Gareth Morgan, MD, FRCP, FRCPath, PhD UAMS Myeloma Institute Interview Date: March 24, 2017 

Clues to be found in more personalized treatment for multiple myeloma can be found in the genetics of myeloma in each individual patient. Dr. Gareth Morgan and the UAMS Myeloma Institute in collaboration with the Dana Farber Cancer Institute and other institutions are working to collect genomic data from myeloma patients with the goal of segmenting patients into groups that could lead to more personalized therapy. Learn more about why this matters to you as a myeloma patient and how you can weigh in to help researchers come to conclusions faster. To find all myeloma clinical trials open at UAMS, click the link below: UAMS Myeloma Clinical Trials Dr. Gareth Morgan on Myeloma Crowd Radio

Thanks to our episode sponsor

Jenny: Welcome to today’s episode of Myeloma Crowd Radio, a show that connects patients with myeloma researchers. I'm your host, Jenny Ahlstrom. I’d like to thank Takeda Oncology for their continued generous support of the Myeloma Crowd Radio Program. Before we start our show today, I want to share for a minute about Multiple Myeloma Awareness Month. As you all know, March is this month, and this is a rare disease that needs more attention. You may not know that patients who are treated by myeloma specialists live longer. Why? Because this disease is extremely complicated and we are best treated for this rare disease by myeloma specialists who are working hard to perform potentially curative research. In honor of these remarkable doctors, and for March and April, we are running the Muscles for Myeloma Campaign. This is a fitness campaign to encourage patients to get moving so that patients have better outcomes and have more treatment options open to them. Many of the major myeloma academic centers have teams that you can join so you can share your fitness goal with your family and friends and invite them to support your activity. All proceeds of each team will benefit the myeloma research for that team’s facility, not our foundation. So far, the UAMS Myeloma Institute is in a lead for funds raised, and one patient there who raised almost 6,000 for the UAMS team said she wanted to do Muscles for Myeloma because it’s a way of thanking her doctors for their incredible care. So, if you were looking for a way to thank your myeloma specialists, you can join the program anytime between now and the end of April. Set a goal and invite your sponsors to help you in thanking these extraordinary people for their efforts to help find a cure for you. This is an easy way to ensure your donation will go precisely to their myeloma research and not the facility as a whole. Now, onto today’s show, we are absolutely delighted to hear from Dr. Gareth Morgan of the UAMS Myeloma Institute. His efforts and that of his team are focused on digging deeper into the genetics of myeloma in order to segment patients into categories that may help find specific treatments for specific types of myeloma. As you may all know, there are nine plus different types of myeloma. And to make matters more complicated, myeloma picks up mutations as patients are treated. So, doctors are chasing this moving target. Today’s show is focused on the personalized medicine project called The Myeloma Genome Project, and Dr. Morgan, we are so thrilled to have you.

Dr. Morgan: It’s great to be here, Jenny, and thanks again for inviting me on the show.

Jenny: Well, thank you. Let me introduce you just before we get started with our questions. Dr. Gareth Morgan is Director of the Myeloma Institute in the University of Arkansas Medical Sciences. He is also Deputy Director of the Winthrop P. Rockefeller Cancer Institute at UAMS and Professor of Medicine. Dr. Morgan came to UAMS from The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research in London, Europe’s largest comprehensive cancer institute, where he was Professor of Hematology and Director of the Centre for Myeloma Research. He’s also a founding director of the European Myeloma Network and is lead for the MyelomA Genetics International Consortium or also called MAGIC. Dr. Morgan is a board member of the UK Stem Cell Bank and Myeloma UK which he helped found. Dr. Morgan has authored more than 430 peer-reviewed research papers. We are so thrilled to have you with us, and maybe you just want to begin by giving us some of the insight and rationale behind the myeloma genome project.

Dr. Morgan: Our interests are aligned in many respect, Jenny. For me, I think one of the challenges in myeloma is how do we treat and design strategies that can improve the outcome of patients with higher risk myeloma. One of the challenges with that is how do you recognize that in the clinic. We used a number of approaches. Historically, we used gene expression analysis, but recognize some of the limitations of that. We’re now exploring imaging features that can allow you to recognize high risk and DNA-based features that identify high risk. That’s what the myeloma genome project is. It’s really a collation exercise, so we’ve collected all of the sequencing data that’s been done on myeloma across the world at different levels, and have assembled it all into one secure site, and analyzed it in a consistent fashion from the bottom up. So, we have a resource for the myeloma community that can be expanded into the future.

Jenny: Okay, great. Maybe you want to talk about, first, your own data because you have a very large pool of very long-term data, which I think is unique and very important. And then, we’ll talk about the other data providers as part of that.

