Dr. Robert Z. Orlowski, MD, PhD MD Anderson Cancer Center Interview date: March 21, 2014 

Dr. Robert Z. Orlowski shares a three-themed approach at MD Anderson to combat myeloma: Using immonotherapy in many new and exciting ways, better therapies to make stem cell transplants more effective, and new small molecules. He describes options for both newly diagnosed and relapsed/refractory myeloma patients using monoclonal antibodies to allow a patient's own immune system to target the myeloma. For high-risk newly diagnosed patients, elotuzumab (that targets the CS1 protein) is being used. For relapsed/refractory patients, daratumumab (that targets the CD38 protein) is being used. He shares the very exciting use of vaccines and how they target myeloma and strengthen the immune system at the same time. These newer vaccine approaches are being used with and without transplant and possibly as maintenance therapy (!). He also discusses an upcoming PD-1 study that takes the brakes off the immune system. These powerful approaches may be what the future holds for myeloma therapies - less chemotherapy and a combination of immunotherapies that will strengthen, support and take the breaks off the immune system to target myeloma but boost the immune system at the same time. With 38 active open trials in myeloma (an exceptionally large number at one center), he shares the benefits of having a large myeloma team. With the complexity of myeloma and a wide variety of newer approaches, it is simply not possible for one expert to cover it all. Dr. Orlowski also describes the work to improve quality of life by using small molecules (like proteasome inhibitors) in oral versions so patients can spend less time in the clinic.  The live mPatient Myeloma Radio podcast with Dr. Robert Z. Orlowski 

Jenny: Welcome to today's episode of mPatient Myeloma Radio, a show that connects patients with myeloma researchers. Patients joining myeloma clinical trials can make a big difference in the pace of research. We could cut research time by a large percentage if more of us participated, and I know we'd all like to find better therapies and a cure sooner rather than later. If you'd like to receive a weekly email about past and upcoming interviews, subscribe to our mPatient Minute newsletter on the homepage or follow us there on Facebook or Twitter, and please share these interviews with your myeloma friends. We have a new site called myelomacrowd.org that's the first comprehensive site for myeloma. There are resources for newly diagnosed patients, patients with more myeloma experience, and links to the best resources in the world of myeloma. You can find myeloma news and work by excellent myeloma foundations and others. Now, today we are very privileged to have with us Dr. Robert Z. Orlowski of the University of Texas MD Anderson Cancer Center. Dr. Orlowski is Professor of Medicine in the Department of Lymphoma/Myeloma with a Florence Maude Thomas Cancer Research Professorship in the same division. He has a dual appointment and is also a Professor in the Department of Experimental Therapeutics. Dr. Orlowski is the director of the myeloma section in the Department of Lymphoma/Myeloma. He's a member of the NCI Steering Committee, Multiple Myeloma Tissue Bank Steering Committee, Computerized Provider Order Entry Steering Committee, the BMTC CTN SOSS Myeloma Committee, and American Society for Biochemistry and Molecular Biology. He's the chair of SWOG, which we'll ask him about a little bit later and is on the Editorial Board of Hematology and Journal of Clinical Oncology. He's received numerous awards over a number of years, including the LLS or Leukemia & Lymphoma Society, Scholar in clinical research, LLS Man of the Year, Emil Frei III Award for Excellence in Translational Research from MD Anderson. He's completed an innumerable number of studies and is a recipient of a coveted SPORE grant from the NIH. This does not even begin to mention the complete list of his accomplishments, so we welcome Dr. Orlowski. Today is our 25th show, Dr. Orlowski. You've got us started on this show, you were the very first interview that we had, so thank you and welcome back!

Dr. Orlowski: Well, Jenny, thanks for having me again and I'd like to congratulate you and your team there for launching this very successful endeavor, which I think has helped a lot of patients in their travels through their course of myeloma.

Jenny: Well, patients love hearing it straight from those who know what they're talking about, which is you. Let me ask you, before we get started on the research, can you explain SWOG and what that is and how that works?

