Dr. Gareth Morgan, PhD, FRCP, FRCPath Interview date: November 8, 2013 

Dr. Gareth Morgan shares his approach to personalized medicine in multiple myeloma. He reiterates that myeloma is not a single disease, but a group of diseases with different prognosis and natural history. He explains how he first identifies high-risk myeloma and then looks at patients at a molecular level with FISH, gene expression profiling, and a new test called RQ-PCR (a quick and inexpensive test) to identify misbehaving genes. He notes that RAS mutations are present in 50% of myeloma patients (he believes it to be driver mutation) and that MYC mutations are present in about 20% of myeloma patients. He believes that the top candidate myeloma genetic targets are drugs that inhibit MEk and the RAS pathway. He gives us a preview that drugs are in development that may be able to switch off MMSET, the gene that is deregulated in the 4;14 translocation. He shares his view of the future - the ability to identify actionable mutations where treatments may already exist in other forms of cancer that can be used in myeloma. He describes the challenge to subdivide patients for more personalized treatments in myeloma without a global, standardized approach for testing. He shares his research hypothesis for the transitions of MGUS and smoldering myeloma into active myeloma, thinking that he would find one or two mutations that drove the activation, but found instead that the trigger may be the effect of myeloma cell secretion that changes the bone marrow environment which then kicks myeloma cells into high gear. As a result, he recommends that we look at how myeloma changes the bone marrow micro-environment. He also recommends that if we want to achieve a cure, that we front load treatment to knock out  the majority of the cells to prevent regrowth. He shares his belief that "knowledge is power" and advocates participating in clinical trials to help move research forward.    The live mPatient Radio podcast with Dr. Gareth Morgan

Jenny: Welcome to today's episode of mPatient Myeloma Radio, a show that connects patients with myeloma researchers. Through this series we are learning about the very latest in myeloma research and learning about clinical trials that are moving us closer towards better treatment and a cure and how we can participate to drive towards that cure. If you'd like to hear about the very latest in a weekly email about the interviews, we invite you to subscribe to our mPatient Minute newsletter. Just go to the homepage,www.mpatient.org. You can find links to our Twitter and Facebook pages there as well. Thousands of you have listened in to past episodes and the numbers are quickly growing. I notice that as we become more educated about myeloma, we start asking more questions. The most important question I hear is, "What does this mean to me?" We all want to know how to make the flood of information personally relevant. This is not an easy thing to do in myeloma because we hear that all myeloma is different and that the disease can change overtime. Today's interview is with Dr. Gareth Morgan, not only a myeloma specialist, but one who is looking to answer this important question: How can we achieve personalized medicine in myeloma? As an introduction for Dr. Morgan, I'd like to describe his background a little bit. Dr. Gareth Morgan is a Professor of Haematology at the Institute of Cancer Research and is a Consultant Haematologist at the Royal Marsden NHS Foundation Trust. After attending medical school at the University Hospital of Wales he completed a PhD and trained in the molecular genetics and management of blood cell cancers at the ICR. He left the ICR to join the University of Leeds where he setup his own research group studying the molecular genetics of non-Hodgkin’s lymphoma and myeloma. He's an internationally respected clinician and researcher who has published extensively on the genetics and treatment of these diseases. His research focuses on using new, targeted treatment strategies based on a deep molecular analysis of individual myeloma types using newer diagnostic tools. One of the major aims of his research group is to develop personalized medicine strategies for myeloma with the aim of overcoming treatment resistance. He has run and continues to run a large number of clinical trials and uses his discoveries in the clinic. He is widely published with over 400 articles. He is recognized both nationally and internationally and has been Scientific Secretary for the British Society of Haematology. He is currently Scientific Secretary for the UK Myeloma Forum. He reviews for a number of journals sits on grant-giving bodies both in the UK and internationally. He has been instrumental in creating the European Myeloma Network. He's a Director for Myeloma UK, Scientific Advisor to the IMF and is on the Board of the UK Stem Cell Bank. Now because Dr. Morgan is located in the UK, we are going to give him a minute. Dr. Morgan, do we have you on the call?

Dr. Morgan: You do.

Jenny: Oh, I'm so pleased. Your timing couldn't have been better. Thank you so much. I am so glad you're joining us. I gave a little bit of background about you, a short bio. When I hear patients ask questions, you'll go to patient's conferences, or you'll be on my website or other websites. Most of the time patients will say, "I have this kind of myeloma. I've gotten this kind of treatment and really, what does all of this information mean to me personally?" They want information and help that matters to them.

Dr. Morgan: Yes, absolutely.

