Learn about all myeloma happenings on the new Myeloma Crowd site: the first comprehensive site for myeloma patients and caregivers. Dr. Stephen Russell, MD, PhD Mayo Clinic Rochester Interview Date: May 30, 2014

 Dr. Stephen Russell, a leader in gene and virus therapy of the Mayo Clinic, shares the detail about the recent success of the use of an engineered measles vaccine for myeloma in heavily pre-treated patients who were refractory to existing myeloma therapies. He describes in detail the creation of the therapy, the first trial, side effects, results of the treatment and the differences in their response. This is the very first time any patient with a disseminated cancer (not a localized cancer) has had a complete response after IV administration of a virus and is a historic achievement. However, Dr. Russell says that it is not yet a one-shot-wonder but only a step in that direction. The Phase II trial for 20 patients will begin in September and is only inhibited by the need to produce the virus. Manufacturing is now happening at the Mayo Clinic but they are looking for expanded manufacturing options. The Phase II trial will use the engineered measles vaccine only without the addition of other therapies. He describes the tests for eligibility and shares his opinion on the future of this type of therapy. This is a remarkable discovery by an outstanding researcher that brings hope to a new class of therapies for myeloma treatment.   The live mPatient Myeloma Radio podcast with Dr. Stephen Russell

Jenny: Welcome to today's episode of mPatient Myeloma Radio, a show that connects top researchers with patients. This is our 32nd show and it's an important tool for patients to learn about the very latest in myeloma research, so please share these interviews with your friends ,on your Facebook page, in discussion groups or on other social media. The more we as patients know, the better our outcomes will be. Now, if you'd like to receive a weekly email about past and upcoming interviews, you can subscribe to our mPatient Minute newsletter on the homepage or follow us there on Facebook or Twitter. We have a new site called myelomacrowd.org. that's the first comprehensive site for myeloma. We just created a new Facebook group called The Myeloma Family and Caregiver Group. That's featured in a post on that site, so feel free to share that post on your timeline to your family so we can connect the entire myeloma community. Now, there has been terrific buzz as of late about the Mayo Clinic measles vaccine used successfully in a very early clinical trial, so we are very privileged today to have with us Dr. Stephen Russell of the Mayo Clinic, the primary investigator of that study and the founder of this therapy approach. Dr. Russell, thank you so much for joining us today.

Dr. Russell: Well, thanks very much for inviting me, Jenny.

Jenny: Well, let me introduce you, if you don't mind. Dr. Stephen Russell is a board-certified hematologist and world leader in the field of gene and virus therapy. He graduated from Edinburgh University Medical School in England having decided as medical undergraduate that he would spend his life attempting to convert viruses into powerful anti-cancer drugs. He received his early hematology training at the University College Hospital in London and his early lab research training at the Royal Marsden Hospital, also in London. He obtained his PhD from the University of London in 1990 for his thesis on virotherapy and became a consultant hematologist at Addenbrooke's Hospital, at the same time, establishing his own gene therapy research lab in the prestigious Cambridge Center for Protein Engineering. During this time, he was the principal investigator for one of the earliest European gene therapy clinical protocols and was the scientific founder of Cambridge Genetics, a biotech startup company. Dr. Russell moved from Cambridge to the Mayo Clinic in Rochester in 1998 to build and direct a new Molecular Medicine Program focused on the development and clinical testing of new, genetically-based therapeutics. He is a professor of Medicine with the distinction of a named professorship, the Richard O. Jacobson Professorship in Molecular Medicine. He serves as an associate medical director for the Department of Development at Mayo Clinic, Associate Director for Translational Research in the Cancer Center, and Deputy Director for Translation, Center for Regenerative Medicine in the Mayo Clinic as well. He was one of the founding board members of the European Society of Gene Therapy and a member of the board of the American Society of Cell and Gene Therapy. He serves on the editorial board with several scientific journals including Human Gene Therapy, Gene Therapy, Cancer Gene Therapy, the Journal of Gene Medicine, and the Journal of Molecular Medicine. He is also the co-author of more than 275 peer reviewed scientific publications. Your background is amazing. Maybe you can start by helping us understand, when you were a medical undergraduate, how did you come to even determine why you wanted to study this?

Dr. Russell: Well, first of all, thanks for that long introduction. I got into this in medical school actually because of a personal tragedy as it happened. I was in my third year at Edinburgh Medical School and I had just sat my Microbiology final exam and I'd done pretty well. We had 150 people in the year and I was one of the top four, so I was invited back for a distinction oral to see who would win the class medal. That was going to be in a few days time when I got a phone call to say that my sister, Miranda who was 25 years old, had died in a house fire, and her husband. I obviously was devastated by the news. To take my mind off it as I traveled home to the funeral, I just read virology books. I saturated myself in virology and during that time, it occurred to me that viruses were the last untapped bioresource. We've used everything else -- animals, trees, all manner of plants, yeast for alcohol, bacteria for recombinant proteins and so on, but we hadn't used viruses for anything. So it was during that time that I decided I'm just going to devote my life to this, work on viruses and see whether they can be developed as an anti-cancer therapy. It occurred to me independently, but it's occurred to a lot of other people. Actually, if you look back in history, it's really since the 1950s when viruses were first isolated. The people have been using viruses in an attempt to impact cancer, so it wasn't -- although it was an original thought, certainly I wasn't the first person to think of it. That's how I got started. Interestingly, I missed out on quite a few jobs subsequently as a result of having that particular goal in life. I remember when I finished medical school, the first thing we had to do was secure what we called house jobs. They're like an internship. They're like the residency here in the US. You have to do two house jobs, one in medicine and one in surgery and they're six months each. I went for my interviews and I had a very strong CV, but I was not offered a job. After about 12 interviews, my wife, Janie, said to me, "Could you just run through what happens in the interview because I don't understand why you're doing so badly." I said to her, "Well, what happens is I go into the room and shake everybody's hands. I sit down and they ask me, 'So tell us what you want to do with your career, Dr. Russell,' and I tell them I want to treat cancer with viruses. And then they quickly wrap up the interview and send me out." She said, "Steve, the first lesson that you need to learn about interviews is that you have to show some interest in the job that you've actually applied to do." That was really priceless advice because after that, I found that it was quite easy to get jobs when I applied for them. Anyway, that's how I got into studying viruses.