Dr. Orlowski: I'd be happy to. There are a number of what are called cooperative groups within the United States that have committees focusing on multiple myeloma. A cooperative group is where a number of different institutions get together and commit to doing a certain clinical trial. Usually, it's a large study like a large phase two or a phase three, which no one institution together or alone would be able to do, but when they all work together because the number of patients that can be put on is much greater, the trial can be finished more quickly and get the answer to the question being asked more quickly. These are funded by the National Cancer Institute, so your tax dollar is hard at work helping to advance the field in myeloma. There again are three groups that have myeloma committees, SWOG, which used to be the Southwest Oncology Group, is one of them. The other two are the Alliance, which used to be called CALGB, and then there's ECOG. It's also important to note that there's the BMT CTN, which is another important cooperative group and they mostly do transplant-related studies, so it's one of those ways that we try to advance the field in myeloma by doing cooperative clinical trials basically.

Jenny: Thank you. And so, SWOG covers the west and ECOG covers the east. What does Alliance cover? I'm just curious.

Dr. Orlowski: Actually, you're right that the original way the committees were put together is geographically, so SWOG did use to be in the southwest, but more recently, all of the groups are nationwide and it's a matter more of which group each institution individually wants to be a part of. For example, even though SWOG used to be southwest and that would include MD Anderson, we have sites which go from California to New York and other areas both north and south, and that's true for all the other groups as well. So really, they're all part of what is now called the National Clinical Trial Network.

Jenny: And that doesn't include anything outside of US or sometimes the studies do?

Dr. Orlowski: There are some efforts to reach out, for example, within SWOG to sites within Latin America and other countries. And on specific trials, there may be international efforts, but right now, the focus is still on doing studies in the United States.

Jenny: Well, thank you for the explanation because I know some people are not familiar with those and how they work. That's part of how clinical trials are constructed and run. Now, when I was doing research for this interview today, I was looking at the studies run at MD Anderson. You have, I think, the largest number of open myeloma clinical trials that I could find, which is a huge number. I know that you're going to need to help us prioritize what we talk about today, but can you share your strategy and your approach at MD Anderson about how you choose trials, how you construct trials, what you're looking for, because you have such a deep expertise with the biology of myeloma, and already with bortezomib, finding cures for myeloma. Can you just share how you go about doing that or what your strategy is?

Dr. Orlowski: Definitely. What we always try to do is to have a large array of clinical trials with what we think are the most exciting approaches, and that way, we hope that patients in the newly diagnosed setting, patients with relapsed myeloma or patients with refractory myeloma will have a couple of options to choose from if standard therapy is not appropriate, and that's in part because each of the trials is a little bit different in terms of what types of patients they're looking for. And so, even if you have, for example, three trials for relapsed myeloma, they may not all be options for an individual patient. So if you have more than one, it increases the likelihood that each patient will have at least one study to pick from. The way we've tried to approach things is by looking at certain themes. One of those themes is to try to advance immunotherapy. Everybody knows about chemotherapies that are available and we certainly need new ones. I'll talk a little bit later about some of those, but we're very excited about immunotherapies because those are approaches that we haven't so far been able to use against myeloma. Basically, the goal is to try to get the patient's own immune system to work for us by being able to better recognize and kill the myeloma cells. Most patients who have myeloma, through various mechanisms, the myeloma is able to keep their own immune system from killing the myeloma cells, but we're looking at ways to improve upon that. One way is with monoclonal antibodies and I think people are probably aware about some of the drugs out there, which includes things like elotuzumab and also daratumumab. These are antibody drugs which attach to the surface of myeloma cells and either alone or in combination with other drugs help to make the myeloma cells more visible to the immune system, and then the patient's own immune system comes in and attacks the myeloma cells. Right now, for example, we have one study open with daratumumab as a single agent in phase two and we also are working to open a large phase three study, which will compare lenalidomide and dexamethasone to lenalidomide, dexamethasone, and daratumumab. Also, in the immunotherapy category, I would put things like vaccines. One example that I'll give you -- this trial is currently closed, but will reopen soon -- there is a study that we're doing in collaboration with the folks up at the Dana-Farber among other places where we're using a peptide vaccine to try to improve the immune response against myeloma in patients with so-called smoldering disease or used to be called also asymptomatic myeloma. The peptide vaccine is basically the same as a flu shot in terms of the way it's administered and the difference is that the peptides, instead of representing part of the flu virus, these are peptides that represent myeloma cells. The hope again is to boost the ability of the patient's own immune system to recognize that they have these abnormal myeloma cells that need to be killed. And in the near future, that will reopen in combination with lenalidomide because these immunomodulatory drugs, we feel, will help the vaccine to work better.

