Today's topic is the microbiome 101, learning about gut health for myeloma patients and caregivers. I am so pleased that so many of you are interested in this subject as am I. The world continues to learn more about the microbiome, and yet we remain fascinated by the power of gut health. The simple amount of bacteria that's in our gut that can really affect how all of the body systems are doing. It's absolutely fascinating, and it's something that we can feed, that we can take care of, that we can control in order to make sure that our bodies are functioning properly. While research still has a long way to go, I'm excited that we can start talking about it, raise awareness, and be able to grow together in knowledge and in how we take care of our bodies. We get to learn more today about how gut health affects our overall well-being, how it's related to myeloma, and what we can do to properly nourish our bodies and improve all of its systems, as I mentioned. I'm really looking forward to learning with you. Here to speak to us today is Dr. Alexander Lusokin. He is an oncologist who specializes in treating people with multiple myeloma. The increase in new treatments in the past several years makes this a very exciting time for him and other specialists who care for people with this disease. His team offers patients the highest quality care, as well as the newest treatments through clinical trials. These research studies will improve care and increase the chance of a good outcome for all their patients. His research work involves developing innovative ways to use the immune system to treat cancer. We were speaking just before the meeting started. He said that's one of the reasons he got so involved with the microbiome and the research relating to myeloma and microbiome because he's so invested in research within the immune system itself. They're conducting clinical studies of medicines that enhance the immune response, as well as laboratory studies aimed at understanding how cancers such as multiple myeloma are able to evade this immune response. They hope to develop new ways to treat their patients through studies and through laboratory research. I'm really excited to hear from you, Dr. Lusokin. Thank you so much for being here today. The time is now yours. Thanks so much for the kind introduction and the invitation to speak today. So this is like the hardest part right now is to actually share the right part of my screen. So just give me a minute. I think that's it. Looks great. Yeah. That's it? All right. Okay, so that's the hardest part. So thank you all for having me here today. It's my pleasure to talk about myeloma as well as the microbiome. I have a few disclosures. So what am I going to talk about today? Well, I'll talk about broadly what is the microbiome and how and why we study it, as Audrey has touched on a little bit. And then I'll speak about specific examples of microbiome interactions in myeloma in terms of disease development and treatment response. And mostly these are the things that we know now, of course, recognizing that there's a lot more work to be done here just to describe the microbiome as it exists in the patients who have, for example, precursor myeloma smoldering, mGus, newly diagnosed myeloma, as well as myeloma on various treatments. And then finally, I'll touch on what we can do to change our microbiome. And here I put a disclaimer that even though we can change our diet, take various supplements that would likely modify the microbiome, exactly how to do this in a way that's beneficial for patients with myeloma or other cancers is still an area of fairly active research. And so there isn't really a specific recommendation that one can give about the best way to do this. So first, I'm going to start with some, I guess, quote unquote, housekeeping in the sense of how do we study the microbiome? And the reality of it is, this is what we're studying. We're studying patients' stool because the main, there are a variety of areas of microbiome. There's microbiome on our skin. It's in our nares, in our mouth, and it's in our GI tract. And the focus of a lot of the work that we are doing is on what's in the GI tract. And the way to really investigate that is to collect stool samples. And these are like the kits we give patients in the clinic to use at home and then bring into the clinic specimens that we can then send for additional study. There are other tools. So those are sort of non-preserved. Those are the kind of sampling that we can do in our clinics because our patients will come into clinic and can provide a sample that day or the day before or what have you. But there are tools available to study these kind of things on a national level that requires preservative containing tubes. And so things like this OmniGene Gut Kit, and I'm not advertising any particular brand, but this is just one that's readily available that we also use. And it's, I think, relevant since there is a myeloma crowd study that we are embarking on that will use these types of kits that require a little more patient participation in terms of sampling and putting sample directly into a tube prior to shipping it to a center where it's studied. So regardless of how a sample is obtained, one needs to isolate the DNA in the sample. So the stool goes through a process where the DNA is removed and that DNA can be sequenced. And that sequence will contain the patient's material, the person's material, the human genes, but it will also contain the non-human genes. And the non-human genes are the ones that represent the microbiome. And one can do sort of a very focused type of sequence analysis focused on specific segments that are shared in bacteria, the so-called 16S rRNA segments that can then be used to identify which bacteria are there and what their relative abundance is. Or one can just look globally at the sequence in a more in-depth way, more complex way, and then understand what the metabolic activities are of the non-human genes that are there. Of course, and I will get more into this, that diet is very important and integral to what's in our microbiome. And I'll show a little bit about that and how diet can have a really rapid impact on the microbiome. So we do collect dietary information and antibiotics also can have an effect. So we collect information about that from our patients. So what is the microbiome? So this is how we collect it, but what really is it? So really it's all the microorganisms that live in and on our bodies. And the main thing that I will talk about is the bacteria. I will ignore various fungi, viruses, other organisms that can potentially exist on our skin or in other areas on our body. So the other thing that's important to sort of point out is that the microbiome is vast. The typical human being has several trillion cells, 30 trillion. And our microbiome in a typical person has 100 or more trillion cells, so like three to four times more. And then when you think about that, the scale of the number of genes, which each gene being something that would represent a function or an activity, is even greater, like the difference in scale. So humans have a little over 20,000 known genes. The microbiome that we live with contains millions of genes. So there's a huge, huge amount of function. So one can imagine that we may know something and it may sound like we know a lot, and sometimes it sounds that way, but there's a lot more that we don't know than there is that we do. So why do we care about the microbiome? Well, it turns out that for one, the microbiome, we feed it, but it also feeds us. It's a very symbiotic relationship. The microbiome is important in absorption of various vitamins. It's important in digestion of complex carbohydrates like fiber and the fermentation process, if you will, and those fermentation products can have health effects, for example, things like short chain fatty acids like butyrate, which I will talk more about. And then so the normal homeostatic scenario exists, but also there are various perturbations to the microbiome that are critical and affect disease states as well. And I'll focus in a little bit more about how this is relevant, for example, in cancer. Now, a lot of the work that we and others have done is focused on various immune therapies such as allogeneic stem cell transplants, so donor transplant and the effects to the microbiome on outcomes there, as well as on immune therapy called immune checkpoint blockade, and a little bit more recently looking at CAR T cell therapy as well. So one of the initial studies really identified that when you look in the microbiome and you sample it sequentially over many days, that you can actually identify a bacteria that is becoming dominant in the intestinal tract before it becomes a bloodstream infection by a week, which is just incredible. And then the other thing that's very important is that there's a very clear relationship between our interventions when we are seeking to improve patient's health, for example, when we give antibiotics and the outgrowth of secondary infections like C. difficile or the VRE type of resistant, it's called the vancomycin resistant entocompyl infection. And there's a clear way in which our normal intestinal bacteria regulate these sort of quote unquote bad players or pathogenic bacteria. And when there's a perturbation with antibiotics, antibiotics, for example, to treat a pneumonia, then that those control mechanisms driven by our normal bacteria are disrupted and these opportunistic infections can develop. The other thing that's been identified is that survival after allotransplant, as well as after autotransplant is affected by the microbiome, as is both toxicity and response to immune checkpoint blockade and CAR T cell therapy. And I'll get into a little bit more of that as we go along there. So again, in myeloma, the initial sort of studies looking at relapse and survival after allogeneic stem cell transplant at our center actually identified a fairly large cohort of myeloma patients in whom the effect of the microbiome was pretty prominent. And this was one of the things that actually led us and our group to kind of investigate the microbiome and patients in the clinic with myeloma to see how those interactions occur. And then diversity, microbial health as measured by a diverse microbiome is also something that's very important in terms of both progression times and overall survival times following an autologous stem cell transplant. We have identified some microbial features of myeloma patients who have responded well to initial therapy, as well as those that have what's known as sustained and minimal residual disease and important outcome measures while on maintenance lenalidomide. And then I think I'll touch on a little bit on some preclinical studies in laboratory systems that have identified a potential linkage between how the microbiome can promote the the microenvironment, the some immune components that allow for myeloma to progress and develop in the context of a model animal model system. So I'll get into this a little bit more now. So like what do we know about the microbiome and the development of multiple myeloma? So I'll talk about this laboratory animal model a little more. So this was a model where so it was a spontaneous animal model of myeloma. And researchers noticed that they had the same spontaneous model developing in individuals with in mouse colonies at different rates, in different mouse colonies. And really, there wasn't much difference in the strain of mice, the food the mice were eating, but the mouse colonies had kind of been bred slightly differently. So there were some just so the researchers were interested in the microbiome because a lot of the microbiome is something that is passed on from like the mother to the offspring. And they noted significant microbial differences. And if they used antibiotic treatment to remove the microbiome, then they eliminated this difference. And what they found was that there were specific bacteria that promoted a like a white blood cell interaction in the microenvironment of the bone marrow via this chemical that cells used to talk to each other, a cytokine called IL-17. As noted in the title. And so the way the model goes is that the microbiome would promote this TH17 or this type of immune cell that would then go to the bone marrow. And then in the bone marrow, they facilitate an interaction with various microenvironment cells that promoted myeloma. And I think there's a very elegant model. Of course, it's not a human system. So we don't know whether this actually happens in patients yet. But what we do know is that when we look at patients with multiple myeloma and compare them with healthy individuals from a study that's relatively small, but yet very provocative. So this study included 19 patients and 18 age match controls. And what they found was that there was sort of like a fingerprint in the microbiome among the patients with multiple myeloma. And what was particularly striking about that was that the fingerprint included bacteria that that took up nitrogen species and kind of facilitated the body's ability to reuse its nitrogen to make additional protein. So when protein gets broken down, it releases nitrogen in the form of something called an ammonium molecule. And I'm going to get kind of a little technical here. And then that ammonium would go into the gut and get excreted. But if you have a bacteria that can capture the ammonium and turn it into something that the body can use, then it can be taken back up and used to make additional proteins. So it kind of makes sense because myeloma cells make a lot of protein and have to constantly recycle protein, that this would be a relevant pathway. It'd be important for the myeloma to coexist with a host that can facilitate making more protein. And so this is a way I think, or at least