Multiple myeloma (MM) is an incurable plasma cell neoplasm, the second most common hematologic malignancy characterized by neoplastic proliferation of plasma cells. Focused efforts are needed to reduce the burden of MM and improve MM specific and overall outcomes once MM is diagnosed. Several metabolic risk factors, such as obesity, diabetes mellitus, diet, and the human intestinal microbiome, have been linked to the pathogenesis of MM. This article provides a detailed review of dietary and microbiome factors involved in the pathogenesis of MM and their impact on outcomes, offering a comprehensive guide on the evidence available to date of the impact of dietary and other lifestyle interventions on the gut microbiome and on MM incidence, outcomes, and quality of life.
Understanding MGUS and Its Progression
Monoclonal gammopathy of undetermined significance (MGUS) is a noncancerous condition in which plasma cells release an abnormal protein into the blood. For many people living with MGUS, their biggest concern is that the condition will evolve into multiple myeloma, a type of blood cancer. MGUS is characterized by elevated levels of abnormal serum proteins produced by clonal plasma cells. Approximately 1% of patients with MGUS progress to multiple myeloma each year. There is no proven way to prevent the progression of MGUS into multiple myeloma. Given its vast impacts, researchers are looking for ways to delay progression from monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) to multiple myeloma. Doctors generally do not offer any kind of treatment for people who have it. Instead, doctors will monitor for any signs that a person’s condition might be progressing. Generally, a doctor will use blood tests to assess the risk of progression. These tests can evaluate the type and amount of abnormal protein in a person’s blood. For people with MGUS who are considered low-risk, follow-ups may be unnecessary, or a doctor may recommend these appointments happen every 12 months. Follow-ups are more frequent for those considered high-risk. This way, if the condition progresses, it can be caught early and treated immediately.
The Role of Diet and Microbiome
Diet is a major modifiable risk factor for cancer, and several studies have assessed the association between diet and MM. Dietary nutrient absorption and metabolism are facilitated by the gut microbiota. The microbiome plays key roles in absorption and energy utilization from soluble fiber, fats, proteins, and vitamins. Nutritional intake, in turn, directly impacts the human microbiome. In addition to participating in the absorption of nutrients, the microbiota also serves a role in immunologic stimuli and regulation of cytokine secretion in intestinal epithelial cells by activation of signal transduction pathways. The findings presented in this review will provide a comprehensive guide on the evidence available to date of the impact of dietary and other lifestyle interventions on the gut microbiome and on MM incidence, outcomes, and quality of life.
Plant-Based Diets and MM Risk
Epidemiologic studies suggested plant-based diets may reduce risk for MGUS and multiple myeloma. A pooled analysis of two large prospective studies (EPIC-Oxford and Oxford-Vegetarian) demonstrated significantly lower risk for cancer overall in fish eaters (Relative Risk, RR 0.88, 95% Confidence Interval, CI: 0.80-0.97), vegetarians (RR 0.89, 95% CI: 0.83-0.96) and vegans (RR 0.81, 95% CI: 0.66-0.98) compared to meat eaters. This difference was even more pronounced for MM in vegetarians and vegans (RR 0.23, 95% CI: 0.09-0.59) and in fish eaters (RR 0.80, 95% CI: 0.34-1.76) as compared to meat eaters. A pooled prospective survival analyses of 423 MM patients from the NHS and HPFS cohorts (345 total deaths, 295 MM related deaths) demonstrated 15-24% lower MM-specific mortality for presumed healthy pre-diagnosis plant based dietary patterns (HR range 0.76-0.85 per 1-SD increase in scores). Simultaneously they also saw a 16-24% higher MM-specific mortality in unhealthy pre-diagnosis dietary patterns (HR range 1.16-1.24, per 1-SD increase in scores). These findings suggest that pre-diagnosis high insulinemic or inflammatory diets are associated with higher MM risk and increased risk of MM related death whereas plant-based dietary habits may reduce risk of development of MM and risk of death once MM develops. Plant-based diets are high in soluble fiber with higher levels of bacteria from Bacteroidetes, Lactobacilli, Bifidobacteria and Clostridium clusters XIVa and IV. The latter groups contain Eubacterium, Roseburia, Faecalibacterium, which degrade fiber and produce short-chain fatty acids (SCFAs), such as butyrate, acetate, and propionate. Western diets are lower in soluble fiber resulting in less SCFA production. SCFAs have important roles in the immune response, preventing inflammatory disease states, and are associated with improved MM outcomes.
