(Guest Lecture) January 2021 Modifiable risk factors that affect Myeloma Pt. 1

Hello everyone and welcome to the launch of our nutrition and wellness chapter. I hope you're having a great morning or afternoon depending on where you are located. I know it has been a bit of a crazy morning for Dr. Shaw and I. I would like to start. So thank you for sharing this time with us. Let's get started on our very first event of this nutrition and wellness chapter. All right. I am Audrey Burton Bethke. I am the Myeloma community director that includes events and building our community in different ways. Our nonprofit is founded by Jenny Alstrom, a Myeloma patient who was diagnosed in 2010. She has worked tirelessly to provide incredible programs and resources to Myeloma patients including this Myeloma community program that you are now a part of. So today we would like to thank our sponsors without whom this event would not be possible. Bristol Myers Squibb, Amgen oncology and Cario Farm Therapeutics. This meeting will be recorded and sent out to all registrants within 24 to 48 hours after the meeting has ended along with the slides that are shared. Let's talk about this event. We often get asked how Myeloma patients can have the best outcome. While this disease runs through our bodies, we want to be as healthy as possible in order to have the best chance of fighting the disease. We want to give our bodies and ourselves the best chance for survival but also the highest quality of life. Just like each Myeloma case is different, there is not a one size fits all diet and a perfect weight that we recommend that you be. But there are things that you can be in control of that help your outcome. And that is what we have invited Dr. Shah to talk about today. Let me introduce Dr. Shah. This is my privilege. Dr. Shah is a faculty on the Myeloma Service Division of Hematologic Malignancies at Memorial Sloan Kettering Cancer Center. Her research focuses on studying the role of diet, microbiome, and other lifestyle related risk factors in plasma cell disorders, as well as identifying interventions to improve outcomes for these patients. She also studies immune therapies, including CAR-T cell therapies for Myeloma. Being a lymphoma survivor herself, she is passionate about helping patients make wise nutritional and lifestyle choices as they face a plasma cell disorder diagnosis, as well as raising awareness about healthy choices to prevent cancer. Dr. Shah, it's such a privilege to have you here and we are so excited to hear more. So with that, I will turn the time over to you. Great. Thank you, Audrey. I'm really excited to be here. I think this is the first of its kind in the sense that patients are now asking these questions, living longer, doing so much better. And I think it's very important that we as oncologists start addressing these issues and not just focus on the medications and only thinking about survival from that point of view, but looking at it as an overall lifestyle and what we can do. So I'm going to go over, like we've done this as a two part series. So the first one, we're talking about metabolic and microbiome related risk factors. And then the next part of the second part will be more based on nutrition and supplements and things like that and what evidence is there behind it. So I feel this talk will be a good segue to that and helpful to understand. Sorry, I'm having issues changing the slide. So this is an outline basically talking about the plasma cell disorders overview, the importance of nutrition, the incidence of myeloma globally, obesity, diabetes and the microbiome. So these are some of the things I'll touch on today. However, I do want to say this, that having myeloma for many patients is obviously very challenging. I do take care of many. And one thing is that all of this is evidence or information to help you choose and make wise choices. But while you're undergoing chemotherapy or while you just get diagnosed, there's a lot of other things that are overwhelming. So I don't want you to feel that hearing all of this means you're more overwhelmed or you have more to take care of. This is more to empower you to think about what you could do. And it doesn't have to be immediately while you've just been diagnosed or while you've just started chemotherapy. This is more a long term thing so it can gradually change over time, but things to think about. So I'm sure most of you know what all of these disorders are, but I just put a slide in because we'll be using these terminology and I don't want it to be confusing for patients. So MGUS, as you know, is the precursor stage where it's very small amount of protein, usually less than 10% in the bone marrow of plasma cells and no symptoms. And this is usually found because they go to you go to a doctor for something else and they do testing and they find it. And very few of these patients eventually do develop myeloma, but there is a risk and it and it's about 1% per year. The small ring myeloma is considered the next stage in some ways where there is a little higher amount of these abnormal plasma cells, the protein levels are a little higher, but again, no symptoms and about 10% per year progress to myeloma. And again, it's usually not treated, although now we do see studies in the high risk small ring myeloma setting. And again, it's a multiple myeloma, which is the same is similar to small ring, but presence of end organ damage as well. So why is this important? Yes, you could say like, oh, I've already got this disorder. Why do I need to do anything different? Because I already have it now, but it's not it's not just about getting diagnosed with myeloma or a plasma cell disorder. It is to prevent one is other cancers or other medical conditions of prevention, treatment, it's hard for a doctor to be giving all the chemotherapy. Like if a patient has cardiovascular disease or the patient has diabetes, cardiovascular disease and carfilzomib is an issue. Diabetes and steroids are an issue. Renal disease, some of the medications are cleared by the kidney. So there are a lot of things that affect treatment stem cell transplants. If a patient has too many medical issues, that's hard to do. So I think improving your health overall with all those things also help to get the best treatments and that would improve outcomes as well. And then if you're in remission after you've finished your myeloma treatment, it's still important at that point because you want to one reduce the risk of myeloma coming back, but you also want to reduce other medical problems and other cancers from developing. So I think this is important at whatever stage you are in whatever disease you have. I think it's important for healthy people as well who don't have any of these medical conditions. So this is just a slide not specific to myeloma, but just to give you a sense of preventable causes of cancer. For myeloma, we'll talk a little bit more in detail, but I just wanted to show you that almost a third of cancers could be prevented by just healthy lifestyle choices. And they play a role in many cancers. We kind of underestimated and mainly think that all of it is genetics. So up until now, like in the 1960s and 70s and 80s, myeloma patients, we told them, oh, we don't have the outcomes. I'm great. We don't have much options for you. There are these few drugs. So the focus was on just getting them these drugs and helping them at least live longer in that time. But now, since the 2010s and 20s now, as we have more and more drugs, myeloma patients are obviously living very long times. So it is important to shift our focus not just to