this suggests that myeloma generates excess of this NH4 and it also comes in this molecule called urea. And the microbiome can take that, turn it into amino acids that can then be used to make protein and promote myeloma cell growth. So this is I think a very interesting and provocative idea. It has yet to be confirmed in larger studies or across multiple populations in multiple different areas. But nevertheless, I think it highlights the idea that our gut interacts with multiple myeloma. So how about in the context of treatment? Well, I talked a little bit about stem cell transplant. So that's a treatment that is very commonly implemented in patients with multiple myeloma. And what these investigators found, and this is actually patients treated at two centers, at our center and at Duke, was that the diversity or the health of the microbiome is altered by stem cell transplant. That's not, I think, surprising to anyone that's either gone through a stem cell transplant or seen someone go through a stem cell transplant where there are significant GI side effects to this kind of treatment. But this diversity then recovers, but it recovers differently in different subjects. For reasons we don't actually understand, maybe, anyway, for reasons we don't understand, I'm not going to speculate further there. But it turns out that the recovery is really important. Those that recover more diverse, meaning more healthy, a microbiome, do a lot better. So it's important to understand what's causing this injury, but even more important to try to understand how can we help repair this problem in the context of our therapy. What about something that may be a target for improving overall outcomes? So we, over the last, I guess, five to six years have been running a lenalidomide maintenance, sort of natural history trial. This is a trial where individuals receive lenalidomide as we normally would prescribe in the context of maintenance after initial therapy. Then we started to collect, initially, microbiome samples and then habitual dietary surveys on these patients to try to understand are there microbial signatures that are associated with outcome here in terms of response to induction treatment, in terms of sustained minimal residual disease negativity, and of course, overall outcomes. So again, this is a five-year natural history study, standard lenalidomide dosing. Individuals would enroll and then we would collect samples sequentially. I will focus some recent analysis on the entry sample, so after initial induction, and then three months when whatever happened before the effects of that could largely subside, particularly in terms of diversity of the microbiome if someone had gone through stem cell transplant. So in our initial post-induction analysis, this is just sort of showing in very small print that I guess maybe you can see if your screen is big. I can't see in my presenter mode, but suffice it to say that this was 34 patients, so not a humongous study, but nevertheless a sufficiently strong effect so that it can be analyzed, where about half of the patients were MRD negative at the time of entry and half were MRD positive, and otherwise they were, because of the practice pattern that we have implemented a few more of the MRD positive patients that had gone through stem cell transplant. And so this is what's called a principal component analysis, and really this is sort of a way, you know, when we look at microbiome we get, you know, hundreds and hundreds of different bacterial species and things, and we get like a lot of information within from an individual, and so how do we kind of look at the entire population of the microbiome and compare it to someone else, and this is one way to do that, this idea to sort of like flatten the analysis in a way by just looking to see who has microbiome that's more or less similar to someone else, and really what this is showing is if something like, for example, the microbiome in these two like this, I guess it's blue and red dot, they're more similar than the microbiome over here, and I think one thing you can kind of visually see is that most of the red stuff is over here, and there's a population of blue stuff over there, and what that just says to us in a sort of broad way is that there is some difference in general in the populations or the quality of the microbiome, the characteristics of the microbiome among the negative, MRD negative patients and the MRD positive patients. And then when we look at it a little bit more closely, we see that there are specific bacteria that seems to be higher in folks that don't have residual disease that are MRD negative, and those that do, so to the right is higher in the MRD positive, sorry, I meant that to the left, and then to the right is an MRD negative, and I think what's relevant here is that these are and I think what's relevant here is that these are butyrate producing, so short-chain fatty acid butyrate producing bacteria, and these are nitrogen recycling bacteria, again similar to that a prior study done elsewhere that I've shown you that where the nitrogen recycling bacteria were present in patients who were newly diagnosed with multiple myeloma. So then what about sustained MRD? So this is looking at patients after at the three-month sample. What we could see is that among individuals who had sustained MRD, which in what we the way we define that is by looking at MRD status in the bone marrow 12 months apart, so those that had MRD for two consecutive measures were more likely to have a more diverse microbiome, were more likely to have a higher relative abundance of actual butyrate producing bacteria, and more importantly they have more butyrate in their gut, which suggests that in some ways that the butyrate levels in the intestine somehow interact with lanolidamide to promote more durable deep responses in patients. Now this is an association, it's not causation, so we don't want to tell people to then go and take lots of butyrate because we don't really know that that's beneficial, but I think it's an interesting observation that warrants perhaps additional interventional trials to see whether or not this will be helpful. So importantly in this study we also looked at dietary correlates and what we can see is that folks that had more seafood and plant proteins in their diet had higher butyrate levels, or the amount I would say that differently perhaps that the amount of these various seafood and plant proteins correlated positively with the levels of butyrate and with sustained MRD negativity, and in addition antioxidants like flavonoids, there were some correlations there as well with butyrate. So microbiome is altered in myeloma and this seems to correlate with response, and I think the idea here is that, and this is again correlation not necessarily causation, but it does provide rationale to investigate this by altering the diet and then evaluating the microbiome and seeing how that