Dr. Morgan: Yes. In order to be able to have power to identify things, size is really important. Each investigator on their own can identify some of the features that you might want to treat. But by collaborating and working together as a team, you’re able to assemble much bigger datasets, and then these bigger datasets give you more power to identify things that are really relevant biologically that you could direct treatment against to improve outcome. One of the first things we’re doing is to try and improve on risk-stratified approaches. Risk stratification means something to patients but it won’t necessarily be so clear by me saying “risk stratification.” Patients frequently ask what stage am I, and really stating it has not been terribly successful in myeloma. It doesn’t always make sense. This International Staging System was made, which identifies three stages that are called ISS 1, 2, and 3. But they lack a certain relevance to individual patients. So, we integrated some genetic features into that ISS system, and that was translated into this revised ISS. But again, the biological features are not, perhaps, as helpful as they could be. What we’re really trying to do in the first instance is to use this 2,000-patient dataset to find prognostically relevant features that we can add into that revised ISS to make that more powerful and able to really get on top of saying if the patient is going to do very well long-term or we should think about new approaches to treatments if their current outcome is predicted to be sub-optimal.

Jenny: You hear in breast cancer that , you know, I’m stage 4 or stage 3 or whatever, and that sort of means something but like you’re saying, not really in myeloma, so you’re trying to match all these things up. Maybe we want to start with some of the tests that you’re using. You’ve already collected these over 2,000 patient datasets. Maybe you want to describe that approach you’ve already taken because there was a paper written that describes some of that.

Dr. Morgan: Currently, it’s a collaboration led between UAMS here in Arkansas and the Dana Farber in Boston. The initial bit has been collation of data that we already have. But what we’re doing now is bringing in other investigators from across the U.S. and globally. The people from Heidelberg in Germany are going to join. We’ve got collaboration from the U.K. group. We’ve got collaboration from the French group. We’re trying to build a global consortium that really will be like a team for patients where we can identify people who have distinct clinical outcomes. Instead of treating myeloma in a one size fits all approach to take a risk stratified approach where we can design specific therapies for people who don’t do as well as they should with current therapies. It will be really important to maintain progress because it will give trialists the opportunity to design specific trials and use specific therapies for distinct risk groups of patients.

Jenny: Well, let’s take a little deeper into the risk stratification that you’re talking about. When you say you’re combining like next generation sequencing type of tests, which I hear you saying is more detailed than the gene expression profile test that was used for the last ten years to get more genetic type information, you’re combining that with imaging, for example, like how many lesions do you have or how fast do they come back, that type of thing, right?

Dr. Morgan: There’s one which is called risk-stratified where you try and predict how the patient is going to perform. And then the other approach is risk-adapted where you see how people respond to their treatment, and suppression of signal from focal lesions is a really important approach to risk-adapted therapy as is achieving MRD negative clinical remissions.

Jenny: So, you’re looking at their outcomes and you’re also looking at their genetics. When you’re looking at their genetics - you know, people have segmented these patients into different categories like you have the 11;14 translocation or you have the deletion of 17p, which is a gene deletion, or you have the addition of one chromosome like the 1q chromosome. Those might be considered or classified as high risk. Are you also looking at the genes that tend to show up a lot on myeloma patients like I’ve heard a lot about the NRAS and KRAS and BRAF type genes?

Dr. Morgan: Yes. That’s exactly the approach. The thing that’s kind of lost if you’re not in the field is that if you have a high-risk translocation like the 4;14 or you have loss of 17p, if you have 17p at low level, that can be associated with a perfectly normal outcome. You don’t want to frighten people unless you absolutely know that it’s specific for the outcome that you’re interested in. So, 50% of 4;14s will be low risk, 50% will be high risk. Currently, you can’t tell the difference. But 17p, one of the findings we’ve got already is that it’s really not loss of 17p that’s important, it’s mutation of 17p. And if you have mutation and loss of 17p, then it really is a poor prognostic factor, and that’s very specific. So, it can refine all of the approaches. We’re also looking for new targets. One of the concepts is a driver gene. This is a really interesting concept and that there could be a thousand mutations in a cell that’s relevant to myeloma. But the reality is most of that is just background noise in mutations and genes that aren’t relevant. What we have to do is find the limited set of genes that drives the process of myeloma. Like you said, one of those genes are the RAS gene family. We found some new members of that family that are relevant to the outcome of myeloma, and we’ve already shown in the clinic that if you target the ras pathway, they can lead to responses. What we want to do is refine those clinical approaches and treat specific pathways and biologically relevant pathways so as we can develop both new treatments and new ways of evaluating those treatments.

