A Pilot Plant Based Dietary Intervention in MGUS and SMM Patients with Elevated BMI Is Feasible and Associated with Improvements in Metabolic and Microbiome Biomarkers of Progression

Abstract

Introduction Obesity, low adiponectin, high leptin, high insulin, high IGF-1, and diets lacking plant-based foods or high in insulinemic foods are all risk factors for plasma cell disorders (PCDs). Patients (pts) with monoclonal gammopathy (MGUS) and an elevated body mass index (BMI) are twice as likely to progress from MGUS to multiple myeloma (MM). Additionally, there is gut dysbiosis in pts with PCDs, and whole food plant-based diets (WFPBDs) increase stool butyrate concentrations. Butyrate has anti-cancer (HDAC and NFkB inhibition) and anti-inflammatory (proinflammatory cytokine inhibition) properties. Prior studies show that increased relative abundance of stool butyrate producers are associated with improved outcomes in PCDs. Therefore, there is a rationale to study a dietary intervention in MGUS/smoldering MM (SMM), given the standard of care is observation despite the risk of progression. Methods Therefore, we initiated a pilot dietary intervention study (NUTRIVENTION) of a WFPBD in MGUS/SMM pts with BMI ≥25 (NCT04920084) with the primary objective of determining feasibility, as measured by weight loss (>5%) and adherence (>70%) at 12 weeks (wks). Here, we present interim results on feasibility, metabolic markers (insulin, adiponectin leptin ratio, IGF-1), microbiome (relative abundance of butyrate producers, short chain fatty acids) and secreted inflammatory biomarkers (CRP, Olink proteomics) for pts analyzed to date. The intervention, consisting of fully prepared WFPBD meals and behavioral coaching was provided by Plantable. Patients received self-selected WFPBD meals (lunch/dinner) for 12 wks, along with guidance for snacks and breakfast. Behavioral counseling was provided by health coaches and a research dietitian for 24 wks. Adherence was calculated as the percentage of kcal that were whole unprocessed plant foods out of total kcal consumed. Plasma total adiponectin, leptin, IGF-1 and insulin were measured via ELISA immunoassays. Stool samples were analyzed with 16S sequencing and gas chromatography mass spectrometry for short chain fatty acids and plasma was analyzed with the Olink Target 96 inflammation panel. We calculated the median at baseline and the median change % (median change/median at baseline) at 4 and 12 wks. Results The study has completed enrollment of 22 pts (2 dropped out within 12 wks for pt preference and were replaced), with 14 having completed the 12-wk intervention. The baseline demographics for 22 pts include median age 62 years (range 40-79), 45% male, 45% minorities (black, Hispanic, or other), 50% MGUS, 77% obese, and 27% prediabetic/diabetic. Preliminary results for clinical and correlative endpoints are provided in table 1. The study met both feasibility endpoints with 7% median BMI reduction and 90% median adherence at 12 wks as described in table 1. Metabolic markers indicate an improvement in LDL cholesterol, HgbA1c, insulin and adiponectin leptin (AL) ratio. The AL ratio is a marker of insulin resistance and higher levels imply improved insulin sensitivity, reduced BMI, and inflammation. Increased insulin, leptin, IGF-1 as well as decreased adiponectin are associated with the development of MM. Microbiome shows an improvement in the relative abundance of butyrate producers at 4 wks and stool butyrate concentrations at 12 wks. Additionally, a decrease in the branched chain fatty acids are seen. There is a decrease in the proinflammatory cytokines IL8, IL12B and TNFB, a decrease in DNER, a NOTCH1 activator and an increase in the protein FGF21 that is known to promote insulin sensitivity and downregulate hepatic IGF-1 production. Butyrate is known to inhibit the formation of proinflammatory cytokines and increase FGF21 via HDAC inhibition and inhibit NOTCH signaling. Conclusions This is the first interventional study in PCDs with mechanistic insights into risk reduction through modifiable risk factors with the potential to empower pts. Preliminary results show that a WFPBD is feasible given the BMI reduction and adherence in pts with PCDs. Our data suggests that a WFPBD improves metabolic profile (BMI, insulin resistance, AL ratio and FGF21) as well as increases stool butyrate producers and butyrate levels which in turn leads to a reduction in proinflammatory cytokines. Positive changes in metabolic, microbiome and inflammation markers are potential mechanisms by which diet may alter disease trajectory. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal