ratio (LMR, p=0.0137), and hemoglobin-to-monocyte ratio (HbMR, p=0.0239). In multivariate analysis, only creatinine and LMR remained significant. These findings suggest that primary refractoriness may reflect more aggressive disease (e.g., higher ISS, lower hemoglobin/albumin, elevated creatinine and monoclonal component) and immune imbalance. Responders showed higher LMR, possibly indicating a favorable effector-to-target ratio, as circulating myeloma cells may fall within the monocyte gate. Elevated LMR also correlated with cytokine release syndrome (CRS), observed in 4/9 patients (all grade ≤ 2). We further analyzed pre-treatment bone marrow using BD PCD and PCST flow cytometry panels. Primary refractory patients had significantly fewer bone marrow B cells and a lower T cell-to-plasma cell ratio (effector/target >2:1 in responders vs <1:1 in refractory, both p<0.02). No significant differences were found in total T cell counts, suggesting the functional relevance of spatial distribution and cellular context. In conclusion, BsAb response in MM appears linked to disease burden and immune contexture. These findings support exploring pre-treatment strategies to reduce tumor burden or enhance effector-to-target ratios, potentially improving BsAb efficacy.