Dr. Brian Van Ness joins the HealthTree for Multiple Myeloma podcast to share the opportunities and challenges of researchers who work with clinicians to understand the core factors of multiple myeloma. The show dives into how this basic research is helping us better understand the genetics of the disease, how technology is making great strides, and how talented individuals like this are making major contributions to the field.

Jenny: Welcome to today's episode of the Health Tree Podcast for Multiple Myeloma, a show that connects patients with myeloma researchers. I'm your host, Jenny Ahlstrom. This year has absolutely flown by and I don't do typically a lot of bragging, but wanted to take a minute to share our progress. It's been an incredible year for Health Tree and I'm proud to share that the Health Tree Myeloma site has been visited by over 560,000 users.

This podcast alone has reached over 32,000 people just this year. To date, we've completed over 160 research projects involving over 150 minimum researchers with 72,000 patient participants. Thanks to those of you who have joined the Health Tree Cure Hub Registry. Our goal by the end of 2025 is to complete an additional 100 research projects using our Health Tree Cure Hub Registry data. And we're almost three quarters of the way to our million dollar goal by year end and we have a $200,000 match. We welcome your support for this great work we are doing - and yet we can do more.

So two weeks ago at the American Society of Hematology meeting in San Diego, we made a major announcement to myeloma doctors that we'll be providing free myeloma-specific HealthTree Cure Hub registries to 21 centers who have joined our beta program. This will provide myeloma researchers with more complete and more accurate data than they have access to today and will also have access to the additional anonymous data we already have in the HealthTree Cure Hub Registry. .

Our goal is to provide free data to the research community so that thousands of simultaneous research projects can be performed  You can help contribute to your own cure by joining Health Tree Cure Hub. And you can find that link by going to our website here. 

Now onto our show. This show began to showcase the research efforts of many myeloma specialists running clinical trials, because frankly, I didn't understand clinical trials as a treatment option and how and why I should join. And we've come a long way. Over the last 12 years, we've dug deep into research and we've also learned about how the entire research community is advancing the field in a variety of ways. We have on today's show, one of my very favorite people and myeloma researcher, Dr. Brian Van Ness, Dr. Van Ness, welcome to the program.

Dr. Brian Van Ness: Thank you, good to be here.

Jenny: Well, let me give an introduction for you before we get started. Brian Van Ness is a PhD and Professor in the Department of Genetics, Cell Biology and Development at the University of Minnesota Cancer Center. He served as the head of the department for eight years and stepped down to serve as co-director of the Institute of Human Genetics. After receiving a Bachelor's degree in Biology and a Master's degree in Chemistry from the Indiana University of Pennsylvania in Indiana, Dr. Van Ness obtained his PhD in biochemistry from the University of Minnesota. He conducted his postdoctoral work in molecular immunology with the Institute for Cancer Research in Fox Chase, Pennsylvania. The research in the Van Ness lab is directed at defining genetic deregulation that contributes to lymphoid malignancies, particularly multiple myeloma. Myeloma results from plasma cell expansion in the bone marrow and is hard to treat.

The difficulty comes in part from the variability in genetic and signaling pathways that are impacted in the bone marrow microenvironment. His lab has been developing single cell analysis to identify subpopulations within tumors that may resist therapy and contribute to relapse. The Van Ness lab is also working on novel therapeutic approaches involving epigenetic modulation to promote therapeutic response with an ultimate goal to contribute to genetic characterization of patients that will direct individualized therapy.

So Dr. Van Ness, we're just thrilled to have you on the program. And this gives us a behind the scenes look at tremendous work that you've been doing for decades. And that's so critical to the advancement of myeloma cures. While patients are really familiar with myeloma docs at academic centers who also perform research, there are many individuals like you that are driving, behind the scenes, deep research.

Can you share the difference between the two types of research efforts?

Dr. Brian Van Ness: We could talk about the basic research that I do as a PhD. I'm not a clinician, so I'm interested in the biologic mechanisms. I'm interested in the characterization of those cells, identifying characteristics that distinguish a myeloma cell from a normal cell or for that matter distinguish one myeloma from another. And as you pointed out, one of the things that we were very interested in was the fact that myeloma is not a single disease in the sense that if you look at one myeloma patient, you're looking at one myeloma patient. There are many variables that contribute to the progression of myeloma that differ among different patients.

Imagine if I want to go from Minneapolis to Chicago. There are a lot of routes that will get me there. Same with cancer in general. There are a lot of routes in which signaling pathways will be deregulated that end up developing a cancer. that because there are many ways in which the cell can become cancerous, that means that there is differences in how it progresses and certainly differences in how it responds to different types of therapy. And those are the things we're interested in from a basic standpoint. Now, that doesn't mean we do this in isolation because the people who are doing the clinical work, the MDs, the physicians who are seeing patients, enrolling them on clinical trials, they are themselves developing approaches of new therapies to treat the patients, following those patients, recording the information of those patients, which becomes invaluable to us in the basic research because they have samples from those patients that we can study and they have outcomes that we can study. And we can ask questions about why did these patients respond to a particular therapy and these patients didn't respond. And the way we do that is we look at signaling pathways, we look at the proteins that are being produced, we look at the genetics of each of those cells and try to identify unique characteristics that would give us better insight to help the clinician understand better why some patients are responding and others are not.

Jenny: That's so critical and that's why some patients get confused. They see people in the clinic that aren't doing very well at all. And then they see others who are living for decades and they can't figure out - why am I not acting like this other patient? And that's the reason, what you're saying is genetically it's so different.

