P-209: The Influence of the Gut Microbiome on Myeloma Progression

Introduction: Our understanding of the microbiome's role in cancer has significantly expanded, uncovering how variations in diversity and composition of gut microbiota contribute to treatment response among cancer patients. However, the microbiome’s influence on multiple myeloma (MM) progression and resistance to immunotherapy remains incompletely elucidated. We asked whether dysbiosis (loss of diversity, depletion of obligate anaerobes, blooms of pathobionts) is associated with MM progression, immune evasion, and inferior outcomes

Methods: N/A

Results: We profiled the gut microbiome of 50 newly diagnosed MM patients who underwent high-dose melphalan conditioning and ASCT by 16S rRNA sequencing of the V4-V5 region. We compared pretransplant gut microbiota features in early progressors (EP, n=25) who relapsed in < 43.5 months (range 3-42) to late progressors (LP, n=25) who relapsed or maintained remission at >43.5 months (range 45-85). α-diversity was lower in EP (p < 0.035), whereas there was no significant difference in β-diversity. Using pairwise comparisons, Blautia and Faecalibacterium were significantly enriched in EP and LP respectively. Random Forest prediction classifier method, a supervised machine learning algorithm and Shapley Additive exPlanations (SHAP), a post-hoc explainability algorithm, identified Faecalibacterium and other short chain fatty acid producers as the most significant microbiota features in LP and Blautia had the highest importance in EP, further validating their significance. To establish causality between the gut microbiome and MM severity, we generated isogenic KaLwRij mouse strains harboring differences in richness and complexity of naturally occurring gut microbiota. We observed increased tumor burden and decreased infiltrating CD8 T cells in 5TGM1 mice with low microbiota richness compared to mice with high richness. The median overall survival for 5TGM1 mice with low, intermediate and high richness was 31, 35, and 39 days post-5TGM1 injection, respectively. We performed fecal microbiota transplantation (FMT) in antibiotic-treated KaLwRij mice. Mice were humanized with pretransplant stool from EP (n=3 donors) and LP (n=3 donors). 5TGM1 mice transplanted with gut microbiota from EP showed accelerated MM progression after 21 days compared to mice transplanted with gut microbiota from LP.

Conclusions: Our findings suggest that lower diversity and specific bacterial taxa prior to ASCT are predictive of early relapse in NDMM patients. We observe that lower microbiota diversity accelerates MM progression, impairs CD8 T cell responses, and worsens survival. This indicates a causal relationship between the gut microbiome and disease severity. Our preliminary FMT studies suggest a cause-and-effect relationship between gut microbiota and early disease progression and further highlight the feasibility and therapeutic potential of microbiota-centered intervention in limiting disease severity.