Dr. C. Ola Landgren, MD, PhD, The National Cancer Institute

Interview date: August 2, 2013 

On this week's show, we learned from Dr. Landgren that new tests in flow cytometry are available that can detect minimal residual disease (MRD) and help us gain more insight into our personal type of myeloma, but that there is a 100x variation factor in the result depths of these these tests, even in myeloma clinics within the United States. Asking the right questions of your doctor and the lab where your work is performed is critical to the understanding of your disease and its accurate diagnosis. We learned how imaging studies like MRIs can give us significant information about the biology of myeloma cells in addition to the flow cytometry tests. He discussed the profile of the MGUS patient and how smoldering myeloma needs to be separated into more specific groupings to be accurately diagnosed and treated. He described his "blueprint" for a myeloma cure and his work on the Black Swan Initiative in asking the appropriate questions that need to be answered to find a cure. He believes a cure can be found if we assume that it can be, and if we ask the right questions that drive to greater discoveries, beginning with more detailed diagnostic work at the molecular level and in early stages of myeloma. The live mPatient Radio podcast with Dr. Landgren

Jenny: Thanks for joining us on today's Interview for the Innovation in Myeloma Series on mPatient Radio. We are thrilled at your participation in this series so far and have had over 3000 of you listen in. We hope that we as patients can help you understand research so you can find and participate in clinical trials that are best for you. We welcome your suggestions about additional topics you may want to have covered, and you can always email me by going to the mPatient website and use the contact link, or you can email me directly at jenny@crowdcare.org. If you would like to call in to ask questions in the later part of today's show, you can call in to 347-637-2631. We are very excited and grateful that we have the opportunity today to speak with Dr. C. Ola Landgren. We are catching him as he travels. So we are just grateful that he's taking the time to be with us. Dr. Landgren is a thought leader and top researcher in multiple myeloma and to introduce him, even in those terms, is really an understatement. He's a senior investigator in the Metabolism Branch at the Center for Cancer Research, the National Cancer Institute in Bethesda, Maryland and is also the head of the Multiple Myeloma Section of the Medical Oncology Branch. He's originally from Sweden and received his M.D. and Ph.D. degrees in Sweden at the Karolinska Institute and joined the National Cancer Institute in 2004. Dr. Landgren's major research interests are in the causes of myeloma and how myeloma is diagnosed and treated particularly in the early stages of MGUS and smoldering myeloma. His research also includes how the immune system both affects myeloma and how it is affected by myeloma. He wants to change our collective mindset to first believe we can find the cure and then create an outline for how we're going to do just that. So with this target in mind, he is leading work on the creation of a blueprint for myeloma, for a myeloma cure with IMF's Black Swan Initiative, and we are so fortunate to have him with us. So thank you, Dr. Landgren, for joining us.

Dr. Landgren: Well, thank you very much, Jennifer, for having me. It's really a true honor for me. Thank you so much.

Jenny: Thank you for taking time out of your busy schedule. Now, your research it seems that we can find a cure for looking for one. So is one of the pieces to creating this blueprint related to understanding actually potential causes of myeloma?

Dr. Landgren: I think the way I view the relationship between causes and the trajectory of disease is I think that clearly myeloma is not one disease. There are different types of myeloma. And I actually think that people who are diagnosed with multiple myeloma probably have more than one type of myeloma going on at the same time even from the very beginning. I think there could be different causes that could lead to what we call multiple myeloma across different individuals. So in one person I think maybe the genetic factors would play a greater role and maybe in another person environmental factors would play a greater role. I do think, based on what we know from research, that in general it is probably the interaction between environmental things and genetic things that are related to our constitutional genetic code.

Jenny: I think that's fascinating. And your research I know is also focused on the rest of the immune system and how it affects myeloma and it also then affected by myeloma after treatment or after the progression of the disease. So can you describe your research in that area?

Dr. Landgren: Yes. So that's a very big area of the investigation. A lot of the very brilliant researchers around the world are looking into the role of immune system in cancer in general and in myeloma in particular. So our contributions are focusing on how normal plasma cells are behaving in relation to the outgrowth of the clone. That starts from MGUS that goes through smoldering myeloma into multiple myeloma. How the role of the normal plasma cells, actually all the mechanisms that are actually are working. We're also looking at other substance of immune cells that's regulated, that could, for example, include something like more natural killer cells. We're also looking at the role of T cells, natural killer T cells also. There are also other B cell lymphocytes beyond the plasma cell. So there's a whole range of immune system, cells in the immune system that probably is involved in regulating. And I'm telling you something that I don't know, but this is kind of my thinking and I'm trying to explore this in a research fashion. I do think that probably at earlier stages of this disease at the MGUS, probably the immune system can't control the cells, but maybe it could be one model. This is what I'm thinking in my research. I'm trying to explore this and try to either prove it wrong or prove it right, but there could be mechanisms in the tumor cells that make the tumor cells basically resistant to the immune system's control aspect. So the immune system controls the early stages, and after a while in some individuals the tumor cells, they start doing things that make them resistant to that. I don't think that is really purely driven by the tumor cells only. I think there is a balance between the immune system and the tumors, and I think we need to look into both, and that's what we're doing. So we're looking into all the substance of cells. We're trying to look at mechanisms that involve that.

Jenny: And have you looked at triggers that might cause it, like a virus also?

Dr. Landgren: Yes, we do. So there are different ways, obviously, you could look at causation. You could do studies where you ask people, "Have you been exposed to chemical things? Have you been working in a certain area? Have you done those types of things?" and then you can see if more people who develop a certain disease such as myeloma answer “Yes” to that question compared to the general population. That would suggest that there maybe is something going on. But we, of course, have to be careful because sometimes it could be that people who do certain things, they also do other things. Maybe they are more smokers, or maybe they are eating certain things or maybe they are just doing other things that we don't really think about. So these are more epidemiological approaches, and we have done studies where we look into, for example, the role of pneumonia in this context, and we found that people who develop myeloma were more prone to have episodes of, for example, pneumococcal infection in the past before myeloma happened; that's the general population. But it is possible that these project manifestations of something else. Maybe the immune system was weakened and that was the reason why the infection happened, and maybe the weakening of the immune system actually was a driver of the development of the disease. So again, you have to be careful when you draw conclusions based on these observations. We don't know if they are causal relationships or if they're just like manifestations of something else.

Jenny: Right. And your research I know mentioned chronic inflammation. So I don't know how that relates to what you're looking at with myeloma, but can you describe how that's related?

Dr. Landgren: Yes, so I think there are a lot of conditions that we as the doctors and people who work in the clinical research field see. We may not always think about them as inflammatory processes. But, in fact, if you look on a molecular level, a lot of conditions actually involve immune responses and inflammation, and one of them is actually obesity. So in fat cells, there are different types of proteins that are released at higher or lower rates than -- or if you have a lot of fats, you have a higher or lower rate, they're always believed like that. So someone who has a lot of body fat has altered levels of, for example, something called adiponectin, and adiponectin is an immune regulatory substance. So just having more of certain types of cells basically manipulates your inflammation levels and your immune status. So obesity could be viewed, I believe, as an inflammatory disease state, and we have found obesity to be linked with myeloma and even with MGUS.  So that's one example. That's one example. And we have studied this in molecular detail also. We are looking into this as we speak.

Jenny: That's great. Now, we were talking about the blueprint. Let's talk about that a little bit more. I know the Black Swan Initiative is part of that blueprint. Can you describe what that is and the whole blueprint and how you're approaching this?

Dr. Landgren: So you want me to talk about the blueprint or the Black Swan or both?

Jenny: Both.

Dr. Landgren: Okay, so let's start with the Black Swan. So the Black Swan is something that Susie Novis and Brian Durie from the International Myeloma Foundation started. So it's their idea, and they invited four more people to participate in this group. The four people are: Dr. Jesus San Miguel in Spain, Dr. Vincent Rajkumar at Mayo, Dr. Michael Kauffman who is involved in biotech in Boston, and myself. The six of us have been discussing. We have been meeting every three to six months for about one and a half years now and the scope of this group is really to sit down, to look at what we do, to look at what everybody else in the field is doing and try to ask the question: What would be an important thing to solve in order to help the field, not our own research agendas, not our own interest, really from a big picture perspective, what would really make a huge impact for the whole field? Who could really go for that? How could we facilitate that? What's the key question? So we have had a lot of discussions. And then we started to rank these things, and we continuously discuss more and more new ideas and we continuously re-rank and we discuss back and forth. For right now the key question we think needs to move forward is minimal residual disease, and the reason we think that is because the newer drugs we are now using can take very high proportion of patients into complete remission which is fantastic, but we need to think beyond that. We need to think how deep of these responses do we actually obtain in individual patients. So having every person reaching complete response is great, but if there is still disease left, then we're not done. So we really believe that minimal residual disease needs to be focused on. That's what that group is currently working on. There will be more areas of focus in the future, but right now that is a key focus. And I'm involved in the development in my own research group, and I'm working on flow based assays and I'm working on molecular tools and I'm also working on imaging tools. So we have a lot of work going on in that process. So that’s kind of what the Black Swan group is doing is to come up with new important questions for the field and try to move those forward. That's what we're trying to do. And we don’t do the work ourselves. I mean we have to do that in collaboration with everybody. So we invite people, we ask people what they think and we try to stimulate discussions. So we basically try to serve as the facilitator when we work in that context.

Jenny: Well, it's a great project.

Dr. Landgren: Oh, thank you.

Jenny: And how does that differ from the blueprint?

Dr. Landgren: So now the blueprint is really something that I've been thinking about this for quite a few years now, but I wasn’t really sure how to approach it. So I've been developing early treatment studies for several years, and I've had a long-term interest in curing the disease. So I talked to lots of people, the people I mentioned. They are very good friends of mine, and I interacted with a lot of very, very smart people around the world who work on myeloma. I talked to the people back at my own institution. We have a lot of very good people there as well. So really what I concluded for myself was that I think the main obstacle why we don’t have a cure for myeloma I believe is because we tell ourselves that it's incurable. That's what I kind of dislike. I didn't like that.

Jenny: Well, neither do we.

Dr. Landgren: So I feel that we have to remove that. We have to stop saying that. So every paper I have written after I kind of came to that conclusion and every paper I will write in the future including papers I will review for journals and I review a lot of papers, I will comment on that to say, "Please remove that because we don’t know that." So now on more realistic or a more pragmatic note, I think we have the drugs now that are so effective, we have the tools to monitor the biology, we have the minimal residual disease tools, and we have now started thinking about treating earlier disease. So for me really writing this blueprint paper with my colleagues, with Dr. Roschewski and Dr. Korde and Dr. Wu, was a way to basically put down our thinking as a map. Well, we didn't have all the answers, but we wanted to at least ask the key questions that we need to work on and other people need to work on that we felt were the important questions. And obviously, there are other questions as well, but basically it was an effort to write down the key questions that we need to solve and then we have to work together to do that. That's the blueprint.

Jenny: And the blueprint questions, are those also beginning with kind of focusing on the predictors and the diagnostic testing that you're doing?

Dr. Landgren: So the blueprint questions translate into this stuff I talked about for the Black Swan Project. In my opinion, the key questions are, for example, can you reach a cure if you treat earlier? Another key question is: if you have the best MRD assays out there, is that a signature for a cure? If you develop therapies that are based on what you know in terms of biology in detail, is that the way to reach a cure instead of giving everybody the same therapy? So I think having the best understanding of biology, maybe treating a little bit earlier and then to make sure that you actually monitor what you do instead of just giving everybody the same number of cycles and then hope that it works. To me that makes absolutely no sense and then you say it's incurable. Of course, it's incurable because you didn’t do a good job.

Jenny: Or it's not detailed enough level.

Dr. Landgren: No.

Jenny: Well, let's talk about the testing that you're working on, both imaging testing and molecular testing. Can you describe what those tests are and how they work?

Dr. Landgren: So this is what I think. I think imaging for myeloma has major potential. I think the way we are using it right now is absolutely not a way to take advantage of current technology. So just to give you a few examples: If you do a skeletal survey, which is still the gold standard, you are looking to see if there are lesions in the bone. Lesions in the bone by skeletal survey are reflective of between 30% and 50% of the bone structure being de-arranged. So for example, if someone has 20% of the bone being wiped out, if you do a skeletal survey, that's going to look normal so it's not a major limitation. If you do a CT, a CAT Scan, you'd probably increase your detection rate by 10 to 20 times so you can pick up smaller holes in the bone. Now this is the most important part I think along these lines. Myeloma is not a disease of the bone. Myeloma is a disease of the bone marrow. So the skeleton has a hard and a soft component and the disease is in the soft component, not in the bone marrow. That's where the myeloma cells live. And when they are active, they trigger other cells in the bone marrow -- we're talking of the immune system we talked about before -- and also cells that are involved in bone metabolism. And when you start seeing lesions, they actually are complications of myeloma. So why are we imaging complications of a disease? Why don’t we image the actual problem, the disease? To me, that makes no sense and we could do that. So CTs are not so good for that. Skeletal survey is completely useless. You cannot image bone marrow with skeletal survey. You have to do an MRI. So an MRI is a very good method to image soft tissue. So you could do MRI of the bone marrow and there are actually people who have done that. So I think a very brilliant researcher in Germany is Jens Hillengass; he's a young and very creative researcher in Heidelberg. He has shown that if you image multiple myeloma patients, most of them have changes in the bone marrow that you definitely can pick up by MRI. If you image smoldering patients, maybe a third of them have very similar changes. If you now start looking into more depth, you can see that some smoldering patients have actually only one of those and some of them have actually multiple. And has shown in his studies that  that those people who have more of them, they have developed multiple myeloma within a year or two. So to me that shows an example that the disease maybe, or it suggests at least, that the disease could maybe start off at a single site and then it keeps on spreading and then it takes off and then it causes complications in terms of holes in your skeleton and then you start having pain and then you go to the doctor and then he or she does a skeletal survey and they image the complication. To me that is something we need to change. We need to think about new ways of detecting the disease earlier. I think to me that's very, very important. So that's an example. We are working on this, and we are trying to implement different types of PETs also in MRI and we are also implementing CAT in CTs. So we are working on that and there are a lot of people that do a lot in this area. I think this is a very important area.

Jenny: Well, it seems like maybe a low-hanging fruit area where the technology already exists and let's go deep on it.

Dr. Landgren: I think one of the problems is that again if doctors who treat myeloma keep on saying it's incurable and they keep on saying that bone lesions are a criteria to start therapy, it stops the whole evolution and development for new thinking just like a major roadblock. So getting rid of this lesion being the indication with therapy, complication is an indication for therapy, I think that's a major thing actually, I think.

Jenny: I think I agree. Can you describe a little bit more about the flow cytometry test that you're working on?

