Sridevi Rajeeve

Supplemental Data 1 from Lenalidomide-Related Diarrhea in Patients with Multiple Myeloma Is Associated with Gut Microbiota Dysbiosis and Disruption of the Bile Acid Pool

Bispecific antibody (BsAb) treatment in multiple myeloma can be associated with adverse events including cytokine release syndrome (CRS), cytopenias, and infections. While granulocyte colony-stimulating factors (G-CSF) can be used to treat neutropenia, little is known about their safety during the BsAb initiation period and whether G-CSF can increase the risk of CRS. To assess the impact of G-CSF on risk of CRS, we included all patients with multiple myeloma who received at least one dose (step-up doses [SUD] and first treatment dose [FTD]), of commercial teclistamab, elranatamab, or talquetamab between November 2022 and April 2024 at Memorial Sloan Kettering Cancer Center (N = 186). Exposure to G-CSF was defined as administration of at least one dose of filgrastim from 48 h before up to 7 days after BsAb SUD or FTD, or one dose of peg-filgrastim between 7 days prior to up to 7 days after BsAb SUD or FTD. Of the 186 patients, 22 were classified as G-CSF exposed. CRS occurred in 16/22 (73%) patients with G-CSF exposure vs 76/164 (46%) of non-exposed. All CRS was grade 1 (56%) or grade 2 (44%) and the majority occurred prior to G-CSF was given (16/22 patients). The median absolute neutrophil count (ANC) at time of G-CSF exposure was 0.5 × 10⁹/L (0.4-0.7). There was a trend towards increased risk of CRS after G-CSF exposure, although not significant (hazard ratio [HR] 1.7, 95% confidence interval [CI] 0.6-4.7, p = 0.3). These results suggest that G-CSF administration can be considered for neutropenia during BsAb initiation.

Nonimmune effector cell–associated neurotoxicity syndrome neurotoxicities (NINTs) are serious, atypical toxicities associated with ciltacabtagene autoleucel (cilta-cel), a US Food and Drug Administration chimeric antigen receptor T cell (CAR T cell) therapy approved for relapsed/refractory multiple myeloma (RRMM). Risk factors contributing to the development of NINTs are poorly understood. In a cohort of 109 patients with RRMM treated with cilta-cel, we identify predisposing risk factors and propose strategies to mitigate NINTs. We show that high-peak absolute lymphocyte count is a strong NINT predictor, which directly correlates with flow cytometry–based peripheral blood CAR T cell quantitation. The observed CAR lymphocytosis was polyclonal with a bias toward CD4 ⁺ CAR T cells rich in memory marker expression. We then identified CAR lymphocytosis–associated CD4 ⁺ CAR T cell populations, which exhibited increased inflammatory pathway gene expression. Last, we characterize NINT-associated CD4 ⁺ CAR T cell populations, which are potential therapeutic targets for future exploration.

Purpose: Lenalidomide is integral to multiple myeloma therapy, but long-term use is frequently complicated by diarrhea, which diminishes patient quality of life. The pathophysiology of lenalidomide-related diarrhea (LRD) is unclear although bile acid (BA) malabsorption has been implicated. As the gut microbiota shapes BA metabolism, we evaluated whether perturbations of the microbiota and BA pool are associated with LRD. Experimental Design: In two prospective lenalidomide maintenance trials (NCT02538198 and NCT04497961), we profiled BAs, microbiota, dietary questionnaires, and patient-reported outcomes. Results: Lenalidomide exposure was associated with increased fecal BA abundance; patients with LRD had enrichment of primary BAs without increased secondary BAs. LRD samples demonstrated reduced α-diversity and altered community composition, with reduced predicted BA-processing capacity. Baseline microbiota, BA, and dietary profiles differed in patients who developed LRD, suggesting that pretreatment features may influence LRD risk. Conclusions: These findings implicate impaired microbial BA metabolism as a contributor to LRD and support investigating microbiota-targeted strategies to mitigate this toxicity.

PURPOSE: Talquetamab is a G protein–coupled receptor class C group 5 member D T-cell–engaging antibody, approved for relapsed/refractory multiple myeloma (RRMM). In the MonumenTAL-1 clinical trial, cytokine release syndrome (CRS) occurred at a frequency of 77%; however, there was no assessment of CRS rates by step-up dose. The primary objective of this study was to characterize CRS rates after each talquetamab step-up dose in a real-world setting. METHODS: Patients with RRMM who completed the talquetamab once a week or once every 2 weeks step-up dosing schedule between September 2023 and November 2024 were identified via the institutional database. CRS rate after each talquetamab step-up dose was compared using the chi-square/Fisher’s exact test. The Kruskal-Wallis test was used to compare difference in median time to the CRS onset. Multivariate logistic regression analysis was performed to identify predictors of CRS. RESULTS: Fifty patients completed the talquetamab step-up dosing phase during the study period; CRS occurred at a rate of 80%. Pairwise comparisons revealed significant differences in CRS rates between the fourth dose (4%) and each of step-up dose 1 (28%, P = .014) and 2 (34%, P = .003). The only CRS event with fourth dose was grade 1. The median time to onset of first CRS did not differ significantly between step-up doses ( P = .441). Previous exposure to T-cell–redirecting therapy had no impact on CRS incidence (odds ratio: 0.20 [95% CI, 0.03 to 1.10]). CONCLUSION: Our findings suggested that the fourth talquetamab dose could be administered in outpatient settings given its high tolerability. The reduced hospitalization period for talquetamab step-up dosing could reduce health care expenses.