Craig Cole, MD
University of Michigan
Interview Date: November 17, 2016

How can doctors treat each myeloma patient in an individualized way? Dr. Craig Cole from the University of Michigan is partnering with the MMRC to do just that. We already know that all myeloma is not the same. And in fact, myeloma changes within an individual patient over time. Dr. Cole shares a study that takes patient bone marrow biopsy samples which are then studied by a computer program at the University of Michigan to test the genetics of that patient sample. The computer identifies genetic mutations and then matches those mutations with possible effective treatments. These treatments are not limited to our standard arsenal of myeloma therapies, but could be identified as treatments used for the same mutation in another disease. The goal is to treat patients in an individualized way for optimal outcomes. Even if you don't go to these facilities for your care, you can have this test run at the open study centers if you have active disease. (The study is not yet treating patients on different arms of drugs, but is at the analysis stage.)

Thanks to our episode sponsor

Jenny: Thank you for joining us on today's show on Myeloma Crowd Radio. I'm your host Jenny Ahlstrom.

We'd like to think our episode sponsor, Takeda Oncology, for their support of this program.

Now, you may know that all myeloma is not the same. There are about nine different kinds of myeloma and even the same patient, a single patient can have an average of five different clones of myeloma at diagnosis. So with that kind of complexity, patients and researchers alike are wondering how we find the right drug for the right type of patient.

With us today is a myeloma specialist who is working on solving this problem, Dr. Craig Cole, from the University of Michigan. Welcome, Dr. Cole. Thanks for joining us.

Dr. Cole: Oh, thank you. It's my pleasure to be here.

Jenny: Well, we're happy to have you. And before we get started, let me just give a brief introduction for you. Dr. Craig Cole is Clinical Assistant Professor, Department of Internal Medicine, Division of Hematology/Oncology at the University of Michigan Hospitals in Ann Arbor, Michigan. Dr. Cole is a member of the MMRC which is the Multiple Myeloma Research Consortium and their "Molecular Profiling Targeted Therapeutics Interest Group" Committee. He is Member and Founder of the Great Lakes Multiple Myeloma Working Group and is Co-Chair for the Big Ten Cancer Research Consortium Multiple Myeloma Clinical Trial Working Group. He served on the Scientific Advisory Board for the MMORE Foundation which was the Multiple Myeloma Opportunities for Research & Education, and is a member of the International Myeloma Working Group.

Dr. Cole’s research interests include: Clinical Application of Novel Biologic Therapeutics in Multiple Myeloma, Laboratory Pathobiology in Myeloma, Measurements Psychosocial Distress in Malignant and Non-malignant Hematology Disorders, Quality Measurements and Outcomes, and Ethnic and Racial Disparities in Myeloma Education, Diagnosis, and Treatments.

Dr. Cole, you are well positioned as part of that Molecular Profiling Targeted Interest Group to talk about this subject today, and you're working on a really fascinating project. So maybe we want to give patients and those listeners just an idea of why myeloma is so complicated or why sometimes you call it heterogenous.

Dr. Cole: Yes. When we previously have thought about cancer, we've always thought that all cancer cells were the same and through time given different therapies that the single clone or a type of cancer cell would just mutate more with one mutation after the other in sequence and would really kind of follow this linear pathway. Of course, things aren’t ever that easy. The more that we looked into cancer and specifically myeloma, we found out that actually instead of the cancer and myeloma evolving in a linear fashion, it actually evolves in an evolutionary way, which means that through time and exposed to different treatments, that different clones and different parts of the bone marrow in different parts of the body can evolve through survival of the fittest. When a person receives therapy, that the cancer, because it has multiple types of escape mechanisms and has different genes that are working or are broken, that exposure to therapy will select out those cells which are sensitive to the therapy and will leave maybe one or two cells that are from a clone that is resistant, that has been resistant by nature since day one. As one clone becomes extinct because of therapy, then another clone will grow in. And then when someone sees another type of therapy, maybe a different sequence of treatments, that that clone may be sensitive and die out and another clone may come in. As someone goes through life receiving different therapies and with the survival of the fittest, maybe the most aggressive myeloma that in time the cells actually do start to mutate. Again, with a selection bias based on therapy, the clones can expand further and further. It's become very complicated and how myeloma works, that is no longer just looking at a single chromosome deletion or a single set of chromosomes stuck together called a translocation. It's become more complex and thank goodness, we now have tools which can explore that complexity.

Jenny: The clones not only are complicated but just as an example, I mean I have a high-risk feature, for example, of translocation but I also have trisomies which is like three copies of chromosomes. I was just doing some reading yesterday showing that if you have those trisomies, then the high-risk feature may not be such a bad thing. There's so much that needs to be understood personally by each individual patient about their own disease. How do you suggest patients learn more about their type of myeloma?