Jenny: I know that your whole approach is to perform personalized medicine for myeloma. I think it's a very bold and wonderful approach. I'm very excited that you have that approach. So maybe you could give for everyone just a background, first of the approach and what your research is trying to do overall and then we can get into a lot of detail because we have a lot to talk about.

Dr. Morgan: Okay. I guess the best way to describe it is everybody sees myeloma and if you look in the bone marrow and what you is a sort of a plasma cell, it looks like a plasma cell, it looks like a malignant plasma cell and you get a diagnosis of multiple myeloma. There's a lot more detail you should superimpose on top of that now. We know that some patients with myeloma won't respond to treatment. Some will respond and relapse quickly and others will stay in remission for years and years and years. Almost by definition, myeloma is not a single disease. It's a group of diseases with different prognosis, different natural history that all just happened to look like plasma cells. The real thing is we don't understand the language of plasma cells to be able to separate the different risk groups. So really, what I kind of like to do or try to do is to understand a sort of language you can superimpose on top of just looking at the plasma cells or say, this is a patient who will respond well, this is a patient who will respond badly, this is a patient who will have more bone disease. I think it's coming to a stage now where we have tools to really answer those questions. That's what personalized medicine is. At one level it's about who has high-risk disease and I think we're at a time now where there should be tests applied to define if patients are high risk when they’re first seen. Then beneath that level there is what molecular subtype and we can use that information to design specific treatments for those molecular subtypes. That's really what I try to do.

Jenny: Well, it seems a lot of that is based on the diagnostics. And then I was reading about your group that you were using some newer diagnostics. Can you tell us what tools you use to try to determine the subtype of myeloma?

Dr. Morgan: There are a variety of tools. One of those tools is called iFISH. iFISH is a technique that is available more or less globally and there are a ton of maybe six important prognostic factors that you can detect with iFISH. You should have a panel of tests for all six and then you can define the risk of the patient as if you have one abnormal lesion you're doing pretty good. If you have two, maybe not so good. If you have three, you really need to consider the type of treatments that you're having. Then we move into the sort of molecular world. There's a test called RQ-PCR which you can use to define many of the risk variances associated with myeloma. And actually it turns out it's not a very expensive test and is applicable. The third level, this gene expression profiles. There has been good work done by ourselves, the group in Arkansas and people in the Mayo, they identify signatures, people who have high-risk disease and maybe 20% of people of presentation can be identified as having really poor prognosis disease who do badly with current treatment strategies that we should be altering the treatment's approach as soon as we know their risk status. And that's about state of the art currently.

Jenny: Now when it comes to FISH, I know that the FISH can tell you the translocation maybe that you have and so can the gene expression profiling. I know some facilities use one over the other. For example, we talked to the Mayo Clinic and they really heavily rely on the FISH analysis and then University of Arkansas and University of Iowa always will use the gene expression profile. So what does the gene expression profile give us over the FISH? What does that give us that is different from FISH?

Dr. Morgan: It will tell you everything that the FISH will tell you but in addition, there are these things called signatures. The signature is like a group of genes that are over or under expressed. They put a lot of reliance on the 70-gene signature from Arkansas and that 70-gene signature identifies people who will have a median survival of one to two years in contrast to the rest of patients who will have a median survival of up to ten years plus. The important thing is that if we don't do those kind of tests, you don't know how people are going to behave to start with and upfront is when we should be maximizing the treatment, to try and get the best outcomes we can.

Jenny: I would agree. I guess I've had this test and it was helpful. But I know that some of the physicians will say, "Well, it's not going to alter your treatment. But if our ultimate goal in my mind is to get to a personalized treatment based on potentially specific genes, then, wouldn't you need this?

Dr. Morgan: I think we've hit a time where it's very difficult to move forward with this. We are continually improving treatment that's being a decade of great excitement and self-congratulation in a way that things have gone so well. There are some new treatments around that they will get increasingly difficult to validate in the clinic. One of the groups that really is under-investigated and a place where you can invest they newer treatments is the high-risk group because we need specific trials, of therapies that actually work in high-risk. We don't even know really what the biology of high-risk disease is and simply investigating that is going to be a big step forward. This is a group of patients that needs to be identified and we need kind of more studies on that group of patients, to understand it and then we need therapeutic trials specifically for that group of patients.

Jenny: Well, that would be really wonderful. And the gene expression profile, is that what's considered gene sequencing or is that a different --?