the drugs, but also to survivorship, prevention of other diseases, other medical conditions. And that's, I think, what we as researchers need to start thinking about where we it's still in the very early stages and very few are thinking about it. So here's a patient I had once. It's an extreme but not uncommon example of a list of comorbidities. So this is a patient with myeloma. Obviously, I'm an oncologist, so my job is to focus on the myeloma, not all the other issues, but all the other issues play into how I can treat the myeloma. Right. Like, can I do carfilzomib? Can I do bortezomib because of neuropathy? Or can I, you know, all of these things affect how much steroids I can do? All of these things affect how I can treat and how treatment gets interrupted. I have highlighted in green some of the disorders that I believe may not have been like having a good lifestyle or healthy diet over the years might have prevented those medical conditions. I'm not saying that everything can be prevented by nutrition and even that, like nutrition is improving your odds, but it's not, it's not the solution to everything because, you know, many of us do eat really well and still develop something, so I'm not saying that that's the only thing, but we can, that certainly improve our odds. So this is a slide showing you the global incidence of myeloma. And what you can see is that the US, the UK, some parts of Europe, Australia have the highest incidence, and you could say that this could be because they are developed countries, they are more accurate in detecting myeloma and capturing it. And so maybe that is part of the reason why it's higher, but it could also be differences in vitamin D levels because these are at higher altitudes or lower, like latitudes. Or you could talk about differences in obesity, differences in diet, maybe genetic differences, but there are environmental differences that could play a role in these differences in myeloma in different countries. So all of us actually make cancer cells all the time, every day, every hour, but we have a good immune system that fights it. And it's literally a battle or a balance between your immune system and cancer cells. And because our immune system keeps it in check, we don't develop cancer. But sometimes this balance goes off and then you end up developing cancer. And that could be in states where there's a predisposition, inflammation, other factors, all the other things that we'll talk about. So here is what I basically explained. Like you have the immune cells. And then you have the immune cells and the tumor cells. And if you have your body is in balance, your immune cells are able to eliminate the tumor cells. But if you have to once the tumor grows to a certain size, your immune cells are no longer able to do it. That's why we need the help of chemotherapy, immune therapy, all of these treatments. And that's when it's usually detected, because if it's very small amounts, you know, where there are a few cells, we're not really going to find it usually. With myeloma, we have the advantage that we have these precursor conditions. So what about the rising? So this study was done in 2019 that showed between 1995 and 2014, there was a rising incidence of multiple different cancers they discussed. And one of them was myeloma. They said there's a 2.21 percent increase in the incidence of myeloma in patients between the age of 25 and 50. Myeloma is generally considered a disease of the older age group. So having starting to see this increase in the younger age group is concerning in from a public health perspective. And what could these reasons be? I think, you know, we can speculate it's hard to make conclusions or prove, but the rising obesity epidemic changes in diet and how we eat more processed than inflammatory foods, which was never the case before. And, you know, other environmental factors, obviously pesticides and things could also play a role. So this is just showing you how obesity plays into cancer. And there are actually 13 cancers that have been very clearly associated and myeloma is one of them. So from 1999 to from 99 to 1000 through 2017 to 18, the prevalence of obesity increased from 30 to 42 percent. So just think about it, that 42 percent of the U.S. population is obese and about one third of the population is overweight. So less than one third of the U.S. population has a normal weight. That is an issue because that's part of the reason why we're seeing increased incidence of so many medical conditions and cancers. So this is a slide showing you high levels of obesity. The U.S. is probably the highest, about 35 percent. Many other countries are at 30 percent, but ideally we should be here, right? Like this should not be an issue. This is a slide showing you overweight or obese, again, very similar. So I'm going to now focus a little bit on myeloma and BMI. So what is the data available? And this is, you know, to understand the slide, just look at the number here. This says one, anything that crosses one, meaning that the red line goes beyond one where you see some of these just go beyond that study is not statistically significant. If it doesn't cross one, these these red lines, that means it's statistically significant and anything on the side of greater than one means there's an increased risk. Anything on the side of less than one means there's a reduced risk. Now, these are all the studies that have been done for myeloma looking at relative risk, odd ratios, hazard ratios, and very consistently you see that the risk is increased pretty much in every study that was done. Some of them were sort of trend towards significance, meaning that it crossed this black line and it wasn't significant. But, you know, looking at the overall slide, you can say that there is an increased risk. I focus on a few studies. These slides are a little bit busy, but I will walk you through them and tell you what to focus on. So this slide looks at obesity and the risk of MGUS. So you have three studies that looked at it. Patients who had a BMI over 30 showed an increased risk, meaning they were 1.8 times more likely to have MGUS than if they were of a normal weight. These studies didn't show significance, but they had a trend towards it in the sense that, you know, the odd ratio is higher than one, similar to what I showed you, but it was not significant. These studies are two of them that looked at obesity. And if you have MGUS and a patient is obese, does that increase the risk of them developing myeloma? Should they change anything? So this hazard ratio of 2.6 and 1.98 and 1.5 shows that having an elevated BMI, this is BMI over 25 includes overweight and obese. And being either overweight or obese almost doubles the chance of progression to myeloma. So obese patients with MGUS are twice as likely to progress to myeloma. So if you're thinking, oh, I have MGUS and what can I do? If your BMI is about normal, not to stress out, it's not something that, you know, you're not going to be able to do. So you're going to have to think about it. If your BMI is about normal, not to stress out, it's not something that, you know, you have to think about like, oh, I need to do something overnight or things. But like over time, if you do change your lifestyle and things, you will get to it. And this is not an overnight process. It's a slow, slow, slow change. So this slide shows you obesity increases the risk of myeloma. So these are three studies that showed. Now, this one was not significant. So the ones that I read are the ones that are significant. If they're in black, meaning these numbers were not significant. So