Dr. Cole: I think that's a great question and the preaching point as I talk to patient groups and talk to doctors is to really stress that patients know and understand their cytogenetics which requires a real good sit down with your doctor and a possibility of referral to a myeloma center. Because knowing those risks and knowing that those type of genetic features is important in a number of ways right now because we're beginning to treat different types of myeloma. As you mentioned, there are five different types of myeloma that we're beginning to discern out of just the entire diagnosis. We're beginning to apply treatment algorithms to each of those types. And to assure that everybody knows the type or treatment they should get, it's important to know that they have what type of cytogenetic abnormality that they have in their myeloma. When I sit down with my patients, I always write down and write down repeatedly, this is the type of myeloma that you have and this is the cytogenetic abnormality that accompanies that disease.

The reason that that's important is that if you go to another physician, if you go to your primary care doctor, if you go anywhere where you're receiving healthcare, it's really important to know what your disease looks like and what type of myeloma it is. That's a relatively new concept for us in myeloma research and for myeloma patients.

Jenny: The way my doctor put it, he would all always say, "You know, you're fighting a war here. We need to know the enemy."

Dr. Cole: Exactly.

Jenny: Totally understand the enemy before we get started with treatment. You are working on a project that will do exactly this, when you were talking about trying to find the right treatment for the right type of patient. So maybe we want to start with just an overview of what that project is, what you're trying to accomplish, and then we'll dive into it.

Dr. Cole: I guess the catchphrase of what we're doing is called personalized medicine. Personalized medicine actually isn't anything new. It's something that we have all been striving for in medicine, in every part and section of medicine. Decades ago, almost a hundred years ago, when people used to get blood transfusions, they would just pull blood off the shelf and give it to people because they didn't know the different types of blood. They didn't know about the A, B, and the O type of blood so people got blood, and people would have these horrific allergic reactions. If they survived, then the blood was great and if they got really sick, then they would try a different type of blood. When the blood banking system become personalized, then what we did was we would test your blood type and then match your blood type to the type of blood that's in the blood bank. You received personalized blood. These days when you get a transfusion, we just don't pull any type of blood off the shelf. We personalize it to you that you only receive if you have A+ blood, only receive A+ blood.

We've been doing this for a while where we match the antibiotic to the right bacteria, and now we're beginning to do this with cancer where we're beginning to understand and find out the different types of cancer on a molecular basis. We now know through large studies done with myeloma patients, we know that there are about 11 genes that are recurrently mutated in the majority of myeloma patients and there are genes called KRAS, NRAS, BRAF, p53, DI53. Those are recurrent in patients, so we're seeing it in the same way again like we see that there's an A, B and O type of blood. We're beginning to see the different types of myeloma based on studies looking at large number of patients. The idea is that if you understand the mutation that happens in the disease, if someone has come up with a drug to address that mutation, instead of pulling a therapy off the shelf like melphalan and just giving it to everybody, that if we match an individual's mutation in their myeloma as small as it might be to detect and match the drug to the individual patient. Part of the personalized medicine initiative in general is to find out those individual things that make individual people have an individual disease and matching, treating that disease with something very specific to that patient just like we do with transfusions today.

Jenny: So that's the goal. Why don't you tell us about your project and study that you're working on?

Dr. Cole: Since 2011, there has been a clinical sequencing program at the University of Michigan called MI-ONCOSEQ and it's spelled MI for Michigan and then ONCO for oncology and SEQ for sequencing. What that does is that it actually linked different almost kind of separate parts of the university together. It linked a  CLIA-certified molecular sequencing lab to the Department of Pathology, to the Department of Computer Engineering and Computational Software and the Artificial Intelligence Project. Marrying those three together, we were able to get different types of tumor and actually come up with a sequencing platform to look at different genes that are mutated in cancer, and specifically 1,600 individual gene mutations that happen. The ones that we're looking for are those that are clinically relevant in cancer. Clinically relevant gene kinases, genes of interest that have been known to cause problems; to cause cancer and those genes that are of biologic interest in cancer. MI-ONCOSEQ also looks at point mutations, amplifications and deletions of genes, loss of heterozygosity and even microsatellite instability which is trying the little parts of the chromosome that are trying to keep it together from mutating. We're looking for microsatellite instability as well as not only looking at the genes and see if they're mutated but looking at the gene expression.

With all that information that is gained and the capture of all of that information, the tumor is sequence against normal samples taken from a patient. A patient has a bone marrow biopsy. We get the plasma cells and other specific cancer cells, sequence those, get a blood sample and sequence the blood sample which is normal, and then you look at the differences between the two to see exactly what is mutated in the plasma cells and what is actually part of the person. And then the computer takes over and then finds the most important and the most prominent mutations that are found in that particular patient. It may be one or two or three of the most prevalent genes that are mutated in the cancer cells. And then the other computers, another supercomputer that takes over that then after the sequence analysis is done, it generates a report, and what that report does is it then combs the medical literature looking for papers that are relevant to the genes found in that patient and looking for therapies that have been invented across disciplines for those particular gene mutations that are found in an individual patient and I think most importantly clinical trials that are available for an individual patient based on those genes. Instead of me telling a patient that I think that you should go on a clinical trial, out of the blue pulling a clinical trial off the shelf, this report actually gives you information that may refer you to a clinical trial that I may not have thought of at the National Institutes of Health or maybe in another country or maybe with a different disease that I wouldn't link to myeloma. The MI-ONCOSEQ does that for plasma cells. We've been collecting information about of so far 50-60 patients right now with relapsed myeloma. I'm having them go through the sequencing project and report generation.