Jenny: If myeloma changes over time, it would have a need for repeated diagnostics and testing, right?

Dr. Morgan: Yes. Our strategies to try and get everybody into a molecular complete response then control it. If you go more, take a more kind of triplet type approach, then at each relapse, you wind up with the acquisition of more mutations and different subclones come to the fore. So, it’s important to understand how the disease evolves over time because what we’re doing really is developing strategies to overcome resistance because treatment failure is one of the big deals that we need to address going forward. The genetic assessment of relapse helps you to understand what is led to resistance of what may be the best treatment approach.

Jenny: It sounds like it kind of cautions against undertreating.

Dr. Morgan: I wasn’t trying to make that point but you have to assume that when you see a patient to start with that there could be some minor high-risk subclones because the disease isn’t the same everywhere in the body. So, our treatment strategies have to take into account potential variation in genetic content of different sites in the body. The way to do that is to use combinations of drugs with different activities. You might have a proteasome inhibitor. You might want to use an antibody. You would certainly want to use an IMiD drug. And adjusting those combinations to overcome resistance is a very important therapeutic strategy, and using single drugs is a very common way of allowing for this selection of resistant clones.

Jenny: And not as effective as triples or other combinations.

Dr. Morgan: I think so. I mean, I don’t know, you know as well as I do that all of the evidence in the last couple of years has favored triplet combinations. In the last year, there’s been quite a lot of evidence but it’s favored the use of triplets in the context of stem cell transplantation as well.

Jenny: Right. Well, let me ask some questions about data sharing because in my opinion or experience, I think the challenge of sharing data across facilities is a big one, whether it’s technically or just a willingness to share data because sometimes data is tied to research at an  institution and then that’s a challenge for investigators who want to advance their particular research. Please share how you’re doing this because this is really impactful and something that patients want to see move forward.

Dr. Morgan: You have to work as a team, and that is the bottom line is collaboration. Everybody has benefit from doing the research. So, I’m sharing data. Everybody that’s been in the project up to now has had the opportunity to publish their data to start with. But then, it’s clear, if you all share that you get more outset long term than simply pursuing a subsequent publication or approach in your own institution. All of the myeloma community has really bought into this idea. The Biden Moonshot Initiative is being taken very seriously as well. There is a Myeloma Moonshot Initiative as well to facilitate data sharing on a different scale with a different purpose that will actually push everything forward as well.

Jenny: I have a question for you from the patient side. I know a lot of patients are not treated at a myeloma academic center, which in my opinion, is not a good thing. But as you bring other patients on -- well, I just think in my opinion, it’s too complicated of a disease. I think it would be okay if it were more simple disease. But with the amount of research that’s happening in the field and with the complexity of the disease and how it changes over time, I think it’s almost impossible for a general oncologist who’s treating 20 different cancers to stay up to date.

Dr. Morgan: The important thing is that myeloma is not breast cancer. It’s not colon cancer, so you can’t use concepts developed for breast cancer in myeloma. We need to have a focused strategy, I believe, at least directed by a myeloma expert. I think it’s completely right. The way I see it though is the U.S. is a very big country. People live at varying distances away from academic centers. What they need to build for themselves, and we need to help, are teams of doctors where there is an academic center that directs the strategy and for very practical purposes, much of the treatment has to be delivered locally. If you can work well as a myeloma expert with a local oncologist who can deliver some of the treatment, then I think it’s the perfect setting for a patient because they get a myeloma-specific strategy, they get risk stratification upfront, and long-term, they have the security of being safe, close to home. The problem is that really for proper risk assessment, you want to touch base with an academic center before you start a treatment so that you can get the vast kind of amount of data that comes out of getting the plasma cells from the bone marrow and investigate those in a specialist lab.

Jenny: Right, because once you start treatment and those cells are dead, then you don’t have any way of tracking it, correct?

Dr. Morgan: Nothing to look at. It's such a shame when people gets sent off, they’ve had three cycles of VRd and then there’s nothing in the bone marrow to look at. If we could only rationalize some of that, we’d be able to benefit from this genomic medicine going forward and help more patients with that information.

Jenny: Oh, I think that’s a great approach to have a local team and to get some peer recommendations and strategies from a specialist. I think that works very well. Now, in terms of patients sharing data, if patients want to add some of their data, let’s say they’re not one of the academic centers that is participating in your project but they’d like to donate information or samples or anything like that, is that possible? Is that something that patients could do?

Dr. Morgan: Yes, it’s entirely possible. The deal is, of course, that when people are in a remission, then there’s often no detectable cancer cells there that could be examined. It’s really when people present having that conversation either with their academic center or with their local oncologist as to whether they can store a sample locally or send some of their sample into an academic center.