Dr. Morgan: No, that's totally -- gene sequencing is the sort of next level of complexity on top of this gene profiling. The gene sequencing takes all of the DNA sequence from a patient and looks for mutations that are driving the disease. You hear lots of people talking about driver mutations for myeloma and we're starting to understand more. MYC is clearly a driver mutation for myeloma and if we target MYC, I think we'll make some progress of myeloma patients. People also say that there is no unifying mutation in myeloma. I'm starting to think that's not correct because in maybe 50% of all myeloma cases, there's a mutation of a gene or gene pathway called the RAS pathway and that I think is a driver mutation. I think it's a pathway that can be targeted. The beauty of these mutations is if they are a driver, and you understand how they're working, you can design treatments specifically against that pathway. Switch the pathway off and get patients into a remission.

Jenny: Now, I want to share with you I guess one of the reasons or the biggest reason that I wanted to interview you. I think patients are hoping and praying that we find this needle in the haystack. One day, I got The Wall Street Journal. I opened it. The front page had a story on it about a patient who was looking at a gene-specific treatment for her lung cancer. The article talked about the ALK gene, the K-RAS gene, the EGFR gene. I can't even share with you how profoundly I was affected by that article. I just kept coming back to it on my kitchen counter thinking, "This is really significant." I wondered if these genes were applicable in myeloma so I started doing some searching online, which led me to you and your group. I just feel that what you're doing is very, very significant. A question about that. I know that some of these translocation like t(4;14) is not a great one to have. It's associated with MMSET or FGFR3, if all myeloma is different, have we matched up different genetic mutations with different translocations?

Dr. Morgan: The t(4;14) you're talking about is one that's sort of dear to my heart in a way. It's a poor prognostic lesion but I think it's really, really important to say that not all patients who have a t(4;14) do badly. If those patients are treated well, one of the dogmas is that they seem to do very well with the introduction of proteasome inhibitors like Velcade. That is one reason for identifying that subgroup of cases. The other is you rightly say that translocation deregulates two genes. We used to think it was FGFR3 that was the target but we're pretty certain that it's MMSET that's the target. So there are at least two or three different academic groups around the world that are trying to make drugs that specifically switch off MMSET. And while we don't have those drugs as yet, within the next year we will have drugs I think that are able to switch off MMSET. It occurs early on in the natural history of myeloma. Hopefully, that's going to put people into remissions. That's a fine example of personalized treatment that is going to work in myeloma. The other example is we did this -- made this test looking for chromosomal translocations and we found that a specific translocation that was exquisitely rare, may have been a one off, that overexpressed the EGF receptor gene. The importance about that is if you had known that for that patient, EGF was over expressed in that patient, there are drugs that are available for colon cancer that may have worked for that patient with multiple myeloma. And so identifying actionable mutations where a treatment already exists in another disease like ALK, say and then translating them into myeloma is really a potential importance I think.

Jenny: Well, that's what this patient was trying to do for lung cancer. She was drumming up people who were doing research for that particular gene mutation in other cancers and she was really inserting herself into their clinical trials.

Dr. Morgan: There's only one trial that's really gone that way as yet. But over the next years, I think instead of people treating diseases in a way, there's going to be a lot of interest in treating mutations because what works for a mutation in one disease should work for a mutation in another. That's the hope.

Jenny: How is a gene like EGFR or other ones like MMSET or the others identified? By which test specifically?

Dr. Morgan: So you have to look for specific mutations. Its sequencing in all its forms. The question with that is do you do a global test that identifies every mutation in every gene? Or do you come up with a list of actionable mutations, maybe 40 to 50 genes where you just look to see if those genes which are modifiable with treatments that exist now are present? Those kinds of tests already exist. There are sort of companies that provide those analyses in the US.

Jenny: Can we go backwards a little bit because I wasn't familiar with the RQ-PCR test you talked about. Can you explain what that test is and what it does?

Dr. Morgan: It's basically a kind of laboratory test that can allow you to ask if a limited number of genes are over expressed. You can design them that are relevant for myeloma. If you want to know how to classify your myeloma in a very simple way based on the TC classification, you can do that for a relatively small amount of money, do something that will turn around, give you a result within 48 hours. You can do that and know what subtype of multiple myeloma you have, which translocations are present and how the disease is likely to behave. Again, it's faster, more robust, more throughput than doing the iFISH test and it's applicable to a smaller number of cells as well which is important.

Jenny: Does everybody do this test, this diagnostic test? Is this being done everywhere that you know of or is this new?

Dr. Morgan: No. it's new. So what we're trying to do which is easier said than done is to actually make these tests robust in the clinical environment so that you can regularly get them. We can have all of our patients get what a result of such a test and avoid this, “The FISH didn't work, we didn't have enough cells” because there's a lot of problems around getting adequate cells, getting a result in a meaningful timeframe and it's not standardized. That's a really important thing to say this, no really global standardized approach and we need to work on that kind of standardization.