Jenny: That's amazing. I mean what you said earlier is true. You could find solutions from other cancers, you could find a treatment that works in lung cancer or kidney cancer or something that might be applicable. Yeah, that gets really complicated.

Dr. Cole: Yes, but what I think is fascinating is that over the past five years that the MI-ONCOSEQ has been doing this, the computer programming has become, you know - it's an incredible huge amount of information that is gathered. But the important part about being a human is that we can kind of distinguish the irrelevant information to the relevant information for somebody. The computer, the artificial intelligence really helps with that in that when you get the report, the report actually is not a 75-page report of every little gene that's in your body. It actually gives a report of the clinically relevant genes, and it gives a list of the possible solutions to some of those problems. Sometimes the solution is not necessarily something that's really exotic. Sometimes you'll find that it will find mutations that are in pathways that we know happen in multiple myeloma and so it can find overexpression of a pathway such as a nuclear factor-kappaB which is one of the real targets for the proteasome inhibitors. If a patient hasn't received a proteasome inhibitor for the past few years that they've had myeloma, the sequencing analysis can remind you, this is a patient who needs to have a proteasome inhibitor in their treatment for their myeloma because we have found that that gene is overexpressed in this particular cancer and can give us information that there's no way that I could know that somebody needs to see a proteasome inhibitor again or a particular drug again. But the sequence report sort of cracks open those plasma cells, gives us an idea of what the mechanism of mutation and resistance is so then we can use drugs to specifically treat that patient.

Jenny: That's just incredible. This is just truly incredible. Since it's been around since 2011, has the university used this for other diseases and now they're just bringing on myeloma, or what's the history there? How was that developed?

Dr. Cole: It was originally developed for prostate cancer, was one of the first personalized medicine approaches that the technology was used for. Of course, it was a lot easier to get a tumor that's located in a particular place and especially with, unlike myeloma which is a sort of interspersed in the bone marrow and you have to sift through the normal and abnormal cells, when you do a prostate tumor biopsy it is 100% tumor so it was a lot easier, and back then the artificial intelligence was not so artificial. It was people that would do the matching and that was kind of based on what they knew about a particular mutation. The really interesting thing that came out is that as more tumors were brought in, not only was there clarification of the heterogeneity of the tumors and the specific mutations that occur but also novel mutations that no one had ever looked for. When you're going fishing for 1,500 types of fish, you may find something that you really didn't expect to find. That was one of the remarkable parts is that there were genes that were unknown to be mutated in prostate cancer and in other cancers that became new targets for cancer medicine. Especially as we found that there were more KRAS and NRAS mutations, then the hunt for a treatment immediately started to address those problems.

That's what we're doing for myeloma now is that as the technology has grown, now we're able to do bone marrow biopsies with patients with myeloma and separate out the plasma cells because that's one of the tricky parts. Unlike prostate or lung tumor, we have to be able to separate the normal cells in the bone marrow from the abnormal cells. Once we have a collection of the abnormal cells and we can work on that and unlike the tumor cell from solid tumor, sometimes with myeloma you have to deal with small numbers of cells. That's kind of the process that we're going through now is how small a number can we actually work with and what's the best way we can get the best yield from a bone marrow biopsy of the plasma cells that we're targeting.

Jenny: Well, it's such a difference from the thalidomide story versus this, you know. Thalidomide was just brought into myeloma therapy because of a patient. A patient said, "Hey, I heard about such and such type of drug," this anti-angiogenesis drug and they said, "Well, those aren’t approved for things but this one is approved, so let's try that." And it happened to work, that whole class of drugs, those immunomodulators worked. So this is a such a more efficient way of going about that process.

Dr. Cole: You're absolutely right. I mean that's really exciting because you go through the history of medicine and so many things are just total mistakes.  There is this divine intervention that we were able to match a drug to a particular disease and that drug actually worked. Through time there have been clinical trials that have failed and failed and failed because they were best guesses at what we could do. Now, you're right, is that no longer do we have to just randomly search for drugs without knowing the target. Now, we're actually targeting -- we know exactly and have a very, very, very good idea of what the target is inside the cancer cell and then instead of divine intervention which happens anyway but divine intervention finding a treatment. Now we have people and computer power to actually bring an individual patient and an individual therapy together which would be more effective.

Jenny: Well, I know you said earlier that these data analytics are -- I mean it's so wonderful that they're coming into the clinic now. And I've heard others doctor say that healthcare data analysts are the most wanted people and they can't find very many. There are only a certain number of facilities that do this or can provide the skill and talent to do it. That's incredible that you have that at your university. It's amazing.

Dr. Cole: I remember just two years ago that it was that the computer power was limited based on space and they had to dedicate these ginormous rooms to these huge -- I mean this is just a few years ago that you're talking huge - computers that had to sift through tremendous amounts of information for individual patients, individual patient samples. Now, the computer power has become much more portable and where individual institutions can actually purchase them. Actually, the computer that does that here is not in the basement in some giant room but actually is in just a regular lab room because the computer power has become so much more efficient. That has really opened up this whole area. Not only does the University of Michigan have MI-ONCOSEQ but other parts of Michigan and other institutions are also part of not necessarily myeloma sequencing but other cancer personalized medicine initiatives. Part of the Cancer Moonshot and part of the Personalized Medicine Initiative has done incredible strides at pushing this technology forward. It is impossible for this to now stay static where the technologies sort of sits there. It has been infused with support from the White House and from the government. It is just taking off at a tremendous rate.

