Our study presented at the ASH 2024 Annual Meeting was the NUTRIVENTION trial. This is a high-fibre dietary intervention in patients with MGUS and smouldering myeloma, so the precursor plasma cell disorders, and its effect to delay progression.
What did your study find?
Our hypothesis was that given MGUS and smouldering myeloma, these precursor disorders, the standard practice is observation. We know that obesity, diabetes, altered microbiome and poor dietary quality are associated with increased risk of these disorders, including myeloma. We wanted to see if we helped patients with these precursor plasma cell disorders improve diet quality, weight, and microbiome, is it possible to delay progression.
This was a 20-patient pilot and so this was a feasibility design. The primary endpoint was reduction in weight by greater than 5% at 12 weeks as well as adherence to the diet for more than 70% of kilocalories consumed for unprocessed plant foods.
The study involved looking at a high-fibre plant-based diet where we shipped patients lunch and dinner for 12 weeks with recipes for snacks and breakfast. There was no calorie restriction. On the study the patients lost about 7-8% body weight at 12 weeks and this was maintained at a year out. Dietary adherence also improved from a baseline of about 20% of kilocalories being unprocessed plant foods to 92% on intervention and even one year out it was about 60%, suggesting that patients may gain long-term dietary changes.
We then looked at other biomarkers such as metabolic markers such as insulin, fasting insulin levels and adiponectin/leptin ratio, a marker of insulin resistance as well. Fasting insulin levels dropped, adiponectin/leptin ratios increased - a higher ratio means less insulin resistance. We looked at the microbiome. In the microbiome we saw an improvement in diversity as well as composition of butyrate producers, suggesting an improvement in microbiome health as well.
Next, we looked at its effect on the immune function and we saw a reduction in CRP, or C-reactive protein, for seven patients who had baseline elevations; it dropped by 50% at end of study. The absolute neutrophil count also reduced as well as looking at further detailed immune subsets by flow cytometry we saw a reduction in the non-classical, or inflammatory, monocytes and an increase in classical, or anti-inflammatory, monocytes. This was consistent with single cell RNA sequencing analysis of the bone marrow as well where paired samples showed similar changes and shifts in the monocyte populations.
Lastly, we also did some exploratory analysis looking at the interaction between cell subsets in the bone marrow. We see that at baseline the myeloid compartment is interacting mainly with exhausted CD8 T-cells but at the end of study this moves to more of an interaction with cytotoxic CD8 T-cells and natural killer cells, suggesting enhanced anti-tumour immunity.
We also confirmed these findings in a mouse model that was done in Dr Matteo Bellone’s laboratory in Italy. What we looked at was a high-fibre diet in a smouldering myeloma Vk*MYC mouse model and showed that the high-fibre diet compared to the standard diet delayed progression. The median time to progression was 12 weeks on the standard diet versus 30 weeks on the high-fibre diet. Microbiome and immune changes were also consistent with what we saw in the human study, suggesting that we are seeing similar findings.
We also looked at the paraprotein changes in the human trial and what we saw was two patients with clearly rising M-spike had flattening or stabilisation. So the rate of change of M-spike before intervention to on and after intervention was statistically significant, suggesting that maybe in a subset of patients we may be able to delay progression with improving diet quality and microbiome and immune system.
So, with that, we are doing a much larger study, the NUTRIVENTION-3, that’s currently ongoing. In this study we are looking at over 150 patients, looking at diet, supplements, and its effect on progression and MGUS smouldering myeloma.
What are the implications of these findings?
As a patient with these precursor plasma cell disorders, the standard practice as of now is observation. It is quite unnerving for patients to be told that they have a pre-cancerous condition that may progress to cancer but there is nothing they can do but just watch and wait. If these findings hold true in larger studies, it can be extremely empowering to patients to make low-risk dietary changes and improve their lifestyle which may delay progression for them.