Dr. Landgren: Yes. So I want to say that the best group in the world with the strongest track record whatsoever is Dr. Jesus San Miguel's group. They are just outstanding. They had done so much work. Alberto Orfao is a star in flow cytometry, in hematologic diseases. They have done more than anyone has done in the field of flow for hematologic diseases. So what we have done is that we have tried to set up all their platforms, and we have done that in our actually clinical operations. So we now have everything they have developed for many years and we are very, very happy being able to do what they have developed. They have done a fantastic job. So if people say that they do flow of the bone marrow, that means that they run a sample in a machine, but it doesn’t tell you anything more. So there are very many things that you have to be careful about. So for example, if you look for abnormal cells, they don’t have like a little signature on them saying "I'm cancer" and the other say, "I'm not." You actually have to do a lot of work to sort out which is which. So you load the machine with colors. They are antibodies that have colors. Some people have two colors; some people have four colors; some people have eight colors. So the more colors you have, the higher likelihood of being able to sort out good from bad. So we are using now 12 colors. We have 12 colors we load in an eight-color machine, and this is what the Spanish groups have done. But many groups in the United States are still using four colors. Some are using six or eight. So that's one thing. Another thing is if you treat and you do a biopsy and you run it to the machine, what's the definition of being positive? So if you find one tumor cell, is that positive? Actually, labs would not call that positive. They would call that negative because many of those cells could be hard to distinguish from normal cells so there is a bit of a gray area. So many groups say that you need to have at least 20, and other groups say you need to have 50. So that's a gray area. How do you determine positive from negative? So that is important to keep in mind when you think about how you've come to that number because some groups they check 100,000 cells in the bone marrow with the flow machine and if they find 50 to be positive, they call it positive. If they are negative, all of them were -- less than 50 are positive, they call it negative. So the Spanish group has shown that you should look for more cells because then you're more likely to find a bad one because they are still there. So what we are doing is that we are looking for three or more million cells. So if you check three million or four million cells, you're more likely to find the bad ones there.

Jenny: Yes, because you have a bigger sample.

Dr. Landgren: So I think what I'm telling you here, how do you conclude abnormality from normal? How do you set the cutoff for abnormal to normal? And how many events are we actually checking? And I can tell you, we just surveyed all the big centers in the US. This is coming out very soon in print, in the Blood journal. We are going to publish this very soon. The difference across laboratories in America in August of 2013 varies with a factor of 100. There's a hundredfold difference. If people tell you are MRD negative, that varies by a factor of 100 for myeloma. Huge.

Jenny: Well, that's stunning.

Dr. Landgren: It's kind of shocking.

Jenny: Yes. As a patient, you want to say, "Well, where is the most detailed testing happening? And regardless of where I live or where I can get treated, I want to go to that place and get my diagnostic at least run to the very deepest level that I can." So if you're a patient, what do you suggest?

Dr. Landgren: I want to be cautious because -- I want to say a few things. The consequence of what I told you is that you could go to a center and they tell you you're negative, and the doctor who treats you think you're negative because usually the treating doctor doesn’t look into the nitty-gritty of how the lab is doing it. Usually, clinical doctors don’t know these details. They believe the reports. I mean that's what they told me at med school also, look at the report? But if you start looking how they came to that, then you start seeing other things. So I think there's a huge lack of deep understanding, and it's not of lack or trying to do a bad job; it's just like the tradition. So someone basically needs to say, "Hey, listen, we need to have the same testing." The consequence of the current scenario is that there are a lot of people that were told they are negative, but they actually are positive in another lab. So that needs to be cleaned up. Now, your question is how shall you pursue this as a patient? I think that although this sounds very obvious that we need the right test and everything this to be kind of the same and all that, I mean that needs to be done, but you have also to be careful because what are clinical implications? Do we know that MRD negativity really, really, really, really, really leads to longer survival? I mean that's a key question. And I think in my mind the answers is that they are clearly indications that the answers is yes, but we need larger studies to really prove that. I think if you want to develop a cure, you have to get rid of the disease. So it depends on what you want to do. If you want to get rid of the disease, you have to be zero. If you want to just extend survival, you probably want to get rid of the disease also. But if you want to have formal proof, then you have to do the studies and really prove what I'm saying. That has not been done in a very, very systematic manner. So that's the missing piece. But I think we need to do this. So you have to prove it in order to really have the hard data. I'm working very, very hard to do this.

Jenny: I guess the question still is for a patient, where do they go? Who is doing the more detailed level and if there's that much variety in it, how do we know as patients that the results that we're getting from some of our testing is accurate? I mean this is a glaring question for me as a patient.

Dr. Landgren: I think that the way to solve the problem I'm addressing to you is if every patient asks his or her doctor, "I want to know how you came to that," that will drive the process. So I don’t know really -- I don’t have the telephone book of every center, but I can tell you the difference is a hundredfold from the best to the worst. So you have to ask, and people can look up online the Spanish group. They do minimum of three million cells. They use eight or 12 color antibodies and they count 20 or more cells as positive. So that's a very high detection rate.

Jenny: Right. And I've heard about the gene array expression profile. Is that test relevant in this mix? Is that part of this testing? Can you describe how that's related?

Dr. Landgren: I think it's fair to say that at the current time, gene expression profiling  (which, by the way, is kind of quite old technology. It's about, I would say, 10 or more years old really) That this type of technology has (in a clinical setting, it's older in a research setting) been used for more than 10 years now. So I think it's fair to say that if someone orders that, it really rarely changes the way the doctor would treat myeloma. I can actually not really say I know of very many cases where that has been the case. However, you could argue and say that if you had certain signatures, you maybe are more alert that the disease should come back weaker. So if that doesn’t happen, then you need to jump on the disease. So you can see if there is any hint of that, that this disease may be of the type but for the up-front therapy, I don’t think it really changed very much. I think in the future though you could do much more sophisticated molecular profiling with the genome sequencing, both DNA and RNA sequencing, where you basically sequence the entire genetic code of the two. It was done 20 years ago when the human genome was sequenced. You can do the human genome of an individual case. That's technically possible to do today, technically possible. The problem is that again it will not change how individual doctors would treat. There is no drug that's kind of this is the drug you shall give if you have this mutation, for example, or if this translocation is there, this is how you do it. So yes, you could do it, you could characterize it, but it will not have immediate implications. I can see in the future that for people who have recurrent disease and you know the signature of the disease, that may be something that could impact the choice of therapy. But today we are not yet there. We don’t have the drugs to match up the biology really. I think that's fair to say. Jenny: I can see that. Progressing towards your specialty which is MGUS and smoldering myeloma, we're hearing a lot about how this disease may be just the early stage of myeloma but not all patients will develop into full-blown myeloma. So how does a smoldering or MGUS patient deal with this or understand it better? And can you just share a little bit about your research in that area?