Jenny: Well, I hope that continues. It's all very exciting what's happening, not only the computing capacity but the knowledge of how to bring this together. For you to have these different labs and pathology and the computer engineering groups together is truly what's making this a wonderful project. So how do you gather samples? You said that you have about 60 patients in this so far and this is a collaboration with the MMRC, isn't it?

Dr. Cole: Yes.

Jenny: You have 11 facilities and do you want to describe how that is constructed, how patients might join, be able to join or submit their samples and get this type of analysis done?

Dr. Cole: Yes. So right now, the sites that have the sequencing project open is the Hackensack University, University of Michigan, UC San Francisco, City of Hope, Mount Sinai, Princess Margaret in Canada, Karmanos Cancer Center in Detroit, Washington University, the Ohio State University and Virginia Cancer Specialists. And there are three more sites that are opening soon and then there's an additional three sites that are in the process of application. At those sites, all of them have of myeloma doctors who are part of the study. It is really relatively simple -  just meeting with those doctors and signing a consent form, and the consent form basically says that we're going to do a bone marrow biopsy, trying to isolate the myeloma cells and take blood. After the consent form is signed, then bone marrow biopsy is performed and 5 milliliters of blood are taken. The blood would be the patient's normal sample and the bone marrow biopsy is going to be of course the abnormal sample. Patients need to have some measurable myeloma.

We actually did try to do the study on patients that had very good responses and were after transplant and there is just no cell to obtain. So patients were usually in a relapsing situation with measurable disease. When their bone marrows came to the University of Michigan that the positive cells have separated out via an enrichment study, enrichment procedure where only the CD138 which is a little tag on plasma cells are taken out, and so the normal cells are left behind and only the cancer cells are taken. And then the cancer cells and the white cells obtained from the blood are then sequenced simultaneously in order to see what's normal in that person and what's abnormal.

The great thing about the project is that you don't want to wait seven weeks for the results. In the past, it used to be. It used to take about 40 or 50 days for the sequencing project to be done. Now, the myeloma sequencing project, it has a ten-day turnaround. It's really great because it then allows very rapid dissemination of the data and if it's something that's actionable, then you can do something immediate for that patient or at least be able to give the information of this is what we know about your myeloma today.

Jenny: A couple of follow-up questions about that process. If you have no M spike but you're MRD-positive or minimal residual disease positive, can you still send in a sample?

Dr. Cole: No, there won't be enough -- that's a great question. There won't be enough plasma cells for that. One thing that that even after the enrichment process, they take a look at the sample and make sure that there's greater than 30% plasma cell than the enrichment in order to do the sequencing. The people who were tested successfully were ones that usually have measurable disease. We did have patients that had nonsecretory where their myeloma didn't produce a protein. And as long as the bone marrow biopsy was positive for a significant number of plasma cells, that they were able to do the sequencing. But you're right in that patients that are minimum residual disease negative and even patients who are in complete responses may not have a yield with the study. I'm sure in the future we'll be able to. If you look at the progress, it used to be a huge tumor to be able to do this. I'm certain that the day is coming where we'll be able to do it on finer amounts of material.

Jenny: Well, still terrific. It's great that you have a solution for nonsecretory people because they really have a tough time. They have to get biopsies all the time to see what's going on with their myeloma because there's only M spike. Another question, if a patient has circulating plasma cells in their blood which is not a good indicator for myeloma and would throw off that norm that you're looking for for the comparison, can they still participate?

Dr. Cole: The other way to obtain normal sample is to use a mouth swab, and so the mouth swab can also collect endothelial cells that are in the mouth. That sample is also able to get sequence as a normal material. So sometimes, just like you mentioned, if the blood sample is really abnormal or maybe if the white blood cell count or the other counts are low, that he can obtain a mouth sample, just a cotton swab in the mouth, just brushes of the cheeks and then that can serve as a normal sample.

Jenny: That's great.

Dr. Cole: If somebody has circulating plasma cells even though the current project is set up for bone marrow sample, I would assume that we could probably sequence peripheral blood too even though there's not a lot of patients that have that many circulating plasma cells (or plasma cell leukemia).

Jenny: You said that you are reviewing approximately 11 gene types in myeloma. Now that you have samples to look at, how many genes are you finding that relate to myeloma or that you're finding that are common in myeloma?