Jenny: Well, for example, Dr. Ghobrial is running the high-risk smoldering PCrowd Study. They have a method where you can just send in, have your doctor pull extra blood or extra bone marrow and send it into them when you get checked, if you have a smoldering myeloma like every six months or every year or something. Is it possible to create something like that for your project that patients could just say, “Okay, I’m going to send it to this specific place and this is exactly the test that you need and this is what I’ll ask for”? Because I think patients would be very willing to do that.

Dr. Morgan: There are issues with that currently. We’re all trying to address them, and that is that the myeloma cells live in the bone marrow. In order to look at those myeloma cells, we focused on the bone marrow because that’s where they are and that’s where you get most information. Over the next three years, say three to five years, then people will be able to look at the peripheral blood more. When the cancer cells break down, they release their DNA into the blood, and so it exists as cell-free DNA. You can look at that cell-free DNA and find the features of the myeloma in it. Very rapidly, I think, it would go from a dependency on the bone marrow to a requirement where everybody will be assessed in their peripheral blood or the presence of mutations, and that combined with next generation imaging technology, it will allow us to do a full genetic assessment of the myeloma close to the patient’s home, which will give more people access to this information.

Jenny: That’s incredible. That would be game changing, I think.

Dr. Morgan: I think it will. It’s just not quite there yet, the peripheral blood technology, but there’s quite a lot of laboratories working on it. I think that really is the future, the bone marrow is always going to be best, but if you’re not there to have a bone marrow, sending your peripheral blood into a central laboratory that can do all of this technology and then give you a bar code that describes your disease, your risk status, and then you can have your treatment adjusted to reflect that information.

Jenny: Well, let’s talk about that a little bit more. With your study of over 2,000 patients thus far, what different kinds of mutations have you found to date, and do you believe that you’ll find even more? And then once those mutations are found or problem genes, like you said with a thousand, and you’re trying to figure out which are drivers and which are irrelevant, how are they matched up with therapies?

Dr. Morgan: Even with a big study like this, it lacks power to find mutations that are present at lower than 2% of total. We found a total of 29 significantly mutated driver mutations, and of these, something like ten weren’t known before. I think that’s a pretty good harvest to know. It’s a real kind of freaky thing for me was, it’s not just the mutations. Perhaps, the most important prognostic drivers come from copy number change in the DNA. If you look at the chromosomes, then what seems to happen is that bits of the chromosome are lost, and those regions contain important driver genes that really are prognostically important. So, there was more prognostically important things in the copy number change than there is in the mutation. There are a number of regions that are lost that contained important genes, and there’s about 80 of those regions. Finding the critical clinical gene within those regions, it’s going to give us another yield and new drivers. Once you’ve got all of the drivers laid out, then you can sort of see if each one have a kind of variable and work out each individual’s risk dependent upon the number and type of driver mutations they have, and integrate that into the IFS and then design studies using -- we can use novel immunotherapies, we can use checkpoint inhibitors, these new bispecific antibodies. It’s critically relevant not only to develop new drugs but to find the right group in which to evaluate those drugs because myeloma is really a success story up to now where we change the outcome from ten months up to ten years. Yet, how are we going to continue to make that progress for people? By argument, finding different groups of patients will allow us to maintain that progress, and the myeloma genome project is an essential component of that approach.

Jenny: Well, before we get to clinical trials, because I do want to ask you some questions about how you think you would reconstruct some things like that. First, you said the copy number changes and the chromosomes being lost, do you see a difference? I’ve heard that when you gain chromosomes and you have three copies instead of two, it’s actually might be better, like let’s say you have a high-risk feature but you have three copies of the chromosome instead of two or a loss, are you also looking at the chromosomes that are lost but also chromosomes that are gained?

Dr. Morgan: Yes. So we’ve come up with a new classification of myeloma based on the copy number change. It’s the odd number chromosomes that it gained, and this is a very theoretical argument but the idea is that on those regions that are gained that are relevant oncogenes that are actually selected for because they are important in driving the myeloma forward. So, it’s not random, it’s odd number copy gain. It’s driven by what’s on them, and if you have three copies, that is driving the myeloma. So, if you look at the copy number change, it’s not just one big group. There’s a basic complement of 5, 9, 15, and 19 that it gained, but there’s variable gain of chromosomes, five chromosomes, seven, and other odd numbered chromosomes. There’s differences in outcome depending upon which group of hypodiploid they fall into. Again, it’s an example of how studying things in more depth with bigger groups of patients allows you to kind of tear through the fog and see things more clearly and be able to use in the clinic.

