IBC 2025 | The potential of non-drug interventions in SMM and MGUS: diet and lifestyle

So when we think about these pre-cancerous or precursor states and the risk of progression to cancer, there are two main factors at play. It’s the genetics of the cancer or the pre-cancer and the immune system that’s trying to keep this in check. So if we could, with modifiable risk factors, affect or improve immune function, could we delay progression to cancer, given the genomics or the genetics is not something that’s so easily modifiable. And so that was the reason behind our new prevention study where we enrolled patients with MGUS and smoldering myeloma with a BMI over 25. We enrolled patients and provided a high-fiber plant-based diet over three months and followed them for a year on the study. These were 20 patients; they also had a BMI over 25, so overweight or obese, because we do know that elevated BMI is associated with increased risk of progression. And we used the intervention of a high-fiber plant-based diet because we know that people who eat more plants tend to potentially have less myeloma based on large population studies, but this is something that we want to study in interventional trials. What we did see is that the intervention was well-received. There was improvement in diet quality, improvement in dietary fiber intake, BMI reduction by about 7% that was sustained to one year later, as well as improvement in quality of life. We also saw an improvement in markers that are associated with progression, such as insulin resistance, the microbiome. So we saw improvement in microbiome diversity, as well as a change in the bacteria with more butyrate producers considered healthier bacteria. And with this, we then wanted to look at what happens to the immune system and does the immune function change when we change the microbiome, the weight, and also the insulin resistance. And what we did see is that the immune system was less inflamed and potentially had more anti-tumor immunity in some ways. So we saw lower C-reactive protein where it dropped by half in those that it was elevated. We saw a reduction in the neutrophil count, so that also suggests less inflammation. And we also saw that there were changes in some immune subsets. So when we think about smoldering myeloma and MGUS and progression, we know that CD14, CD16 monocyte balance is altered. And we did see this alteration kind of reverse or switch back into more CD14 monocytes that are considered anti-inflammatory and less CD16 monocytes that are inflammatory. We saw similar patterns in the bone marrow where we looked at single-cell RNA sequencing between baseline and one year. And what we did see is there was an increase in these CD14 monocytes and granulocyte monocyte progenitors suggesting increased immune potential but just not circulating neutrophils given there’s less inflammation. And then lastly, when we look at interactions between immune cells, we did see that at baseline, the immune cells, the myeloid cells, so the monocytes, were interacting more with the exhausted CD8 T-cells, so an exhausted immune system. And then at the end of the study a year later, they were interacting more with the cytotoxic CD8 T-cells, suggesting enhanced immunity. In collaboration with Dr Matteo Bellone, we evaluated this in mouse models, too, and were able to show that a high-fiber diet in mice leads to a delay in progression to myeloma in the smoldering myeloma mice. And half of the mice on the high-fiber diet never progressed versus all the mice in the standard diet progressed to myeloma. And this effect, based on further experiments, we think it’s related to the effect of the fiber, not just calorie restriction, because sometimes people think maybe the person’s losing weight, and the calorie restriction is all that’s needed, and they don’t need to change diet quality. So that’s basically a summary. And then lastly, the most important thing is whether this could truly delay progression. This was a small study with a very heterogeneous population in terms of progression time, and some of them didn’t have M spikes before going on study. But there were two patients who went on the study who had clearly progressing disease before going on the study, and we did see slowing of disease progression by looking at a rate of change of M-spike per month for 20 months after the study compared to before the study, and these were statistically significant, suggesting that at least in some patients, we may be able to delay progression with improvement in immune function.

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