In honor of Multiple Myeloma Awareness Month, Dr. Rahul Banerjee, Assistant Professor at the University of Washington and Fred Hutchinson Cancer Center, and member of the Oncology Data Advisor editorial board, speaks with Dr. Urvi Shah about the importance of ensuring proper diet and nutrition, as well as the impact of the microbiome, for patients with multiple myeloma.

Rahul Banerjee, MD: Welcome to Oncology Data Advisor, a digital resource for the multidisciplinary cancer team. My name is Dr. Rahul Banerjee. I'm one of the editorial members. This month, in honor of Multiple Myeloma Awareness Month in March, I'll be speaking with faculty experts across the country about things that we think are very important for patients with multiple myeloma and that don't really get discussed quite as much.

Today it's my privilege to be interviewing Dr. Urvi Shah, an Assistant Attending on the Myeloma Service at Memorial Sloan Kettering Cancer Center in New York, who is an expert on all things in myeloma but most particularly an emerging expert in diet, nutrition, microbiome, and those kinds of things that we really get zero exposure to in medical school. Dr. Shah, Urvi, if I may, it's a pleasure to speak with you today.

Urvi Shah, MD: Thank you, Dr. Banerjee. I'm excited to speak to you about these topics.

Dr. Banerjee: Absolutely. I'll start with the fact that I think the number of days I spent in medical school learning about diet and nutrition is officially zero. With that in mind, what should doctors and patients know about diet and nutrition in this setting? Let's start with active myeloma, so not so much prevention; but for patients who have myeloma, what's important, do you think, for physicians to know? And then what's important for patients to know?

Dr. Shah: That's a very, very important question, and it's a relatively understudied area. We have a lot more data in the prevention setting and survivorship setting around cancer, but during treatment, there is a little less data just because those require randomized studies or better trials to be done. That being said, I think it's important to meet a patient where they are in terms of what they want at that time. Often, I think oncologists tend to dismiss these questions or feel that a patient needs to focus on other things, but I think looking at the whole picture is important. If a patient is very motivated to make changes during their treatment, then it's important to discuss that with them.

For the most part, however, I would also caution patients that when they are on active treatment, the treatment is, of course, priority—getting used to it in terms of the chemotherapy side effects and the treatment response. Trying to make all the changes at once can sometimes be challenging or difficult, and I would not rush to that, because dietary changes can be gradual over time. It's important to start learning about it and thinking where the changes can be made, but they don't all need to be made immediately when we start the treatment.

The last thing I'd say around this topic is that patients have different nutritional needs, and we also need to understand that, especially around treatment. Depending on the treatment and depending on how much weight loss they've had from the diagnosis—or maybe they've had no weight loss and they have a high body mass index (BMI)—what is their dietary pattern to begin with, and how different is it from something we would recommend? A simple way to look at it is by looking at the American Institute of Cancer Research guidelines. Those are mainly around cancer prevention and survivorship, but they do talk about plant-based diets and why that is important.

Within the myeloma space, Dr. Lesokhin and I have done a study at Memorial Sloan Kettering where we looked at stool microbiome, stool metabolites, butyrate levels, and dietary factors, and we correlated this with looking at sustained measurable residual disease (MRD) negativity, meaning a long-term complete remission in patients on lenalidomide maintenance. This is after their induction chemotherapy, and maybe transplant, but when they're in the survivorship space. Then we look to see if there were any changes that were associated with response and a sustained MRD negativity. What was interesting is we saw that patients who had more microbiome diversity, as well as increase in stool molecules such as butyrate, had higher rates of sustained MRD negativity or complete remission. These butyrate molecules are molecules that have anticancer, anti-inflammatory effects, so we think that may be what's playing a role in this association.

Then we looked at dietary factors, because we know from other studies, not in myeloma, that patients on plant-based diets actually have higher butyrate levels than patients on animal-based diets. We saw that patients who have higher plant and seafood protein intake actually had higher butyrate levels. We also calculated the plant chemicals that patients ingested in terms of the phytochemicals in flavonoids—these are healthy molecules seen in plant foods. What we saw is that patients who consume more of those foods actually have a higher butyrate level, suggesting that the plant-based sources of protein are likely to be associated with the butyrate. Of course, this is a small study, and this is exploratory, so I would caution in terms of what we see, but this gives us food for thought in terms of what we can do going forward or what to think about.

With that, I feel that quality of protein is more important than quantity. In the US, we are protein-obsessed, but I think we need to be quality of protein—or quality of food—obsessed. We also need to think about fiber. Nobody thinks about fiber, but fiber is, I think, a bigger friend than protein, and it only comes from plant foods. In the US, less than 5% of individuals meet their fiber requirements. Actually, if you survey the general US population, 67% of the US population thinks they meet their fiber requirements, but in reality, only 5% do. But when we talk about protein, it's almost the opposite, where most people think they need more protein, but almost everybody meets their protein requirement. As long as you're not calorie-deficient or malnourished, or you're not eating, you will get your protein. I think understanding that is important.

Dr. Banerjee: This is very helpful, and I appreciate those specifics, as well as the quick "food for thought" joke. I don't know if it was a joke or not, pun intended, that you had in there earlier.

Dr. Shah: Yes.

Dr. Banerjee: I just want to stress to the audience that this is not just bench to bedside; this is almost like molecule to mouth—surveying patients and then also looking at their microbiome, levels of proteins, and their stool. I think it's just a very wide-scoping translational and clinical project, so thank you for leading that. Segueing from past to future, I know that you have a couple of trials open right now looking at some of these topics prospectively in the New York area. Can you speak to what you're working on now?

Dr. Shah: Sure. We have four NUTRIVENTION trials either open or going to open in 2022, and I can discuss them briefly, but maybe I'll just give you a short background of why we're doing these trials. In cancer, we know that diet plays a role in terms of the large epidemiologic or population studies saying that patients who eat healthier diets—meaning more plant-forward or plant-based diets, more plant foods—tend to have less cancer. This has been seen in cohorts of three large-scale studies of more than 50,000 participants: one in the UK, one in the US, and one in France. One of those studies, the EPIC Oxford cohort, was part of a study of over 60,000 participants from the UK. In that cohort of participants, 65 of them developed multiple myeloma. They divided the patients in that cohort into meat eaters, seafood eaters, and vegans and vegetarians combined, given that was a small population. What they showed was a 77% relative risk reduction in development of myeloma amongst the vegans/vegetarians compared with the meat eaters. They had less myeloma overall.

That's one large population study, and then the second large one that we have in myeloma is the Nurses' Health and Health Professional study from the US. They looked at over 160,000 participants, and in that, they found 423 cases of myeloma. They looked at the pre-diagnosis diet, and they linked it to myeloma risk of death. What they showed is that patients who ate more of Mediterranean, Prudent, or Dietary Approaches to Stop Hypertension (DASH) diets—all of these, again, are plant-based diets and healthier dietary patterns—were associated with 15% to 24% lower myeloma death on diagnosis. The Western inflammatory diets were associated with a 15% to 24% increased risk of death, so we are seeing similar patterns across multiple studies.

Then we also know myeloma is one of the 13 cancers associated with obesity, and we know that BMI plays a significant role. There are hundreds of studies that have looked at BMI and myeloma, and we published a review around that. One of the studies showed that obese patients are 1.8 times more likely to develop monoclonal gammopathy of undetermined significance (MGUS), and another study showed that they're twice as likely to progress from MGUS to myeloma. Similarly, there are studies showing increased risk of myeloma development with increased BMI, as well. We also know that diabetes is associated with cancer and myeloma. We just don't know whether it's causative or just a correlation in terms of the same risk factors causing both of them, but we know that there's an association there.

We know that there are all of these metabolic risk factors, and we know that nutrition plays a role. We also know that there are preclinical studies and smaller studies around the microbiome showing that bad bugs are associated with progression and things like that. We felt that it would be important to study it in a prospective setting, meaning in an interventional study setting. We also surveyed patients around this topic and said, "Do you want studies like this?" or "Is something that you would be interested in?" Overwhelmingly, 82% of participants, over 400 that we surveyed, said that they would be interested in knowing more around diet and nutrition, that they had questions around it, and that they'd like to make changes. That's part of the background of why we do it, and then I can go through the studies.

Dr. Banerjee: I'll ask one question, and then I would love to hear that, and you may be about to answer it. In most of the studies, is it unclear whether it's just higher rates of plasma cell dyscrasias in general, including MGUS, or is it that once you have MGUS, the inflammation leads to a high risk of progression to myeloma? You did mention one where you said that obesity was independently linked with both higher rates of MGUS and plasma cell dyscrasias, and also with a higher risk of progression for the MGUS patients.

Dr. Shah: Correct. That was for obesity. We don't have data around nutrition for that, but their risk is similar to what it is for myeloma; it could be for MGUS, but we don't really know.

Dr. Banerjee: Flipping to prevention, for patients with MGUS or smoldering, I think some of your NUTRIVENTION studies are in that space, so I would love to hear more about them.