Jenny: And who provides this RQ-PCR test? Do multiple providers sell this test?

Dr. Morgan: No. It hasn't got out there to providers. It's rather easier for the providers to go along gene expression profiling but hopefully within the next year that the people from Arkansas will be working on moving some of these tests out into the general arena where patients from around the world will be able to get this kind of analysis done.

Jenny: My doctor likened myeloma to fighting a war. He just says, "You need to know as much about the enemy as you possibly can." He was very focused on the diagnostic testing to provide as much information as possible. That was a much better approach than the general oncologist that I started out with that took a blood sample and said, "I think you have myeloma. We'll start you on Velcade on Friday."

Dr. Morgan: Yes. I agree with you. It's a really interesting concept because the old fashion approach was, "It's myeloma. We treat myeloma with Velcade or Revlimid or transplant," and not do any list stratification, just one size fits all. As soon as you start thinking about it, I mean, it doesn't make any sense. It's a kind of scary disease. It is a bit of a battle. The more that you know, the more empowered you are to make the right treatment decisions. The next few years are going to see an explosion in four-molecule therapies that target specific kind of cellular pathways. And if you know those pathways are deregulated in your disease, then it exists as a possibility. Knowledge is power and I think you want to be empowered as a myeloma patient.

Jenny: Absolutely. And I think if I had the t(4;14) and MMSET, I would do a lot of personal research on that one. I happen to have the t(14;20) MAFB which is not very common and so -

Dr. Morgan: No. Less than 2%.

Jenny: Right. So for me, I would like to track that particular one down because maybe the other genes don't have anything to do with me personally and I know every time patients just ask that question, "How does this relate to me personally?"

Dr. Morgan: I think that's a very good statement. For you having MAF-deregulated myeloma that there's a whole series of information about that type of myeloma that I think is relevant and least of all there was a paper like last year or the year after in Blood from an investigator called Annunziata who works in the NCI I think in Bethesda and they showed that MEk inhibition maybe a particularly good way of targeting MAF-deregulated myeloma. Is that relevant to all myelomas? I think that's worth looking at. It doesn't mean it will necessarily work for you but at least you see the people are specifically working to find solutions to the MAF subtypes of myeloma.

Jenny: Well, I think that every patient should do this individually because not all myeloma is the same. It is a very empowering feeling to know more about your disease.

Dr. Morgan: Yes. I'm not sure it's a one-size-fits-all. Some patients prepare to bury their head in the sand, but actually the people I think that really do dig in to their disease actually do better long term.

Jenny: Well, I did that for the first two years just because it's too overwhelming and everything is so new but I think you go through phases and it's good to have an empowered educated phase.

Dr. Morgan:  There could be.

Jenny: I'm having that phase right now. I know that you were studying how myeloma progresses, the factors that turn MGUS to myeloma or to maybe smoldering, or to full-blown myeloma and the progression that turns smoldering to myeloma. Can you share with us what you found?

Dr. Morgan: I've kind of jibbered on a lot about mutations and the role mutations have in driving cancers forward. I was determined to find the mutations that push myeloma forward because if you can find those mutations, those are the ones that you should target. We ask really specific questions so for patients with smoldering myeloma and smoldering myeloma shouldn't have any end organ damage, what makes these patients turn into myeloma where suddenly they start to have lytic bone lesions, anemia, bone pain? What causes the symptoms? The hypothesis was simple, was there would be one or two mutations that actually caused that kind of transition and they'd be targetable. What I was surprised to find was that we didn't really find a clear answer. That raises the issue of what is it that the cancer cells, the myeloma cells are doing to the microenvironment, the surrounding cells that nurse and keep the myeloma cells alive. I think there's the potential at least now that the cancer cells modify their environment and as time goes on, it reaches a critical stage beyond which the myeloma cells suddenly get switched on into a more proliferative state and rapidly grow and it's that transition that's mediated by the microenvironment rather than by a kind of series of mutations in the cancer cell itself. The conclusion to that is there are mutations that push the disease forward but also the microenvironment in the bone marrow is really important in the transition as well.

Jenny: Can you talk for a little bit because that's called -- let's see. I have it written down, is the NF-?B pathway. Is that the bone marrow environment or is that what regulates that environment?