Jenny: Now, let's go back just for one second because I know daratumumab and elotuzumab for monoclonal antibodies, they work differently. Daratumumab is targeting the CD38 protein, correct?

Dr. Orlowski: Correct.

Jenny: Can you explain the difference between daratumumab and elotuzumab, just how they work basically?

Dr. Orlowski: Sure. Well, elotuzumab recognizes a different protein, which is called CS1, so they attach to completely different protein molecules on the surface of myeloma cells. Both CD38 and CS1 really are expressed on virtually all myeloma cells, but I think the exciting thing is that it may be possible in the future to even combine them so that there would be an all antibody-based approach to treatment without introduction of chemotherapy drugs.

Jenny: Wow! I didn't know that CS1 was expressed on almost all myeloma cells -- almost all myeloma cells or all myeloma cells?

Dr. Orlowski: Pretty much all. I would say probably maybe 1% of patients may have myeloma that expresses either no or very low levels. The same thing is true for CD38. Actually, CD38 has been used for many years by the pathology doctors when they look at bone marrow biopsies to make sure that the diagnosis is in fact myeloma. And so, if the pathology doctors who make the diagnosis use it, you know that it has to be very widely expressed.

Jenny: And for whom are these studies most appropriate? And is this with transplant, without transplant, just the combinations? I know you said you were -- did you say you were doing it single agent? I mean, you're doing len-dex and then you're doing len-dex daratumumab for that study. Can you go over for whom that would be appropriate, those two studies?

Dr. Orlowski: Definitely. The elotuzumab, we right now have a study for patients with newly diagnosed myeloma that is high-risk where we're combining lenalidomide, bortezomib, dexamethasone, and elotuzumab for these patients in the newly diagnosed setting. The reason that we're targeting high-risk is that those are people -- and that's about 15% to 20% of newly diagnosed patients. Those are people who would not really have a good outcome with current standard therapy. And so, we hope that by adding an immunotherapy that this would improve the benefit of the chemotherapy. In terms of daratumumab, we have a study right now with daratumumab by itself in the relapsed setting. And in the future, to try to improve the efficacy further, we're hoping to be able to open this study with daratumumab plus lenalidomide and dexamethasone. So really, we have antibody-based treatments for newly diagnosed patients, for relapsed patients, and for people with myeloma that has been refractory to their last therapy

Jenny: Well, that's great. A lot more options are better. Can you give us a little history about how they monoclonal antibodies were discovered?

Dr. Orlowski: It's interesting. All of these antibodies were rationally designed, meaning that rather than going out and looking randomly for a drug that might or might not work against myeloma, studies were done that showed that these proteins, the CD38 and then CS1, were good targets because they were expressed on so many patient's myeloma cells and then the antibodies were developed in the laboratory to attach to these targets and then they were moved into the clinic. So this is, I think, an example of the direction that we're going in the future, which is to learn enough about myeloma biology that we can hopefully predict ahead of time what will be the good targets and develop drugs against them rather than just try a hundred random drugs and hope that one of them will work against myeloma.

Jenny: And it looks like daratumumab has -- and I don't know about elotuzumab -- but that they've shown single agent activity, which seems like it gets everybody excited, that it works by itself. Do you think eventually that these will always be used in combination? Because I know myeloma is very wiley and it gets around therapies because it's so complicated and different in each patient. What do you think will happen with the whole monoclonal antibody platform?

Dr. Orlowski: I think what we know right now is that elotuzumab by itself has modest activity against myeloma. I think it's fair to say that it will probably always be used in combinations with other drugs like either lenalidomide or bortezomib. Daratumumab seems to work by itself, but there again, when you add lenalidomide, the activity is even greater. I think ultimately that both of those antibodies will be used mostly in combination. It's possible that other antibodies will be developed that works so well by themselves that they don't need to be combined, although in general, we find in myeloma that if a drug works well by itself, it's going to work even better in combination.

Jenny: In the study that's the phase three -- so you're having good results in your phase two study - in the study that's open or that's looking to open, the phase three, how many patients will be desired for that study? Do you know?