Jenny: And then you said the bone marrow microenvironment was really critical for myeloma growth. As you’re studying the myeloma cells, what kind of information are you capturing from the bone marrow environment itself?

Dr. Morgan: One of the components of this study with tooling like Rosetta, because we need information about the microenvironment to explain how to design studies, how to use immunotherapies better. We’ve taken biopsies from patients with myeloma over the years, not just the sucky component but codes of bone marrow with the myeloma cells in. We’ve looked at ways of extracting the signal from the myeloma cells, and then to look in the microenvironment itself to see if that varies between patients, and it clearly does. There seems to be very different types of microenvironment that may impact on outcome, and certainly, may impact on the response to treatments like daratumumab or checkpoint inhibitors. We’ve just started off on this direction, but one of the big, big growth areas in myeloma is understanding how the cancer cells modify their microenvironment to generate a high-risk microenvironment that pushes the disease forward because arguably, that could be our best hope for future curative treatments by modifying the microenvironment to deal with the cancer cells.

Jenny: And give it a place where it can’t survive.

Dr. Morgan: Yes, absolutely. It’s changed it, so it’s conducive to its own growth. We don’t even consider that in our treatment. We target our treatment to just getting rid of the myeloma cell. But you imagine if there was a receptor on a microenvironmental cell that facilitated the survival and growth of bad cells. Then if you could block that, you could lead to eradication of the cancer, so it doesn’t come back. I’m very optimistic about using the immune system and using antibodies to manipulate the immune system to deal with the abnormal genetics of the cancer clone. I think that’s really a strong area for research going forward.

Jenny: Do you know of any current drugs either in the pipeline or like the monoclonal antibodies like daratumumab or those that do affect that microenvironment?

Dr. Morgan: There are many drugs that deal with , like antibodies that deal with adhesion molecules. I think they offer some help. But single agent daratumumab works in 30% of patients. You have to ask yourself, “Why does daratumumab work in some patients and not in others?” If you can parse that out as to why that’s happening, then there’s a fighting chance you’ll be able to take something that acts with the daratumumab to improve the response rate. That’s been sort of one of the premises of Western medicine which is trying to understand what’s going on and then use that information to make better treatments.

Jenny: Well, let’s talk about the segmentation when it comes to clinical trials. Right now, patients will -- like phase 1 trial is just testing a drug out to see if it’s safe. And then phase 2 is testing in a larger group once it’s tested out safe. The third is kind of comparing an existing treatment with this new treatment to see if a new treatment is better. How would you see that? Feel free to take as much time as you need to answer this question because this is kind of a long one. How would you see that changing once you have these patients segmented into these different groups?

Dr. Morgan: The real challenge that I see is how to design phase 3 studies going forward. I’ll try and explain why designing a phase 3 study is now difficult. It’s difficult because of the success we’ve had. When we started with phase 3 studies for newly diagnosed patients, the median survival was two years. To see an improved clinical outcome of 10% you needed 300 patients. That was feasible and doable. Whereas now, with average survivals of low-risk patients being at ten years, you need 2,000 or 3,000 patients, and you need to follow them up for seven years. It’s becoming very difficult to have the number of patients and funding to move that forward in a timely fashion. We have to address it. That really is going to need us to find high-risk groups or subsets where you can do a study that takes two to three years to complete, because otherwise, the pace of progress comes down to be very, very slow. I think this is a very, very crucial point for making progress in myeloma. We still have relapsed and refractory cases where we can find agents in phase 1 and phase 2 studies to see, does the drug work? Does it not work? How do we get drugs from that setting to be available for newly diagnosed patients? Because it’s also important and key. You need to get things for newly diagnosed.

Jenny: I don’t know what the FDA requirements are to get a drug through the whole process and everything, but it seems like it might require some changes on their side about how these things are constructed in the first place. Is there work being done right now on modifying that?

Dr. Morgan: Very much. It’s all about endpoints. In follicular lymphoma, there is an endpoint which is being free of disease up to three years. So, that can be an endpoint for follicular lymphoma, which is another type of blood cancer. Whereas for myeloma, for PFS (progression free survival, the power fits as I described. But what we would try to do is to get minimal residual disease as being a clinically valid endpoint where we would try to see for a new drug presentation, we would want to increase the number of people getting to MRD negative states. So, there’s been a lot of discussions with the FDA about this, and they’re taking it very seriously, but we still have a challenge with getting together a set of data that is well thought through and presenting that to the FDA but people are in the process of doing this, and I think the MRD negativity will become the endpoint in myeloma maybe within two to three years.