Dr. Landgren: We see a lot of people at the NIH. You probably see, I don’t know, we have very, very many people coming to us, and we have very many smoldering patients we are seeing. I think that a couple of important comments I would like to make is number one, that MGUS in the vast majority of cases, they will never ever, ever, ever have any problems. Life is full of risks. Driving a car is dangerous. Doing a lot of things are dangerous. So MGUS on a relative scale is not a big problem. It's not. Unfortunately, if someone is told that they have MGUS, they think about that a lot, but there are a lot of things that people don’t know about it. It could be other diseases that are going on in the body, cardiac or other diseases. If you don’t know about it, you don’t think about it.

Jenny: Ignorance is bliss, right?

Dr. Landgren: So I usually tell people with MGUS that this is not a big problem. That's number one. I also think what is important to think about is that the risk is not the same for every person. Clearly, it's very, very different. It's actually very different. I think there are some MGUSes where the risk is probably as close to zero. We couldn’t, of course, guarantee that but it's probably as close to zero as we possibly could say because the risk factors are really, really, really not there. Now I'm talking about doing a very careful molecular characterization of a lot of things. And then there are people where the risk actually could be quite high. We have a study that is probably going to be published in a month or two where we have looked through close to one thousand people with MGUS in collaboration with my Swedish colleagues where we actually show that there are some MGUS patients where the risk could be maybe even close to 50% at ten years of follow-up. That's a very high risk, but that's a very tiny proportion of people with MGUS that have that high risk. Most people don’t have that. They don’t have any risk at all, numerically very, very low. So my second comment is that the reason there is a lot of variation across individuals. So I think it's a thorough workup point to understand the risk profile I think is very important if you are thinking of doing something about it in terms of interaction. In terms of smoldering myeloma, I think I would like to be almost as bold as this to say that I wasn’t sure smoldering myeloma in the next step. I think it may actually not be correct because I think a lot of people that are currently diagnosed with smoldering, they are more on the MGUS side of the spectrum. Some of the smoldering patients actually have molecularly and also clinically if you start looking with sophisticated techniques, very close to myeloma. I would call those early myeloma. There's maybe a group in the middle where we cannot really tell if they should go to the left or to the right. They may be the true smolderers, but I think numerically they are very few. So I think if you're thinking about smoldering and it's even more important to try to do a very thorough workup to try to come up with a characterization of the beast, so to speak, like how high is actually the risk? I think that's a very, very, very, very important question for the future, and I think those individuals, if we are starting to treat earlier and we are not yet there but I think those individuals are the ones with high risk that probably should be candidate for that, for those people who think that's what they want to do, We need to see what studies show if it's really beneficial to do that. We have some preliminary data, but we need more studies.

Jenny: And about how long do you think that will take to be able to identify?

Dr. Landgren: So already now we have certain tools we use in the clinic where we can say that around a third of the people we see with smoldering, they have what we call a higher risk, and their risk is probably developing multiple myeloma in less than two years, one and a half to two years. There are certain hallmarks that basically lead to multiple myeloma within six to 12 months. We already have that. Some of these are not yet published so it needs to be replicated, but I think we have some tools and there are published tools as well. But, again, the vast majority of smoldering patients don’t have this higher risk. They have a high risk, but the highest risk is maybe only a third of the individuals.

Jenny: That are classified as smoldering today, you mean?

Dr. Landgren: The third of the smoldering patients probably have this very high risk, and the others they have elevated risk. Maybe a third of the smoldering have close to MGUS risk, and a third of them have very high risk and then there is this third in the middle that I don’t really know. Some of them could maybe be categorized as lower and some of them as the higher, and there may still be someone in the middle but we don’t really know what risk they truly have. So that's kind of a problem we have for right now.

Jenny: I want to also cover your open clinical trials and you have a long list. So are there some you would like to describe for us in detail?

Dr. Landgren: We have a very active program. Our focus, as I have tried to outline for you, is to try to understand the mechanism of this disease at an early stage. In our clinic, we are 100% committed to our patients. Every patient is getting 100% of our attention. We are trying to use our clinical operations as a framework to understand these questions and others. So although we are very research interested, we are very, very clinical in our approach. So I think that's important to say about our program. When it comes to the treatment trials where I think we are the strongest on a relative scale is probably in the setting of newly diagnosed and for thoroughly understanding the disease. So we have molecular profiling, for example. Patients with smoldering can have a very, very detailed workup along the lines I'm trying to outline. In terms of treatment we have for high-risk smoldering patients we have actually treatment studies open for that so people who are interested in that. And we are not trying to counsel anyone to do something they don’t want. We are just trying to show what the options are and the standard of care, we are very, very clear about that - still it's watch while waiting. And then we show what's available in the literature, and we always ask people to ask other doctors. I always encourage people to seek another doctor's opinion before they decide to do things, something that's kind of more experimental, always.