Dr. Shah: Thank you. Yes, the NUTRIVENTION pilot study that we started last year in June is a 20-patient study open at Memorial Sloan Kettering Cancer Center. It's currently enrolling, so if a patient is interested, they could reach out to us. We are taking patients who have either MGUS or smoldering myeloma with an M-spike more than 0.2 or a normal light-chain ratio and a BMI over 25. Patients are given three months of a whole food plant-based diet. We actually ship them meals, and we provide nutrition counseling as well. For 12 weeks, we provide the nutrition counseling, and then we follow them for a year on the study. We look at changes in weight, inflammation, microbiome, and metabolic factors. The study is enrolling pretty quickly, so I'm hoping by the end of this year, we'll be able to share some data around it.

Dr. Banerjee: Thank you. That's very impressive, because I agree with you that I think most patients want at least some counseling about what to do in terms of diet and nutrition. I think this is a more robust study looking at what outcomes you'll see if you actually give them the whole plant-based diet. This is very helpful, and I think the takeaway, at least for me and for the audience, is that a plant-based diet—and I might ask you at the end for what specifically you counsel patients about on a plant-based diet—is certainly helpful, or at least the study suggested might be helpful. Two, you don't need to do it all in one day. I agree with you—I think that for a lot of our patients, we tell them, "Do this, do that, get your echocardiogram done, start the aspirin," and in the course of the week, everything changes. This is more of a gradual and durable change you're hoping for them to do and not something to rush into.

Dr. Shah: Right. For the study, we are partnering with a company, Plantable^®, that provides their meals and then also some of the health coaching for the patients. We know they're high-fiber plant-based healthy foods with low oil-processed ingredients. The second study we have is the NUTRIVENTION-2 study that will open later this year. This is in partnership with the Health Tree Foundation. We'll only enroll patients with smoldering myeloma across the United States, so patients can be in any state as long as they live in the US. This will be a very short telehealth study where they will ship us stool samples and we will be sending them either supplements or diet to their homes. All of it will be through telehealth virtual interactions. It's only a two-to-three–week intervention, but it will give us an idea, because microbiome changes happen quickly. This is what we'd like to see with different supplements and diet: what the changes are on the microbiome. This will be a 100-patient study.

Dr. Banerjee: It's multistate, and I like the decentralized idea of working with patients by not making them come into the clinic to do all of this. They provide stool samples from home.

Dr. Shah: Yes. We're trying to simplify it as much as possible. If this works, we could do more studies quicker because of that too.

Dr. Banerjee: I totally agree. I'll pivot slightly—so for patients who actively have myeloma, the ones that we see most typically in our particular respective clinics, a lot of them ask about diet and nutrition changes. This is sometimes for the myeloma itself; but a lot more, they say, "Look, you told me bortezomib causes neuropathy; you told me lenalidomide causes fatigue; you told me dexamethasone makes me angry and irritated and not sleep well." Are there specific things that you recommend to patients in terms of diet and nutrition, or anything holistically in terms of the treatment toxicities they can expect with therapy?

Dr. Shah: One of the vitamins that I always check and follow up on is the vitamin D level. I do like to see them close to 30 ng/mL, or a little bit over 30 if possible. There are studies in myeloma showing decreased overall survival with lower vitamin D levels. Of course, these are association studies; it's not an interventional study showing that if you increase the level, it's going to make a difference, but with the data we currently have, that's the best we could do. Sometimes there is association with taking vitamin D and improvement in fatigue or a generalized feeling of wellness, so I think it's something that has a low risk and possible benefit. That's one thing I do. The other thing is looking at anemia and if there are any causes that are easily fixable.

All of these are medical things, like thyroid levels, but then I also talk about overall lifestyle changes. It really depends on if a patient's interested, because many are, but many aren't. It just depends on where they are in their stage of treatment and if they're interested. Things like overall diet quality, I think, can improve energy levels and feeling better overall. Trying to move to eating a healthier diet and more fiber-rich foods are things that I talk to patients about. Then, of course, I talk about exercise, weight management, and other lifestyle changes, because all of those things can be associated with inflammation and fatigue. If it's something like bortezomib-induced neuropathy, then it's mainly due to the side effect of the chemotherapy; but if they have modifiable factors like diabetes or any vitamin deficiencies, then I think those could also be addressed. I always check B12, B1, B6, vitamin D, and A1C when they have neuropathy, just to make sure there's no modifiable factor that we could quickly fix.

Dr. Banerjee: That's a good point, because these patients are in it for the long haul in terms of living with myeloma for years, hopefully. Identifying the modifiable things is important. This is very helpful. Thank you, Dr. Shah. The last question I'll ask is another future-oriented question about the microbiome, so poop samples. I could imagine a future where you titrate someone's intake of plants to titrate a certain amount of butyrate in their stool, or perhaps you tailor what supplements you give or even what therapies you use based on what their microbiome or their stool samples show in terms of composition. What do you see? Where do you see the future of the stool movement going, so to speak, in terms of what it might hold for the future of myeloma?