Dr. Brian Van Ness: I think that's been one of the hallmarks of why this disease for many years was difficult to treat, was because one size fits all did not fit in the treatment of myeloma. Having said that, there were newer therapies that started to get developed that were doing better and better jobs. And maybe as we'll talk about a little bit later, research has identified unique markers in myeloma cells that gives us a lot more insight as to where the vulnerabilities are that can be treated. And that's been kind of an exciting area.

Jenny: I interviewed Jim Allison one time about checkpoint inhibitors and asked him how do you cure a disease? And he just said, you have to understand the biology of the disease. So if you don't understand it at that core level, that's what you're saying is so critical. what you're saying is so obvious now because we have targets for BCMA and we have targets for GPRC5D and all these new targets that we didn't even know about when I was diagnosed.

Dr. Brian Van Ness: You know, there's one other thing that I think is important and that is I was leading an effort at NIH which was several different group projects and they were all studying different cancers. So people were studying lung cancer and people were studying prostate cancer and people were studying leukemias. We were studying myeloma, our group with the Mayo Clinic was part of that group. And what was really interesting is that you actually start finding some common themes as you start even looking at other cancers, some of those areas of deregulation cross the boundaries. And so I learned a lot more than I ever thought I would in hearing what people were doing in lung cancer and colon cancer, thinking, well, that's a very different cancer. Well, you know, they have one thing in common. They are cancer cells and they progress and they move to places they shouldn't go and they forget how to die and they don't always respond to therapy. So there were a lot of common themes that now the cancer biology community is cross talking a lot more with, think, a lot more benefit.

Jenny: That's fantastic to hear that they're doing that. I think that's valuable for everybody. You talked a little bit about the difference between basic research and translational research. And when I first heard that term, I didn't really know what translational research was. But can you just explain the difference between those two things? You did a little bit in introducing what you're doing.

Dr. Brian Van Ness: They're not mutually exclusive by any means. And that is, you know, the basic research involves understanding mechanisms of how a cell works. Mechanisms of when a cell works in the wrong way. Understanding the biologic characteristics, identifying new approaches, new tools to study these cells. And then, I can't do this, even though I don't see patients. I can't do what I do without having good conversations with clinicians who are interested in the translational research. And simply put, it's applying what we learn from the basic research to understanding the disease better and understanding which therapeutic approaches might work best.

Jenny: When you see a disease like multiple myeloma that they say is very heterogeneous, which means just it's very different in every different patient, like you said at the beginning, you saw a single myeloma patient. How do you go about dissecting all of that and separating it into different pathways? it's so complicated biologically, it seems. How do you prioritize what you're going to study?

Dr. Brian Van Ness: You know, that question is in part dependent on the paradigm of the blind men defining an elephant. And it depends on where you're standing. So if you feel the trunk, the elephant is a trunk. you feel the tail, the elephant is a tail or a foot. And I must admit that I have my own biases in what I look at. Well, why is that? Well, this, has to do with my training.
I was trained as a molecular immunologist. I was trained to look at DNA and look at genetics. And so because my expertise is in genetics, that's what I think is the important component. That's my own bias because of my expertise. But it's certainly very clear that one way to look at this heterogeneity is to look at the genetics, that is, look at the DNA of every individual myeloma, identify the sequence differences of that DNA and how that impacts function.
So I think one of the high priority areas is to look at the DNA, how it's expressed in a myeloma cell, and how that alters that cell in its progression and response. Now having said that, I talk a lot to people as well who are more interested in proteins.

So they're looking at the proteins that are in a myeloma cell. They're looking at the cell surfaces of myeloma cells. Well, those proteins are encoded by the DNA, so we have something in common. So I'm very interested in identifying the genetic differences, but then functionally, I have to talk to the people who are doing the proteins and saying, well, how does that affect the protein function? And of course, again, now you talk to the clinicians and say, if I can identify genetic differences, if I can identify protein differences, if I can identify unique characteristics on the surface of the cell, how does that affect the therapeutic response of the patients you're seeing? So that's where we all have to be sitting together and working together to get a complete picture of myeloma and how it responds.

Jenny: it sounds like it's very collaborative work because you're not only working with the doctors who are treating, you're working with your other colleagues who are doing similar biological work. And you're probably working with people who are investigating the bone marrow microenvironment or other aspects of the immune system. And I wrote down, I have to ask you a lot of questions about the immunology too. But since you started in myeloma, have you discovered additional biological or genetic targets?

Dr. Brian Van Ness: I'm not sure I would say we identified additional targets. What we identified were groups of genes whose expression better defined whether a person was going to respond or not. So what we would do is we would gather patient samples. And we know that some of those patients would respond to a particular therapy and others didn't. We then took those samples that responded and looked at their DNA and the DNA sequence, which is the code. And then we looked at the code of the patients that didn't respond and we compared them. And we said, where are their differences? And I can tell you there's an enormous amount of noise because genetically we're all different to begin with.

Jenny : I can imagine.

Dr. Brian Van Ness: So now you're saying, how do I find the differences that are meaningful in disease, not just the difference between me and you, which there are a lot of those genetic differences too. And the way you go about that is you reduce the noise by increasing the sample number. So I could look at three patients that responded and three patients that didn't respond, and I'll guarantee you, I'm not going to find much because there's just not enough sample differences there that would be myeloma specific and the differences between the individuals would just overpower any differences I would see relative to the myeloma.

So the best way to do it is to see 300 patients that respond when 300 patients that don't respond. The noise starts settling down and now those differences start arising.

And that was a lot of what we were doing in the last few years was identifying what we refer to as genetic signatures that define whether a person's going to respond to a particular therapy or not. And of course, the usefulness to clinicians is imagine if you could get a genetic signature before you treat them. Now you get a genetic signature and you say, well, let's not use this therapy because based on research and it's not just ours, there are many labs that do that, but based on this genetic signature, we've got a shelf full of compounds to choose from. And if we do this often enough and compare them with different therapeutic approaches, we can tailor make the best therapy based on a genetic signature. And that was kind of the approach we were taking.