Jenny: And from what I understand, you started working in other areas besides myeloma before this recent clinical trial that has garnered so much attention, so do you want to back up for us and take us through your progression of what you've discovered and how you've discovered it, and then how you got to myeloma?

Dr. Russell: Well, I've always been interested in myeloma. In the UK in my early days, I worked at University College Hospital, which was a very busy hospital with a great deal of activity in hematologic malignancies. We were doing a lot of stem cell transplantation, particularly through acute myeloid leukemia there. I just got interested in multiple myeloma while I was there. I thought that this was the most interesting of the hematologic malignancies to work on. Because of the virus obsession, I moved from the University College Hospital to the Royal Marsden Hospital to their research labs where I found a lab where I could learn about how to engineer viruses. I mean, it was at a time back then in the late 1980s when there were very few places where you could actually go to learn this kind of engineering technology, so I worked there and then moved from there to Cambridge where I could get back into my hematology clinical practice and at the same time develop my lab activity, so it was this hybrid of lab, science, and clinical practice. In Cambridge, I was fortunate to be given responsibility for the care of the myeloma patients. I sort of completed my clinical training there and became a consultant. And as a consultant in Cambridge, I was given responsibility for multiple myeloma. And so, I could bring these two different areas together much more effectively when I had clinical practice and lab research activities that connected with each other, but myeloma was very difficult to model and work on. There are many other cancers for which the tools are really much, much easier and more convenient and accessible. One of the things, if you don't know the research game, you probably don't have much of a feel for this, but you can grow cells in suspension so they're not sticking down to plastic and they just grow in solution, or you can grow them adherent where they stick to plastic. Myeloma cells, they grow in suspension and that makes them much more difficult to work with for testing viral infection in laboratory and testing what virus does to the cells because you can see it all much more easily down a microscope with adherent cells, so that's one thing that pulls you away from multiple myeloma. Another thing is that when you take cancer cells and you implant them in to mice to mimic the cancer that you want to treat, it's actually much easier to do that with other cancers other than myeloma just because of the few models that are available. Things have gotten better actually over the years, but when I started, it was really a problem to work on multiple myeloma, so everything pushed me in the direction of other cancers. It was in Cambridge that I decided that the measles virus would be a great starting point to work on mainly because if you look at all the infections that are out there and all the viruses that you could choose between to try and destroy cancer cells, you really want to have one that's going to be safe. That's the absolute first consideration that we had because we were doing something that wasn't really being done many places at all. People immediately have the thought of, "Oh no! What could go wrong? You're working with a virus. You're trying to teach it how to destroy something. How is that going to be safe? Could the virus change in such a way that it damages normal people and that it can spread from a patient to carriers?" and so on. So with measles, the idea there was we had a virus that could already damage blood cells and natural measles infection really hurts the immune system quite badly because the virus infects immune cells and destroys them, so we thought that's a good starting point. The virus is already out there. We already know what worst it can do to people is, and it already knows how to infect and damage the cells that we're interested in. So what we have to do is we have to constrain it and we have to make sure that that's all it can do. If we're able to do that and able to get it to be effective as a therapy, then we won't be putting the population at risk because everybody is already immune to measles, and so it won't be able to spread from the patient to other people. And so, it was really a big safety to population question that drove us to choose this virus as the first one we would work with. Now, of course, that also gave us a big problem. If everybody is immune, then how are we going to actually use the virus as a treatment? That's where the advantage of the immunosuppression that occurs in multiple myeloma, is that many multiple myeloma patients have very, very low amounts of antibody against measles virus. And so, they're ideal subjects to treat with the measles virus.

Jenny: So it's an advantage and a disadvantage because you could get measles easier because your immune system is depressed, but for your experiment, it was perfect.

Dr. Russell: As long as you stay clear of wild type measles, then the loss of measles immunity is an advantage for this treatment.

Jenny: Can you explain the engineering process, what you are doing to make it an engineered measles virus?