Jenny: These are important decisions.

Dr. Landgren: Yes. And for newly diagnosed we have also -- we have a program where we have very, very good results, and we have actually been so bold so we have collected stem cells but we do not do the transplant (that’s the standard). We collect the cells but we don’t do the transplant. In the event that someone were to recur, that's something that could be considered an option, but the transplant in this study is actually built in as a delay so you do therapy and that's it. There's no transplant. We have excellent results.

Jenny: Do you do transplants at your clinic?

Dr. Landgren: We have a transplant program at the NCI, so we're working with the transplant team and our myeloma section in very tight collaboration.

Jenny: I wanted to talk about that because sometimes when you think about the NIH you just think about research, but you have a very thriving myeloma practice. So I think that's important for patients to know. As patients, I think we all believe that a cure can be found, so our question for you is how patient can best support your work and the work of the Black Swan Initiative, or asking these important questions.

Dr. Landgren: Well, I think that asking the local doctor if they say that the results came back from the samples and it shows that it's MRD negative to ask “What does that mean and how was that determined?” I want to know exactly how they came to that conclusion. And I'm afraid that a lot of doctors, probably 95% of doctors, don’t know that. I think that's something that we need to change together. So working together, we can change that. I think that's a very, very fundamental question. In terms of support, I think that IMF is a fantastic organization. They are very committed, so I think helping them with their mission in various ways I think is another important thing that people could do. Again, I think working alone you can only do so much but working together you usually can do much more. We are very, very collaborative and we try to help other people. We do that at different levels. We try to share our data. We participate in meetings. We give talks. We mentor a lot of students and young doctors. We try to be very generous. That's our way. I think that would be my advice to people and families to try to continue. I know a lot of people are very, very committed. I'm very, very committed myself. I think just being honest and committed and work hard. That's the only way for it.

Jenny: I agree. Just so people know if they do want to support the IMF, their website address is www.myeloma.org if you would like to support that. I think we need to move forward into the question because we have several questions that had been sent in and also people that are on the phone. We ask that your questions are specific to Dr. Landgren's research and that if you like to ask a question, you just have to hit 1 on your keypad and then when you hear the system say "unmuted," it will mean that your call has been taken and you're free to ask your question.

Caller: Yes. Although I'm a five-year smolder and of course extremely interested in your smoldering work, I'm also in a support group and I have a question about your clinical trials with other patients. We have a patient who has been recommended by both her myeloma expert and her local oncologist to get an allo transplant there at your facility at the NCI. However, the question, of course, first, is whether or not you in your effort there at the NCI have some clinical trials for people in relapsed and refractory states as well as smoldering myeloma that might be interesting.

Dr. Landgren: You're asking me if we have therapies for relapsed/refractory and you ask me if we have therapies for smoldering, if that's correct?

Caller: The former. You've already mentioned the smoldering.

Dr. Landgren: We do have protocols for people with relapsed and refractory. We have currently one study open where we are using two more targeted approaches and drugs in combination. One of them is an mTOR inhibitor and the other one is an HDAC (Histone deacetylase) inhibitor. We have done a little research at the NIH trying to understand what type of molecular mechanisms are driving the disease when it gets refractory, for example. And we have in our research found that these types of mechanisms that involve these targets are important. So we have developed based on that research one treatment trial and we've done this in collaboration with the Mayo Clinic. So that's one study we do have open. (Find the study here) We just completed another study that is is not currently not open for enrollment. There are other as well that we do in collaboration with the National Heart, Lung, and Blood Institute for relapsed and refractory. We have one that's led by Dr. Rich Childs where he uses activated natural killer cells from the individuals. We take out the natural killer cells from the blood and then you grow them in the lab, you activate them and give them back. That basically is an immune therapy. Also, Dr. Steven Rosenberg at the NIH has therapy with cell therapy which is similar to what recently was published in the New England Journal for CLL with the UPenn group with Carl June. They showed that using activated immune cells, they actually were able to cure, they claim, some people with CLL. And at the NIH, Steve Rosenberg has developed similar approaches for other cancers. So far no patients with myeloma have been treated, but there a couple of lymphoma patients that do and it looks very promising. So those are examples of studies that are ongoing for relapsed and refractory.

Caller: Thank you very much and if I might add one thing, we recently heard from Dr. Durie and others that allogeneic should probably be delayed for people who might be eligible for exciting drugs emerging because I suspect that an allogeneic transplant might disqualify anyone from just about most other clinical trials. Is that in fact the case, that the coming drugs are so exciting that maybe allogeneic should be put off to keep people eligible for potentially productive clinical trials?