Jenny: That would be so amazing. That's the dream for a patient too, to show up in the clinic and say, I'm younger and I have these genetic features and give me the best optimal therapy. I don't want to have to blow through four different lines of therapy before something starts working. And I don't want to take drug if I know it's not going to be working. So it's so necessary for the patient too.

Dr. Brian Van Ness: It is, and I did, I have to admit, I got myself in trouble not that long ago, was a few years ago. I was talking to a patient support group and I was talking about the value of all of these genetic signatures. And the reason I got in trouble is because people came up to me and said, when can do it for me now? And I realized that to be honest with you, I oversold the timeline. And that takes a lot of data collection, a lot of data analysis, and then a lot of data verification. So if I look at 300 patients respond 300 that don't and identify a genetic signature, I still have to test it on another set of patients to see how accurate it is. And that takes time.

Now, interestingly enough, the best outcome to measure obviously is survival for patients. But that's becoming a problem. And that's because it's a good problem because patients are living longer and it's getting to the point where if I'm going to use survival as my endpoint, I'm now having to wait seven, eight, nine, ten years to get a valid endpoint. And that means it takes way too long.

So what I'm seeing in the field now is people are now starting to look at response as an endpoint. And that's much quicker. You get a much quicker data set if you ask, how do I categorize people based on their genetics, simply based on whether they responded to a therapy or they didn't? You get your answers a lot quicker. And I'm seeing a lot more of that in the clinical trials. Response rates and duration of response is becoming a really key data set.

Jenny: Depth of response and like, I know MRD negativity has been proposed to the FDA. I think they did an FDA meeting on that and they had 12 counselors recommend MRD as a new clinical trial endpoint. I don't think the FDA has voted on that yet, but that would be amazing.

Dr. Brian Van Ness: Just so your patients are aware, MRD is the minimal residual disease. And that in itself has evolved because 10 years ago, we would look at the remaining myeloma cells. So a patient would be treated, they would respond and we'd ask, well, how many myeloma cells are still there? And the methods that people were using would allow them to see 1%.

In other words, they start with certain percentage of myeloma cells and now you can see instead of there being 30 % of the marrow is myeloma, it's now down to about 1%. So that's a good response. But 1% is still 1%. And that's not very sensitive. Now with the molecular techniques, the ability to genetically identify the myeloma cells, we're now able to see remaining myeloma cells down at the level of .00001 percent. That, you know, now minimal residual disease (MRD) is a much more refined definition. And that is if I can get that disease down to .00001 percent or lower, that's much more effective in defining a successful response than the old way of doing it 10 years ago. And that's in part because the technologies and the genetic tools have become much, much more sensitive.

Jenny: It's incredible the innovation that's happened and it's amazing to be able to take advantage of it. I have a few questions for you. So if you need data and you need samples, where do you go to get the data and the samples?

Dr. Brian Van Ness: In my history is primarily I would go to the Mayo Clinic because that's where my colleagues were. I'm in Minnesota. I developed some very good relationships with the Mayo Clinic. Obviously, they see lots of patients. So a lot of the data that I would receive, I would see from the Mayo Clinic. Having said that, it's still a matter of numbers and being able to find enough numbers of samples to work with. And that's where I think HealthTree, the organization that you're running and assembling thousands and thousands of samples that are not dependent on one institution is going to, I think, significantly advance the field because we're going to have access to a lot more data. And I'm encouraged by the fact that some of the data sets that people would assemble into these groups would often have things like the patients’ name, age, diagnosis, and one other feature.

Whereas what you're collecting now is the entire clinical data record. And so now we can look at depth of response. We can look at proteins. We can look at all kinds of parameters that we didn't have available in the past when we look at the kind of things that Health Tree is doing in assembling that data. And I know you didn't ask me to pitch HealthTree, I'm doing it totally voluntarily that this can be an incredibly good resource.

Jenny: Well, thank you.

Well, we're actually doing a project right now with an investigator on that. And they ran out of samples that they could collect from their own facility. So now we are going to all patients and saying, hey, if you want to donate some of your original bone marrow slides to this investigator, just sign this consent. then our patient navigation team reaches out to the hospital. You get a block of slides when you’re first diagnosed (about 200 slides) and we take five of those and send them to the investigator. And then we're asking patients to link their medical record too. I would like to hear about your perspective with computer analytics and just advancements in technology to help you be able to assess that. But their goal is to use computerized technology to do some of those analytics and see what are the different genetic features that we're seeing and then, then link that to the outcome data. So we're trying to do that right now for a particular project that we're working on. It's one of our most exciting projects, I think.

Dr. Brian Van Ness: So I have to ask, you know, part of my getting samples from the Mayo Clinic or from other institutions, I was often hit a roadblock of their IRB and their need to maintain patient privacy.And you seem to have overcome that in the sense that there's a willingness now to get beyond the idea that privacy is a roadblock. Patients deserve privacy. There's no question about it. But you can make data accessible without names and addresses. And they're very useful.

Jenny: Yes we can. This is the differentiator in what we've done. We've gone directly to patients because as a patient, I want a faster cure for myself. If I could give you all my data, Dr. Van Ness, I would do it in a second, in a heartbeat, because I know you're studying the deep biology of my disease and I want you to be successful in finding a cure for me. So we go to patients and just say that and patients can do anything they want with their data. They can sign a consent and request slides to be sent over to a different facility or to you. That's the beauty of it. And the institutions are really blocked by HIPAA and they can't share the patient data because it's a big privacy concern. But if I know that my information is going to you and I know what you're using it for, I am so willing to share everything I have with you because I know you're brilliant and you're going to come up with something based on what I give you.

