A High-Fiber Dietary Intervention (NUTRIVENTION) in Precursor Plasma Cell Disorders Improves Biomarkers of Disease and May Delay Progression to Myeloma

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.

Shah:Sanofi: Honoraria; Bristol Myers Squibb: Research Funding; Janssen: Honoraria, Research Funding. Korde:Janssen: Membership on an entity's Board of Directors or advisory committees; Remedy Health 8/2022: Other: part of (Patient Power); CCO, OncLive, and Intellisphere: Consultancy; Amgen, Janssen, Epizyme, and AbbVie: Research Funding. Tan:Sanofi: Honoraria; Janssen: Honoraria, Research Funding; Takeda: Research Funding. Hultcrantz:Abbvie, GlaxoSmithKline, SpringWorks Therapeutics, Daiichi Sankyo, Cosette Pharmaceuticals: Research Funding; Curio Science LLC, Intellisphere LLC, Janssen, Bristol Myers Squibb, and GlaxoSmithKline: Consultancy, Honoraria. Hassoun:Janssen, Takeda: Research Funding. Shah:Janssen, Amgen, Beyond Spring, BMS, GPCR, DSMB with ArcellX.: Research Funding. Scordo:IDEOlogy: Honoraria; Amgen: Research Funding; Medscape: Honoraria; MJH Life Sciences (Cancer Network): Honoraria; Kite - A Gilead Company: Consultancy; Angiocrine Biosciences, Inc.: Research Funding; Sanofi: Research Funding; Miltenyi Biotec: Consultancy; Omeros Corporation: Consultancy, Research Funding. Landau:Janssen, Alexion, Protego, Prothena: Research Funding; Abbvie, Immix Biopharma, Legend Biotech, Alexion, Prothena: Consultancy. Peled:DaVolterra: Consultancy; Prodigy Biosciences: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Postbiotics Plus Research: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Canaccord Genuity, Inc: Consultancy; MaaT Pharma: Consultancy; Crestone Inc: Consultancy; CSL Behring: Consultancy; Seres Therapeutics: Patents & Royalties, Research Funding. Bergsagel:Novartis: Research Funding; Omeros: Consultancy; Janssen: Consultancy; Sanofi: Research Funding; Cellcentric: Consultancy; Oncopeptides: Consultancy; BMS/Celgene: Research Funding; Pfizer: Research Funding. Mailankody:BMS, J&J, GSK, Springworks Therapeutics: Research Funding. D'Souza:Abbvie: Research Funding; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Caelum: Research Funding; Novartis: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kedrion: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Prothena: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Regeneron: Research Funding; Takeda: Research Funding. Landgren:Theradex: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Membership on independent data monitoring committees.; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Membership on independent data monitoring committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Membership on independent data monitoring committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Membership on independent data monitoring committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Membership on independent data monitoring committees; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Membership on independent data monitoring committees; Adaptive: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Membership on independent data monitoring committees. Usmani:TeneoBio: Consultancy; SkylineDX: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Pfizer: Consultancy; Genentech: Consultancy; Gilead: Research Funding; Amgen: Consultancy, Research Funding; Array Biopharma: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Bristol-Myers Squibb - Celgene:: Consultancy, Research Funding; EdoPharma: Consultancy; GSK: Consultancy, Research Funding; Merck: Research Funding; Pharmacyclics: Research Funding; Oncopeptides: Consultancy; Sanofi: Consultancy, Research Funding; SeaGen: Consultancy, Research Funding; Gracell: Consultancy; SecuraBio: Consultancy; Abbvie: Consultancy, Research Funding; Bristol-Myers Squibb - Celgene: Consultancy, Research Funding; Johnson & Johnson - Janssen: Consultancy, Research Funding. Lesokhin:Serametrix, Inc.: Patents & Royalties; Memorial Sloan Kettering Cancer Center: Current Employment; Arcellx: Consultancy, Honoraria; F. Hoffmann-La Roche Ltd, Janssen, SVB Leerink: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding.