A Randomized Placebo Controlled Study of a Plant-Based Dietary Versus Supplement Versus Placebo Intervention in Patients with Monoclonal Gammopathy of Undetermined Significance (MGUS) and Smoldering Multiple Myeloma (SMM) - the Nutrition Prevention (NUTRIVENTION-3) Study

Background and Scientific Rationale Plasma cell disorders (PCDs) are associated with gut dysbiosis and multiple myeloma (MM) patients with increased stool butyrate producers appear to have improved outcomes (measurable residual disease negativity) (Pianko et al Blood Adv 2019). Interventional studies of whole food plant-based diets (WFPBD), omega-3 fatty acid, and curcumin supplements have shown beneficial alterations in the stool microbiome and increased butyrate levels in patients without PCDs. Butyrate inhibits the NF-κB pathway and histone deacetylases that play a critical role in MM development; and exerts anti-inflammatory functions through reduced formation of pro-inflammatory cytokines. Therefore, there is an opportunity to study the effect of these interventions on stool butyrate levels among patients with monoclonal gammopathy (MGUS) or smoldering multiple myeloma (SMM), for which the standard of care is observation, even though some patients will eventually progress to MM.

Building upon our NUTRIVENTION pilot study (NCT04920084), where preliminary results suggest feasibility and increases in stool butyrate producers and concentrations, we are conducting a randomized study of a WFPBD versus dietary supplements versus placebo supplements in MGUS/SMM patients. This study will aim to evaluate increase in stool butyrate levels and assess changes in biomarkers of disease including the gut microbiome. We expect that the findings will enable larger lifestyle-based studies of prevention and survivorship in PCDs.

Study Design This is a randomized, placebo controlled, multi-center, multi-arm (dietary, supplement and placebo) pilot study with 150 MGUS/SMM patients (50 per arm). Randomization will be stratified based on BMI and MGUS/SMM status. Randomization in the supplement and placebo arms will be double blinded.

Inclusion Criteria

1. MGUS or SMM

2. M spike ≥0.2 g/dL or abnormal free light chain ratio ≥10 or bone marrow plasma cells ≥10%

3. ECOG performance status 0-3

4. Willingness to comply with study-related procedures

Exclusion Criteria

1. Patients that already follow a WFPBD

2. Legume allergy

3. Severe allergies to nuts

4. Concurrent participation in weight loss/dietary/exercise programs

Intervention On the WFPBD arm, patients will receive fully prepared self-selected WFPBD meals (lunch/dinner) from Plantable, along with guidance for snacks and breakfast for 12 wks. Behavioral counseling will be provided by health coaches from Plantable and a research dietitian for 24 wks. The meals will have a low glycemic index and contain vegetables, whole grains, and plant-based fats that have undergone minimal processing.

On the placebo and supplement arms, patients will receive algae omega 3 (TheVeggieDoctor) and curcumin supplements (Sabinsa) or matching placebo twice daily respectively for 24 weeks. Patients on these two arms will also receive 12 weeks of the WFPBD and coaching intervention from week 13-24 to evaluate the combined effect of a WFPBD and supplements (Figure 1).

Objectives The primary objective of the study is to assess change in stool butyrate levels at 12 weeks compared to baseline.

Secondary and exploratory objectives include changes in stool butyrate levels at 24 weeks compared to baseline, changes in weight, quality-of-life measures, metabolic, myeloma and inflammatory markers, dietary pattern, fecal microbiome, and body composition.

Statistical Methods The primary endpoint is change in stool butyrate levels on the intervention at 12 weeks when compared to baseline. Based on prior data from our pilot trial (NUTRIVENTION NCT04920084) and other studies, we expect the study to be adequately powered to detect an increase in butyrate from baseline to 12 weeks between the WFPBD and placebo of 40% of 1 standard deviation, which corresponds to ≥30% of baseline level with a two-sample t-test.