Dr. Morgan: It's what regulates that environment. NF-kappaB is one of the important pathways that we can target in myeloma and at one level, you can target NF-kappaB with proteasome inhibitors (Velcade). And so I think there's a whole kind of series of work now that goes on, that's building on the next generation of proteasome inhibitors and inhibiting molecules that are upstream and downstream so as you can get effect in plasma cells. The NF-kappaB pathways are really important pathway that lots of people work on and try to target.

Jenny: Is there anything else that affects the bone marrow environment or that's causing myeloma that that we should be aware of?

Dr. Morgan: I think we need to understand it but I think there's the potential for the myeloma cells to secrete factors which modify the stromal cells. And so the MAF thing is an important thing in terms of the microenvironment. I think it's Integrin beta-7 that's upregulated by the MAF translocation which makes the myeloma cells bind more strongly to the stromal cells and when they bound strongly they're more resistant to chemotherapy treatment. If you could use antibodies or molecules that disrupt that binding to the stroma, maybe you'll make the myeloma cells more sensitive to the chemotherapy and then you'll get a better outcome after your chemotherapy. That's just one way that you can think of modifying the microenvironment therapeutically to improve the outcome of treatment.

Jenny: And I know there are a lot of new cell-signaling pathway and monoclonal antibodies -- that's just barely starting -- it seems like it's just beginning and there are a lot of them in this Phase I kind of approach. Is there such a thing as monoclonal antibody for a particular gene or is it just these proteins that are expressed or things that are secreted in the cells?

Dr. Morgan: So it's mainly the things that are secreted in the cells at one level but I'm no expert at immunotherapy but it looks to me like there are a number of antibodies now that can improve the activity of the immune system against the myeloma cells. I guess the paradigm for that was that Revlimid seems to work by enhancing the immune effect against the myeloma cells and that could be improved by adding in Elotuzumab, which is one of the antibodies but there are now antibodies that are being developed in melanoma not myeloma that may actually be effective for myeloma patients. And so one of the ways forward to overcome this reliance on targeting specific mutations is to enhance the immune system which just works against all cells in many respects. This immune enhancement may be a way of keeping people in remission for a longer period of time.

Jenny: I was doing a little research on just my translocation with that particular gene. And got online and found a site called GeneCards that tells you what all these genes do specifically. I found this list of monoclonal antibodies that target that specific gene. So I was just kind of curious with your genetics background if you've ever heard of monoclonal antibodies that target that particular gene like MMSET or something like that.

Dr. Morgan: There's a difference in the terminology. By definition monoclonal antibodies are specific against more or less a single target. So if you wanted to stain for MAF, you would use a monoclonal antibody directed against MAF and you'd be able to specifically see if the cell expressed MAF or not. That may not block the activity of mass so you've specifically don't want to detect that you want something that interfered with its functionality and that may be something that's not a monoclonal antibody.

Jenny: Well, that makes sense. Now I was reading on a patient's blog. She is very knowledgeable. She was just saying that how MGUS to smoldering and to myeloma is all just sort of progressing towards plasma cell leukemia for everyone and myeloma is kind of a stage in that. Can you explain what that is? And I guess, is that why after treatment or just maybe time the disease starts getting more aggressive?

Dr. Morgan: I kind of need to take a step back with this. I think that patient is right, that really we're all dying in a way, it's just the rate at which that happens that's important. Similarly in myeloma, everybody is progressing to plasma cell leukemia but the rate is really important. If you’ve got MGUS the rate could be measured in hundreds of years and so some patients, they never get to that stage. You need to put it into that sort of context although conceptually, that's right. For an individual patient, that could be very worrying if they all think that they will develop plasma cell leukemias. I'd really like to make that point. But if you just take it as a simple concept and I think it's true, it's all about evolution. Myeloma is not, even within a single patient, there are different cells belonging to the same type of myeloma that have different mutations, different behaviors, and when you put treatment onto it, a myeloma in a person, what you do is kill the sensitive cells and you tend to leave cells that are resistant. And so over time, the resistant cells come to dominate and that's why people relapse. And it's why if you have one type of chemotherapy to start with, when you relapse, your doctor will give you a different type of chemotherapy with a different mode of action. That's why a lot of the time, we've make good progress by specifically get in people to remission by killing cells that are sensitive to different agents. That's why continuing to find new agents is really important for myeloma patients. Some of the lessons from this - it's called intraclonal heterogeneity, are that if you want to get the best results of patients, if you want to try and specifically cure patients, you need to frontload the treatment so that you get rid of all of the bad clones that are present as soon as you can and you don't leave them to strengthen over time. I'm not sure if that makes sense.

Jenny: That's a more hit-it-hard-at-the-beginning kind of approach.

Dr. Morgan: Yeah. I think that's one of the lessons from what we're understanding about from this intratumoral ,intraclonal heterogeneity that we see.