So that's the concept behind the HealthTree methodology and why we decided to go directly to patients. Because what I saw was everybody was going to the hospitals trying to say, well, we need to find these collaborations or these hospital to hospital collaborations and create a consortium and all that. You have so much regulatory and so many institutional barriers that bog you down. We just wanted to remove all that and just say, it's the patient's data. They own it. And even in our platform, they own it. If they want us to delete it, we delete it immediately. It's gone. We don't have a history of it.

Dr. Brian Van Ness: I can't compliment you enough on getting through that. One of the worst cases I had was I worked for many years with the Eastern Cooperative Oncology Group, which is a large multi-institutional cancer group. And there's a myeloma group in there. And I was interested in accessing some data. And I'll make a very long story short. By the time I requested the data and went through all the regulatory forms and the processes, it took me two years to get the data released from them. And I was very frustrated with that. But I think institutions now cooperating with you and HealthTree, I think that barrier is getting reduced significantly.

Jenny: The barriers to progress are crazy. We've had over 700 patients say yes, they want to donate their samples and we've had hundreds of samples already processed with the genetic testing. So come to us, we would love to help you with any of your projects. You talked a little bit about your background and experience as a researcher. there anything else you want to add to what we've already shared and then we can continue with various questions?

Dr. Brian Van Ness: That’s terrific. You know, this is sort of the story of basic research and that is you're never quite sure where life will take you. I started off in biochemistry, so I mean was a biochemist, but I started getting interested in genetics and immunology, so I did my postdoctoral training in molecular immunology and I was interested in how antibody genes get expressed - what regulates the immune system to produce antibodies. And various times in my career, I have to say when I moved to Minnesota and I was studying immunology and I was studying antibody genes, and the one place that you can study antibody genes that you get a big supply of cells that do that are plasma cells that make lots of antibodies. Where do you get plasma cells? You get it from myeloma. So I was recruiting myeloma samples not to study myeloma, but to study antibody genes. And then I got a visit from one of the chairs of the Eastern Cooperative Oncology Group, Marty Oaken. And Marty Oaken sat in my office and he said, you're doing all this immunology. Why don't you study the disease? And it was one of those head slap moments of, you got a point.

There might be something that really would be kind of nice and fun to be looking at. And so I think Marty started me on a completely new track that I spent the next 25, 30 years working in myeloma.

Jenny: It makes sense. Well, it's incredible. We're so grateful that you're in myeloma. I know you specifically have great connections to myeloma patients themselves. I know you say you work with clinicians who are working with myeloma patients. But I think in particular, you're one of the very few that I've seen really engage with patients and know how to talk to patients in a understandable way, even though you're so brilliant with the biology. What motivated you to do that and how do you remain connected to patients?

Dr. Brian Van Ness: That is an interesting story. I had been working in myeloma for probably about five or six years and I was at a conference in France and I was waiting for a train and a gentleman came over to me and started chatting about at that time the use of a drug called alpha interferon and it was kind of an effective drug but it had terrible side effects and I said something to him about, it's a useful drug, but it has terrible side effects. And my understanding was that patients often relapse, and when they do, they relapse quicker than with other therapies. And he looked at me and I didn't know this until he said, “You know, I am a patient.”  And it was one of those moments. It was literally a head slap moment - this is the first time I've ever talked to a patient with myeloma. And I've been working in this field for five or six years. And it just didn't seem right. And so when I came back home to Minneapolis, I started connecting with patient support groups. And I was invited to give a talk to one of the patient support groups. And word got around and I started giving talks to patient support groups in Florida and in Tennessee and California and Texas.

And I can tell you, it really does feed the reason we're doing this. Because talk about an interested and captive audience. If there's an audience that has an interest in what you're doing, it's the people sitting there that have myeloma who are interested in what is new that's happening in myeloma and somebody that can talk to them at the level that they understand was part of the challenge and I enjoyed doing that.

And as I said, sometimes I oversold my enthusiasm. Again, I once had somebody came up to me afterwards, this was a health professional. He said, I really enjoyed your talk, but you're way too enthusiastic. And I looked at him oddly and I said, what do mean I'm too enthusiastic? And he actually gave me pause to think and he said, you're overselling what we can do right now.

And I, you know, you're right. I become so enthusiastic about the possibilities that I oftentimes, yeah, I maybe overshoot the potential to reality, but I still believe there's real potential there.

So I became more engaged with patient support groups and, one connection led to another, led to another that I would get these invites and then I also got invites to talk to patient support groups through the Myeloma Research Foundation as well as the International Myeloma Foundation run a lot of these forums and so I would participate in a lot of those forums and of course my job to the patients was to explain genetics.

And you know we had to do science class but we had to do it in a way that would keep their interest and keep their understanding.

Jenny: Well, I met you over decade ago at one of Pat Killingsworth’s events. And I just think you're spectacular. So I'm so impressed with you all the time. You talked a little bit about a few challenges that you see in accessing data. Are there other big challenges you face as a researcher?

Dr. Brian Van Ness: Well, there's no question funding is one of those big challenges. We are in a competitive environment scientifically. And so we have to make a case for the fact that our science is worth supporting to go to the National Institutes of Health or to the foundations, to pharmacy. And I can say that that challenge can be frustrating because you think you have a great idea and you go into what's called a study section, a group of people who evaluate it, and they may well say, you've got a great idea, but we've got 34 people ahead of you who have great ideas and they're gonna get funded and you're not.

And so you're constantly in that battle. One of the ways I approached that was although I would get support from the National Institutes of Health, I also recognized that pharma was developing new drugs, so I often would go to pharma companies at these national conferences and sit down with them and say, “Okay, you've got a new drug. What if we could identify genetic signatures that would identify whether your drug is going to work in all patients or a subset of patients and get some funding from them to do some of those studies?”