Dr. Russell: One of the big concerns about using a virus as a therapy is that in contrast to the drugs that are routinely used for the treatment of myeloma now, this is the drug that goes into the body and then amplifies, so the dose that you give of the virus increases because the virus grows in the body. When this virus infects the myeloma cells, the myeloma cells produce large number of progeny viruses which are essentially clones of the virus that went into the cell and those progeny then go on to infect other cells, and that's how the virus spreads, so it's a self-amplifying therapy. In order to use this self-amplifying therapy, we thought it would be very important to be able to see to what extent it was amplifying. And so, we built this gene into the virus that allows us to see where it's got to in the body. It's the gene that naturally is expressed in the thyroid gland because the thyroid needs to harvest iodine from the blood in order to make thyroxin, which is a hormone that controls your metabolism. The thyroid gland has learned how to very efficiently extract iodine from the blood. There's not much iodine in our diet, so over the years, it's been a very important thing that this gland has learned how to concentrate iodine. We know that the way in which the thyroid gland extracts iodine from the blood is using a protein called NIS. And so, we've built the gene coding for that protein into virus. And now, anything the virus infects can efficiently extract iodine from the blood. If you want to image the thyroid gland -- people have been doing this for about 70 years -- you give radioactive iodine and then you put the patient in front of a scanner and you can see the thyroid gland lights up because that's where the iodine goes. And so, we now are able to put the patient in front of a scanner and anything that lights up -- well, the thyroid lights up, but then also wherever the virus has got to also lights up, so we can see using a noninvasive imaging test where this virus has actually got to in the body, so that was the change that we made to the virus to make it suitable as a cancer therapeutic that we could carefully monitor as we used it for therapy. The making the virus safe piece is that the wild type measles virus obviously we wouldn't want to use for this because it can cause measles. And so, what we've taken is a weakened strain of measles that has been grown for many, many, many years in the lab on cancer cells and which has learned how to very efficiently infect and replicate itself on cancer cells. It just so happens that it does that really very well on myeloma cells, but in adapting to grow on the cancer cells, it's lost the ability to cause measles. And so, it's a vaccine strain attenuated measles virus that retains the ability to kill cancer cells. And so, that was our starting material and then we engineered it to include this gene which acts as a snitch and which allows us to see where the infection has got to in the body.

Jenny: Tell me the name of that gene again that you added.

Dr. Russell: It's called NIS, which actually is a bit counterintuitive. NIS means sodium-iodide symporter. The "N" is for natrium, which I think was the Latin name for sodium, so it's a natrium-iodide symporter and as I said, it transports iodine into the thyroid gland. That's its natural function. Actually, one other interesting aspect -- and we haven't yet got there with this treatment -- but one other interesting aspect of the NIS gene is that if you get thyroid cancer, the thyroid cancer quite often will continue like the normal thyroid to express the NIS gene and to concentrate radioactive iodine. One of the treatments that is routinely used for patients with metastatic thyroid cancer -- that's thyroid cancer that is spread from the thyroid elsewhere in the body -- is to give a very high dose of radioactive iodine sufficient to destroy the tumor cells that take up the iodine. And so, that is something that we have shown in mice that if we give our virus to a mouse with myeloma and then we give radioiodine, the virus works better. We call that radiovirotherapy, but obviously that's something that we haven't yet tested in the clinic, but we will do later once we've established the safety and activity of the virus that we've developed as a single agent.

Jenny: I know some patients get worried about that radioactive iodine when they go do that PET scan, so maybe there is a bonus. I don't know.

Dr. Russell: If you target radioactivity to the right place -- it's definitely the case that myeloma is responsive to radiation because you know that anyone who's had a skeletal lesion that needs to be controlled because it's causing pathological fracture or bone pain, local radiation is a really effective way of controlling that. And if you have a solitary plasmacytoma, then radiation therapy can be curative. So we know radiation is quite a good modality, but this is potentially a way where you would be able to target the sites of tumor growth with the radiation, so we're excited to get there. It's going to take us some time unfortunately.

Jenny: And you began with mouse models for this approach and then just completed the results for the clinical trial. Do you want to describe what you found on the mouse models and then how you decided to construct this trial?