it didn't increase the risk. But this study showed an increased risk where one BMI is over 35, well, 1.4 times more likely to have myeloma and here 1.2 or 3 times more likely. Now, a few studies actually looked at BMI at different time points. And they said, like, what if a patient was had an overweight or obese when they were young? And then at the end of the time when they entered the study, does that increase the risk more? Because they've been obese or overweight for a longer period of time. And the answer was yes, it was higher than 1.4. It's 1.7. And then they also looked at people who have extreme weight cycling, meaning that they have lost 20 pounds or more and then gained it back. And or, you know, significant fluctuations in weight that was unintentional. And that also had an increased risk. So we want to lower the weight to a normal, but keep it at that as well. Now, in patients, these studies show that the weight of the patient is a little bit different than the prior because they're looking not at the risk of myeloma, but they're looking at the risk of death in myeloma patients. And what they show consistently is that there is a higher risk of death in myeloma patients who have a higher BMI, about 1.5 times. That's like 50 percent more deaths. Now, you could say that it may not be the myeloma. It may be other medical issues that stem from having an elevated BMI. So I this study doesn't differentiate that is it the myeloma. But like I said, all of these things are interconnected. Now, what about newly diagnosed myeloma patients? And this study looked at like after you've been diagnosed with myeloma, if you do have an elevated BMI, patients actually maybe did better than patients who had a low BMI, like less than normal. So less than 18.5 is underweight. And what it means is that patients that lose weight unintentionally, you know, during the course of getting diagnosed or because they have are very sick from the disease are more likely to do worse. These are all statistics and just helps to empower you to think about. So it's not to scare you to say that, oh, if you're in this category, that means it's worse. It's just to know that these are things available in terms of research and what you can do to help get yourself eating better or, you know, things like that. BMI at stem cell transplant. So they look at like patients who had a transplant. They said those they found no difference in survival for patients who had an elevated BMI, whereas this study, which was a smaller one, showed some some increase in death or worse survival in patients who had an elevated BMI. Also, sometimes patients who have very high BMI because they have more comorbidities, they're less likely to be taken to transplant because they're not fit enough for it. And so some of these studies are not including those patients because we're only looking at those who have their transplant. So it's a little bit difficult to fully interpret. Now, how does obesity increase myeloma risk? So there are many different ways in which it can do it, but these are some of the ways. So increased fat in the body increases the fat inside the bone marrow as well. This is where your plasma cells live as well. Right. So the bone marrow fat serves to help the myeloma cells grow. And so having more of increases blood vessels, inflammation, all of that. Same thing with these are hormones in the blood that change with obesity and lead to increase in cell growth, proliferation, survival. And then you have the insulin. Higher levels of obesity means higher insulin means higher IGF. You might have heard of insulin like growth factor. It's a growth factor that increases risk for certain cancers and inflammation. Obesity is associated with inflammation. Inflammation is associated with cancer, especially chronic inflammation, because your immune cells are not functioning well enough to take care of the cancer cells that form like the slide I showed you before. And then having elevated fat cells actually make hormones and having elevated levels of these hormones again, through these mechanisms can do it. So what about, you know, that was a summary or overview of obesity. And then what about diabetes? And again, this study looked at 2.3 million adults in Israel and they looked to see if a patient had diabetes, did they have an increased risk of cancer? And they said diabetes increase the risk of cancer overall. They looked at all sites and they said like it's about 1.4 times. For myeloma, they said, you know, in males, it's about 1.8 times and in females, it's about 1.6 times. So it is elevated. But the risk is highest, closest to the diagnosis. So I'll show you this. This was a study we looked at where we looked at a Swedish population wide cohort where we looked at, you know, a large number of cases and controls. And what we saw is diabetes diagnosed before the plasma cell disorder was associated with an increased risk and increased risk of cancer. So it was associated with an increased risk and increased odds. But this odds was the highest when the diabetes was just six months before the myeloma or the amdas or whatever it is. And some of that could be that when you get diagnosed with one of these things, you're going to the doctor more and the other thing gets diagnosed. So it may not truly be an increase because of causation, but it might just be because you're seeing the doctor more or a detection bias. And we also adjusted for the number of visits. And then this was not significant. So what we're saying is that maybe some of this is just detection because you see a doctor more, but there are other studies. I haven't put them here just because it will be too many studies. But studies show that diabetes worsens outcomes in myeloma patients. So they do worse if they have diabetes. They're more likely to have steroid induced high blood sugar. That's expected because the diabetes impairs blood sugar. And then you also have steroids and then diabetes damages nerves, kidneys, heart, eyes, which can also be impacted by myeloma and its treatments. So, you know, you're having two medical conditions impacting the same issues. So how does diabetes increase the risk of cancer? It's important to know that there is a very high percentage of the population that has diabetes and it increases with every decade. And then pre diabetes is also pretty high, 34. So about 45 percent of the population is diabetic or pre-diabetic. So when I mentioned it could be correlation or it could be causation. So correlation means that the same reasons why somebody develops diabetes are the same reasons why somebody develops cancer. And it's just a coincidence that we find them both at the same time. Causation means that a person has these problems, develops diabetes and the effects of diabetes, the high sugar, the high insulin, the high insulin like growth factor. That's what causes the cancer. So it's very hard to prove these, whether it's correlation or causation. But there are some studies that do suggest that there is some causal effect. Now, what about inflammation? So this study looked at actually a specific drug, Anakinra, where they gave this drug for six months to patients with smoldering myeloma or indolent myeloma with just a little bit of bone disease. And what they saw is that this is an anti-inflammatory drug. Basically, it decreases this IL-1, Interleukin-1, and Interleukin-1 is an inflammatory cytokine. So if you bring it down, you're bringing down inflammation. And they showed that when they reduce, when inflammation is reduced, CRP is a good marker of inflammation. And patients whose CRP was down had a median