So I've had, research support from some pharmaceutical companies as well.

So even though it's a challenge, if you believe in what you're doing and your career is dependent on moving forward, you do what you got to do to find the funding to keep the laboratory operating.

Jenny: Absolutely. Money is always an issue. And you see that evolve in myeloma too, where you see like a venetoclax go after a particular genetic target. Or I even heard some information that was presented at that American Society of Hematology meeting about maybe isatuximab being better for 1q gain patients. And all those nuances are critical to understand going back to your first point, just to be able to personalize care for treatment.

Dr. Brian Van Ness: In the early days of genetics, a lot of what was being done was identifying genetic markers that were associated with high risk or low risk disease. And it always bothered me. And it bothered me because it failed to ask one really important question. You've just put a person into a category of high risk or low risk disease. What are you going to do about it? I mean, that became a really important question. It seemed to me very unsatisfying to simply categorize a group of patients based on genetic markers, but then not really be able to say, well, I've got a solution to this. I think that's gotten a lot better. And as you point out, now we're identifying genetic markers that people are being treated based on some of those genetic markers. So I think things are moving in the right direction in that regard.

Jenny: Can I ask you about that? Because when I was first getting started with starting HealthTree and building HealthTree, there was this huge personalized medicine theme, really, that if we can identify the right genetic markers, then we can find a specific drug for the right target. And it just seems like if patients have hundreds of mutations or even tens of mutations, just logistically, that's really hard to do to find five different drugs that you put together in a single combination for a particular type of patient. How have you seen that whole personalized medicine approach evolve?

Dr. Brian Van Ness: I think there's been a little bit of a reversal in the direction that we take. For example, in days when people were being treated with melphalan, or for that matter, even bortezomib, it was a great drug, and then you would identify which people respond and don't respond, and then you'd go look for markers that would correlate with the response or the lack of response. What we're seeing now is identifying markers first and then developing therapies against those particular markers. As you point out, BCMA - BCMA is a marker on myeloma cells that people were well aware of, but now people said, well, it's unique to the myeloma cells sufficiently that if I can develop a therapeutic to that marker, then not only might it be effective in myelomas that express that marker, but it won't have as bad side effects on all those cells that don't have that marker. So what we're developing now is more specificity.

Melphalan was a chemotherapeutic agent and was very, very toxic. And the good thing was it was toxic to myeloma cells, but it also had some pretty nasty side effects. Now, as we get to some of the more directed therapies, the specificity gives us a better target for a particular myeloma and it's specific to the myeloma and doesn't give you quite as bad side effects in many cases.

Jenny: Now I want to ask you questions about combining your immunology work with your genetics work because you've seen immunology just explode and sometimes they're saying it doesn't matter what genetics you have, some of these immunological approaches can work for pretty much everyone. So what have you seen in terms of the development of immunology generally? How has your work in both of those fields advanced in myeloma care?

Dr. Brian Van Ness: I think the immunotherapeutic approach in the last three or four years has been just a boom. I think, it has been exciting to see. And it's funny because even 20 years ago, people were thinking there's gotta be a way to rev up a person's immune system. If we can rev up the immune system to attack a bacterial that's foreign to that individual, then we ought to be able to develop an immunotherapy that takes care of those foreign cells, now the myeloma cells, in a similar way. And the immunology has been refined enough now that two things have happened. One is the ability to genetically engineer the immune system. So now we can take cells out of an individual, genetically engineer them so that they will attack that specific marker and then give it back to the individual. So I think that ability to use genetics to engineer new therapeutic immune approaches has now brought together the genetic characteristics of a cell, the genetic technologies, the ability of genetic technologies to take things out of an individual and in a laboratory, genetically alter it and modify it, such that it is now effective as a therapeutic agent. I think that's been really exciting. Now having said that, you'll notice that, you know, there are not a lot of clinical trials that only use immunotherapy. It's still a combination. So I think there's still, there's still a need for the chemotherapeutic agents, but I think in combination with the immunology, I think it's becoming more effective.

Now the side effects were a little bit disconcerting in the beginning because the good news was you could rev up the immune system to attack the myeloma. The bad news was you revved up the immune system. And so now you've got this immune system that was somewhat hyperactive in an individual and that had some toxic side effects in which the good news was the immune system was revved up. The bad news is, you don't always want an immune system that's totally revved up and is causing problems. But again, they've gotten better at designing appropriate therapies for that. know, CAR T cells in myeloma kind of hit a roadblock for a while. And they've gotten better at it. They've gotten better at genetically engineering and being more effective.

Jenny: And you see new ones coming out too that don't have some of these side effects. It's pretty exciting.

Dr. Brian Van Ness: You see these bispecific antibodies have an antibody that actually has two branches and the antibody has two recognition sites on it. Now the typical antibodies, those two recognition sites are the same. That's your normal antibody. It has two recognition sites. But what they've been able to do is genetically engineer it, so that it recognizes the target on one of its sites and it recognizes an immune cell on the other side to recruit it to attack the myeloma. So these bispecific antibodies are now being engineered to both recognize the myeloma and recruit the immune system to kill that myeloma. That's really exciting.

Jenny: It's incredible and you see trispecifics coming out and you see vaccines coming. I don't know. It's really, really exciting. Well, we talked about the biggest challenges that you face as a researcher. Some are data samples and things like that. What are the biggest opportunities that you're seeing as a researcher?

Dr. Brian Van Ness: I think probably the biggest opportunity is the technology development. think technology has, I could never have predicted that we could look at the entire DNA sequence of an individual 20 years ago, took about 20 years, and three billion dollars worth of funding to get a genome.