Dr. Russell: Well, the main mouse model that we used was a mouse model that was developed here at Mayo Clinic. There was a patient here at Mayo Clinic -- well, actually, this has been the case of many patients here at Mayo Clinic, but this was a patient who had a pleural effusion with myeloma cells in the pleural effusion. The myeloma cells were grown in the tissue culture dish by Diane Jelinek here. And then Dr. Jelinek showed that the cell line that she'd created from this patient's myeloma cells could actually grow in a mouse if you put it under the skin, as a tumor under the skin. It could also, if you inject it into the bloodstream, give the mouse myeloma. It would hone to the bone marrow and would grow there. And so, that was the model that we used because it was a human myeloma cell line that could efficiently grow in mice. What we found was that if we gave increasing doses of our virus to the mice, not only could we then do the imaging study and see the virus infection real time, but we also got very good control of tumor growth and complete cure of some of the mice provided we gave a high enough dose. The other thing we learned from those studies, if we gave the mice anti-measles antibody before we gave the virus, it didn't work. So there were two things that came out of that. One was you needed a very high dose of this virus intravenously in order to destroy myeloma, and two, antibody was going to be a problem if it was there. And so, really based on those studies, we went to FDA and they asked us to do a whole lot of other studies to prove safety to their satisfaction before we went ahead with the clinical testing. They also asked us to demonstrate that we could reliably and reproducibly manufacture this virus. It's so different to manufacture a virus that you're going to give to people versus manufacturing a virus that you're going to give to mice. It has to be so much cleaner and so much more rigorously tested. Of course, you need a great deal more of it to treat people than you need to treat mice. There's a huge set of FDA regulations called GMP, Good Manufacturing Practices, which you have to adhere to. They're a whole story in their own right. For example, if you go to the FDA and you say, "Look, mouse number six in this group of mice, number three had a hemoglobin of 10 on day four after giving the virus," then FDA says to you, "Okay, prove it." We want to see the records to show that the mouse was actually given that dose of virus, that someone witnessed it, that the person who gave that dose of virus was qualified to do so, that the blood taken from the animal was taken from that animal specifically, that it was tested on a machine that is known to be reliable, so where are the records on the machine to prove that it actually was calibrated appropriately, where are the training records on the individual who did the testing on that machine to prove that that individual can actually do that. So you can get a sense from that that it's a very different approach to doing lab research to do these FDA mandates at studies where everything has to be backed up by training and documentation and so on. So we did those tests and we took all our data to the FDA and they said, "Okay, you can start at the dose of one million virus particles per patient." We said, "But we need to get at least a billion to even hope to see a glimmer of anything." They said, "Yeah. Well, sorry, you're starting with a million. So we started at a very low dose. I think it's one of the difficult aspects of phase one clinical trials, is that FDA does typically consider safety and safety only for a phase one trial, and they're absolutely fixated on the question of is this going to be completely safe. So we started at a low dose and it wasn't very popular trial (a) because the dose was low and (b) because we knew that the low dose wasn't going to be particularly effective. And so, we shared that information with our patients obviously. Anyone considering the trial, we tell them what we had. The clinicians here weren't that keen on offering it to people especially if they were in need of something urgently and the patients we saw at the clinic weren't too keen on it, but eventually we got through the lower dose levels. We got up to the dose level that we finished up on. It was 10 to the 11, which is 100 billion infectious particles per patient, so way, way higher than anyone had ever received before. It was the second patient to receive that very high dose level who was the first patient actually at that dose level who had no anti-measles antibody who had this remarkable response. She, Stacy Erhotlz -- well, she's a 50-year-old lady now. She was 49 at the time. She'd had myeloma for about ten years. She had been treated with stem cell transplant at the outset. Subsequently when she relapsed, she had received Revlimid and dexamethasone for about two and a half years before she started relapsing through the Revlimid and dexamethasone. She then went on to CyBorD therapy, cytoxan, bortezomib, and dex. She had a good response to that, but then relapsed through that, so she was still taking the medication while her myeloma relapsed. She then had a second high-dose melphalan autologous stem cell transplant in August of 2012. She came back in May of 2013 with -- there had been a change in the nature of her myeloma actually because originally the myeloma had been just diffusely infiltrating the bone marrow and she hadn't had lytic lesions. She came back in May with a large tumor on her left forehead. Her children had called it "Evan" and it was growing pretty fast and it destroyed the underlying bone. On the PET scan, she actually had five plasmacytomas. She had another one in her skull, one in her clavicle, one in her sternum, and one in the T11 vertebral body. We looked at the bone marrow and the bone marrow was diffusely involved with myeloma. Her tumor marker is free light chain, the lambda free light chain, so the lambda free light chain was increasing. And so, she clearly needed therapy and she was resistant to all the standard classes of drugs, so she elected to go on the measles therapy. When we started the infusion, I think it was on June 5th last year, we started the infusion and she got a headache, a really bad headache within a few minutes of starting infusion, so we stopped it. We said to her, "Well, what do you want to do?" She said, "I want you to finish. Keep going," so we gave her some Benadryl and -- well, actually one previous patient had the same thing and said, "No, don't give me anymore," so it was kind of brave of her to persevere because we didn't know what the potential dangers were of continuing. Anyway, Benadryl made the headache go away and she finished the infusion and she was fine. So after the infusion, she said it was a bit boring. Her mother was with her, went across the road to get some food for her. When she came back -- this is now two hours after to completing the infusion -- Stacy was shaking. She was having rigors. She was vomiting and her temperature went up way high. It went up to about 105. We used cooling blankets and things to bring it back down. She stayed in the hospital overnight and the next day, she had a recurrent fever again. Her temperature came down and then she had -- over the next few days actually, she had a few recurrent fevers that settled spontaneously. She also got some inflammation on her arm where the virus had been infused into the vein. The other thing that happened to her was her platelet count fell quite precipitously, and so did her lymphocyte count. They came back pretty quickly, but just for anyone who's wondering is this a totally innocuous therapy, which I think some of the media outlets have been saying that, I don't think it is totally innocuous, but she recovered completely from that. She said that by 36 hours, she could feel that Evan was shrinking. Over the next six weeks, the free light chain level returned to normal. Evan disappeared. The bone marrow cleared completely and the PET/CT-scan, we sort of repeated on a regular basis and that became negative at six months. This was just a single dose of virus with nothing else, no other anti-myeloma drugs, no maintenance therapy, no nothing. Stacy says that the toxicity is trivial in her mind. I think she sometimes doesn't think about what it actually was. I think that the people who were with her, they say, "No, Stacy, it wasn't trivial," but she says, "Yeah, it was. Compared to stem cell transplant and the other treatments I've had, it was trivial." She very much enjoyed her remission because there was no other drug therapy. She said she felt better during this remission than during any other that she's had. Nine months after we gave her the therapy, she noticed that Evan was recurring. We looked at her PET/CT-scan and we looked at her bone marrow again and they were completely clear, so we just gave local radiotherapy to that lesion on her forehead. She's continuing to feel very well. I spoke to her earlier today actually and she's feeling well. That's where we're at now with Stacy. Stacy is longing to find a companion who has as good a response as she's had. The reason she's a historic patient is because she's the first patient ever anywhere with disseminated cancer to have a complete response after intravenous administration of a virus. See, there's a lot of history and a lot of work going on to use viruses as cancer therapy. We've known for a long time that it can be effective in mice, but nobody previously had demonstrated that this could happen in a person with cancer. And so, there's sort of been some, I think -- again, it's the way things get distorted in the media. It's something you can't really control, but people have been saying, "Well, this is a wonder cure," but it isn't. That's not what it is. It's a step in that direction. What we're very excited about is the possibility that this may herald in a new era of treatment where we can have a drug that you give once that will ultimately be capable of curing myeloma. We certainly have seen that happening in our mouse models. What's happened with Stacy has been pretty amazing, but it does fall short of a single-shot cure and she is the only patient so far to have had such a wonderful response.