Dr. Cole: That's a great question. That's what we had talked about just a few days ago about what are we finding. We're finding the standard or the commonly mutated genes in multiple myeloma, the KRAS and RAS and BRAF, and also we're finding the patients that have had myeloma quite a while, the p53 mutations. But also again there are several -- and again the number is a little small to be able to really make sure of what we're seeing, but there are a few leads that we have, very novel mutations that have happened. Because the studies that have been previously just a few years ago used older technologies, and so they have a couple leads on a few new mutations that may be occurring in myeloma using this platform. That's what's really exciting. The more samples that we get, the more information that we'll be able to discern. Ultimately, with the Multiple Myeloma Research Foundation sequencing our project will ultimately enroll 500 patients within the next two years, and we had just -- gosh, I think the sequencing study has only been open about six months and we are 76 patients in right now. We're still plugging away at getting a really good sample of patient numbers. Five hundred will be double that of the last sequencing project, in fact more than double of the last sequencing project, that was a large-scale sequencing project that was done in myeloma.

Jenny: Now when the patient gets a report or you get a report back from these patient samples and they have BRAF and NRAS and KRAS, is there a way of identifying the dominant mutation for that patient like this one needs to be worked on first, or maybe that doesn't matter because one of the mutations might overgrow like you talked about at the beginning of the show?

Dr. Cole: Of course, these are super good questions. That's a very good question and that was one of the things that we sort of worked on and at the very genesis of this. It comes up with an incredible amount of information and what's the most relevant information. When the sequencing report comes back, it gives you the mutations and their incidents. In a particular patient, we'll find 24 somatic point mutations but they'll be three that will be the most prevalent. Out of those three, then it will say that maybe a KRAS was present in the initial clone but something novel has come up that is like the p53, that would be more important to treat immediately. It will give you the percentage of the clonal events, and therefore you can prioritize it based on the incidence of it. If it's 45% or 50% KRAS and that would be something that you really want to address.

It will also give you a number of subclonal events that may have occurred not at the time of diagnosis but sometime later and are of a lower frequency, so it will list those too and that would be important because if sometime in the future after they have successfully received the therapy and let's say that they relapsed, then you can do another bone marrow biopsy, possibly sequence it and see if that disease has changed at all. It does prioritize for you, the report prioritizes for you which mutations occur and the priority to them and what's available for a certain mutation or not.

Jenny: Do you plan on doing repeated tests for somebody? Let's say they go and they get their initial done, are you going to do it at -- can they go ask their doctor, "Hey, just send the sample back over" in six months or a year?

Dr. Cole: Well, the ultimate plan for the sequencing study is for it to be married to a clinical trial, and that clinical trial is currently in the late phases of the development stage. I should mentioned that with the clinical trial that's associated with the molecular profiling project, in order to address one of the things that you had mentioned that as patients have myeloma longer, the disease can become more heterogeneous and they can have more and more mutations. How do you pick one mutation to target when a possibility is that one of those other clones can then become dominant? The way to avoid that problem is to treat patients earlier in their course using the molecular sequencing.

So right now, the clinical trial and drug portion is still in development but the clinical trial part will have the clinical sequencing done and then patients will be assigned to an arm of the study based on their mutational status. The patients that have a RAS or RAS mutations that are commonly found will go on a MAP kinase inhibitor. Patients that have Cyclin-D activating alterations will go on cylin-dependent kinases inhibitors. These drugs are available right now, being used in other cancers right now. Patients with p53 deletions would go on MDM2 inhibitors which are drugs to enhance the activity of p53 to overcome the deletion part of that. It's kind of that match part that we have talked about where the disease is matched to a particular experimental drug that is -- and these drugs aren't that experimental. They're being used in other cancers but now we're matching them to patient's myeloma. In order to avoid the super heterogeneity of late phase myeloma, the trial is going to be really centered on patients who have early relapses, so those patients that have relapsed myeloma after one prior therapy who have been exposed to a proteasome inhibitor and an IMiD or who are an early relapse, having relapsed disease three years after a transplant or while on maintenance or 18 months after transplant if they didn't receive maintenance therapy. Or I think one of the most important groups that we should offer these therapies to are the patients who have primary refractory myeloma, so the patients who received their initial therapy right at diagnosis and then don't respond to that initial therapy because those patients are by definition high risk because they won't respond to their initial therapy and also patients who weren’t on the trial. Because the earlier you find the myeloma, the less heterogeneous the disease is, the less clonal heterogeneity, the more targeted the targeted therapies become.

Jenny: Yes, and the better outcomes you are going to get.

Dr. Cole: And the better outcomes that we're hoping to get. There will be patients that won't have detectable lesions. They'll go on a novel non-targeted arm of the clinical trial and the patients to who are matched, they'll go on the targeted drug for a period of time and if it works, then they stay on just the targeted drug. If it doesn't work, then an additional myeloma drug will be added on in consideration of that we're trying to limit the clonal heterogeneity and clonal escape from the targeted part of the disease.

Jenny: And then when do you expect that study to open?

Dr. Cole: That's the million-dollar question. We're hoping in the middle part to late part of next year.

Jenny: Okay, so late 2017.

Dr. Cole: Yes, or mid-2017.

Jenny: So once you roll this out to myeloma specialists through the clinical trials and will that be open at multiple centers?

Dr. Cole: Yes, that would be through the Multiple Myeloma Research Consortium sites.

Jenny: Okay. And then how do you roll this type of thing out to general oncologists? Let's say you get it vetted and then you have this idea of these optimal treatments for people. How do you roll out that message to general oncologists who, in my opinion, are not -- it's very difficult for them treating several cancers to just know what's going on in this level of depth for myeloma.