impacts on multiple myeloma, and the associations are listed here where higher levels of plant proteins and seafood proteins, flavonoids, dietary fiber promote diversity and butyrate production in the gut, and that can have some theoretical effects on myeloma and it seems to be associated with disease control in the presence of lenalidomide. So what about in the context of other therapies? Well I mean one of the most exciting I think treatments for our patients now are immune treatments like CAR T cells or by specific therapies. We don't know yet how the microbiome correlates with response and toxicity there, but we do know in another patient population treated with CAR T cell therapy, and that's lymphoma patients for whom these therapies have been available a bit longer than they have for myeloma folks, that when one looks at sort of overall diversity as well as effects of antibiotics that would impact negatively on microbial diversity in the gut, one can see that this has a fairly profound effect on progression survival. So progression free and overall survival in the sense that those that are exposed with antibiotics, to antibiotics, would have lower diversity and inferior outcomes, and you can see that this is sort of the difference in diversity shown here. And interestingly also those that are exposed to antibiotics that affect the microbiome or disrupt the microbiome more had higher levels of both CRS and ICANNs relative to those that were not exposed to these types of antibiotics. And then as I said, we feed the gut, the gut feeds us. There are a variety, one can look at biological processes that occur in the intestinal tract and then see how particular biological processes, for example, in this case, peptidoglycan biosynthesis can associate with a complete response, whereas other processes with a less complete response. Now this is a lymphoma, this may not, these associations may be very different in myeloma, but nevertheless they highlight the relevance of looking at these kind of features for both response as well as toxicity. So I think we can say that the microbiota may impact myeloma development in natural history. So there's an animal model system that is very suggestive and the mechanism is via an interaction with the innate immune system. The myeloma patient microbiome appears distinct from healthy individuals and there are patterns that are associated with treatment of this. So the questions are, you know, are these observations generalizable across multiple regions? In other words, if we look in a larger study in multiple parts of the country, across multiple individuals, across multiple ethnic groups, are we going to see similar findings? We would expect the flora to be significantly different in regional ways as well as in cultural, because of cultural aspects of the way folks eat. And then can we modify the gut flora in a meaningful and helpful way? So what are we trying to do? What are we doing to do all this? So I'm just going to focus on a couple of trials. So here's one, this is a registry trial for smoldering myeloma patients and the goal here is to understand the natural history of the disease. In other words, does that animal model actually, does that translate to patients? So do folks that progress or not have any differences in their genetics of the plasma cell? Probably they do, although there are very intriguing studies suggesting that, you know, a lot of the genetic features exist in lemgus and smoldering myeloma that are present in patients with myeloma. Is the immune environment at the disease site distinct? And then what are the host factors? How does the microbiome impact things? What about diet? All of these things. So this is a registration trial where individuals with smoldering disease can enter and on every annual basis there's collection of peripheral blood and bone marrow and stool and dietary information for analysis and it's happening around the country through a collaboration with five centers, including ours. So what can we do to change our microbiome? I think this is the thing that everybody's really very interested in, but I really want to say that a lot of research is needed to recommend specific treatments to modify microbiome in anyone and specifically in myeloma patients. But here are some of the things that folks look at and think about. So the first thing is that so again, our system is the gut microbiome, right? And a lot of folks talk about prebiotics. Oh, prebiotics essentially is a fancy word for food. Things that we digest and that we provide to the bacteria and, you know, if you have sugary drinks, they are going to cause one type of bacteria to grow. If you eat fiber, other kinds of bacteria, if you eat animal products, different kinds of bacteria and those bacteria are going to make different things, butyrates or acetate and so on. Then there are probiotics. Essentially these are bacteria that can survive the stomach and that are thought to be beneficial. But I think they're, my view on those is a little skeptical. There are antibiotics, of course, that will have a significant impact on altering the microbiome. There are fecal transplant, which can be used to help folks with certain kinds of disease, for example, C. difficile infection. And then there's postbiotics and those are sort of the fermentation products or the products of what the bacteria do when they see complex starch or carbohydrate and they break it down into smaller molecules, bioactive molecules that our bodies use in various ways. So I'm going to talk mostly about prebiotics, diet, and I'll mention one thing that we're doing with postbiotics. So I would just say that here that diet rapidly and very reproducibly alters the gut microbiome. And so this is a very interesting, it's a small study, but basically nine individuals, five days of a diet, plant-based diet, and animal-based diet, which you can see here. And I think the details here are perhaps not as relevant in my view for the purposes of our discussion today, but what you can see is that there's a significant difference in fiber intake and you can see significant differences in the production of butyrate and acetate and isobutyrate, various things that is different between the plant-based diet and animal-based diet. So there's a clear imprint by a dietary change on what's in the microbiome and what the microbiome actually produces. So the idea here is, can we use food as medicine? And this is a slide I'm shamelessly taking from Irvi Shaw, my colleague, who is a very devoted and energetic proponent of dietary interventions. And so there's a program that she's working on at MSK to study nutrition, and in that context, look and see what the effects of the nutritional changes are on the microbiome and how that interacts with multiple microbiomes. So we've called it the Nutrivention Program. And so this is one of our pilot studies that is now fully accrued where individuals that were obese enrolled