progression free survival, meaning before it actually progressed the myeloma of one hundred and four months. And for those that it did not come down, it was only 11 months. So there was a significant difference if you have inflammation or you don't have inflammation in terms of the likelihood of developing. Myeloma. So that's it for diabetes, inflammation. And now I'll switch over to the microbiome. The microbiome is interesting and I think we're just scratching the surface in general, but also especially so in myeloma. We have few studies with very little data. I'm going to go over all of them, but I think we need to watch out for the next few years. I think we will see some interesting things in this area or space. So just to think about it or put it in perspective, we are more microbiome than human cells. This is how many human cells we have, but this is how much we are the microbiome. This is how much human genes we have, about less than one percent, and this is how many microbial genes we have. And so even though we think about ourselves as all invisible organs, these invisible microbiome is very, very important to make us who we are. And it's different in every person. It's like you're like the genetic code is different for every patient that similarly for the microbiome. Now, this is just a slide showing you just the magnitude of the microbiome. This is interesting. The gut microbiota can weigh up to two kilos. So we have a lot of bacterial cells in us and it's important to have them. So we can't say like, oh, we don't want them because they're actually doing us a lot of good. Ninety percent of disease can be linked in some way back to the gut and health and microbiome. And. Yeah, so just this is an infographic giving you some statistics with it. And what about the role of the gut microbiota in health and disease? So this was a nice figure in this paper that showed that. The microbiome can truly affect whether a patient is healthy or has disease. So for increased fiber intake, increased probiotic intake, all of these things lead to all of these good things, lower gut inflammation, improved lipid metabolism, increase antioxidants, increase short chain fatty acids, I'll talk to you more about it, increase insulin sensitivity, reduce risk of other infections, just having a healthy microbiome and then having an unhealthy microbiome, meaning taking high sugars, high fat intake, excessive protein intake, proton pump inhibitors, antibiotics, all of these things can lead to decrease short chain fatty acids, the increased TMAO. This is a molecule that's made after from phosphatidylcholine, and that's usually seen more in animal based foods. And that increases risk of cardiovascular disease and other things. So you see more gut inflammation and insulin resistance. So to understand the studies in microbiome, I just wanted to explain a couple of things to you. We all hear the terms prebiotics, probiotics, but what really are they? And so prebiotics, you have to think about as substrate for like food for the bacteria. So a prebiotic is like fiber or something that the bacteria actually uses. And the prebiotic increases the healthy bacteria because the healthy bacteria increase in number when they get the prebiotic. And they should not be degraded by our host enzymes, but they should be left for the bacteria to eat. And there should be evidence that this actually in a trial, short improvement. So a lot of these probiotics, prebiotics that are just mentioned on food products, many have not been actually tested. And so they have not been tested. They cannot truly call themselves a probiotic or a prebiotic because a probiotic, the difference between prebiotic and probiotic is that a probiotic means that there is an increase in the number of like the probiotic actually contains the bacteria, the prebiotic contains the food for the bacteria. So probiotics are more like kombucha, sorry, probiotics, food, foods that have probiotics could be yogurt, kombucha, fermented foods, sauerkraut, all of those things have probiotics in them or it could be just probiotic supplements. Prebiotics is like the fiber. Now, to understand microbiome research, you have to understand the concept of diversity in the microbiome. So think about these birds and look at these two communities. So think if this which community looks more diverse to you, is it community A or B? If you look at both the communities, you see that there are four types of birds in both of them. So you would say that they have the same birds, so they're not any different. But you can see that there is one type of bird that has kind of taken over and there's very little of the other birds, very few of the other birds. But in this one, there's more of an even distribution and more all the species seem like equally abundant in some ways. And so this community is more diverse than this one. So think about these birds as bacteria. And then that's how you think about microbial diversity. You want many different types of bacteria to think about it as being a more diverse microbiome. So now I'll talk about microbiome in MGUS and in myeloma and what data is available. You have to take all of this with understanding this is very preliminary data. We are still in the very early phases. You can see this is an abstract. These two are papers, but you see the number of patients, very few. So we're talking about really small numbers here and it's hard to fully draw conclusions, but you can look at trends, overall trends in what these studies are saying and maybe draw conclusions from that. So this study looked at myeloma, 10 patients with myeloma, 10 patients with MGUS and 10 healthy patients. Each line here is a different bacteria and what and the color red means higher abundance, the color blue means lower abundance. So as you see more, you can see in myeloma, there's more of these bacteria in the healthy patient, there are more of these bacteria. And in MGUS, it's somewhere in the middle. So what it is showing us that there is some change in the microbiome in patients with MGUS and myeloma, and it progressively gets more imbalanced as the disease progresses into the different stages. Now, this study looked at 19 patients with newly diagnosed myeloma and 19 patients who are controlled, so they didn't have myeloma. And what they said is that patients who had myeloma were more likely to have nitrogen recycling bacteria and less likely to have a short chain fatty acid producing bacteria. Remember, I said these were the good bacteria. And so we'll talk about them later. These bacteria, so these nitrogen recycling bacteria, they then put them into mice and then they showed that the mice developed myeloma faster if they had these bacteria. So this gives you proof in mice that having the bad bacteria actually increases or accelerates myeloma progression. Now, this study looked at changes between, again, the same newly diagnosed and controls, controls meaning healthy patients. And what they showed is that the myeloma patients had decreased diversity. You remember, I showed you the slide before that shows the different bird patterns, so we want more diversity because that means we have the same way as we think about diversity in a forest or something. You want more species because that means it's a healthier forest. So the diversity is down in patients who have myeloma compared to controls. And they're also different bacteria that are high in the myeloma patients compared to the controls. Now, this was a nice study in mice and because we don't have a lot of data in humans, I thought I'd show this to you and hopefully it's not too confusing. But, you