Jenny: For patients who might not know what PFS is and things like that, what you’re saying, and feel free to correct me if I’m wrong, is that normally, historically, you’ve looked at progression-free survival or how long it takes for the disease to come back, or overall survival, how long someone is living as these endpoints you’re talking about. Instead, because this minimal residual disease testing is more sensitive and can detect smaller levels of disease, you think that bringing people (because you can be MRD positive and have just a few cells hanging out there, or MRD negative which means it’s the best technology that’s out there right now and you still can’t pick up anything) that if you get people on that state, maybe you could use that as a different endpoint.

Dr. Morgan: We’re using it as a surrogate for a ten-year survival, say, or ten-year disease-free survival. We absolutely need all to get together as a myeloma community to push these ideas forward because it is so important for the myeloma patients to be able to get new treatments upfront, and without getting this MRD negativity as an endpoint, or some other endpoint, progress will be painfully slow.

Jenny: I think patients might not understand why, because in my opinion, I see all these newer drugs coming out for myeloma, which is really, really exciting, but it kind of causes a problem. So now, when you’re trying to create a study and you’re trying to say does this is the combination of drugs work and you’re comparing it to something that already works. Now, you’re creating a study that you may not have a result for five or ten years because it’s out so long.

Dr. Morgan: Yes, for ten years possibly.

Jenny: Yeah. So, that takes forever.

Dr. Morgan: Yes. I mean, it is rather for some people as things stand. That’s not a situation that we can allow to exist for much longer. We have to be able to do trials, get things approved for therapies in that setting. We should all put our efforts into getting new endpoints agreed by government for patients with myeloma. It looks to me like the best one currently is MRD negativity, and yes, we should all get together and do what we can to getting that approved.

Jenny: Well, if patients can help weigh in and any way, I think they want to accelerate research as much as possible, and that’s been our goal. If you have suggestions, I think we’d be open. When it comes to other clinical trials, when you say, “Okay, we’ll look at MRD negativity instead,” could you come up with a trial that says, “Okay, everyone with 4;14 translocation can enter this study”? Would you create it like, okay, group A is going to get a stem cell transplant and then maintenance therapy, and group B is going to get a monoclonal antibody in this combo? Is that how you would create a study like that, or how would you do that?

Dr. Morgan: No, that’s exactly it. That’s how you would use your segmentation test. What I was describing before was high-risk and low-risk. That’s called a risk-stratified study. But it would be equally valid or even more valid to try and find specific treatments, specific molecular subsets. You would have a test that would identify the 4;14 group, and then you would randomize them to treatment A or treatment B. In that way, it would make progress for a specific subset of disease. It’s a difficult concept for pharma companies to buy-in to because they want to design medicines that all patients receive. But the example, currently, that I think is going to bring this into the clinic is a drug called venetoclax, which targets the ability of a cell to survive. It targets BCL-2, which is kind of irrelevant but scientifically correct. If you could make a cell die by targeting its survival equipment, then you can do very well. The deal with venetoclax is it seems to work best in the 11;14 subgroup. You can see attempts now with people trying to find 11;14 patients and put  those into studies with venetoclax because we know, predominantly, it’s the 11;14 group that responds to the venetoclax, whereas, the other groups don’t respond so well. That’s the first example that we can talk about clinically where you can see that there’s going to have to be some sort of segmentation of the disease because the response rates are really good in the 11;14s with venetoclax, where they’re not so encouraging in the other groups. This will play out over the next couple of years as well, and I think will provide an exciting driver that will get these approaches to myeloma patients.

Jenny: I think that stresses a point. I think you’re making an important point too because patients need to understand their disease, and I think a lot of times, we talked about this before the show started. Sometimes patients, feel like “If I don’t know, maybe it’s not going to happen or be real” but I think this is the value of knowing your disease because if you say, “Oh gosh, I know that I have an 11;14,” a drug pops up someday like venetoclax or something else that specifically applies to that. You can say, “Wow, this is a clinical trial that I want to join because it’s going to be the most appropriate, potentially, for me.” But if you’ve never asked for those tests to be run, those genetic types of tests, and you have no idea, you don’t know what you are dealing with.

Dr. Morgan: No, actually. Knowledge is always power in these situations. You can never know too much about your disease. It is really important because it’s not all the same disease and it’s clear if you're in the clinic how different people’s diseases are. Some people have no bone lesions, some people have bone lesions, some people have disease outside the bone marrow. There’s a lot of variation and it’s this type of MGP Project that will allow us to identify the basis for that clinical variation and then design treatments for those groups.

Jenny: When we talked about the clinical trials being constructed for a specific type of myeloma, how about for genes too? Because when I talked to someone, it’s probably two years ago, in one of the shows, they said, you know, sometimes we have to stop thinking about cancer as a body-specific or location-specific disease and more of a genetic type of mutational disorder. Do you foresee patients with different types of cancers joining one clinical trial that have the same genetic mutation?