Fruits, Vegetables, and Whole Grains
In the AGES-Reykjavik prospective cohort study, fruit consumption (≥3 times per week during the adolescent period) was associated with reduced risk of MGUS (Odds Ratio, OR 0.62, 95% CI: 0.41-0.95). Additionally, fruit consumption during late life was associated with lower risk of progression of MGUS to MM (HR 0.34, 95% CI: 0.13-0.89). A recent case control study using the National Health and Nutrition Examination Survey (NHANES) showed low intake of fruits and vegetables was associated with lower odds of MGUS. Fruits are rich in dietary fiber and polyphenols. Dietary fiber is composed of soluble and insoluble carbohydrates including pectin and inulin among others. Pectin makes up 35% of fruit fiber cell wall and has shown to increase butyrate producing microbiota species such as Clostridium cluster XIV. Inulin, a natural storage polysaccharide, present in fruits like bananas, has been shown to increase Faecalibacterium prausnitzii, another butyrate producing bacteria. Additionally higher levels of SCFA have been seen in individuals adhering to a Mediterranean plant forward diet. Vegetables also have a similar favorable impact on the gut microbiome. Cruciferous vegetables are known to contain isothiocyanates, dithiothiones, glucobrassicin and indoles, as well as flavonoids which inhibit cancer development in laboratory animals. They also contain vitamin C, an antioxidant that reduces endogenous formation of oxygen-free radicals. These findings suggest an association between higher fruit consumption and reduced risk of development of MGUS and progression of MGUS to MM and higher consumption of vegetables especially cruciferous vegetables and tomatoes and reduced risk of MM.
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The AGES-Reykjavik prospective cohort study also demonstrated that midlife intake of whole wheat bread ≥5 times per week was associated with lower risk of MGUS (OR 0.75, 95% CI: 0.57-0.99). The NHANES study similarly showed that low intake of whole grains and high intake of refined sugars and sugar sweetened beverages was associated with the risk of MGUS. An integrated case control study in Northern Italy showed that higher frequency of whole grain food intake (>3 days/week) is associated with reduced MM risk (OR 0.5, 95% CI: 0.2-1.1). Whole grains also have a lower digestion rate and glycemic index with consequent lower rise in insulin and insulin-like growth factor-1 (IGF-1) levels. Both insulin and IGF-1 have been implicated in the pathogenesis of MM by promoting MM cell growth.
Fish Consumption and Omega-3 Fatty Acids
Most case control studies have shown an inverse association with MM risk and fish consumption. In the Connecticut women’s study, fresh fish intake >4 times/month (OR 0.4, 95% CI: 0.2-0.7, Ptrend < 0.001) and shellfish intake >3 times/month (OR 0.5, 95% CI: 0.3-0.9, Ptrend = 0.05) were inversely associated with MM risk. A similar protective effect of fish consumption for MM risk was observed (OR 0.7, 95% CI 0.5-0.9; Ptrend 0.012 for high vs low tertile of fish consumption) in the above-mentioned case control study. Fish and fish oils contain polyunsaturated omega-3 essential fatty acids (PUFAs) that are mainly responsible for the protective effect of fresh fish. They competitively inhibit arachidonic acid utilization in the production of eicosanoids, which have been implicated in tumor progression. PUFAs have been shown to decrease ratio of Firmicutes/Bacteroidetes, and increase abundance of butyrate-producing bacterial genera such as Bifidobacterium, Lachnospira, Roseburia and Lactobacillus. Thus, fish consumption maybe protective through multiple mechanisms.
Red Meat, Eggs, and Dairy Products
There was no statistically significant association between intake of red meat and MM risk (OR for the highest vs lowest tertile 1.4, 95% CI: 0.9-2.2) in a case-control study conducted in Northern Italy. The case-control study from Belgrade, Yugoslavia, suggested that MM cases more frequently consumed meat (7 times/week) when compared with controls (OR 1.9, 95% CI: 0.9-3.9). Additionally, the EPIC-Oxford Cohort and NHS and HPFS studies showed a reduced MM risk in those eating a plant-based diet and increased risk in meat eaters and those eating a Western diet suggesting that meat intake impacts MM risk.