Jenny: Well, it is historic in nature. And so, any step is a great step and this is a huge step. So comparing Stacy to the other woman, was the effectiveness for Stacy versus the other patient more a matter of dosage that was given or do you think it was the genetic nature of Stacy being -- now, as you said, she was light chain only, right?

Dr. Russell: Yes. No, I don't think it was that. I can't know the answer to that question. There were a number of differences between Stacy and the other patient that we reported in that paper. One of those differences was that the second patient -- so both Stacy and the other patient we reported had no antibody. That's why I think responses were seen in those two patients, so that's the first important point, but why was the response transient in the second patient? She had a different distribution of disease, so she had many very large plasmacytomas in her leg muscles particularly and in her abdomen and pelvis. And by very big, I mean very big, so 10 cm across. You could easily feel them, and she'd had a great deal of treatment before. She'd had a bone marrow transplant. She'd had all manner of different drug combinations. She'd had the VTD-PACE regimen that was developed at Arkansas, sort of everything and the kitchen sink. Her most recent treatment had been carfilzomib, pomalidomide, and dexamethasone, and so very highly treatment refractory disease. She had a free light chain level, a kappa free light chain level of 31 and had all these large, palpable tumors. And about day eight, she came back and we were very excited because at that time, her free light chain level had fallen from 31 to 8. The tumors were hurting and she thought they were shrinking, but she said with all the previous therapies that she'd had that hadn't been effective, these tumors had not caused her any problem at all, but they were hurting. And so, the light chain was falling, the tumors were hurting. She thought they were shrinking. We did this radioiodine scan to see where is the virus. We had done the radioiodine scan the day before we gave the virus and there was nothing being taken up by these tumors. And on day eight, they all lit up. And so, we knew that the virus was growing in them. We knew that something was happening and we were very excited. Within the next three weeks, they stopped hurting. The free light chain levels started coming back up and the repeat radioiodine scan showed that the tumors became negative, so it fell short of being sufficient to have a useful impact on the disease, but what we learned from that study is that the virus really does target the sites of tumor growth in a patient with multiple myeloma because the imaging data was so clear. The other thing that the imaging data showed us was that there was a different degree of virus uptake in the different tumors, so they didn't all light up to the same degree and that was quite interesting. What that says to me is that if we could push the dose higher, we might see a much better outcome because as I told you before, one of the lessons we learned from our mouse studies was that you have to get up to a high enough dose in order to impact the cancer. So one thing about this second lady was the distribution of her disease and the other was the amount of disease that she had because the size of these tumors are much larger. There was quite a bit more myeloma in her body than there was with the first lady.

Jenny: I have a question about that because as we talk to other researchers, they've mentioned that being hyperdiploid may mean you have a slower-growing type of myeloma, but it might do more bone damage. I read somewhere that Stacy was hyperdiploid. When you think about the aggressiveness of the disease or the extent of the disease, and you're saying that there was more disease in the second patient, how does that all relate? Does the hyperdiploid have anything to do with it?

Dr. Russell: It might be. I think these genetic subtypes, they mean a great deal at the outset, but I think by the time somebody with hyperdiploid has gone through a couple of stem cell transplant and become resistant to all other therapies, I think you're dealing with -- you can't say, "Oh yeah, great prognosis disease. Now, we're ten years out and it's come back after all these therapies." I think the prognostic implications of the different genetic subtypes do change over time just because relapsed myeloma has a worse prognosis than newly diagnosed myeloma. And so, I don't know. Again, it is an important question you're asking. I think it's a good thought, but we just won't know until we have a lot more information. I think the critical thing for us to do is to keep on working as hard as we can to learn as much as we can about where, when, and how this treatment works. That's what we're planning now. We're planning a phase two clinical trial in which we will treat a large number of patients who have multiple myeloma resistant to all therapy who also do not have anti-measles antibody detectible in their blood. Those will be the criteria that define the eligibility for the trial. We'll see what happens. I think it's very important that we determine how often is it going to be effective and that we look very carefully at each of the patients in whom it is or isn't effective, and try and understand why. The bottleneck we have is the manufacturing. Unfortunately, we can't even restart the clinical trial until September just because of the time it takes to do the manufacturing of this huge amount of virus. At the moment, we're manufacturing it in our academic lab here at Mayo Clinic, so it's not a huge virus production facility. And so, that makes it difficult for us.