know, let's see if, you know, if it makes sense to you. So this study, a group of researchers were looking at mice developing myeloma. So they would have mice that they would put myeloma cells into them and see how long it takes them to actually develop myeloma once they get these cells. What they saw were and they had these mice, the same mice in Italy and they had the same mice in the US. The mice in the US before 2015. So they looked at these mice over many years and the mice before 2015 actually progressed to myeloma at a similar rate as mice in Italy. But the mice after 2015 in the US developed myeloma much faster. Now, if the cells for myeloma like the same kind of cells are given, you would expect they're similarly aggressive and they should have the same speed to develop myeloma. And so then the researchers felt that this suggests that there is an effect of the environment. And so what they did is they looked at the microbiome of the mice. What they saw was that in this group that developed myeloma much faster, there was an increase of Prevotella, this group. And so they said that this may be what is driving it compared to the other groups. And so they decided to do further experiments with that bacteria. So the experiments they did on mice were divided them up into three different figures to just for simplicity, show you where what they did is they give since they said the microbiome is affected, they give some mice antibiotics and they give some mice no antibiotics. And the mice that got the antibiotics actually develop myeloma much slower than the mice that did not get the antibiotics, suggesting that the antibiotics killed those bad bacteria. And so they actually took longer to develop myeloma. But if the bad bacteria were kept as is and nothing was done, then they just develop myeloma much faster. Then this second figure shows you that the bad bacteria they identified as this one, Hipparanolytica, and then they took a similar bacteria. But this is the good one. They put it into different mice. Some of them got this one and some of them got this one. And what you can see is that the patients that got the melaninogenica one actually had a longer time and it survived longer than the mice who had the pathogenic bacteria or the bad bacteria. Then they said, how does this bacteria actually cause myeloma to progress? So they looked at inflammation. They said IL-17 is a marker of inflammation. And they showed that if they knock out the inflammation that's in the IL-17 knockout, which is in red, it takes a longer time to develop myeloma than if the inflammation is present. So in conclusion, what they're saying is that having this bad bacteria accelerates myeloma development in the mice and they do it via inflammation and these inflammatory cells. And here is a summary of what they say. So gut microbiota induce these T helper 17 cells. These cells cause inflammation. These cells move to the bone marrow from the gut. They migrate. And once they are in the bone marrow, they interact with the myeloma cells and they actually lead to progression of the myeloma. So that's what they think is happening, of how the microbiome is leading to myeloma progression. So then they decided, like, OK, we've seen this in mice, but what about humans? And it's hard to do such a study in humans. But what they said is at least we can look at this inflammatory marker in myeloma patients and see smoldering myeloma patients and see if they had more of it. Were they more likely to develop myeloma? And the answer is yes. So what you can see here is they progressed in more than three years, meaning slowly progressed. They had lower levels of this in less than three years. They had higher levels of this. So more inflammation. Now, this is a slide showing you the microbiome in myeloma post induction. So meaning after a patient has gotten the initial chemotherapy, whatever it might be, VRD, KRD, or whatever they got, post that and maybe a transplant. But post that, they looked at their bone marrow and said, which patients had no evidence of disease and which patients had a little bit of residual disease in humans. And this study was done at MSK by my colleagues. And so what you can see is that the ones that had residual disease actually had less of these two bacteria. And what's common about these two bacteria is that they're short chain fatty acid bacteria. So we're seeing a theme here of very similar bacteria causing changes in outcomes. And then here, those that actually had a clear bone marrow had more of these good bacteria. Again, it's a small sample size. It's hard to know whether it was just by chance or whatever. But if we see this consistently across studies, if we have longer follow up, we have bigger studies and we still see this, we know that this is true. And we have seen it in other diseases that short chain fatty acid bacteria are supposed to be good. So we already know that. This is post post pre transplant and post transplant. So this study looked at pre transplant. What is the microbiome like? So the one in yellow is pre transplant. The one in pink is one week post. The one in blue is two weeks post. And this is patients who developed ulcerative mucositis and those who did not. And what they showed, I've actually put these dotted red lines to sort of make it easier for you to see, but before going into the transplant, the yellow. So, you know, you see this black line in the middle of these bars. That's the average or the median for that group. So you have to look at those black lines in the middle and you will see that this red line which goes through it shows that it was not much different before transplant. But after transplant, if you look at this blue bar, two weeks after the diversity was much lower in those who develop mucositis than those who did not. So what they are suggesting is that a reduction in diversity that's more significant leads to breakdown of the intestinal barrier or the oral barrier and leads to this inflammation. So having more diversity is good. Now, this study looks at this very similarly, the fecal bacterial diversity, meaning the stool diversity on day plus seven, meaning seven days after a transplant. And those that had less diversity had more diarrhea. Again, very so what these studies are basically saying the same thing, right? Less diversity, more diarrhea, more toxicity, more mucositis. Now, these are two other studies that showed post-transplant. This study was not a microbiome study, but I put it here because what they're showing is that patients who had antibiotics post transplant did worse than patients who never needed antibiotics. Now, that's not to say you shouldn't use antibiotics, because if you need them, you need them if there is an infection. But what it does say is that the antibiotics might be disrupting the microbiome or something like that in affecting outcomes. It could also be that they're just sicker because they have more infections and so they're doing worse. So it's very hard to know from a study like this what to fully interpret. But it gives you, again, a trend. Now, this study looked at 30 myeloma patients. And so this study was looking again, it's an abstract, very few patients. But what it showed was that seven patients post transplant had decreased diverse post-transplant myeloma had decreased diversity. And you can see that the patients that progressed to myeloma actually had increase in the bacteroidy species. So this post transplant bacteroidy is increased in two patients at progression. So what they're saying is that there was that bacteria increased in patients who had progression. Again, it's