Dr. Brian Van Ness: Because that is the definition of an individual, is their entire genome and that code of the entire genome. And that is comprised of three billion of these bases, these molecules that represent the code. And in order to sequence those three billion, the technology 20 years ago was such that it took years to get one person's genome done. Now? Now it can be done in an afternoon.

Jenny: Wow, it’s incredible.

Dr. Brian Van Ness: It's the technology has just gone crazy in the speed and sensitivity and the other part that's really important that the platforms that are doing it are becoming more accurate. So the ability to have high throughput, highly accurate technologies, I think has created enormous opportunities. And again, the first genome, the estimated cost was about $3 billion in all the funding.

Jenny: Shocking.

Dr. Brian Van Ness: Now you can do it for $500. I mean, it's incredible. I mean, it's a genetic test, but it's basically the cost of a clinical test. Now, there is a challenge with that opportunity. Let’s go one step further. Let's say I have 300 patients that respond and 300 patients that don't respond. Now I have 300 times 3 billion base pairs to look at and try to find out where the similarities and differences are. And that's where the computer technology has also just absolutely gone bonkers in the ability to look at these complex data sets. And as much as we are afraid of the capacity of artificial intelligence, AI is having a tremendous impact in the ability to ask questions that we never thought we would even ask in the past. In fact, one of the things that AI often can do for us, it can actually give us the questions. You you can go to an AI program and say, what are the good questions that I could use? It goes through all of what everybody has done in all of the other cancers and said, well, you might want to try this in your subgroup analysis. And there's a computer program that does that. This is where I think the other part of the collaborative efforts and my role as a basic researcher, which was, think, really key. A person would come into my lab and we would talk about a project. And I'd say, you know, I have a certain expertise. In fact, my expertise is little bit dated. I was trained years and years and years ago. I keep up to date. But the fact of the matter is if our laboratory sits in a silo and is limited by my expertise, we go nowhere. What we need to do is we need to find good collaborative efforts with people that have expertise we don't have. And it even got to the point where I had a postdoc who had incredible expertise in computational work. I don't have anywhere near that expertise, but he came into the lab and got all excited about seeing these data sets and developed these genetic signature programs that I would never have been able to develop. But that's the fun of bringing people in the laboratory that have different areas of expertise. You collaborate with them and you collaborate with people outside that have different areas of expertise, particularly the clinicians.

Jenny: it takes a whole community to do the data work and the basic science and the integration with the patient.

Dr. Brian Van Ness: It really does.

Jenny: So you asked, what responsibilities should a patient have in their own treatment? I want to hear what you'd like to say about that.

Dr. Brian Van Ness: You know, we talk about personalized medicine and the idea is that you go to a physician and you say, I want you to treat me as an individual. Well, every physician will say, of course I'm treating you as an individual. But you know, the term individualized medicine or personalized medicine means you treat me as an individual and you understand the characteristics. What that also means is that the person has to be an advocate for that personalized treatment.

They need to go to a physician and say, what are my options? And what are the benefits or the problems with those options? And again, when I talked to the myeloma patient support groups, I was amazed at how well educated they were in their disease characteristics of what was going on in the clinics and the research.

So my advice to the people who are going through treatment is become educated. There is so much information on the internet and that to look at. And find a patient support group because those people will talk with each other about their commonalities and about, you know, I'm doing this new treatment at the Mayo Clinic and the person says, well, I never heard of that. And they talk about it. So I think the idea of personalized medicine also means personalized responsibility of the patient to become educated about what is going on in their treatment.

Jenny: Yeah, I wholeheartedly agree. And we say that all the time. We have so many resources. We have patient navigators. We have a university. We have webinars. We have social media groups. I there's so many ways that you can get involved in all these different programs that there's no excuse really that you shouldn't, especially in myeloma, because there are so many resources. And I see some patients who kind of stick their head in the sand. They don't really want to understand it. And if you don't understand the science, it's okay. But if you do, it will help you. You will get better care. You will ask better questions in the clinic. And you might be able to take advantage of new things like a clinical trial that you've never considered before. Just by asking.

Dr. Brian Van Ness: And so I do think again, patient support groups can be incredibly valuable in learning from other people that are going through the same experiences. You know, I talked to some patients that would reluctantly go to that first patient support group, and they would often come out absolutely surprised at how incredibly upbeat those people were. They were enthusiastic people. They liked to talk about what was going on. They liked to talk about their successes. They liked to talk about some of the difficulties. But at the end of the day, it was like a group of friends having an

Jenny: Yes, it's not depressing.

Dr. Brian Van Ness: It's sad to say good time, but they were actually enjoying the opportunity to share that information. And I was always just absolutely amazed at how upbeat people were in those meetings.

Jenny: I’ve met some of the nicest people, including you, because I had myeloma. I mean, these are peers and friends and doctors and it's a very encouraging, uplifting group. And it's just incredible to make those personal connections. It does really help with you being able to navigate your disease.

Dr. Brian Van Ness: My sister had breast cancer and she often would say to me that her connections with other patients and that it was just, she said, I just really love it. If I didn't have this disease, the other part of this has been really enjoyable. She really valued that.

Jenny: Yes, that’s the downside. You're part of a club you never wanted to join, but there are nice people in the club. Another question about genetics. You know, we talk about genetic differences from patient to patient, but have you seen racial differences in genetics in multiple myeloma?