Dr. Shah: That's a great question, and I think we're going to see a lot more of that personalization going forward, especially with immune therapies being around. We are actually more microbiome than human cells. If we think about the number of cells, we are more microbiome cells. The genetic code of our body is something that we can't really change; it's kind of what we are born with. But the microbiome is something that's easily modifiable, and it has a significant immune modulation potential and properties, so I think we're just scratching the surface in terms of looking at it—not just in myeloma, but in general with cancer and overall health. I think there is significant opportunity in that to make an impact.

The question now is more about how we can tailor it to individual needs and understand what each person needs or what is going on in the microbiome, especially with certain diseases. We know that diet is one of the biggest factors that modulates the microbiome, so we can obviously work with that. Then we know that there may be some supplements or things that could be affecting it. That's why in our NUTRIVENTION-2 and -3 study, we are looking at supplements that can modify the microbiome to maybe improve these better bacteria and better stool metabolites. If we see a signal around that, then we know that maybe this could have a long-term beneficial effect—so trying to modify the microbiome, ideally. I think diet is the most data we have just now, but if a patient doesn't want to change their diet, can we do it with supplements? Trying to figure that out for the future is part of what our trials are looking at.

Dr. Banerjee: I think that's tremendously important. With a lot of our patients who are hospitalized with myeloma, I joke to them that their number two is my number one priority, in terms of just having regular bowel movements. So this is another level—it's not just the bowel movements that matter. By that looking at the stool microbiome, exactly as you said, I think the microbiome modulates both the underlying myeloma and our therapies for myeloma much more than we realize.

Dr. Shah: There's a good example from the melanoma world where checkpoint inhibitors—although we don't use those in myeloma much—had the longest progression-free survival (PFS) in patients who were taking sufficient dietary fiber and no probiotics. This was published in Science. Probiotics didn't help and may have had a negative effect in that study, but the fiber was what was important for patients to be taking—not as a supplement, but dietary fiber.

Dr. Banerjee: This is fascinating. I did not know that, and it's a good example of why we need future research in this area. I'm glad that you are at the helm of this ship, driving the field forward. Any parting remarks or anything else you'd like to say before we close?

Dr. Shah: I'd just like to mention two other studies that are going to open in case patients are interested. The NUTRIVENTION-3 study, similar to our NUTRIVENTION pilot, is a more than one year study for patients. We have three arms in that study: there's going to be a diet arm, a supplement arm, and a placebo arm. The supplement and placebo arms also will get the diet eventually; so everybody gets the diet, but there will be some who also get the supplement. We're going to be able to see the effect of just supplement alone, supplement with diet, and diet alone, and we'll be able to see what the changes are on the microbiome and myeloma progression in MGUS and smoldering patients.

Then the NUTRIVENTION-4 study is for patients in the survivorship space. This is the one study of patients who are post–induction/chemotherapy and who are on maintenance therapy. We have a study open, so they need to be part of that study to go on this one, and that study is looking at lenalidomide versus daratumumab as a quality-of-life study. It's a 100-patient study of maintenance therapy, and amongst that we will have around 30 patients—15 in each arm—go on to get a diet and then evaluate the effects combining it with the immune system, immune therapies, and the microbiome.

Dr. Banerjee: That will be fascinating. I'm sure that lenalidomide and daratumumab will affect the microbiome in different ways based on their properties in cells, so this will be interesting. I'm looking forward to seeing these. Dr. Shah, thank you so much again for your time. This has been really illuminating for all of us, and as you said, food for thought. Again, thanks to the audience for listening. My name is Dr. Banerjee, and this has been Oncology Data Advisor.

About Dr. Shah and Dr. Banerjee

Urvi Shah, MD, is an Assistant Attending Physician in the Myeloma Service at Memorial Sloan Kettering Cancer Center in New York. She specializes in the treatment of patients with multiple myeloma, smoldering myeloma, and related plasma cell disorders. Dr. Shah's clinical and translational research focuses on nutritional and metabolic factors in plasma cell disorders, as well as immune therapies. She is studying the link between nutrition and myeloma via immune, epigenetic, and microbiome mechanisms. In 2021, Dr. Shah opened the first nutrition trial in plasma cell disorders to date, the NUTRIVENTION study, which is currently enrolling, and she has 3 other NUTRIVENTION studies in development that will open in 2022.

Rahul Banerjee, MD, FACP, is an Assistant Professor in the Division of Medical Oncology at the University of Washington (Seattle, WA); he also holds a faculty appointment at the Fred Hutchinson Cancer Center. He previously completed his Hematology/Oncology Fellowship and Advanced BMT/CAR-T Fellowship at the University of California, San Francisco. His clinical interests are in multiple myeloma, AL amyloidosis, and CAR-T therapy. His research interests are in toxicity management, digital health, and the patient experience.