Impact of obesity on CRS and icans in patients with multiple myeloma receiving bispecific antibodies: A real-world analysis

Abstract Background: Bispecific antibodies (BsAbs) are novel immunotherapeutic agents used for treatment of various hematologic malignancies but are frequently associated with immune-related toxicities, namely Cytokine Release Syndrome (CRS) and Immune effector Cell-Associated Neurotoxicity Syndrome (ICANS). Both toxicities are driven by pro-inflammatory cytokines such as interleukin-6 (IL-6) . Similarly, obesity is a chronic inflammatory state characterized by adipose tissue infiltration by macrophages and CD8+ T cells, leading to elevated levels of IL-1β and IL-6. In other hyperinflammatory conditions like sepsis, obesity has been associated with worse outcomes. Prior studies showed mixed results evaluating risk of CRS after chimeric antigen receptor T-cell therapy in obese patients. However, the association between obesity and the risk of CRS or ICANS in patients with Multiple Myeloma (MM) or other hematological malignanies receiving BsAbs has not been previously studied. Methods: TriNetX, a global health research network, provides access to real-world, HIPPA compliant, de-identified data from diverse healthcare systems. We conducted a retrospective cohort study with the primary outcome of evaluating the risk of CRS and ICANS in patients with multiple myeloma and obesity who received BsAbs. The secondary outcome was to assess risk of CRS/ICANS in obese patients compared to other World-Health Organization defined weight categories. There was no time restriction but only patients aged ≥18 years with a diagnosis of MM and exposure to FDA-approved BsAb therapy (talquetamab and teclistamab) were included . Data was analyzed using hazard ratios with 95% confidence interval. Propensity score matching by age, sex, ethnicity, co-morbodities, and inflammatory markers was done to adjust for confounding variables. An exploratory subgroup analysis was conducted to identify potential predictors of risk. Results: A total of 302 obese patients diagnosed with MM and received BsAbs were identified from 38 health care organizations. The mean age was 68 ± 10 years, with 50 % male, 73% non-Hispanic, and 61% White. The cumulative incidence of CRS in obese patients was 28%, highest being in the first 14 days (15.25%). The risk of ICANS is 6.78%, and is similarly highest at first 14 days (3.39%). Although the risk of CRS was higher in patients with obesity compared to patients who were overweight (1.165, 0.749-1.812), underweight (1.276, 0.827-1.97) or those with normal weight (1.132, 0.72-1.77) , the risk was not statistically siginificant. In parallel, ICANS did not show a significant increase between the different cohorts. A subgroup analysis did not show significant differences between males and females, >65 and <65 years, African-Americans and Whites, and use of talquetamab vs teclistamab and risk of CRS/ICANS. Conclusion: In this real-world cohort, obesity showed modest risk of CRS/ICANS. However, it was not associated with an increased risk of CRS or ICANS in patients treated with bispecific antibodies compared to other BMI cohorts. The results are limited by the inherent heterogeneity of registry data, including variability in data quality, completeness, and coding practices across sites. Further prospective studies are needed to confirm these findings and guide personalized management strategies.