Dr. Brian Van Ness: It's just starting to emerge. My colleague Linda Bowne at the Mayo Clinic. She was a postdoc with me, worked in my lab for a few years and then has her own position at the Mayo Clinic. She's been very, very interested in that question of racial differences. And it's a sensitive topic because you don't want somebody defined by race. But let's talk about what race means. And race means you have a certain common country of origin. And people who live in my background of England and the Netherlands tended to marry within that group and that genetics evolved within that group. Likewise, people in Africa had groups of people that intermingled that their genetics would develop and evolve. Our genetics is always evolving. So our genetics is shifting, our genetic information shifts over time, and it's not surprising that populations of people that are located in one place tend to have their genetic information that may be different from somebody that was 10,000 miles away in another group. So we can define people by their racial genetics, but not as a skin profile, but as a profile of what distinguishing features did that group of people have that might distinguish how their disease progresses or how it responds to therapy. And there are examples in other diseases where there are some very clear genetic differences in Asian responses versus Caucasian or even African responses. So I think Linda is working very hard right now. And you can imagine the limiting step there is to get enough samples from people of different ethnic backgrounds to be able to start looking at the common genetics as it impacts myeloma. They're going to have certain common genetics as it impacts their racial or country of origin identity, but then there's going to be certain genetic features that may impact their risk for the disease.

The data suggests that African Americans are about three times more likely to get myeloma. Is that genetics? Is that environment? And there needs to be work on that because African Americans have about a threefold increase incidence of obesity. Obesity is also a risk factor for myeloma. So is it the genetics of the African Americans or is it socioeconomic cultural issues that might influence the risk for developing myeloma? Myeloma is a genetic change that occurs. And so the one thing patients will always ask, and this is independent of racial background, why me?

You know, why did I get this disease? And there are three components to your genetics. One component is what you got from mom and dad, so you can blame them. Okay, so some things we'll blame them for. The other is what you expose yourself to. You know, if you smoke, if you eat certain foods, that actually can impact your genetics by things you expose yourself to. The third one is a tougher one. And the third one is, I'm saying, bad luck. And that is, you start off as a single cell, and that cell divides into trillions of cells. And every time those cells divide, and even in our blood system, in the marrow, we're constantly making new cells.

So every time a cell has to be made from another cell, it divides, it has to copy three billion base pairs of DNA accurately to pass it on to the next cell. Fortunately, evolution has done a really, really good job of being accurate. The ability to accurately copy all of that genetic information one cell and pass it to the next one is pretty good. And I said that carefully, but it's not perfect. And occasionally, just random mistakes get made. And most of those random mistakes have no impact. But if you're to have that kind of random mistakes happening to develop these millions and millions of cells, every once in a while a mistake is made in a gene that has an impact. And so what you expose yourself to, what you may inherit from your parents in terms of risk, and also just the idea that every once in a while the genetic systems make mistakes. In a population of three billion people on the planet, there's going to be chances where those result in cancers. And that's not a satisfying answer, but it's a reality.

Jenny: It's a true answer. Absolutely. Well, we have some patient questions too, if you don't mind responding to some of these. Richard was asking how do we, and maybe you talk about this from a genetic standpoint, but how do we improve the diagnosis of these precursor conditions? Because I know if you've been working a lot with Mayo, especially in the Minnesota area, they've done a lot on smoldering myeloma. Do you look at genetics of smoldering myeloma patients or MGUS patients or things like that to make any kind of determinations?

Dr. Brian Van Ness: We have not, and in part, I think there was another question, there’s something to add to that. Our ability to detect hallmarks of myeloma, whether it's chromosomal translocations or particular genetic genes that are frequently altered or mutated in myeloma. The ability to detect those at a much more sensitive level earlier has gotten better and better. Even to the point where now blood tests, people can take blood samples and actually identify small numbers of cells that have genetic alterations. And that whole idea of genetic testing through the blood -

Jenny: I was going to ask you about that.

Dr. Brian Van Ness: - is gaining a lot of interest. Obviously, not taking a marrow sample would be something that most patients would be happy not to have to do. But, you know, getting a blood sample. The other thing is, and this is kind of important, particularly in myeloma, if you take a bone marrow sample from the right hip, you're going to get a collection of myeloma cells. And they're going to have certain genetic characteristics. If you take one from the left hip, they're going to share a lot of those genetic characteristics, but there might be some unique characteristics at a different location. And that's one of the difficulties in myeloma is that if you look at a population of myeloma cells, even within one patient, in one sample, there's going to be a little bit of genetic diversity in there of samples that have cells that have slightly different genetic characteristics. So now if you sample from one location versus another, you may get a slightly different genetic picture. So it becomes dependent on where you took the marrow. On the other hand, the blood is kind of the big mixing ground. So the blood kind of gives you a mix of a lot of different access to all of those different sites that are spilling out into the blood, for example. So in some ways, and I don't know if I've got proof of this, but I think the data is starting to demonstrate that the ability to detect diverse genetic clones is actually some benefit in a blood sample compared to a single location bone marrow draw. So I think that's kind of an exciting area to keep looking at.

Jenny: it makes a lot of sense. Carolyn's question, maybe we covered it already, but do genetics play a role in determining future care like immunotherapy? Are you seeing those links? You talked about immunotherapy being used in combination.

Dr. Brian Van Ness: Yes, there are two ways to answer that. One is we talked about venetoclax and there are certainly genetic features that people with certain genetics, a BCL2 gene, people with certain features respond better to venetoclax. So identifying that genetics upfront is a better indicator of what therapy may work. But there's another area that's really important and that is relapse. Because in relapse, what may be happening is that mixture of myeloma cells, you have within any individual a little microcosm of evolution. And in that microcosm of evolution, you have cells that are copying DNA, but not always really accurately. So you now end up with subpopulations of cells that have slightly different genetic characteristics. And in sort of the classic paradigm of evolution of survival of the fittest, if you have 99% of the cells responding to a therapy, but one of those new cells that came out as a genetic variation that now resists the therapy, that one's going to grow out. And there's your relapse. So now characterizing the genetics of the relapse becomes really important to define why that therapy may have failed. BCMA, for example, people that may fail BCMA-directed therapies, turns out they stop producing the BCMA protein on the surface of the cell. Something happened genetically that the production of BCMA goes down and they no longer express it on the cell. That cell's now resistant to BCMA therapy. I think diagnostics, it plays a role in identifying genetically what the best therapies might be, but particularly in relapses, redefining the genetic characteristics to now take your next shot at the best therapy and identifying why a particular therapy failed.