were given a diet and various metabolic aspects were evaluated, including weight change, BMI, as well as microbiome samples, blood samples, and so on. And so that analysis is now currently ongoing. And there's, based on essentially our understanding that this was quite feasible, we have designed a randomized trial in patients with precursor myeloma, so MGUS or smoldering, evaluating a whole food plant-based diet intervention, which is about to open at MSK and will open also in Atlanta at Emory. And then there's a study that she's partnering with HealthTree to look again at short-term intervention. What happens if we take a whole food plant-based diet and give it in a short term? What's the short-term effect on microbiome and various quality life things? And then what is the impact of probiotics? I mentioned probiotics, I'm a little bit skeptical, so we're actually going to look at it and see what is the effect on microbiome and what is the effect of various supplements that our patients take. So I think this is a very important study and I'm looking forward to its fruition. And then what about in transplant? So I mentioned that in transplant, diversity is significantly affected. So overall sort of gut health is impacted by transplant, diversity is diminished, and those that more rapidly recover microbial diversity do better. So can we affect a change there? And so this is a clinical trial, and I see now I neglected to write here that David Chung is the PI of this trial at our center, but this is a trial of a fermentation product, a postbiotic called GP22, that promotes gut diversity and it's being used in the context of stem cell transplant to promote increased diversity during the peri-transplant period. And this will be evaluated with sequential sampling while patients are inpatient as well as outpatient to understand what the impact is of this postbiotic on diversity as well as on various other features of recovery from a stem cell transplant. So this is just sort of some of the effort that we're making to try to understand how to impact patient's health by targeting the microbiome. So I will end with this saying that you know that the human body is really a pretty complex ecosystem. We have our own cells, we have our own genes that perform vital functions for our life, but we also coexist with a very, with a vast universe of microbiome that's on our body and in our body that facilitates our health and is responsive to environmental factors, diet, and supplementation or various supplements. And so this is an area ripe for study and a very exciting field and you know I think it's also an area that's obviously of significant interest to our patients and their caregivers. And so with that I'll thank you for your attention and I'm happy to take questions. Wow Dr. Lasocan, thank you. That was amazing. Every time I think I understand what the microbiome is, I stand corrected. I think it's just such an amazing complex like you were saying ecosystem that lives within our own body and so there's so much more research to be done. I'm excited to watch it unfold. There's lots of great questions already in the chat. We have a very educated audience with us tonight and I'm really excited to get started. One of the things that I want to ask before we got started was does fitness play a role in improving the microbiome? Have you guys looked into this? Do you think you will? And actually before you answer that question, just a big thank you to you and everybody at MSK who's really made this one of their priorities in their research because I think it's really important to us to be able to do research on this. And so I think there's a lot of positive effects of fitness on immune health in general and I think one of the, it's in fact I think one of the I guess I think the most important thing is that it's a very interesting area. I think there's a lot of positive effects of fitness on immune health in general and I think one of the, one of the I guess frequent criticisms particularly of the type of work that I've highlighted today which I have to say is descriptive. We need to describe what we're seeing before we can impact what we're seeing or intervene on what we're seeing. And one of the criticisms is well if you have a more fit individual are they going to have a more healthy immune system and a more healthy microbiome, a more diverse microbiome? And you know the answer one wants to give is well yeah probably. But have we studied directly the impact of fitness on the microbiome? Not in myeloma to date but that is definitely something that's happening in the field and I think it's certainly ripe for a more in-depth investigation. Definitely, thank you. Another question I just wanted to make sure I got right. Microbiota is synonymous with microbiome, is that true? Okay. Yeah well I guess to be more precise about it I guess microbiota are like the specific things and microbiome is like the whole thing. Okay that makes sense. Humanity versus humans. Yeah yeah yeah okay so then another one of my questions and I see that it's shared here by several people was about the MRD negative studies. Those were absolutely fascinating and as you said just the tip of the iceberg to incredible research that can be done in the future. As we think about the future do you personally think about maybe separating by genetic subtypes seeing how they respond? Because I know well I don't know personally from my interactions with myeloma specialists there are certain genetic subtypes that are harder to achieve an MRD negative you know sustained response and one of the questions that I really liked here was do you believe a healthy microbiome increases durability of response even if not MRD negative? Like is the principle the same but do you know what I'm trying to ask? It's an awesome awesome question and I wish I could give you like a clear answer. I think most of the answers I'm going to give today would be like I don't know but you know the the thing is is that so there are it's a complex system you know for sure individuals that have high risk cytogenetics so when we look at sort of MRD and look at the effect of like transplant versus not let me let me backtrack when we look at the effect the impact of the microbiome and the differences in microbiome and try to correct for the effect of transplant the effect of cytogenetic status it seems like the microbiome is independent. Now this is still a still a small study just because it happens to be independent in our study I would still be very cautious about saying definitively that it is independent or not so I think that it this highlights to me the importance of doing sort of like these larger kind of like the smoldering registration trial that I alluded to to look at these kind of things across broader patient populations. We actually at our center have a variety of other maintenance studies and maintenance discontinuation studies with where we are investigating