a very small number, so we can't put too much weight on it. But they also said that they looked at like diet for different patients. And they said that most patients are not even meeting the diet fiber intake requirements, most patients are not meeting whole grain and vegetable intake requirements. This is post transplant to which shows you different changes in diversity in the interest of time. I just wanted to mention that what they showed is patients who had higher diversity did better than patients who had lower diversity, similar again. So we're seeing some trend here. And this study looked at changes in the diet. And what they did is they had patients eat nine individuals, completed both arms. Five days, they made them eat a very plant heavy diet and five days an animal food heavy diet. And you can see that the fiber intake obviously changed, but the changes were there in metabolic markers, too. So the short chain fatty acids that I've been talking about are these two. Those that ate the plant food had more of these good short chain fatty acids compared to those that eat more of the animal foods had less of those good short chain fatty acid. So what are the short chain fatty acids? They're like like nutrients. They inhibit his the the inner age, they inhibit the inflammatory pathways and inflammation. And so they have anti-inflammatory and anti-cancer effects. And that's why we think that having these good bacteria probably reduce the risk. This study looked at food quality and again, very similar. What you can see is that when you see the rows that say plant, you can see that the bacteria show a certain pattern. There's more of these bacteria. There's less of these. When you look at unhealthy foods, it's actually the opposite. Less of these and more of these. So we want to have a similar microbiome. And what we eat does affect the quality of it. And this is this is also showing you the same thing that healthy plant foods and more of these bacteria, but not healthy plant foods did not have these bacteria. And maybe animal based healthy foods had some of these bacteria, but less healthy animal foods had none of these bacteria. So something to think about is how many types of plant foods do you eat in a week? What I mean is not how much do you eat or how many servings, but how many types. So I would say, like if you eat broccoli and cauliflower, that's two types, not one serving of vegetables. So if you eat rice and you eat quinoa, that's two types. So thinking about fruits, vegetables, legumes, beans, grains, seeds, nuts, I'm talking about all these plant foods. And if you can just write it down and think about how many you can do this and maybe share it with us for next time, but think about how many you eat per week. This study showed that if you eat more than 30 plants, you actually have more diversity because every food you eat is full for certain bacteria, so if you eat a more variety of food, you have more variety of bacteria, decrease antibiotic resistance and maybe increase in some of these good polyunsaturated fatty acids. So here I'm just summarizing what the gut microbiome does. So these are factors that we talked about, antibiotics, low fiber diets, processed foods, having a cancer, obesity environment, all of these lead to microbial imbalances. And the mechanisms are these fatty acids, inflammation, bile acids and lead to all of these issues that I kind of covered with you with the different studies. We'll talk about these studies at the next talk in more detail, but I just wanted to show you overall that there is a 77 percent relative risk reduction in patients who eat predominantly plant based diets. In this big study of sixty one thousand people of how many patients develop myeloma eventually. So we do see less myeloma in patients who eat plant predominant foods. This is showing less cancer in patients who eat predominant foods. I'll go over these studies next time. This is showing less cancer again in those who eat plant predominant foods. And then these two studies are specific showing that inflammatory foods, Western diet, unhealthy foods are higher death compared to a healthy dietary pattern, which is again, a plant predominant pattern, more whole grains, more fruits, vegetables. This study showed that there is an increased risk of myeloma in those who have an inflammatory pattern of their diet. And so with this, I just want to conclude that obesity increase the risk of myeloma and myeloma related deaths. Diabetes is associated with myeloma, lower diversity, lower butyrate producing bacteria, the short gain fatty acid producing bacteria associated with side effects and worse outcome. And plant predominant diets have less cancer, less myeloma and more diversity. So and processed refined inflammatory diets have higher risk. So I think it's important to think about food as medicine. It may not be the solution to everything, but it can be complementary, definitely. And so we at MSK are working to develop a research program to study nutrition, microbiome and the metabolism in myeloma. And so I just wanted to mention and we'll talk about this next time, but we have a study opening in March that will be looking at a diet for three months and look at changes in the microbiome in patients with MGUS and small ring myeloma who are obese or overweight and will be open to accrual or enrolling in a few months. And then we're also planning a study with myeloma crowd, which is exciting where this would be a larger study. It would be on a national level. So this is something that anybody can participate in from any state. And we're hoping that in the next year we can get this going. And I think myeloma crowd has been very good about setting up a crowdfunding page and trying to get funding towards doing a study like this because they can be challenging otherwise. So with that, I'll take questions. And hopefully this was helpful and we can talk more at the next time as well. That was amazing, Dr. Shaw. Thank you. I feel like I learned so much. I feel a lot smarter than I did an hour ago. We have a couple of questions, but as Dr. Shaw said, we do invite you to ask your questions in the question and answer section that should be at the bottom of your screen. The first question, Dr. Shaw says, considering the level of evidence we have, are you currently recommending probiotics to your patients with multiple myeloma? And if so, at what point during their treatment and what strains? No, I actually don't recommend it because, you know, some of the probiotics are unregulated, we don't have enough data with them. So what I recommend is I know it's easier to take a supplement than change what you eat, but I would say think about that 30 plant foods that I talked about, see what the difference what you eat and slowly try to move towards that. It just has to be a variety and moving towards more. So we'll talk more about diet next time and supplements. But I don't think that at this point I would recommend just going on a probiotic. Thank you. Another question says, how about dietary effects? I'll answer that and just say in our next session, which is on February 16th, I'll show a slide when we're done here with our question and answer section, I think it's the 16th. We'll make sure when I look at it, but we will actually be going way more into depth about what a diet should look like for a myeloma patient, because this one said specifically, well, what about myeloma patients? Because as on those studies, sometimes there weren't very many myeloma cases. So please tune in next time. You know, we've talked about the risk factors that are in your