Dr. Morgan: Yes. That’s called mutational directed treatment and the studies are called basket studies. If you’re interested in targeting the RAS pathway, you could put a variety of different tumors into a RAS targeted trial. The problem with mutational directed treatment is that this is something that we’ve been pushing forward and done a lot of work in myeloma on this that if the mutations aren’t present in all of the cancer cells, when you treat with something that say kills all of those mutations, if it’s present in 50% of the cells, you can only possibly kill 50% of all of the cancer cells. We have to work out ways of using the knowledge from the sequencing to design strategies where we inhibit a pathway that is relevant biologically but isn’t really directed specifically at a mutation. Some mutations are only present in 20% of the cells, and others are present in all the cells. Like the 4;14s as an example, 100% of the cells have it. It’s present in the roots of a tree. So, if you go for the roots, you kill the whole tree. But if something is present in just a branch and you’d kill that, all you’ll do is sort of prune bits of the tree. So, we need to design therapies that we would get at the roots of the cancer. It’s finding those early genetic lesions that really, we’d like to do.

Jenny: My final question, I think, and that was just a really valuable information and then we’ll open up for caller questions, but do you use next generation sequencing now as your standard or what do you use for these genetic tests that you’re running on your patients?

Dr. Morgan: We try to get a global assessment of the patients. We’ll use PET-CT scans to look for activity in the lesions. We’ll use diffusion-weighted MRI to look throughout the marrow for evidence of tumor cells. We would then take some of the marrow out and get a gene expression profile. We will send samples for a targeted sequencing panel so we don’t try and look at all of the mutations. We just use the mutations that we find to be relevant to multiple myeloma, and then try and take our clinical decisions based on all of that information. At relapse, the sequencing data is the most appropriate, not so crucial as the newly diagnosed patients. But we take material from them, so as we could learn more about it and try and understand how these groups are behaving. Where we’d like to go in the next year or two is to use the information from the myeloma genome project to define a set of markers against which we can design a test, so as we can define prognostic groups accurately and really get that test available to everybody. And then if we could do that on the peripheral blood, then that would be the optimum way forward. That’s really the next three years of this project is make the test, look at what the markers are, design the test and then disseminate the test to as many centers as we can. That’s one of the overriding goals of this project is to be collaborative and to be inclusive rather than being exclusive and discouraging.

Jenny: Well, absolutely. Well, let me open it up for caller questions and then I may ask you one or two more before we end. But if you have a question for Dr. Morgan, you can call 347-637-2631 and press 1 on your keypad.

Caller: Hi. Good afternoon, Dr. Morgan. This is Dana Holmes. I’m a smoldering patient. I wanted to start out by just thanking you for taking the time deliberately trying to explain this very complex information in terms that we, patients, can grasp and understand. That’s just so helpful, so I thank you for that. I have a question, a couple, actually. Do you hold the philosophy that treating myeloma at earlier stages, (in my case I’m questioning in smoldering myeloma), as a curative strategy? And if yes, would it be because the complexity of the disease may be more sensitive to treatment at that stage?

Dr. Morgan: I am deliberately not going to refer to you specifically, if you don’t mind, but as a concept, I think it makes academic sense to treat people earlier in their disease course. So, I’m waiting until the end of that disease course where there is high-risk disease and almost by definition, current treatments can’t work. There is a lot of provisos about that though, which is that the treatment that’s used shouldn’t damage the patient long-term, that we understand the people go into clinical trials. I think the whole community has moved to thinking that treating smoldering myeloma in clinical trial is both acceptable and desirable and is the way forward. I would argue though that what we really need to know and what we’re trying to focus on with Jenny are -- what happens to the microenvironment in smoldering myeloma? Why is it that some MGUS patients are immunosuppressed and others aren’t? Is there some way that we can use the immune system or the microenvironment to either stamp down smoldering myeloma to decrease its rate to progression with response and improve it with the outcome? The answer to your question is yes, people all buy-in to the concept of treating earlier. There is some reticence about treating outside this clinical trial. But there’s a lot of thought and movement forward in clinical trials for the treatment of smoldering myeloma, and people really want to use immunotherapies rather than cytotoxic chemotherapy.

Caller: In other words, just so that I understand, that approach in that concept would not then include a stem cell transplant?

