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.