Jenny: And then our last interview was about progenitor cells. Have you done any research on how we can not only just get rid of all the fully developed, heavily produced, potentially plasma cells but the earlier cells?

Dr. Morgan: I think I keep looking at this data and it seems to me that the target in myeloma that we need to kill is a cell that looks and behaves like a plasma cell itself. So I think we know what the target is. Some of the cells become -- have the capacity to self-renew and proliferate and any cell that has that capacity is capable of transferring myeloma from one place to another. We've taken some cells from our patient, put them into a mouse model and we can clearly see that the plasma cells transmit the disease and that within the myeloma clone that there are multiple stem cells that have different characteristics. They can have a different phenotype and they can also have different genetics. At any one time there are probably multiple myeloma-propagating cells that prefer to call them that are able to divide, proliferate and pass the myeloma clone from one place to another. And another thing that comes from it is we all tend to think of myeloma as being the homogeneous disease. It's a bit like leukemia that’s in the bone marrow. But actually these new scans that we're doing like diffusion weighted MRI actually shows that I think myeloma is a metastatic disease where you have a tumor at one site that can move to another site but then can move to another site. These focal lesions that we see in the myeloma patient's bone marrows with these technologies are actually the site of myeloma-propagating cells, cells that have different characteristics to the rest of the marrow that we really need to understand the biology of these cells.

Jenny: Now when you talk about the mouse model, have you taken an MGUS or a smoldering type of myeloma and try to put that in a mouse and then try to add things to it?

Dr. Morgan: This is was mainly with cell lines that we could -- if you can inject the cells directly into mouse's leg bone you can get good engraftment. So we did this with several plasma cell leukemia patients and we were able to get good engraftment into the mouse and that's where that data from that heterogeneity in the myeloma stem cell comes from. To the best of my knowledge nobody has really done that type of experiment, looking at genetics of what are present in the mouse when the mouse is being engrafted.

Jenny: Well, I think it will be really interesting because I know you look at studies that show certain lines of work like farming or something and maybe there are something being added to that mix that's the trigger, I don't know, that could trigger to progression but I'm not sure. You had an article in August that came out about the TERC gene related to myeloma and aging. Would you like to share what you have found for people who have not have a chance to read that article?

Dr. Morgan: Do I want to share that? Just remind me exactly of the context that you're asking.

Jenny: It was an article that came out about myeloma and that gene for aging and it said, "It brought the number of genes that we know about myeloma to seven," so I was kind of curious about what those seven are.

Dr. Morgan: The bottom line of this sort of term, one of the things that patients always ask is, "Why have I got myeloma? Why me?" and there's a tendency then to focus on things in the environment and we've done a lot of studies on what causes myeloma over the years but really nobody has come up with a good environmental cause of myeloma as yet. So in order to try and understand what the factors are that may predispose people to develop myeloma, we did a study which is called a G-WAS analysis where you take hundreds of patients with myeloma and compare their genome to hundreds of people that don't get myeloma. If you see associations with specific genes in the patients with myeloma that aren't present in the normal controls, you know that they are predisposed myeloma. That's basically the scientific approach. We did a number of those studies and found genes that seem to predispose people to developing myeloma. We found six genes in total which seem to predispose an individual, that has that genetic makeup to developing myeloma. The risks for any individual are not high so people shouldn't worry that they're passing the risks for myeloma onto their children because these are genes that don't really behave in that sort of fashion. There are now six genes which seem to increase your risk of developing myeloma that you could actually look for in the cells that you have that are not cancerous. The interesting thing is one of the genes -- so you talked about translocations and you've got a MAF translocation. Where there's a translocation called the t(11;14) which actually deregulates the gene called Cyclin D1. That's kind of interesting because if you inherit a variant in Cyclin D1 that you can measure, your chances of getting a translocation into the gene into your myeloma are increased substantially. And so there are genes now that predispose you to getting myeloma and genes that predispose you to specific molecular subtypes of myeloma. It's probably not one single gene. There may be as many as 20 or even more that contribute to the risk in an individual but across the population, they really do start to explain some of the reasons why there are people who develop myeloma.

Jenny: So Cyclin D1 and (11;14) is a less aggressive form of myeloma, from what I understand, right?

Dr. Morgan: That's right.

Jenny: And more people have that it seems like?

Dr. Morgan: Yes, about 20% of the total. I was going to say there's a couple that's interesting. Scientifically, it seems that some of the pathways that get mutations later on in the gene process, in the disease process are affected early on so it looks like MYC again is a gene that's deregulated. You can inherit them and affect the way MYC behaves that may predispose you to developing myeloma.