Dr. Landgren: Well, I think that's a very good and very difficult question. So as you probably know, allogeneic transplant is used in different types of diseases, not only myeloma and is also well known is that it's a quite toxic type of approach. So unfortunately, the treatment-related mortality is not trivial and also for those people who undergo it, the people you follow them overtime who go through allo, they have chronic graft vs. host disease, so it can be quite tough. So having that said, we are talking about very potent therapy that also has a lot of downside. But if you have someone who's very young, who has a very aggressive disease, I guess you have to think about pluses and minuses here. And if you really want to fight the disease, maybe there are people who are willing to do that at the expense of these toxicities and these risks, because if you don’t control a very active disease, the disease may be the winner. So that's kind of the difficult thing. And then you throw in the question you're asking, what about using other drugs? What's the timing? How shall you do that? So I think some treatment protocols for new drugs, they do allow people to having done an allogeneic transplant, but others they don’t. So if you do new drugs and they work, then that will turn out to be the right way. But if you do new drugs and they are not successful, you may end up in a situation where you may not even be able to do the allogeneic transplant because the patient could get too sick. So it is a very complicated question, and I think every single case has to be reviewed in full detail and all the options have to be put on the table. And in the event that the therapy that was chosen works, perfect. If not, all the options have to be put on the table again, and it has to be done every time for every single case. That's my way of thinking.

Caller: Thank you, sir.

Dr. Landgren: You're welcome.

Jenny: Thank you so much. Okay, we'll go to our next caller, please go ahead with your question.

Caller: Thank you. Dr. Landgren, my favorite question to ask the heroic folks like yourself that are making a headway in this diseases is -- and you've spoken a little bit about this but maybe we can be more specific. My question is what is the greatest barrier for you in moving your research forward and moving towards your? How might the myeloma community help you? What is that one thing that could be taken out of your way to move forward quickly?

Dr. Landgren: You mean for me leading my current research program?

Caller: Yes, exactly.

Dr. Landgren: Well, that's a hard question. I think we are very well positioned to do many of the  things I have been talking about. So I guess the thing that would speed up would basically be more resources. That's really the major limiting factor because I think the questions are pretty clear to us, and we need to work harder. I can give you some examples. For example, I took five patient samples this past week and I want to do whole genome sequencing and I want to do that in more than one sample from the same individual. And we're talking about $100,000 expensive assays. So out of the grants that I have, I spend a lot of money on very few samples, and I think at the end of the day we're not going to be able to solve all the questions with such few samples. We have to do it in smaller steps. So the Black Swan Initiative is meant to take care of that because if we can point out some of the key questions that IMF is trying to collect research funds from various sources and then support projects around the world that focus on this area. So that's the way to kind of overcome this problem. A lot of research is done in small chunks and it really doesn’t make the major breakthroughs. So I think if you want to do a major breakthrough, you have to be very serious about it. You have to not do just one small, little thing. It takes a lot of time, a lot of energy. So someone needs to really do this and that requires a lot of sustained support. So that's my answer to your question.

Caller: Thank you. I appreciate that.

Dr. Landgren: You're very welcome.

Jenny: Several patients have written in with questions and a question from Bob is, "I recently read somewhere that around 80% of all people over the age of 50 carries some cancer cells which may or may not exhibit some type of aggression to cancer. I agree that there should be an ongoing effort to reach minimal residual disease, but is it worthwhile to reach zero residual disease and would it be possible?" And I think you spoke about this a little bit.

Dr. Landgren: Well, I don’t know if it's possible and I don’t know if it's meaningful. I think you could envision the following kind of scenarios like major scenarios. One is that you actually can develop a test that is a true test. So if people are negative with this test, the disease will never come back. That would be like the dream scenario. But I guess you could also envision a scenario where you still could pick up a little bit of disease and maybe the immune system can control it and it may not become a problem. It's like MGUS. And you could also envision a scenario where there is a little bit of -- I mean what's the definition of disease? I guess the definition of disease is that someone is sick so if you have something detectable, it's not necessarily a disease. It's like a condition. So a little bit of a condition and then if you need to add some drug to control it, as long as you don’t get sick and it doesn’t get worse, I think that's still a major, major breakthrough and that's possible that that is where we're going to end this whole work that we may be able to pick up some positive MRD with the best technique we have. It still won't get worse, and I would perfectly happy with that as long as people don’t get sick. So I think to me it's a matter of having non-arbitrary tests like yes/no, positive/negative. We want to have a few measures and that means we have to have very sensitive techniques that allow us to quantify over time. For example, I can tell you if you do bone marrow biopsy, you take out the DNA -- we have already done this -- and you sequence the tumor and then from half a milliliter of plasma we can already know in our lab, we can find the signature of the tumor cells in the bone marrow in half a milliliter of plasma. We can pick it up. We can already do that. We can quantify that. So I think if we work a little bit more on that, we then will have tools to see if it goes down to zero. Then we can use that as blood test overtime. We don’t have to do bone marrows. So I'm very, very excited about that. That's one of my key interest areas right now.

Jenny: I think we would all love less bone marrows (tests) as patients.

Dr. Landgren: We are working super hard. This is probably where I work the hardest right now to do that.

Jenny: We have two more questions. One is from Carolyn who asked, "Can a patient join your clinical trials even though they may be treated somewhere else and then logistically how they go about doing that and in general, how does that work?"

