Francesca Castro

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

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.

Figure S2 shows clinical biomarker changes including body composition, healthy eating index, paraprotein, LDL and IGF1.

Figure S7 shows the effect of SCFAs on myeloma cells and immunodeficient mice.

Figure S4 shows change in peripheral blood CRP and inflammatory biomarkers, bone marrow cell proportions and differentially expressed genes in paired samples by BMI and microbiome diversity as well as cell interactions.

Consumption of a Western diet and high body mass index (BMI) are risk factors for progression from premalignant phenotypes to multiple myeloma, a hematologic cancer. In the NUTRIVENTION trial (NCT04920084), we administered a high-fiber, plant-based diet (HFPBD; meals for 12 weeks, coaching for 24 weeks) to 23 participants with myeloma precursor states and elevated BMI. The intervention was feasible and improved quality of life and modifiable risk factors: metabolic (BMI, insulin resistance), microbiome (diversity, composition), and immune (inflammation, monocyte subsets). Disease progression trajectory improved (n = 2) or was stable. Findings were translated to Vk*MYC mice modeling the myeloma precursor state, in which a high-fiber diet (HFD) delayed disease progression through improved metabolism and microbiome composition, leading to increased short-chain fatty acid production that reinvigorated antitumor immunity and inhibited tumor growth. These effects from fiber consumption were independent of calorie restriction and weight loss. A HFD is a low-risk intervention that may delay progression to myeloma.Significance:A HFPBD in participants with precursor plasma cell disorders and an elevated BMI improved metabolic, microbiome, and immune biomarkers of disease. In a subset, it may delay progression to myeloma. In mouse models, a HFD delayed progression to myeloma independent of calorie restriction.See related commentary by Fairfield and Reagan, p. 623