Jenny: And is MYC associated with a particular translocation or it's just present across…?

Dr. Morgan: No. We've described this as kind of a-- there's a load of translocations into MYC that really hasn't hit primetime. We've just sent a paper off to Blood. Twenty percent of patients present with a MYC translocation and again it's another one of these poor prognostic lesions. But people aren't even aware of the whole testing for that as yet.

Jenny: Is this the new t(7;17)?

Dr. Morgan: No. This has nothing to do with the immunoglobulin genes. It's due to translocating kind of different parts of the genome in front of MYC which make it get up-regulated and sort of drives the cells to grow faster.

Jenny: Well, I've taken a lot of time asking you about your research but would you like to talk about your clinical trials, the ones that you have open right now?

Dr. Morgan: We are trying to do a number of things with clinical trials. One of the things I'm interested in doing is Pomalidomide, great new drug with Dexamethasone you seem to get responses in 30% to 40% of people. It would be good to have a test that said this is one of the 30% to 40% of people who are going to respond or you could look at it the other way around which is how can we identify before we start treating people those who aren't going to respond because you're wasting their time, you're not active against the disease. So identifying non-responders to a drug would be really interesting. I'm also interested in maintenance treatment I think maintenance looks like a really good way forward to me. The Revlimid as maintenance I'm convinced with the results that it does improve outcomes. It does improve overall survival. There are a number of studies that are already there. They'll be new data at ASH, all that's consistent with Revlimid being a good approach for maintenance. Personally I'm interested in looking how these new oral proteasome inhibitors function to improve the outcome of myeloma by using them in the maintenance setting so we're trying to setup a maintenance study that addresses that question. All of these questions I think are important and we have a network of centers in the UK where we try to do studies together so as we can kind of bring these new drugs close to patients so they can access them close to their home without having to travel to tertiary centers.

Jenny: When it comes to maintenance I know this might be popular now, so I guess learning more about it, do we want to do maintenance for how long? How long are we talking? Is it at lower doses?

Dr. Morgan: I think that some of the important characteristics of maintenance are that it doesn't impair the patient's quality of life. Quality of life is really important. It's difficult to know if you use something for six months, that's not really maintenance. That's consolidation aimed at reducing the amount of the tumor cells present. Sometimes you might consider that continuing treatment until disease progression really is what maintenance is about because it affects the biology of the disease. So I've got a lot of sympathy for continuing maintenance until disease progression. But you can make arguments for doing it for a limited periods of time like for two to four years. There's no specific answer to your question and only time and good clinical trials are really going to address what the best way of doing it is. But it looks very much like when you get into a remission, that maintenance is a very powerful way of keeping them in a remission long term.

Jenny: And maybe we can talk about that, the importance of clinical trials because I know with over 400 articles you're running many clinical trials, how important is patient participation in clinical trials for you?

Dr. Morgan: It's very crucial. Again, we have a powerful -- I think that's the wrong word, it's a very helpful informed patient organization in the UK called Myeloma UK that actually provides information to patients. They set the trials to see that the trials are useful for patients and they encourage patients through their information to participating in clinical trials. Clinical trials are a really important way forward. You really should, if you're going to treat somebody, you need to use that as an experiment really because the experiment is if a patient does good, why do they do good and if you can learn from that and use that to make the outcome of the next patient better, then that's a very positive thing and most patients would encourage their doctors to behave like that, to collect the information, review their results and use it to improve outcomes.

Jenny: Well, the reason we started this series is because with less than five percent maybe more like three percent of patients participating in myeloma clinical trials, it's just going to take a really long time to get to the conclusion that we need to get to. If we can do something as patients, I guess a follow up question probably my last question will be how can patients help you further your important research?

Dr. Morgan: The really interesting thing about patients is that they always, always want to help. If you ever ask a patient, "Can we do this? Do you mind if we do that?" they always agree and yet a small minority of the vociferous people have kind of made the whole environment about getting tissue from people, studying in the laboratory, entering into clinical trials, they've made that all very top-heavy with legislation which has slowed down the kind of ability to set up a clinical trial and to look at material. And so I think the silent minority of patients who I know to be helpful should speak up and encourage clinical trials, and encourage biological studies based on their samples. I think patients and patient organizations can do a lot in that respect.

Jenny: Well, we are happy to help.

Dr. Morgan: Thank you. As always I've said, patients are always willing to help. They're amazing.