Dr. Morgan: I think it depends on your risk of progression. We’ve done some stuff with gene expression, and we can use the GEP40 or the GEP70 with a different cut point, and there are clinical risk stratifiers as well. So, the Spanish have one approach with flow cytometry and the Mayo has one based on the light-chain ratio. If your risk of progression is more than 80% in the next year and a half, then I would see that being a group of patients where you should seriously consider treatment. If you have a very low risk of progressing in the following year and a half to two years, I would think that’s a group where watching and waiting may be not appropriate. It all comes down to a discussion between the patient and their own doctor and the patient’s viewpoint and the doctor’s viewpoint.

Caller: Dr. Morgan, the tailoring approach that you discussed with Jenny, could that, I guess, ultimately translate to potentially treating smoldering myeloma patients earlier as well?

Dr. Morgan: Absolutely. If you look into the future, a world without myeloma would be good.

Caller: Oh, you said it.

Dr. Morgan: We are managing to do better in treating it. But if we could move into primary prevention before people have end organ damage, I think that probably is the future. So, finding cases of MGUS, looking at their microenvironment, using immune approaches and antibody-based approaches to prevent progression is, I believe, really the future We’re  certainly not there now. What I’m talking about is the far future.

Caller: And when you say far, you’re talking years, 10 years, 20 years, or you’re talking something that gives me more hope like five years?

Dr. Morgan: I was talking about ten years into the future. I’m not really talking about yourself.

Caller: Yes. No, no, I realize that. I realize that this is more general --

Dr. Morgan: I think there are therapeutic approaches that work in smoldering myeloma now. The Spanish did a study of Revlimid and there was an apparent survival benefit for with people with smoldering myeloma treated early. Surely, there is the daratumumab study in smoldering myeloma at three different doses, and the people I’ve put into that study and treated myself have responded well, but we don’t have enough follow-up to know if it’s improving outcome. But I think MGUS is a far future; smoldering myeloma is the near future, and I think they’re more and more inclined to want to treat smoldering myeloma with immune approaches.

Caller: Well, thank you, Dr. Morgan, for your time, and more importantly, thank you for what you do for the myeloma community. I appreciate it very, very much. Jenny, thanks again for taking the call.

Jenny: Thank you, Dana. Okay, our next caller , go ahead with your question.

Caller: Yeah. Dr. Morgan, I have a question. For patients that have a relapse, what is the practical way to be part of your MAGIC project and have their tumor sequencing? Is the trial open? How can one participate?

Dr. Morgan: That’s a very difficult question. Yes. Currently, as it stands, we’re not set up to receive materials from around the U.S. Currently, you’d have to attend here to have the bone marrow done. If you’re in a remission, then it’s not possible at all because there’s no disease to look at. We haven’t really addressed the organizational approach to having people mail in bone marrows just yetthis year.

Caller: Thank you. Could this be possible in the future though?

Dr. Morgan: Yeah, it makes sense to me. The future really will be around what Jenny said Irene was talking about in MGUS and high-risk smoldering which is to develop test strategies that work on the peripheral blood because then it’s very easy to have peripheral blood mailed in and to have genetic tests. But at present that’s not really possible.

Caller: Thank you.

Jenny: Okay. Thank you so much. Dr. Morgan, if you’re using collaborative data from different facilities it looked like the MMRF data was included in the original study. I don’t know if it was not. I don’t know if that’s helpful to go to centers that are running that genomic study or just come to UAMS and get the test done. That’s an option too, right?

Dr. Morgan: Yes. We’re happy to do the test. We’d be happy to see people. I think that the COMPASS study has fully recruited now and is just following up people who have entered into the study. I guess it’s find an academic center that’s close to you that has genetic assessment of the tumor at multiple levels: using iFISH approaches, using next generation sequencing approaches, and using gene expression. There’s a whole new approach and a lot of scientists are setting up with sequencing panels. So, it’s going to be the big academic centers that focus on myeloma. They’re going to have this technology first of all.

Jenny: Well, it’s exciting what you’re doing and we’re just thrilled that you’re doing it. We know that you’ll make some very important discoveries between your talents and that of your team. You are the top when it comes to myeloma research, so we are just really excited for you. We’re thankful that you joined our show today. I don’t want to keep too long over our time but I just want to thank you for all you’re doing, like Dana said, for myeloma patients in general and for joining the show today.

Dr. Morgan: Thanks, Jenny. Thanks for the opportunity. I always enjoy these things. It’s good to have the grounding that patients bring. So, that kind of, even though I do research, I really like the fact that patients can input into it and direct the kind of treatment and make everything relevant because it is all about the patients, it’s not just about the experiment. So, thanks to all the patients for the help they give you and to us as well.

Jenny: Well, thank you for all you do. We’re just very grateful. And thank you to our listeners for listening to Myeloma Crowd Radio. We know that patients can help advance a cure through their participation and hope that you’ll join us for Muscles for Myeloma and help support your favorite institution.