control. Now, the next session is going to be a case of what steps do you take now, diet wise, wellness wise, as a myeloma patient? So hopefully that doesn't deter you too much and instead excites you about attending with us next month. Dr. Shaw, what are your thoughts on the role of GMOs in food, participating in increasing risk for M.M.? I ask this, she says, I ask this because I read somewhere that Roundup found an Agent Orange and other defoliating agents were associated with increased M.M. Yeah, it's a good question. Though many of those studies, you know, it's not it's not just like Agent Orange is more it's not from food, it's from, you know, most of them are Vietnam war veterans with Roundup and things like this. Some of it is more farmers or people who are actually working with it are mainly affected. Those that are eating the food or fruits and vegetables, it's less likely. But I actually am going to show you a paper next time about this, where patients who who the increase in risk of cancer from pesticides is on fruits and vegetables is significantly smaller than the decrease in risk of cancer from eating fruits and vegetables. So just because, you know, going towards eating organic because you think like, oh, that's the only way I can eat it and then it's too expensive and it's not affordable. That's not worth it. There is something called a dirty dozen where those fruits and vegetables are more likely to have pesticides on them. If you really are concerned about it, try to find that list and follow that in the sense that those ones you can buy organic. But the rest of it, I think just eating more of it is more important than worrying about this and you help yourself much more that way. Awesome. Thank you. We have a question that says, will the recording of this session be made available? That is a definite yes. Twenty four to 48 hours after this concludes, you will be receiving an email with the slides that I shared today as well as the recording of this session. All of Dr. Shaw's slides will be shared after our second section, our second session on the 16th of February. So we have another question that says, does the Pritkin style look to be best? I'm not sure what that is. Do you know what that is? I heard of it. I just cannot remember, but I think it is a plant predominant food. We can talk about it next time. I'll just look it up. There are some good things about it, if I remember, but there might be some issues and I'll look it up for next time. Awesome. Thank you. Is there any studies being done with the? I need to learn how to pronounce these words better. Curcumin effect. Yes. So that's the study we want to do with myeloma crowd to understand the effects on curcumin, on microbiome, on metabolic markers. And that's what myeloma crowd is crowdfunding for just now. And hopefully we're able to launch that. But irrespective of that, there is a little bit of data from prior studies. And I will be showing that next time in diet and supplements. So that's an incredible answer to your question. You can become a part of a study if you are interested in doing that. That's great. I think that's an incredible opportunity. Yeah. Let's see again, there's specific dietary advice. Would you give us besides the plant based foods, she's food diet. She's going to be talking more about that next time on February the 16th. Let's see. We have a lot of questions about diet, so I kind of want to save those next time. There is one question that says, how do you suggest patients connect with experts to help guide them through evaluating their microbiome? This is almost mostly ignored by the medical community. So how would you answer that? Yeah, so that's a good question. I think the issue just now is that there is like oncologists or even physicians, I can't order a test and say, let me give you a microbiome analysis and have you understand that. There are some companies that do this, private companies where you could send in your stool sample. We again, that's what we want to do with Milo McCloud and have this as part of the trial. I think eventually we are going to head there and we're going to have that information for patients. You could consider reaching out to organizations and submitting your samples with those companies. But I don't know that that data is going to be very helpful to you because they will give you all these lists of like, oh, this is increased and this is decreased. But until we actually know what to do with every specific bacteria or how you can change it, I would say, when you have little data, go with overall trends. And I just showed you the overall trends of what food groups and things will help. So diversity of foods, more plant foods. That's really how you feed your microbiome. And I think if you're doing that, then you're probably doing it right already. And if you really want to dig deeper into it, you can again look at we're doing it as research, but we are not able to give this out clinically yet. And hopefully that will change. Awesome. Thank you. I would like to mention, if you are asking a question about diet, I am not ignoring them. I will make sure that we keep record of all of the questions that were asked here and we will make sure that we answer the questions about diet that you are answering in our next session. I'm not trying to say don't ask questions about diet because we'll never answer them. I'm just saying, feel free to ask your questions about the diet, but we will answer those in the next session. I wanted to make that clear. Several questions about when the next session is, again, I will show that at the conclusion, but February 16th at the same time, 1 p.m. Eastern. I know there was a couple of people asking to share your experience, Dr. Shaw, as a lymphoma survivor. Do you want to briefly tell your story and we'll end with that? And then whatever questions have not been answered again, I will take note of those and we will answer your questions. We'll make sure to leave more significant time for questions and answers in our next session and make sure that those are answered. Sure. Happy to. So I just wanted to say I basically had Hodgkin's lymphoma four years ago. I was actually doing my Hemong fellowship at that time. And this was at the end of first year, beginning of second year. So you can imagine how traumatic and stressful it was to try to finish fellowship and deal with chemotherapy, losing your hair, all of those things. But at the same time, you know, I think I had a lot of family members and everybody who said, like, oh, you should have this supplement. You should do this. And it's not like I'm not a doctor or an oncologist. And I know these things, but like I'm getting all this advice from people who are not in the field, but still think that they need to do something to help me. And I would also wanted to like look at things and think about what can I do to reduce my odds of it, you know, not coming back in the future and just staying in remission and all of those things. And so I started spending some time after the diagnosis, you know, looking into this and reading about it. And I was like, there's so much literature, but we don't really spend time as physicians reading it or even looking into it or thinking about it. And I think patients, this is a big disconnect because the number one question asked by patients is diet. The number one question not answered by oncologists or physicians is about diet. And so we need to bring both of these together and have something where physicians are able to answer these questions for patients in a more in a less biased way and at least understand it. So that's