Shah:Janssen: Consultancy, Research Funding; MJH Lifesciences: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Research Funding; ACCC: Honoraria; MashUpMD: Honoraria; Sanofi: Consultancy. Joseph:Janssen: Research Funding; BMS: Research Funding; GSK: Research Funding. Adintori:VidaFuel, Inc: Consultancy, Current holder of stock options in a privately-held company; Fig Health, Inc.: Consultancy, Current holder of stock options in a privately-held company. Mailankody:Evicore: Consultancy; Janssen Oncology: Consultancy, Research Funding; BioAscend: Consultancy; Optum Oncology: Consultancy; Allogene Therapeutics: Research Funding; Takeda Oncology: Research Funding; Juno Therapeutics: Research Funding; Bristol Myers Squibb: Research Funding; Fate Therapeutics: Research Funding; Plexus Communication: Honoraria; OncLive: Honoraria; Physician Education Resource: Honoraria; Legend Biotech: Consultancy; Memorial Sloan Kettering Cancer Center: Current Employment. Tan:Janssen: Honoraria, Research Funding. Hultcrantz:Amgen, Daichii Sankyo, Cosette, GSK: Research Funding; Intellisphere LLC: Consultancy; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Curio Science LLC: Consultancy. Hassoun:Janssen Pharmaceuticals: Research Funding; Takeda: Research Funding; Celgene: Research Funding. Lahoud:MorphoSys, Inc: Membership on an entity's Board of Directors or advisory committees. Shah:Janssen: Research Funding; Amgen: Research Funding; Beyond Spring: Research Funding. Scordo:Kite - A Gilead Company: Other: Ad-hoc advisory board (past); Amgen, Inc.: Research Funding; Medscape, LCC (CME): Honoraria; i3Health (CME): Honoraria; McKinsey & Company: Consultancy; Omeros Corporation: Consultancy, Research Funding; Angiocrine Bioscience, Inc.: Consultancy, Research Funding. Peled:CSL Behring: Consultancy; MaaT Pharma: Consultancy; Seres Therapeutics: Other: Intellectual Property Fees & Travel Funding , Research Funding; Postbiotics Plus Research: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; DaVolterra: Consultancy; intellectual property applications related to the microbiome: Other: He has filed intellectual property applications related to the microbiome (reference numbers #62/843,849, #62/977,908, and #15/756,845). ; Seres Therapeutics: Other: Memorial Sloan Kettering Cancer Center (MSK) has financial interest relative to Seres Therapeutics ; Arjun Pai: Consultancy; KongresKompagniet A/S: Other: Speaking; Clinical Immunology Society: Other: Lecture/Speaking; University of Nebraska Medical Center: Other: Speaking; University of Pennsylvania: Other: Lecture/Speaking; HayMatick Meetings & Events: Other: Speaking; apanese Society of Hematology: Other: Speaking; French National Cancer Institute (INCa): Consultancy; William Blair & Company, L.L.C.: Other: Speaking; University Hospital Regensburg: Other: Speaking; Parker Institute for Cancer Immunotherapy: Other: Attending a conference , Research Funding; Hanson Wade Limited: Other: Speaking. Landau:Janssen: Consultancy; Janssen Scientific Affairs, LLC: Other: grants/pending grants; Alexion: Other: grants/pending grants; Memorial Sloan Kettering Cancer Center: Current Employment; Karyopharm: Consultancy; Pfizer: Consultancy; Juno: Consultancy; Celgene: Consultancy; Legend Biotech USA Inc: Consultancy; Takeda Pharmaceuticals: Consultancy, Other: grants/pending grants; Caelum Biosciences: Consultancy; Prothena: Honoraria. Iyengar:Novartis: Honoraria, Research Funding; Seattle Genetics: Honoraria. Usmani:Abbvie, Amgen, BMS, Celgene, EdoPharma, Genentech, Gilead, GSK, Janssen,Oncopeptides, Sanofi, Seattle Genetics, SecuraBio, SkylineDX, Takeda, TeneoBio: Consultancy; Amgen, BMS, Janssen, Sanofi: Speakers Bureau; Amgen, Array Biopharma, BMS, Celgene, GSK, Janssen, Merck, Pharmacyclics, Sanofi, Seattle Genetics, SkylineDX, Takeda: Research Funding. van den Brink:Seres Therapeutics: Current holder of stock options in a privately-held company, Honoraria, Other: IP Licensing , Research Funding; Rheos Medicines: Honoraria; Vor Biopharma: Honoraria; Pluto Therapeutics: Current holder of stock options in a privately-held company, Honoraria; Notch Therapeutics: Current holder of stock options in a privately-held company, Honoraria; Frazier Healthcare Partners: Honoraria; Nektar Therapeutics: Honoraria; Ceramedix: Honoraria; Lygenesis: Honoraria; GlaskoSmithKline: Honoraria; Da Volterra: Honoraria; Thymofox: Honoraria; Garuda: Honoraria; Novartis (Spouse): Honoraria; Synthekine (Spouse): Honoraria; Beigene (Spouse): Honoraria; Kite (Spouse): Honoraria; Juno Therapeutics: Other: IP Licensing ; DKMS: Other: fiduciary role on the Foundation Board ; Wolters Kluwer: Patents & Royalties. Lesokhin:BMS: Honoraria; Janssen, Pfizer, Iteos, Sanofi, Genmab: Honoraria; Trillium Therapeutics: Consultancy, Research Funding; Sanofi: Research Funding; Serametrix, inc: Patents & Royalties; Pfizer, Genmab, Sanofi, Iteos, BMS, Janssen: Consultancy; Amgen: Honoraria; Janssen, Pfizer, BMS, Genentech/Roche: Research Funding; Memorial Sloan Kettering Cancer Center: Current Employment.