Jenny: Okay. So in a phase two trial, how many patients are you looking to include?

Dr. Russell: At least 20 patients for the phase two. We're probably going to have to stagger that because the current manufacturing lot -- again, it comes back to the manufacturing. In our Mayo facility, we use these 75-liter wave bags, which can take so many cells and we grow the virus up in them. We harvest it and we clean it up and we get it tested. We pass through all the FDA regulatory guidelines that we have to. With a single 75-liter production run, which takes about six months from start to finish because all the media materials that we use have to be custom-ordered and the environment in the facility has to be controlled and so on and so forth. And then after we've made it, we have to characterize it and do all the safety testing, so that's why it takes rather a long time from start to finish. A single run typically gives us enough virus for only five patients.

Jenny: And how long does the run take?

Dr. Russell: The run from start to finish takes about six months, but we can stagger them so we start one now, but we start another one in a month and another one a month after that, so we can keep it coming. We envisage that in September, we're going to have enough viruses for eight to ten patients. Our next lot of virus will be available in December or January to treat the remaining patients on the phase two trial.

Jenny: This will be only at the Mayo Clinic in Rochester, that facility, I would assume?

Dr. Russell: Yes, it's only at Mayo in Rochester. Now, obviously we don't want to be constrained in this way. And so, what we're doing is we're looking at -- there are what we call contract manufacturing organizations for a business who virus-manufacture and they have the ability to take the scale much higher. And so, they can do 1000 or 2000-liter production runs or even 10,000-liter production runs. And so, we are actually working as we speak with a contract manufacturing organization that is going to really sort of push up the scale and get us much larger amounts of virus for trials that we will be doing next year.

Jenny: Okay, a few follow-up questions on it, how do you test for the lack of antibody presence? What tests are you doing to determine that?

Dr. Russell: Well, we do two tests. There's one that's a routine lab test that looks for immunoglobulin against measles virus, an ELISA, enzyme-linked immunosorbent assay, and they run that in the Mayo lab. I think quite a few labs around the country run that, so that's one test. The other test that we do is much more specific to our virus. We take the serum from the patient and we mix it with our virus, and then we look at the infectivity of our virus, so we check whether the patient's serum can actually neutralize our virus. If it can, then that's an exclusion at the moment. Now, what I should say actually on that question of antibody is that we obviously need a way to get around the antibody barrier because if we have an active agent but we can't get it to the target, then the question is well, how do we do that? So in the mouse models, what we've shown is that if we use cells as carriers of the virus -- so what we do for that is we take cells. We put the virus on them to infect them and then instead of giving the virus, we give the cells that are loaded with virus into the bloodstream. Then they can actually act as Trojan horses and carry the virus to the myeloma cells. We've shown in our mouse model that using cells as carriers gets us back to efficacy even after we've given the animals anti-measles antibody. So we want to move that approach forward as well and that's something we're actively developing, the use of cells as carriers for the virus so that people who do -- so that it then won't matter whether you have anti-measles antibody or not. Obviously, initially because we just have the naked virus as our therapy at the moment, we want to focus on people who do not have antibody.

Jenny: And that would be a nice work around.

Dr. Russell: Yes, for sure. There are also other viruses that we're developing now for which the antibody barrier is much less of a concern. Again, down the road, we anticipate that we'll be looking at testing other viruses for which the antibody really is much less of a concern.

Jenny: I read about that in the Mayo Clinic proceedings and it talked about how other viruses like the parvovirus, which is I think in the same family, the measles or rubella type of family, was also being considered.

Dr. Russell: Which virus?

Jenny: The parvovirus?