Dr. Cole: Exactly. The incredible thing about this is that it's not just happening in myeloma but it's happening in other cancers. The sequencing project for myeloma, there are also other sequencing projects that are happening in other cancers. So there are two things in development. One is the actual technique of being able to sequence patients with myeloma and then second finding the drugs and the correct drugs. As we get more and more experience in sequencing myeloma, the more and more applicable it will be across the board. So doing cytogenetics for FISH was kind of the same thing about 10, 15 years ago. Doing FISH cytogenetics was not only relegated to very specific institutions and the data appeared very complex and very experimental and sort of thinking out of the box and how could the old cytogenetic method that we had used for the past 50 years, how could that be supplanted by this new FISH study? Well, now, there are commercial places that do FISH testing. Every myeloma patient now should have FISH cytogenetic testing done on their bone marrow biopsy. That technology grew unbelievably fast. I think that it took longer for me to date and marry my wife than it took for the FISH cytogenetics to go from something that was experimental and something that didn't have a lot of information, that was not universally applicable to it being through Quest Diagnostics, through Mayo Clinic. Every institution now has access to FISH testing. That will soon happen for myeloma sequencing. This the next step. This is the next level of detail that we'll be looking at myeloma.

I was worried three, four years ago, is this technology going to be expanded? Because it is more complex then FISH testing but with the Cancer Moonshot Initiative and the amount of attention and money being put into this, it really is moving unbelievably fast. In the next few years, it will probably be testing done at myeloma centers by myeloma doctors in very quick order with as fast as technology is growing, this will be universally available for myeloma patients. I would bet you, I will guarantee you that there will be a day that we'll look back in 2017 and say, gosh, remember we used to talk about translocation (4;14) and chromosome 17 deletion. We'll be talking about p53 deletions and KRAS and FGF mutational status as the highlights and the therapeutic interventions that we'll be taking in myeloma in just the next few years. People ask me, is this like going to Mars or going to the moon or going into orbit? And I would say, this is like something that is like going into a high orbit around the earth, that we're really close at being able to do this.

Jenny: Well, it's fabulous what you're doing so I congratulate you. It's amazing. Now, if somebody listening wanted to go to your center or the other open centers, even though they're not treated there to have this done (I would probably go to something like that because I've become kind of myeloma geeky) but could somebody do that? Could they just say, "Hey, I want to come to your facility and have this test done, have this report done"?

Dr. Cole: In fact, at the Multiple Myeloma Research Foundation, it has a link to the centers that have the clinical trial open or I bet that through the myeloma clinical trial searching engine --

Jenny: Yes, when we post your show with the full transcript, we'll add a link to that clinical trial so people know which centers they can join.

Dr. Cole: Perfect. It really is just sort of calling the center. At each center, there is a project manager who handles the appointments and sets up everything and even between institutions, between like Karmanos in Detroit and us in Ann Arbor, we then have patients come to either site, which one is available, to have the sequencing study done.

Jenny: Okay, terrific. Well, I have so many other questions for you. I wanted to talk about your other open clinical trials, and I wanted to talk to you about ethnic disparities but I think we might have to do that in another show. We have five minutes left. Maybe you can just briefly address it -- in the last show we did with Dr. Giralt, he said that 40% of Caucasians are getting a stem cell transplant which in my mind is far too low, but then only 25% of African Americans do. If you had to say in general how we could improve this number or how we could reach these patients, how would we go about this as a myeloma specialist, in your opinion?

Dr. Cole: The one thing that we do know about that statistic is that patients of ethnicity don't get enough second opinions. The universities and the big institutions do appear very intimidating and foreboding. Actually, knowing a lot of the myeloma doctors at the centers, the myeloma centers are actually very small little, honestly kind of cozy places inside these gigantic universities. So one way to overcome that and the reason that a lot of people of ethnicity don’t get transplant is that they don't get second opinions. And the places that they get diagnosed don't offer stem cell transplant and it's impossible to get something that you don't know about.

The one way to overcome a lot of those statistics not just the disparity in transplant but also the similar disparities in access to the newest myeloma therapies, a way to do that is to get second opinions. When people come to myeloma centers, we don't mean to take them away from their primary oncologist because they have a great relationship with their primary oncologist. It's an opportunity to really educate the patient, educate their primary oncologist and tell them what the options are because these days in multiple myeloma there are so many options and so many ways that we can design therapy for a specific person. Getting a second opinion and having a primary oncologist and a myeloma specialist working together is the best time to do that more than anything, and that education would help to overcome a lot of the disparity in care.

Jenny: That's a great first step I think because there are so many options. I know it's just tough to stay up to date on everything that's coming out of ASH or the development of myeloma. I know one of the doctors, Dr. Raje in Mass General, is working on BRAF mutations and NRAS mutations. How do you get to that level? It's just a challenge.

Before I open it up for caller questions, are there any clinical trials that you feel impressed to share?  I want to give you an opportunity to do that.