also the microbiome both as a marker of durability of response when you stop lenalidomide and durability of response you know is it lenalidomide dependent or a different maintenance drug dependent depending on if we're using different maintenance drugs to try to sort of parse out some of these questions. Now we're focused a little bit more on the therapeutic side of things because we you know are humbly understand that our patients come to us with whatever cytogenetic profile they have. We have to take that into account but at the end of the day in the context of these types of descriptive studies where we're trying to understand the associations and you know what we need to target and what we can't target is our focus is largely on the therapeutics right and how they interact with the microbiome. It will be interesting to see you know as these studies continue Rob's question you know does a healthy microbiome increase durability of response? I mean these are excellent questions that I'm excited to get answers to because again as you and I were talking about earlier it puts the patient back in control. There's so much uncertainty with myeloma. It's like you take the most complex thing ever of myeloma and you combine it with the complex microbiome and we're trying to find one solution but it's all answered. It's not going to work but I'm excited to see what we can figure out when analyzing these two complex things. Yeah no absolutely absolutely. I think it's a very yeah very important question. I think that you know if I were to reference the stem cell transplant the autologous stem cell transplant study where a healthier microbiome was associated with better overall outcome so recovery to a more diverse and healthy microbiome resulted in better more durable or longer progression pre-survivals meaning longer durability of response then the answer from that seems to be that yes a healthier microbiome is associated with longer responses. If it's is it associated with specifically durable MRD or not? We don't have that answer. We don't have that data. Yeah lots of different ways that this conversation could go. Again I'm so excited with all the different kind of questions we have. Let me try to hit a couple really quickly. So John's wondering about the use of Bactrim in multiple myeloma treatment. Does that interfere with the normal microbiome? So not so much. You know it's Bactrim. So I'm not an infectious disease expert and so when I've asked infectious disease folks about this the answer has been not so much because it mostly is targeting gram positives and you know the the focus is more on like gram negative anero. So like a type of bacteria that that is less sensitive to Bactrim. So not so much. Okay. What about your thoughts on colonoscopies? Do you recommend that all of your patients are getting regular colonoscopies or what's in terms of making sure their gut is healthy? Yeah so I mean I think that you know for sure screening colonoscopies would be recommended for all. I tell them I frequently encourage my patients to do them simply because I think you know it's much easier to address a small polyp and remove that than it is to address a colon cancer. Yeah secondary cancer. Yeah secondary cancer together with you know multiple myeloma treatment. So I for sure encourage all of my patients to go through routine screening colonoscopies and if they require colonoscopy for some sort of clinical reason then yeah absolutely. So there's no direct impact of colonoscopy on microbiome and so I think it's a I think that this is a tool that should be used as clinically rather you know as indicated by. Yeah it's interesting here because people are saying you know I've have even when stopping the medication they have issues with nausea, chronic diarrhea, things like that and I'm wondering if there's any research on fungal infections or you know persistent colon infections when it comes to cancer treatments? So in terms of fungal infections and not so much in the microbiome when it comes to sort of myeloma treatment per se that is being looked at in general in the context of like sort of stem cell transplant and even compromised individuals like allogeneic stem cell transplant. So I'm going to sort of leave that aside. I do want to actually address a question that I think Robin asked here if it's okay. So medications like Wellcall right which I take to to deal with diarrhea due to revlimid effect the microbiome right so a lot of our patients on lenalidomide maintenance have developed loose stools and the thought is because there's like a bile acid dumping diarrhea or like a pathotic diarrhea from a lenalidomide effect and I would just say that we are very interested in this question and have done this study and are currently analyzing it so I and hopefully if we see something difference or no difference we will present that at the ASH meeting this year so yeah I think that this is a it's a good question I think yeah a lot of our patients. Encouraging that research is being done in this field because as you know it affects many many patients. Let's go on to like feeding your microbiome or trying to you know help it the best that it can. There's some concerns about you know Dr. Shaw let me let me preface for people that might not know Dr. Shaw is very whole food plant-based diet eat 30 different vegetables and fruits in a week I mean she is gung-ho about this and a lot of patients get a little bit nervous when they still have animal products in their diet or they still you know have animals. We saw that seafood and plants are higher in butyrate is that what it is I can't remember now. What do you recommend for your patients personally in terms of animal products in the diet? Yeah right so I think this is certainly not something that should cause stress for patients. I think it's really important to know that we don't really know exactly what's the best thing for patients. In terms of diet we do know that there's a lot of benefit to fruits and vegetables and foods high in fiber. Fiber is soluble fiber is one of the main things that feeds the bacteria that make butyrate. So there are no foods that are really as far as I know that are like high in butyrate. But you know someone is I welcome someone to correct me on that but soluble fiber is the thing that sort of helps us our gut flora to produce things like butyrate. But you know a lot of these studies are our association studies and it's really important to recognize that association is not really causation. So we need to do these interventional kind of studies to really see what happens. What happens to the myeloma when we do A or B or C in terms of giving a certain kind of diet. So what I tell my patients is exactly what I just said. We don't know exactly what the right diets are but there are these large population-based studies that are really suggestive that you know things like fruits and vegetables are good. So try to have more