the beginning of where I felt it was important for me prior to the diagnosis. I was vegetarian, meaning I've been vegetarian always. So I would but I would eat a lot of eggs, dairy, because I thought those were very healthy for me. Again, this is my personal belief or experience. I've showed you what the data is. So I'm not saying that everybody has to do what I do because it may not be right for everybody, but I felt that based on the information and data that I saw that I need to move towards being ninety ninety five percent plant predominant in terms of reducing odds and things. So I moved towards cutting out dairy as much as I could, cutting out eggs and things like that and moving towards a lot of grains, beans, seeds, fruits, vegetables and all of that. It is a big shift because it's difficult when you're in a social environment where you go out with different people and things like that. But as time goes on, you get used to it and you find things that you like. And I'm a strong believer in that you adapt. You know, we always feel like, oh, I could never do this. If you had asked me five years ago, would you ever change your diet and start eating this certain thing? I'd say I'd never do it because I could not imagine a life without milk or without eggs or something, but or cheese, for instance. But like I eventually over time, our taste buds adapt. Can we actually start liking it? So now if you give me eggs to eat, I actually don't like it, even though I used to love them before. And that's not because, you know, I've read or I feel, but it's just that my perspective on it has changed. I'm not saying that everybody needs to do this. I'm just saying this is what ended up happening for me. And all I think is in terms of a healthy diet, just now, most of the US like plants and fruits and vegetables are a really small component of the meals and everything else takes over. We believe that protein, we are all protein deficient, but in true, actually, we're all fiber deficient and there's a big difference. Nobody in the US probably is protein deficient in terms of if they're getting enough calories because most foods have some protein. We can talk about that next time, too. But I think if you can just I'm not asking you to switch your diet to say, like, oh, I'm a vegetarian or I'm a vegan or I'm such and such, because that's not so important, the labeling of it, it's more important is how many meals are you able to eat healthy and how many different foods are you able to eat? So moving towards that and switching or substituting things out, I think is important. Awesome. Thank you so much again for those that asked questions that we didn't get to. We will be taking note of those questions and answering them in our second session. Speaking of our second session, part two of this series will occur on February 16th, twenty twenty one at 11 a.m. Mountain Time, 1 p.m. Eastern, because you signed up for this event, you have automatically enrolled in our nutrition and wellness chapter, meaning that you will receive notifications when new events have been created. It does not automatically enroll you into the event, but it does give you the option to know when new events in this chapter are created, such as when I create the event page for our upcoming event in three weeks and will send you an email so that you know to sign up for it. Stay tuned on our Facebook and social media if you would prefer to see it that way. I will also send out an email to all registrants when when that. Event page has been created just in case something glitches within our system, we want to make sure that you hear part two. And I would just say if you haven't filled out the survey that we send across, please do, I think that would help us understand what everybody's thinking and how it's important to do such research or help us guide future research. Thank you. Definitely. This is the link to the survey that she was talking about. I did email registrants yesterday. There have been people that signed up between when I sent the email and now. If you haven't taken this survey, please take the time. It's only, you know, it took somebody five minutes, takes the other person 15 minutes, but it won't take very much of your time. And the information that you provide is so valuable to us as we study how we can find the best nutrition and wellness for myeloma patients to improve their outcomes and give them highest quality of life. So please fill out that survey. Part two of this project, including the survey, is that study that we were talking about, you are not automatically enrolling the study if you take the survey. So don't worry about that. But we do want to give everybody the chance to enroll into the study if that interests you. There is also a link here. Again, I will be sending out all of these slides post meeting 24 to 48 hours after. But this link is a crowdfunding donation page. If you have felt inclined under no obligation to donate whatsoever. But if you have felt inclined, excited about the potential that we have for more research and just furthering the myeloma field, the cure to myeloma, I should say, then you are welcome to donate at this link. If you have any questions, you are free to email me. My work email is Audrey at HealthTree.org. Myeloma crowd is a nonprofit within a greater organization called Health Tree Foundation, which is by that is my email. Audrey at HealthTree.org. If you have any questions about today's meeting or our next meeting, again, you will be receiving these slides to your email so you have access to what my email is. We have upcoming events that you might be interested as part of interested in as part of the myeloma community program tomorrow on January 27th at 1 p.m. Eastern, we have our cell and XOR support group launch. Cell and XOR is a new drug in the myeloma arsenal and clinics are still learning how to use this drug, patients are still learning how to manage side effects. So we wanted to create a cell and XOR support group. We have the CMO of Cario Farm, Dr. Jatton Shaw, who is going to be discussing cell and XOR. So if you if you or your loved one is taking cell and XOR, you are invited to that Thursday, January 28th at 1 p.m. Eastern is the plasma cell leukemia support group launch. If you or your loved one have plasma cell leukemia, we invite you to join us as we launch this very unique, very special group for people that have a rare form of myeloma. Tuesday, February 2nd at 11 a.m. Mountain, 1 p.m. Eastern is our myeloma financial coach chapter. We are going to be talking about estate planning. While this is something that you wouldn't really discuss over a dinner table is a conversation that needs to be had. So we invite you to our estate planning meeting on on February 2nd. And then on the third is a more interactive class. We are going to be learning. We're actually going to be participating in a yoga class. Even if you're not very mobile, we can do chair yoga, that's part of our fitness for myeloma class. So if you're interested in that, interested in any of those events that I just mentioned, you can go to www.myelomacrowd.org events and you will be able to see the events and register for whichever ones you are interested in. Thank you to everybody for spending this virtual time with us. I apologize for taking a little bit more of your time than we originally expected, but we appreciate your patience and your participation. And we hope to see you next time. Again, if you asked a question that wasn't answered, we will make sure to answer that in our next session on February 16. Thank you and have an incredible day. Thank you. Bye.