Jenny: It's so complicated because that changes over time and some patients don't know that, that their genetics of their disease can change. So we need to know that. As you think about how to create clinical trials, I mean, you're doing this amazing research and you have these discoveries. When you think about clinical trials, they're very expensive to run. They're very hard to recruit patients into sometimes. And if you do subgroups with very small numbers of patients with specific genetic features, that might be even more challenging. So how do you see the research field evolving with this more personalized approach as we learn more and more with our technology and our advances?

Dr. Brian Van Ness: I may get pushback from my clinician friends a little bit because I'm not a clinician so I'm not qualified to say, right? So now I'll say it. And that is, you know, in the past, a lot of the therapies were directed at therapy A versus therapy B, right? A new therapy versus an old therapy and you would compare the outcomes. And what do you have in that? You have winners and losers. You know, if the new therapy is more effective than that group, one, the people that were in the old therapy are saying, why wasn't I in that group? Well, we didn't know it was a better therapy until we tried it. Even then, some of the people that were in the therapy that didn't work for most of the patients, it actually worked for some of them. And likewise, the better therapy, it didn't work for everybody, but in conglomerate, it was a better therapy. What if when a patient walks in the door, we have sufficient genetic information to say, based on the genetic information, you get therapy A, based on the genetic information, you get therapy B, and based on the genetic information, you get therapy C. And if we do it right, you all win. And I would love to see that tested. I would love to see the idea that a clinical trial is developed based on best therapy, based on genetic information. Are we there yet? Maybe not quite, but I think we're getting real close to being able to direct a clinical trial that way.

Jenny: That would be amazing because then you would already know that you want to participate in that treatment arm. You know, don't feel like you've got the short end on the stick in any way, right? “This is for me.”

Dr. Brian Van Ness: Well, it's true, I mean, a patient going in saying, we have this new therapy, but we're going to randomize you. And you're saying, well, no, I want the new therapy. Well, you know, we don't know if the new therapy is going to be more effective until we do the clinical trial. I'd like to have a little bit more predictive capabilities. I mean, that's where I'd love to see genetics and proteomics. Because I think the protein work is coming fast now as well. It's one thing to understand the genetics, you've got to also understand how is that protein being produced, how much of it is being produced, where is it being produced. So you've got to bring them both together. So I think a combination of genetic information and proteomic protein information is going to get much, much better at predicting which therapies may be most effective. I'm hoping I see that really soon in clinical trials.

Jenny: That'd be incredible. Well, that's a great segue into the last question from Herbert and I. What in your opinion, what's blue sky? What do you see coming next? What looks most promising both in the development of the research and in myeloma care?

Dr. Brian Van Ness: I think there's still work to be done in immunotherapy. The other area that we haven't really talked a lot about is genetic engineering. Now I did say that you're genetically engineer the immune system, but are there ways to target the myeloma and genetically engineer cells that you want to get rid of? That's still a bit blue, high in the sky - 

Jenny: Is this like CRISPR and stuff like that or is that what you're talking about?

Dr. Brian Van Ness: Yes, that’s right, genetic engineering. I can take a myeloma cell out of an individual and I can genetically engineer it. I can change its genetics. I can change it. And I learn a lot by that. But if I can change the genetics in the laboratory so that that cell no longer survives, then let's do it in the patient - that's not so easy. It's easy to do it in the laboratory, but how you get the genetic material to the right cells, to all of the cells, to be effective. That's a challenge yet in genetic engineering.

But, you know, people are working on that. And, you know, there are people who doing this in liver cancers, for example, and liver disease. I mean, the liver is an easier target, and people are learning ways to genetically target the right cells at the right time with the right, in this case, genetic drug. Because at this point, the genetic manipulation becomes the therapy itself. I think there's more of that to come.

Jenny: It'll be so fascinating to see what, computer work and AI and, and all this brings to the whole thing as well. In addition to all the research things that you're mentioning, the advancements in proteins and genetic studies and just genetic modeling. It's like you were saying, whole exome and whole genome sequencing was so expensive and now it's so cheap and affordable. just, just to watch it since I was diagnosed is truly incredible.

Dr. Brian Van Ness: And would you say that it's had a benefit? mean, think our survival rates have gone up. Survival rates have gone up significantly. Long-term survival is not a rare event anymore. I think that the field has advanced significantly to give people better outcomes. Now, are we going to cure the disease? It's always that, do you cure it or manage it? And I think we're getting really close to being, you know, a more manageable disease than inevitable relapses.

Jenny: Well, it's very promising and it's in large part because of the work you're doing. So I want to thank you for participating to share this with us. I think the work that you're doing is incredible and you're just superior and I believe really truly brilliant.

Dr. Brian Van Ness: Okay, I'll have to make sure my relatives hear this.

Jenny: I will call your mom and tell her the amazing work that you're doing. :) I just want to thank you from a patient standpoint. It's so encouraging as a patient to see people who are so smart be dedicated to this work of saving our lives. So thank you.

Dr. Brian Van Ness: Well, you're welcome and I appreciate the opportunity to have the discussion.

Jenny: Thank you for listening to the Health Tree Podcast for Multiple Myeloma. Join us next time to learn more about what's happening in myeloma research and what it means for you.