Dr. Cole: It's kind of like who's your favorite kid? To say that which one is the best? We're really fortunate to have a number of clinical trials and we've tried really hard to have those clinical trials very broad reaching, meaning that we to try to have clinical trials at every stage of where someone with myeloma would be. We will be opening a study for smoldering multiple myeloma with Dana-Farber pretty soon using one of the checkpoint inhibitors and Revlimid and dexamethasone. We have just closed a trial using daratumumab of the new antibody therapy for smoldering myeloma. For newly diagnosed myeloma, we just closed elotuzumab, Revlimid, Velcade and dexamethasone,  an Elo-RVD trial. We hope to open very soon an elo-carfilzomib-Revlimid-dexamethasone trial. For patients who are recently transplanted, we have two trials, oh, I guess three trials. One trial is for patients who immediately have measurable protein after transplant. They go on a brief therapy with one of the checkpoint inhibitors so that it improves and stimulates the immune system to destroy any residual myeloma after transplant. And then we have a trial using a checkpoint inhibitor called Atezolizumab which has different arms. One arm is for relapsed myeloma combined with Revlimid in patients who have had less than three prior therapies, a checkpoint inhibitor Atezolizumab late after transplant and then the newest arm of that trial is Atezolizumab, the checkpoint inhibitor combined with daratumumab.

We have a number of trials with checkpoint inhibitors. And then we have a trial that's one of my favorites. We have a trial that is trying to answer the question of in-patients who are minimal residual disease positive, do they benefit from either Revlimid-dexamethasone or Revlimid-ixazomib-dexamethasone? In-patients that are at least 30 days but no more than 120 post-transplant, we have a trial where we actually pay for their minimum residual disease measurement by a molecular study. If they're minimal residual disease negative, then they got a free MRD test. If they're minimal residual disease positive, they then get one year of either Revlimid-dex consolidation therapy versus Revlimid-dex-ixazomib or Ninlaro therapy. And then for patients who have had more than three prior therapies, we just closed the elotuzumab-pomalidomide-dex trial and we're going to open an elotuzumab-pomalidomide-Velcade-dexamethasone trial as well as having a study with a drug called ABBV-838 which is actually Super elotuzumab -  is an elotuzumab antibody directed towards SLAMF7, but it's supposed to have greater adherence to the SLAMF7. But the special thing is that it has an inert toxin attached to the antibody so you infuse the antibody in, it goes directly to myeloma cells like elotuzumab does, then the myeloma cell brings the antibody into the cancer cell, and then those inert toxins become toxic and kill the myeloma cell from within. So it's super targeted therapy.

I think I'm missing one of the kids, but those are the hot clinical trials that we have.

Jenny: Well, this is the difference to me between going to a myeloma specialist with so many different options. I mean you really have options for every stage of disease versus being seen by a local oncologist. I know people want to go and it's much more convenient to get your infusions locally but if there's some opportunity to participate in one of these types of studies, I just highly advocate looking into it because it could completely change the course of your care. And there are people like you who are doing such amazing things.

Dr. Cole: Well, thank you. I'm part of a huge group of folks so it's just not me. I am part of a really, really good team.

Jenny: And I think the whole community is very collaborative in myeloma even across facilities. So it's very good.  If you have a question for Dr. Cole, you can call 347-637-2631. We're overtime so let's keep our questions short. I apologize for hogging the time. Caller, go ahead with your question.

Caller: Yes, hi, Dr. Cole. Thank you for taking my call and for being here today. I just wanted to know if myeloma changes over time like if it mutates, is there any way of knowing if certain treatments cause certain changes?

Dr. Cole: That's a very good question and that's kind of difficult. That's a super good question. I know people who used to be on melphalan and prednisone can bring about certain mutations in myeloma at later stages. But I think because of the heterogeneity of myeloma, it's really difficult in all the new therapies are coming out. That's a fantastic question and it's a super difficult question because the therapies are changing every three months. It seems that is something new to offer, and definitely the antibody therapies have added a very different selective bias on which myeloma cells would continue. There are some ancient answers that we have to that question that date back to therapies that we don't use much anymore, and I think that that would be something that we're looking at now. As we do the sequencing study today, it will be on patients retreated with modern therapy and with the modern therapy we may see the different patterns of evolution with myeloma than what we saw in the past. I hope that answers the question.

Caller: Yes, thank you.

Jenny: Okay, thanks for your question. Our next caller, go ahead with your question.

Caller: I have a question. How has the sequencing study that you describe differ from the foundation one report?

Dr. Cole: The great thing is that they're all quite similar. That is part of the collaborative process that has happened is that a lot of the genes that are explored on the platform that's here are very similar to the genes that are on other sequencing platforms through other projects, and it's because really people have shared information that a lot of this information and a lot of the sequencing information and part of the Personalized Medicine Initiative is to have the information of these projects on the public domain. As they are on the public domain, then as things are done, as there are projects done through other sequencing projects in Alaska, we can then apply those to the sequencing project here. As we find things on the sequencing project here, they can be applied to other platforms across the country and across the world. There are some peculiar and specific things that are about the platform that may be different from other projects, but the good thing is that there are major databases that people go to that house a lot of the information about this is a sequence or a mutation that we found. You may want to include that into your sequencing assay. And that actually has happened here that the MI-ONCOSEQ, the platform that used to look for 1,500 genes is now expanded to 1,690 something, and it continues to expand as other places and here add to the knowledge base. Hopefully, there wouldn't be that much difference as everyone continues to collaborate with these projects.