of them. But I also think that you know we have to live our lives and it's really hard to make these kind of changes and you don't want to beat yourself up over it. I think you know if you make a shift and you get like 70 or 80 percent of the way there you're probably going to get 95 percent of the benefit of it and I'm making those numbers up. I'm going to be very clear about that. We don't know. It's a complex thing. It's really complex. So more fiber, more you know more fruits, more vegetables are great. But you know I like steak too. Yeah well I love that point you know of being aware of things you can improve but not stressing about it because I think stress induces problems in your immune system and your body as well. So you don't want to be stressing out about eating healthy and then having negative effects that way. So I totally agree and support what you said there. Thank you. Let's jump back really quickly to the lenomide and lenin-litamide induced diarrhea because there are patient concerns due to this chronic diarrhea. What's even the point of trying to diversify the foods that I'm eating if it's really going straight through me? Excellent question. How would you speak to that? I mean I think our actual our study speaks to that that those that ate more foods, more plant-based foods, more seafood proteins seem to have a more diverse and microbiome and higher levels of butyrate. So I don't think you know the diarrhea that's associated with lenin-litamide is definitely a major quality of life issue but it's seems that these dietary factors may overcome that. Now part of this natural history study is to try to understand what the microbial impact is that's like associated with like diarrhea. Are the microbiomes different between folks that do or don't have diarrhea but that is a part of the study that we're still working on. I'll keep my eye out at ash. Retta was wondering, we read a lot about sugar impacting cancer growth. Does this relate to the work that is being done about the microbiome? Yeah so I think this is one of those things that a lot of my patients ask about me. It's like it's become it's not quite a pet peeve yet but it's getting there because I think you know sugar is one of the main molecules that our body uses to feed itself. So if you don't eat sugar your body's going to make it. If you starve yourself your body's going to make sugar. Your brain requires sugar. That's the only thing it can use sugar. Can't use fatty acids, can't use proteins, sugar. So if you eat a stick of butter your body's going to turn that into sugar. Eventually it's going to be pretty complicated in how it gets there biochemically but it'll get there and it's going to feed itself. So I think yes sugar does feed the cancer and this comes from the idea that cancers really don't have often depend on specifically sugar molecules. They don't have a lot of the metabolic processes in order to fully use all sorts of materials for energy but there are probably ways to target that pharmacologically but not eating sugar is not one of them. Okay thank you. I'll remember that next time I'm eating a donut. I would say that eating highly processed food and all of that is probably not an excess extra sugar like sugars that you get from fruits and vegetables are probably okay but extra sugar that's probably not a healthy thing and we actually have just a study that has looked at eating sugary foods affecting negatively impacting the microbiome. This was in the context of allogeneic transplant patients where outcomes and diversity were worse among folks that had you know sugary drinks. Right awesome thank you. While we're on this topic how does alcohol affect the microbiome? Yeah it's a good question. I'm gonna so there was a large study that looked at this that I think that I don't have that at the tip of my tongue. I'm gonna draw a blank on that one. The effects are not precise or specific but I think when one looks at the impact of various dietary features on the microbiome as a whole across populations it's very difficult to make sort of broad statements. I think features that in our dietary intake that seem to impact or correlate significantly with microbiome in the general population I think are caffeine intake and smoking. I think those are two things that impact had major impact. I will add here with the different registered dietitians and clinical dietitians that we've had throughout the nutrition and wellness from myeloma chapter they've all been very clear about that limiting alcohol for various reasons can be beneficial not necessarily related to the microbiome but in terms of other comorbidities other issues that you could have in your systems that limiting alcohol is suggested. For sure if you're on treatment of any sort you want to avoid sort of alcohol because of the potential for liver toxicity that can be augmented with other medicines that you're taking. Awesome thank you. Okay just marking off some of the ones that we've answered. John had a good question was wondering if there was a difference between patients who achieved MRD negative status after stem cell transplant versus those who achieved it after induction therapy. Is this something that's maybe in the works to be studied or has been looked at? So difficult to say what we do know is that at least in our study which again I have to qualify as saying by saying is relatively limited in size given the complexity of the microbiome the differences we saw were not impacted by the presence or absence of stem cell transplant to the patients as part of the patient's induction therapy. So it wasn't necessarily like a certain timing of the MRD negativity was just within the scope of their journey? Is that what I'm understanding? So when we looked at this in the immediate post treatment time frame and some of the patients had received transplant and some had not. Okay. And it didn't seem that there was a clear correlation between the microbiome and when one looked at MRD transplant and microbiome like the microbiome features were independent of transplant like the association with the MRD status. I don't know if I'm maybe saying that in statistical speak but anyway that's the point of that is that the transplant did not seem to affect the result that we observed and that was the same also in the setting of like when we looked at later on post treatment three months post initial treatment. Thank you. Several questions and please that you disclose what you mean by caffeine affecting the microbiome. Is it good? Is it bad? What do we know? What do we not know? We don't know if it's good or bad. We just do that. Very good. But I would say that I have yet to see a study that shows that there's a detrimental effect of caffeine and I particularly have been very attentive to that. Yeah. Out of self-interest. What about fluid intake? Does that think like improve or what's the other word the microbiome? I'm not aware of an investigation