Jenny: Yes because our lives are on the line because we have a very vested interest in helping. I would like to open it up for caller questions. I've taken up a lot of time so I don't know if we'll have time for many but if you have questions about Dr. Morgan's research, you can call in to (347) 637-2631 and once you're on the call, press 1 on your keypad. I also have a question or two that came in via email. The first caller, go ahead.

Caller: Hey, Jenny and Dr. Morgan. Thanks for taking the phone call. It's been a pleasure listening to this and at some levels it's been one of the more exciting interviews as we think about getting into the details of personalized medicine. Treating mutations rather than treating the disease has hit me like a ton of bricks. So do you have any plans to run a trial that is gene-specific or know of any trials that are gene-specific?

Dr. Morgan: So I think Bart in Little Rock is thinking about taking patients as they come in to high-risk studies, doing mutation analysis for actionable mutations and then really thinking about adjusting the treatment based on the presence of those mutations. The key candidate gene currently is probably MEk inhibition and inhibitors that target the RAS pathway. Scientifically the 50% of all myeloma patients have RAS mutations. It has to be meaningful about something I think. I think it's a clue that we can't afford to pass upon.

Caller: Okay. So that's Little Rock. Anything other than Little Rock?

Dr. Morgan: I don't know. In London we're trying to do something similar, high-risk patients but I think it's still not really at a primetime as yet but I think it will take off over the next one to two years and they will become very commonplace in that time.

Jenny: I have a follow up question for that I guess. Would there be any benefit to constructing plasma cell leukemia kind of trials that involve myeloma patients?

Dr. Morgan: Yeah. I think that falls into the high-risk kind of disease. It's difficult for people when they get plasma cell leukemia because we really don't know what's the best approach and we need to maximize the chances of the time of improving the outcome of plasma cell leukemia, people with extramedullary disease, people with metastasis in their liver. All of these are really important questions.

Caller: I just want to follow up to the other question. And this may be off into the weeds so you don't have to answer it. I've read about patients organizing themselves into patient-organized trials and I know that's fingers on a chalkboard to a doctor. But what if the patients got together and I'm not suggesting that this is a great idea, this is a question, and organize themselves into the different mutations and if there are --

Dr. Morgan: I get what you're saying. I kind of think it's a very interesting kind of idea. Part of that issue with being a doctor is that we're self-interested because we're doctors in treating people and our own ideas. Politicians, healthcare providers, you name it, they kind of don't always give doctors that credibility they deserve. If you were a patient or a group of patients with specific variants it's very difficult for providers of any sort to ignore patient power because you're the ones that have the issues, you're the ones with the disease. It is all about you; it's not about doctors. And so, it's not such a bad idea. How it would pan out, I have no idea of course but it's just an interesting approach.

Caller: Cats and dogs running in the streets - it would be pandemonium.

Dr. Morgan: The lunatics in charge of the asylum :)

Caller: All right. Well, thank you for taking that question.

Dr. Morgan: You're welcome.

Jenny: Okay, thank you. And maybe a related email and question from Sondra was, "If someone wanted to join an international trial like yours and lived in the United States, how would they go about doing that?"

Dr. Morgan: There’s absolutely no infrastructure or legal framework to allow it. That's a really incredible thing to say, that you would need legal frameworks to do it like that because you'd think it would be the most simple thing in the world for somebody who wanted to go on to a trial to go on to it. But the rule makers have made it really quite constrained. And yeah, this made it very difficult. I think we need to pull back a little bit from the current legislation which is aimed at protecting people because protecting people so much these days that it's slowing up the pace of change in research and I think it needs to come back a bit more to the midline.

Jenny: So someone who wanted to join your trial they physically couldn't, they wouldn't be allowed in it or they would have to pay for it themselves or what do you mean.

Dr. Morgan: They would have to be in the UK, in the UK healthcare system and the trial would have to be approved in that hospital, they’d have to have that treatment in that hospital or one of the hospitals where the trials were being run. Otherwise it will be really, really difficult and that's an issue across Europe and across the different states in the US as well I think.

Jenny: Well that is fascinating because I would have never thought of that. We have taken a lot of your time. We are very, very grateful for your research and for your participation. We are all looking forward to your learning more about personalized medicine for myeloma patients. We are eager to help you make it a reality and we wish you the very best in continuing your excellent research and work.

Dr. Morgan: I'd like to thank you for your hospitality, insightful questions. You didn't make it easy for me. It's educational so thanks a lot. Look out for yourself.

Jenny: Well, thank you so much for your participation.

Dr. Morgan: Bye.

Jenny: Thank you for listening to another episode of Innovation in Myeloma. Join us next week for our next mPatient Radio interview as we learn more about how we can help drive a cure.