Dr. Russell: I don't know. There are a lot of viruses in development at the moment as therapy for cancer. There's a herpes simplex virus that Amgen are probably very soon likely to get approval for as a treatment for malignant melanoma. I should just take a step back and explain something about viruses as a cancer therapy and how they work just so that you get an understanding of this. A virus works in two ways against the cancer. The first way is that it infects and kills the cancer cells and the cancer cells make more progeny viruses and they spread to other cancer cells. The second way the virus works is that after the cancer cells have been killed, the virus infection is eliminated by the immune system. Once it's been eliminated, the immune system is now in better position to destroy uninfected cancer cells. And so, there are these two stages of virotherapy. We call the first one the oncolytic stage when the virus is destroying the cancer. The second phase we call the immunotherapeutic phase where the immune system is mopping up residual cancer cells. The Amgen virus really catalyzes on the second of those two. What's done in this melanoma study is that patients who have melanoma that has spread over their skin to multiple places, they get the virus injected, and it's a herpes simplex virus. It came from somebody's cold sore and it was adapted to make it safe. It's injected directly into the melanoma skin lesion into one of them. What happens is that the virus doesn't spread to the other skin lesions, but the immune system is alerted to the presence of the cancer. And subsequent to destroying the virus infected cells, it goes on to wipe out the other melanoma cells in the skin. This really looks pretty good. A phase three study has recently been completed and Amgen have the data from that study and it looks quite promising. There's anticipation at the moment that that virus may well be approved as a treatment for melanoma. There you have the two paradigms. The paradigm that we've demonstrated here in multiple myeloma is the oncolytic paradigm where the virus was given systematically, but it may also be an immune mediated mopping up after the virus has done its work on the cancer. This Amgen virus really just goes with the immunotherapeutic side. Those are the two extremes. Now, if you look at other viruses that are actively being pursued as cancer therapy, there's vaccinia derived from the smallpox vaccine which is being used both as an intratumoral and as an intravenous therapy. That's looking promising, although nobody has tried that in multiple myeloma. There are some adenoviruses which are common cold viruses. Quite a few of those are being developed by different companies for different cancers either given by intratumoral injection or intravenously. There's a company in Canada that has a reovirus, a virus that nobody really knows what it causes. It doesn't seem to cause disease. It's found in the human population and about 50% of people have been exposed to reovirus and they're giving that virus intravenously. They are actually testing that virus in patients with multiple myeloma, and that's an ongoing clinical trial at Ohio State, so that's an interesting one. Then there are these other pipeline viruses. We have one here at Mayo called vesicular stomatitis virus that we're pretty keen to take forward and test as another myeloma virus. We have submitted an application to FDA, what we call a pre-IND application. It's just to get FDA's input on what we need to do in order for them to be satisfied that we can start a clinical trial with that virus, but it works very well in the mouse models. I think there's going to be a great deal of activity in this area. I think we really will see other viruses being tested and hopefully we'll see benefit coming from them.

Jenny: Oh, there's no doubt about it. The phase two trial is -- I would imagine since this is so early that it's the virus alone with no other therapies, so you can determine exactly what it's doing and not -- I would assume that, but is that the case?

Dr. Russell: Yeah, that's precisely it. Actually, it's interesting because when I first discussed this -- you know we have an enormous group of myeloma doctors here at Mayo and we meet every Friday morning and we sort of talk through this and that. The first discussion we had about the measles virus therapy after Stacy had had her response, we talked about the possibility that we might combine the virus with something else and everybody said, "No, absolutely not." You have to prove that the virus could do something because many of the drugs that are being developed for myeloma at the moment are being combined with Revlimid or with Velcade or whatever, and it becomes difficult to discern what the impact of each agent is. So the view of the group here was don't cloud the issue. First of all, before you look at combinations, find out whether you really do have single agent activity, so that's what we're going to do.

Jenny: Well, that opens up a whole new host of options because you could use it -- and I don't know -- I'm sure we have lots of questions. I have lots of emailed in questions if we don't have lots of live questions. So we're going to keep you over, if that's okay on your time, and open it up for caller questions. If you have a question -- and I have so many questions that I would like to ask, but I don't want to hog all your time. If you have questions for Dr. Russell, you can call 347-637-2631 and press 1 on your keypad. Sometimes we have some very shy callers, but we would encourage you to ask a question because you're an amazing resource. I'm going to start with an email question that I have by Lori. She says, "Dr. Russell, I noticed the next measles vaccine trials starts in September and patients who have had an allogeneic stem cell transplant are not eligible. Is this just for trial purposes or do you anticipate a vaccine, if it becomes broadly available, will not be effective for myeloma patients who have previously undergone allotransplant?" She says that, "Allotransplant is not a guaranteed cure, so we're wondering what the future holds in terms of immunotherapy." She also asks, "Are there other patients in your current trials with high risk cytogenetic markers like del(17p) or t(4;14)? And if so, what are your thoughts on how those patients will respond to the vaccine?"

Dr. Russell: The allogeneic transplant question, the reason allotransplant is an exclusion criterion is because patients who've been through allotransplant are quite severely immunosuppressed over and above their multiple myeloma, often on immunosuppressive drugs to prevent graft-versus-host disease. And so, FDA were unhappy with us including allotransplantations in this clinical trial, but assuming it's safe -- and I think what we have learned from the phase one trial is that it does appear to be quite safe even in fairly severely immunosuppressed myeloma patients, I see no reason why it wouldn't be also used in people who've been through an allotransplant. I think that's that question. The other question was relating to different myeloma subtypes and I think we sort of briefly touched on that question because you were asking about hyperdiploid. It's just too early to say. We don't have preclinical models that can tell us and we'll find out in the fullness of time.

Jenny: Okay. We have several caller questions.

Caller: Good afternoon, Dr. Russell. Thank you so much for taking my call. Thank you for this work. It's just so intriguing and so promising. I realize that it's very, very early in the process. I'm a smoldering multiple myeloma patient, so I'm of course always looking to see if such therapies that you are developing for multiple myeloma patients could someday translate into the smoldering population and try to use it when the disease burden is much lower and perhaps less resistant. My second question is, is the phase two trial coming up in September open to existing Mayo Clinic patients only or will it be expanded to anyone who gets referred to your facility?

