A High-Fiber Dietary Intervention (NUTRIVENTION) in Precursor Plasma Cell Disorders Improves Biomarkers of Disease and May Delay Progression to Myeloma
Authors: Shah Urvi A. , Cogrossi Laura Lucia , Derkach Andriy , Castro Francesca , Fei Teng , DeWolf Susan , Garces Juan-Jose , Policastro Anna , Grioni Matteo , Sisti Sofia , Jenna Blaslov , Adintori Peter , Hosszu Kinga K. , McAvoy Devin , Baichoo Mirae , Cross Justin , Anuraj Aishwarya , Pohl Charlotte , Ramos Ruben , Sanchez Jenny Paredes , Gipson Brianna , Maclachlan Kylee H , Gradissimo Ana , Boiocchi Leonardo , Koche Richard , Chaligne Ronan , Block Torin , Korde Neha , Tan Carlyn Rose , Hultcrantz Malin , Hassoun Hani , Shah Gunjan L. , Scordo Michael , Lahoud Oscar B , Chung David J. , Landau Heather J. , Peled Jonathan U. , Clementi Nicola , Chesi Marta , Bergsagel P. Leif , Mailankody Sham , Pollak Michael , D'Souza Anita , Landgren Ola , Chimonas Susan , Giralt Sergio , Usmani Saad Z. , Iyengar Neil M. , Lesokhin Alexander M. , Bellone Matteo , van den Brink Marcel R.M. 
Published: December 2024

Introduction
Poor diet quality, elevated body mass index (BMI), insulin resistance, microbiome dysbiosis, inflammation as well as immune dysfunction have all been implicated in progression from monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) to multiple myeloma (MM). Plant-based diets have been associated with reduced risk of MGUS and MM in epidemiological studies. Whether a dietary intervention can impact these modifiable risk factors and delay disease progression has not been investigated.
Methods
We conducted a pilot, single-arm trial providing controlled high fiber plant based dietary (HFPBD) intervention for 12 weeks and health coaching for 24 weeks in 20 patients with MGUS/SMM with BMI≥25 (NCT04920084). The primary endpoint was feasibility (adherence and BMI reduction). Secondary and exploratory endpoints included quality of life, metabolic markers (insulin, adiponectin, leptin, LDL cholesterol), microbiome (diversity and composition by 16S and shotgun sequencing) and immune profiling in peripheral blood (flow cytometry and Olink inflammation panel) and bone marrow (scRNAseq and ATACseq).
We also conducted an in vivo study in transgenic Vk*MYC mice fed a high fiber or control diet at the phase of mouse(m)SMM. The mice were monitored for the progression to active mMM. Differences in microbiome and immune response profiles between high fiber- and control-treated mice were assessed via microbiome 16S sequencing and flow cytometry.
Results
The HFPBD intervention was safe, feasible, improved quality of life and addressed modifiable risk factors - metabolic profile (improved BMI, insulin resistance, adiponectin leptin ratio), microbiome profile (increased alpha-diversity and butyrate producers) and immune (decreased inflammation and increased anti-inflammatory classical monocyte) subsets. A reduction in long-term progression trajectory was observed in 2 patients.
Consistently, the high fiber diet delayed progression from mSMM to mMM in Vk*MYC mice increasing median progression-free survival from 12 weeks in the control arm to 30 weeks in the high fiber diet intervention arm. Additionally, in the intervention arm 40% of mice did not progress to mMM during the study period whereas all mice in the control arm progressed. Both human and mouse data showed that HFPBD modulated gut microbiota composition favoring the expansion of butyrate-producing bacteria. Additionally, short-chain fatty acids were increased in the feces of mice fed a high fiber diet.
Integrated analysis from human bone marrow and peripheral blood analysis indicated that the dietary intervention reduced inflammatory biomarkers and skewed the immune response towards T helper and CD14+ monocytes. Consistently, the bone marrow of Vk*MYC mice fed high fiber diet was more infiltrated by IFNg-producing T lymphocytes while displaying less exhausted T cells and immunosuppressive myeloid cells.
Conclusion
This is the first interventional clinical trial and in vivo study to show that a HFPBD intervention may delay progression from MGUS/SMM to MM. To our knowledge there has been no similar dietary interventional study in hematological cancers or solid tumors. Together our in vivo and clinical data support the beneficial anti-inflammatory role of a HFPBD providing a link between diet, microbiota, and immune modulation to delay disease progression in MGUS/SMM.