Caller: Thank you.

Jenny: Okay, great. Thank you so much. This will be our last question, go ahead with your question.

Caller: Hi, Dr. Cole. I'm a smoldering myeloma patient, and I'd like to adopt your super elo kid. That just sounds such an exciting drug what you just described.

Dr. Cole: Yes, it is an exciting drug and actually it has the idea of the Trojan horse, the antibodies with an inert toxin attached to it which then becomes active inside the cancer cell is actually used in other cancers with other specific antibodies for their cancer.

Caller: It just sounds so exciting.

Dr. Cole: Yeah. In fact, for some of the other cancers that haven't had a lot of changes in what they used to treat with, it has become revolutionary. Brentuximab is kind of a similar drug that's used for a T cell lymphomas and Hodgkin's lymphomas. It was immediately approved by the FDA and brought to the forefront because some of those cancers didn't have the extensive treatment options or the number two options that are available for myeloma. It's a proven concept and we just needed the right Trojan horse to take that toxin into the plasma. Yes, it's an exciting drug.

Caller: That's terrific. I actually administer a Facebook group for smoldering myeloma patients. We have about 400 members and we use it really to share information about clinical trials and just info about smoldering myeloma in general just to become better informed. We actually highlight the recommendation to seek consult with true myeloma specialists while we're still smoldering patients think it's really important to kind of get the team in order before you have to kind of ring the myeloma bell. I'd say about a half of our members have taken this step, and we all want to do our part to add to the knowledge base. Many of us are enrolled in the Dana-Farber P-Crowd study. I myself enrolled over a year ago and I've donated both bone marrow biopsy samples as well as my serum samples which we procure at my regularly scheduled quarterly labs. That's exciting for patients in the smoldering category who may not be eligible for these early treatment clinical trials to still have something to engage in and feel like we're making a difference.

I realize the pathway what you explained about this sequencing study is to find actionable genes to actually personalize treatment, but is there a consideration to do it in patients who have earlier disease stages such as smoldering myeloma patients? I realize that you were limited by that 30% enrichment criteria to actually be able to sequence those plasma cells, but is there a goal to bring it even further down into the earlier stages?

Dr. Cole: I would say that undoubtedly that we'd like to bring it further and there are two reasons. One is that the area of smoldering myeloma has as really taken off. It used to be sort of, oh, gosh, this is just another type of inert plasma cell disorder. Now, it's really being aggressively pursued especially with the Spanish data showing that there may be benefits for early treatment. It's an area of need and also it would be very important to do molecular studies. Those are going on right now to see who with smoldering myeloma really needs to be treated because there are some patients that with smoldering myeloma that we know whose disease biologically is really not that much different from MGUS and really would not progress. And then there are those who have smoldering myeloma who really do have true out and out multiple myeloma and because the disease has different kinetics and characteristics. It's really finding those kinetics and characteristics to be able to find who should we treat and who shouldn't we treat. And with every one of these studies or a lot of the studies that are done, therapeutic studies on smoldering myeloma, there are also correlate studies looking to see what made the patients who received these therapies really not change at all and what are the characteristics they had that people progress which would give us some insight into what are the drivers of smoldering myeloma.

Caller: How close are you to actually finding that information and finding and pinpointing that data? Are you guys near to that or are we still looking at years of being in collection?

Dr. Cole: That's the trick. The good thing about myeloma today is that people live longer and in order to get the data about how things change, things change on a slower scale. The technology that's available, we have to wait about five to ten years before we actually know what happens to smoldering myeloma. Some of the early things, we can find the some of the earlier drivers, but the one that you really want to know is will I have smoldering myeloma, discover when I'm 40 and I'll still have it when I'm 80?

Caller: That would be a really nice scenario.

Dr. Cole: But the trick is that you have to wait those years in order to find out the characteristics that would have the disease behave that that slow. That's still in evolution.

Jenny: Well, Dr. Cole, I know we've kept you overtime.

Caller: Thank you.

Dr. Cole: Oh, thank you.

Jenny: Thanks for your question, Dana. I just wanted to thank you for participating on the show. What you're working on, we're just thrilled that you're working on this and we're thrilled that your collaboration with MMRC and what you're doing and just keep doing it.

Dr. Cole: You keep doing what you're doing. The Myeloma Crowd is great. I have been singing your praises across the country over the past few days that I've been traveling a lot. So keep doing what you're doing.

Jenny: Well, thank you very much. It's nice to be able to provide information to patients that can really make a difference in their outcomes. What you're doing is really going to provide dramatic differences in people's outcomes. Thanks for all you're doing. We're thrilled that you joined us on the show today.

Dr. Cole: Oh, thank you. Thanks. I'll come back anytime.

Jenny: Okay, thank you so much. And thank you to our listeners for listening to another episode of Myeloma Crowd Radio. Join us for future shows to learn more about the latest in myeloma research and what it means for you.