There is no definitive data for egg consumption and MM risk. The case control study from Connecticut outlined above demonstrated a higher risk for MM with the highest intake quartiles of cream soups (OR 2.5, 95% CI 1.3-4.6, Ptrend = 0.01), ice-creams and milkshakes (OR 1.5, 95% CI: 1.0-2.3, Ptrend = 0.01), pudding and custard (OR 2.4, 95% CI: 1.4-4.0, Ptrend < 0.001). Consumption of yogurt in the case-control study from Belgrade, Yugoslavia was also associated with increased MM risk (OR 3.1, 95% CI 1.6-6.0).
The NUTRIVENTION Trial and High-Fiber Diets
At the ASH (American Society of Hematology) Annual Meeting in December 2024, Dr. Shah presented promising results from a clinical trial called NUTRIVENTION that she led. The trial used a food company to deliver high-fiber, plant-based food to 20 participants with MGUS or SMM for three months. The trial also provided health coaching for six months. Over the course of a year, the trial found that people lost weight, enjoyed better quality of life, improved metabolic markers such as cholesterol and insulin, and saw an improvement in biomarkers that measure the health of the immune system and microbiome. Two participants had improvement in their disease-progression trajectory as well.
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The researchers observed improvements to several modifiable risk factors in these patients, including:
- Metabolic profile (improved BMI, insulin resistance, and adiponectin leptin ratio)
- Microbiome profile (increased alpha-diversity and butyrate producers)
- Immunity (decreased inflammation and increased anti-inflammatory classical monocyte)
Additionally, a reduced long-term progression trajectory was observed in two patients.
The researchers also conducted a separate trial on mice presenting a pre-cancerous condition similar to MGUS. Forty percent of the mice that were fed a high-fiber diet did not experience progression to cancer during the study, while all mice in the control group progressed.
Overall, these findings suggest that a high-fiber, plant-based diet has the potential to delay progression from MGUS/SMM to multiple myeloma.
Dietary Recommendations for Patients with MGUS/SMM
Patients can benefit from a diet primarily made up of whole foods that are low in processed sugars and saturated fats. Here’s what you can recommend to patients to help them incorporate more fiber into their daily lives:
Read also: Weight Loss with Low-FODMAP
- Fruits and vegetables, like berries, apples, pears, bananas, leafy greens, and cruciferous vegetables
- Legumes and beans, which can help provide protein in a plant-based diet
- Nuts and seeds to improve satiety and support metabolic health
It’s important to emphasize quality over quantity. Some patients on the trial will say, “I feel like I’m eating way more carbs than I used to.” Or they worry that the meals on the trial might be too carb-heavy. But they don’t realize that they are also high in fiber - whole grains, beans, vegetables.
Patients also wonder what exactly it means to eat whole-food, plant-based. Some people go vegan for ethical and environmental reasons, because they don’t want to hurt animals and know about the increased global-warming potential of animal-based foods. Vegetarians are often motivated by ethical or religious reasons.
People should try to get at least 80% to 90% of calories from unprocessed plant foods. If a patient tries to go 100% plant-based for a few weeks without planning the foods they will eat, then they may not be able to sustain the diet. So it’s more important that the changes are gradual and sustainable.
Addressing Common Misconceptions
People often think that eating carbohydrates will feed their cancer, so they try to cut them out of their diet completely. However, it is important to know that not all carbohydrates are the same. They can be refined (simple) or complex. People should avoid refined carbohydrates such as cookies, cakes, and croissants. But they should not avoid complex carbohydrates such as whole grains, beans, fruits, and vegetables. They are associated with reduced cancer risk.
Also, people will sometimes say, “A plant-based diet is not for me because I am not satisfied.” Or, “I won’t get enough protein.” However, contrary to popular belief, dietary fiber is associated with people feeling more satiated.
Clinical Trials and Specialty Centers
Some hospitals have specialty centers that bring together research, clinical trials, and clinical management of MGUS and smoldering multiple myeloma (SMM), both of which are considered multiple myeloma precursor conditions. Examples of these specialty clinics include:
- Center of Excellence for Multiple Myeloma and Multiple Myeloma Precursor Clinic at Mount Sinai Tisch Cancer Center, located in New York
- Center for Prevention of Progression at Dana-Farber Cancer Institute, located in Boston
- MGUS Clinic at Penn State Cancer Institute in Hershey, Pennsylvania
Clinical trials - research studies evaluating treatment effectiveness on people - are underway to test prescription medications and lifestyle interventions. You may qualify to join a clinical study on MGUS.