Dr. Landgren: So for people who are treated for multiple myeloma elsewhere, again as I said before, we try to be generous. If people really want to come and see us, we usually offer that. I don’t know, maybe it's risky to tell you that, but we actually would do that without any charge. Probably, many people will want to come. We actually would do that. So our website is www.multiplemyeloma.cancer.gov. So that's our website. So my patient coordinator gets a lot of these weekly, so that's possible to do. For people who are treated elsewhere, I don’t think it's good to pick a doctor, start therapy and next week come and see us because that kind of distracts the other doctor. We're happy to see people of course, but I think if someone picks a doctor, then you kind of make a choice. Go with that. We are always happy to see the patient after therapy has been delivered or if there is some issue or whatever, but I think it's not really fair to pick one doctor and then immediately challenge it. I don’t think that's the right way of doing it. Then there is a mistrust. I don’t think that's a good idea. For people who have smoldering myeloma, we follow people with smoldering myeloma. So even if they are treated elsewhere, they actually can be followed by us for our smoldering program. So that's a little bit different. So we have a follow-up program for people with smoldering. So that's different. For newly diagnosed, we probably would offer a second opinion visit.

Jenny: That's great. The last question is from Margaret. She's a well-known blogger, she has a blog called Margaret's Corner, and she has smoldering myeloma. Her question is related around the psychology really of just changing the name from smoldering myeloma to potentially "early myeloma". So she says, "Words have a profound effect on us, the patients. The idea that some high risk smoldering myeloma patients should start thinking that they are early myeloma stage is abhorrent to me. I don’t even like the expression smoldering myeloma. I prefer inactive myeloma." So she says, "Why jump ahead? Is it necessary?" She says eight years ago she was diagnosed and she's still going strong with no symptoms, no chronic infections. So it's a definite tricky balance. Can you address like logically how we encourage patients to get this treatment they need but maybe not treat what they don’t need? Anyway, how do we keep it in a positive and not a negative sense?

Dr. Landgren: I think that's another excellent question and I think it's very, very, very, very important. I completely agree. For people who are asymptomatic, I even said before, what's the definition of a disease? I think if you're not sick, do you really have a disease? I don’t think so. I think it's more of a condition and we all have conditions. If you start looking through every single organ system in every single person, there is always something. It's just a matter of how much you look. I think my personal take on this, in my opinion, I think if someone has an early stage of a cancer and you can do something about it, for people who want to know that, I think it's unfair to just say watch and wait until it becomes horrible. I think that's not right. At least that needs to be addressed in a careful manner in a resource setting and that's the reason why we have done these studies. But I think what's also important to keep in mind given that and I think we have talked about it today, the smoldering category is not like one size fits all. Some people have a very high risk. People don’t have that. If, for example, we hear someone now has this for more than five years and nothing happens, everything is fine, that sounds like it's a low risk. So I would, of course, never propose that something should be done for someone who has a very low risk profile. I think the risks and the benefits have to be very well balanced. You cannot introduce more harm. So first of all, we don’t know really if early treatment is the way to go although there was a paper published yesterday in the New England Journal that you probably saw from the Spanish group and we have been waiting for that to come out for a long time, when they used lenalidomide and dexamethasone versus nothing and they showed that if you treat high risk smoldering patients, the overall survival was highly reduced. The risk of dying was 60% to 70% lower three years after the diagnosis. That is huge. And there are a lot of comments to be said about that study, but nevertheless , it is a randomized study and it shows what it shows. My answer to the question is that I think we have to be very, very respectful. We cannot treat every person the same and we cannot tell people they have a disease because there is a lab abnormality. That's wrong, in my opinion. I think looking into details and then counsel people and say, "This is what it is," and be honest and say, "There is very limited information in this area. We don’t know if early treatment is going to become the standard and this is information that's available." But for those people who prefer to do intervention in the setting of having a high-risk signature, this is what's available out there. And I think that's kind of a very descriptive way and I think for people who want to know that, I think that information should be available and I think that they should also talk to more than one person. But I agree; you should definitely not treat every person. That will be wrong and you have to be very respectful.

Jenny: Thank you so much for addressing that because the psychological impact and the stress and everything is a very big factor in patient's treatment. I think one thing this is pointing to is that the more information that we have about the disease specifically, or the personal aspects of the disease, of our diseases is so important. So I will be posting the Spanish results as part of this blog post. Thank you, Dr. Landgren, for joining us today. We know you have to catch a flight, but we are completely delighted that you shared such great information with us. We look forward to hearing more about your findings as your research continues to progress, and thank you so much for joining us.

Dr. Landgren: Well, thank you very much for having me, Jennifer, and I wish you a wonderful weekend. Take care.

Jenny: Thank you for listening to another episode of Innovation in Myeloma. Join us next week for another mPatient Radio interview that helps connect myeloma patients with researchers to drive better outcomes for us all.

Dr. Landgren's open clinical trials:  Carfilzomib, Lenalidomide, and Dexamethasone for Smoldering Multiple Myeloma Natural History Study of Monoclonal Gammopathy of Undetermined Significance (MGUS) and Smoldering Myeloma (SMM) Carfilzomib, Lenalidomide, and Dexamethasone in New Multiple Myeloma Patients Lenalidomide Maintenance Therapy for Multiple Myeloma Panobinostat and Everolimus in Treating Patients With Recurrent Multiple Myeloma, Non-Hodgkin Lymphoma, or Hodgkin Lymphoma   Dr. Landgren's Upcoming but not yet Open Clinical Trials Phase II Study of Subcutaneous (SC) Bortezomib, Lenalidomide and Dexamethasone for Relapsed and/or Refractory Multiple Myeloma; Followed by SC Bortezomib Maintenance MLN9708 and Dexamethasone for High-Risk Smoldering Multiple Myeloma Imaging Studies and the Development of Multiple Myeloma