that's looked at sort of the amount of fluids that people drink. I think in general fluid intake is good. We want people to it's good for your kidneys and your to drink lots of fluids particularly for our myeloma patients. This would be something that we I frequently recommend to folks just to help protect the kidneys as much as possible. Yeah definitely. I saw a question about you know we're talking about eating you know fruits and vegetables and whatever but what if that like enhances the diarrhea makes it worse. Again I am not a dietitian but from the experts that I've had the privilege of speaking to find comfort first make sure that you're healthy and strong and then slowly reintroduce those foods back into your diet. Your health is first and then we can think about getting healthier. Do you have any other thoughts on that Dr. Lasogun? I agree 100% I think that drastic changes in anything like you can't go out and run a marathon tomorrow you have to kind of get up to it and so I think major shifts in diet are difficult. Your body needs time to adjust to that. Fun fact I had a friend in college who did wake up one day and decide to run a marathon and he could not walk for a week after that day so don't do it anybody. Okay so Nora is asking do you know research on long-term use of PPIs and impact on gut biome in relation to multiple myeloma? Yeah hasn't been looked at. All right so much more to study in this field it's exciting. How can people get into your studies? How can they sign up for these studies that you've mentioned? Well so I mean I think there will be a study that we're running together with HealthTreat so I think that that'll probably be something that they can access through you know myeloma crowd health tree you're sort of your organization there. And then some of these other trials that are a little bit more involved like the registration trial there are five centers that I listed there two in New York NYU and MSK one in Alabama University of Birmingham one in Miami Sylvester Cancer Center and Houston MD Anderson. So and I think the thing there is that those studies require just one time a year sampling so that the registrations trial at least so that's a little bit maybe not as burdensome if it's even if you live several hours driving from one of these centers. Of course it doesn't cover the entire country which which is unfortunate which we wish we could do that. And then the randomized sort of neutro-vention study that Dr. Shaw's that that's a study that's open with us and will be open at Emory as well in Atlanta and so you can just reach out to us if that's something of interest. And the transplant study is you know if you're getting transplanted at MSK that of course you know transplant is complex so it's hard to nationalize that if you will. Awesome thank you. Again a lot of great questions here. Let's clarify Steve's remarks he's wondering would you consider then GI symptoms of unknown etiology to be perhaps something that's signaling multiple myeloma? I don't think that's what you're suggesting here but. Not at all not at all. I mean I think that you know there are multiple potential causes for GI symptoms and just need to sort of be persistent and patient and did I say persistent with your physicians to really go through all of the different potential possibilities and to go through a thorough evaluation to make sure that you have a clear understanding of what's happening. And sometimes it's very difficult to understand some symptoms so sometimes we label those specifically as a neopathic or unknown cause and manage them symptomatically and with time we gain understanding and learn about new disease entities and things like that. Well I just looked at the time I didn't realize we were so late I apologize. A couple just two more questions before we go. How does do are we aware of how sleep impacts the microbiome? So that isn't something that we that that that I'm aware of is being studied quite yet certainly not in the context of myeloma. We are looking using various digital tools to measure folks activity and sleep in the context of myeloma treatment and I think perhaps in time as we add other studies as we do other studies of this type and evaluate microbiome in that same context we'll have a better answer to that question. Thank you and then last question is how long does it take to improve gut microbiome? I know you talked about that earlier in the study but if you want to reiterate that. Yeah for sure so I mean I think drastic changes in diet will have drastic effects on the microbiome within within a matter of days. Which we are not suggesting necessarily. No we're not suggesting that you go one way or another because I think drastic shifts in your microbiome are going to affect how you feel too. So I think you know you want to do gradual things. Yeah because then it's like it lasts longer you're more you're more prone to do it if you're feeling good and excited about it and things like that. So anyway lots of incredible questions we didn't get to answer today. I do apologize but Dr. Lesokin do you have any other finishing thoughts before we finish today? You know I think I really appreciate everybody's interest in this topic. I do think it's a really important topic for our patients and I hope that we will continue to you know do studies together with our patient community to try to provide more understanding and knowledge that really you know allows folks to take control of what they're doing in their disease. Definitely thank you so much. Thank you for your time. We're going to finish with just a couple of outro announcements. If you're interested please join us next month December 6th as we talk about having a healthy relationship with food during the holidays. A registered dietician from Texas is going to be coming to speak to us about that. You might be interested in other events we have upcoming. On the first is our financial chapter. We're going to be talking about preparing for survivorship financially. That's going to be a discussion between Diana and John Borland who is one of the coaches. November 2nd is our healthy moves for myeloma chapter. We're going to be having a yoga class and discussing the benefits specifically for the myeloma community that yoga can have. And then November 3rd we're going to be hosting our southeast chapter. So that's anywhere from Delaware all the way to Georgia. I know Delaware and Maryland don't really count themselves as south but that's just the way we kind of organized it. You're welcome to meet with us if you live in those areas at 6 30 p.m eastern. We're going to be discussing building your health care team together. Special thank you to our sponsors, Bristol Myers Squibb, GSK, Genentech, Abbey and Amgen. And thank you to each of you for helping us build this nutrition and wellness community. It's a pleasure to be with you all. Hope you have a great rest of your night. Thank you everyone. Bye bye.