Dr. Russell: Okay. The first question on smoldering myeloma is -- it's an interesting question actually. From what I've been saying about the anti-measles antibody being something of a roadblock, my sense is that there's a higher likelihood that you will not have anti-measles antibody if you've had myeloma for quite a long time and have had all the other therapy. I think it's a great option at this point in time to try if you have myeloma that's failed all other therapy. Now, generally what you see with new myeloma treatments is that they used it earlier and earlier in the course of the disease and it might be that someday, measles virus or the other anti-myeloma therapies that we have available will be routinely used for smoldering myeloma, but for the time being, all I can say is congratulations to you that it's smoldering and hasn’t become symptomatic and long may that continue.

Caller: Yes, I agree. Thank you so much for that wish.

Dr. Russell: So the second question is something that we actually have under active discussion at the moment. I think that the trial is open to people from anywhere, not just to existing Mayo patients. That is something that has only recently been discussed and that's a preliminary conclusion of those discussions I'm giving you. The fact is that now that the information is out there, there's a great deal of interest in it and it would probably not be appropriate for us just to exclude people who are not currently Mayo Clinic patients. The interest in the trial has been quite overwhelming as you can imagine based on the media interest that has been, and so we're committed to having a fair process, but we haven't finalized what that process is yet.

Caller: All right. Thank you so very much. Well, hopefully if you do reach your goal to get around the existing antibody barrier, someday maybe it will be available to someone who's smoldering because it's certainly a unique approach as opposed to trying to use the novel agents that are currently available in some of the smoldering trials, so I thank you. I thank you for what you're doing and what you hopefully will do down the road.

Dr. Russell: Thank you very much.

Jenny: Okay. We have another caller , go ahead with your question.

Caller: Yes. Thank you, Dr. Russell. I'm really impressed with your results. I'm actually a myeloma patient and a hematologist at the same time. I'm about nine years out and coming up against some of the issues that you were discussing. My question to you is a really simple one, which is, is there an age exclusion for undertaking this kind of treatment? Do you think that's generally true of other immune-mediated treatments like PD-1 blockers and things like that or vaccines? Do you need somebody younger to gain entry to those or do you think that it would be equally as successful?

Dr. Russell: Yes, an interesting question. Right now, there's actually no age requirement for participation in clinical trials. It's something that obviously we'll look at as time goes by and as we treat more people. I don't know what I would predict on that. I think that probably the most important age factor is going to be whether you were vaccinated against measles as a child or whether you've got a natural measles infection as a child. Generally, people who have actually had measles start out with a higher antibody level than people who were vaccinated against measles. And so, it takes longer after getting myeloma and being treated for myeloma for it to come down to zero, so that may actually prove to be a factor, but we'll see. We just don't have information on that yet.

Caller: Okay. Thank you. That's very helpful. I appreciate it. Bye.

Dr. Russell: Thanks.

Jenny: All right. Thanks for your question. Our next caller, go ahead with your question.

Caller: Yes. Thank you for taking my call. Recently, my husband was in the hospital for five weeks, extremely ill, and received the treatment of IVIG, which is antibody from a hundred healthy people. Would that exclude him from your trial?

Dr. Russell: It would not exclude him from the trial, but it would delay participation in the trial because IVIG contains anti-measles antibody, and after receiving IVIG, it takes quite a long time before that's eliminated from the body. And so, the likelihood is if you've had IVIG within the last month or two, then there is going to be a significant amount of anti-measles antibody in the blood, so it would influence the eligibility on the basis of how long since the IVIG.

Caller: Great! Okay. Well, thank you for all your work.

Dr. Russell: Thank you.

Jenny: We had one from Doug who says, "If the virus is effective for a certain period of time, would you give it as a repeat therapy and/or even at a lower dose as a preventive therapy for reoccurrence?"

Dr. Russell: I don't think it would be valuable at low dose as preventive therapy. Would we give it as a repeat therapy? It's problematic because all of the patients who we've given the virus to have subsequently developed high levels of anti-measles antibody. So I think it has to be seen as a single cycle therapy unless and until we develop the cell carrier approach. In which case, we would be able to give it repeatedly.

Jenny: Okay. That's very informative. One last question from Karen, she said, "I saw that this therapy had some impact on CD46, so are these viruses just attacking specific proteins, kind of like some immunotherapies do with CD38 or CD138?"

Dr. Russell: No, it's more complex than that. The virus, in order to get inside the myeloma cell, first attaches to the surface of the myeloma cell and then subsequently injects its material in there. The receptor to which it attaches is CD46 and CD46 is expressed at very high levels on multiple myeloma cells and that's one of the reasons the virus has become specific for multiple myeloma.

Jenny: Okay. That makes sense. Well, Dr. Russell, we've kept you over, but we are so very grateful for what you're doing. This is remarkable and really game-changing work that you're doing, so we hope that you continue. We're very excited to see what your phase two clinical trial holds. I know there will be many patients interested in that and we hope that this virus can be engineered in greater quantities so a lot more patients can take advantage of what you are learning.

Dr. Russell: Well, thank you, Jenny, for everything that you do. I think this is a wonderful resource you're providing here with this radio station. And I think it's been very helpful to spend an hour with you, clarifying an awful lot of things because it's so easy for the story to become distorted if you don't have time to discuss things, so I really do very much appreciate the opportunity, so, thank you.

Jenny: Well, we're so very grateful for all that you're doing, so please keep going.

Dr. Russell: Will do.

Jenny: All right. Thank you so very much.

Dr. Russell: Goodbye.

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