Dr. Orlowski: Sure. The phase two, by the way, in the current cohort that's open, it has about 60 slots and you may know that daratumumab has a designation from the Food and Drug Administration as a breakthrough therapy because of the very encouraging data. In the old days, that used to be fast track status. That means that the FDA is very excited about the data and they will review it very quickly when available for a possible approval. The randomized study is much larger. I don't remember the exact number, but it's somewhere in the 600 to 700 patient range, I believe. So the good news about that is that it will be open for quite a while and hopefully give lots of people the opportunity to participate.

Jenny: But you still have places open for the phase two. Is that what you're saying?

Dr. Orlowski: Correct.

Jenny: So as patients, if we are interested in a monoclonal antibody approach, that would be something great to ask you about.

Dr. Orlowski: Definitely. We're happy to have you.

Jenny: I apologize for jumping backwards. If you want to continue talking about vaccines and give us a more broad approach about how they work because the idea of a shot that could cure myeloma is totally exciting.

Dr. Orlowski: Definitely. I mentioned earlier that one of the things that myeloma unfortunately does is suppress the patient's own immune system, and I think people understand this because people with myeloma are more at risk for infection, for example, than people who don't have myeloma. That's in part because the myeloma has not just suppressed the reaction against the myeloma itself, but generally reduces the effectiveness of the immune system against myeloma. It's therefore important to try to improve the strength of the immune system and there are a number of ways that that can be done. One is we mentioned these antibodies, which help to flag the abnormal myeloma cells for the immune system. Another is by using drugs that may be able to take the breaks off the immune system. An example of that is an antibody to a protein called PD-1. We actually have a study that's about to open with lenalidomide and dexamethasone plus an anti-PD-1 antibody. I know sometimes people can get confused by hearing all these different drugs, but the important thing to remember is that these are approaches which we're hoping will unleash the immune system against myeloma. The concept behind the vaccines is that we can train the immune system to recognize proteins that are expressed on myeloma cells, but not on normal cells. And again, it's kind of like the flu shot. What the flu shot does is you get an injection of protein that looks just like the influenza virus. And so, your body is able to build up immunity against that so that if you're exposed to the flu later, you have a better shot of fighting it off This is the same concept. We're injecting peptides or small proteins for example that represent CD38 or CD138, and even CS1, and the hope is that that will train the immune system. Ultimately, what we probably will be doing is using these various immunotherapies together, meaning that we'll be using a vaccine with an antibody that recognizes a myeloma cell plus an antibody that takes the breaks off the immune system and probably with an immunomodulatory drug because each of these really helps the immune system in a different way. The stronger we can make it, the better the chance that the myeloma will go into remission. And I think if we're going to cure myeloma, we really need to take advantage of the patient's own immune system and not knock it down with a lot of the chemotherapy drugs that we use all too often.

Jenny: That's a great idea and approach. A question, what's the difference between CD38 and CD138? Are those two different proteins?

Dr. Orlowski: They are two different proteins. Both of them are very widely expressed on myeloma cells and there are antibodies that are being developed against CD138 as well. I think, again, the more drugs we have and the more targets, the better because that will allow us hopefully to use them one after another, or even use them together. We still have to prove that, but my feeling is that combining the antibodies will eventually result in better effects.

Jenny: And patients can know if they have CD38 or a CS1 or CD138 expressed. It's the FISH test, right, or am I having a chemo brain moment?

Dr. Orlowski: The FISH test actually looks at chromosome changes inside the myeloma cells --

Jenny: So it's the flow cytometry, right?

Dr. Orlowski: Correct, exactly. It's the flow cytometry, which tells you -- it's sort of like a fingerprint of the myeloma cell. It tells you what proteins are on the surface of the myeloma cell, which of course are very different than the proteins that are on a B lymphocyte or a T lymphocyte or a neutrophil, and that's how the pathology doctors and the myeloma doctors can differentiate between various cells in the bone marrow.

Jenny: And a question about the vaccines. I've seen some studies that are using the vaccines in combination with transplant. I can't remember if they're before transplant or after transplant, but are your studies involved with transplant, using transplant, or just alone?

Dr. Orlowski: Good question. We actually have both. We have one study that we're doing. You mentioned earlier our SPORE Grant from the National Cancer Institute and of one of the studies that is being supported by that grant is a vaccine study, which is being done after stem cell transplant. The way this works, it's kind of interesting. I think people with myeloma are hopefully used to following their M-protein or M-spike or monoclonal spike. This is a protein that the myeloma cells make that we can detect in the blood because the only cells in the body that make this protein are the myeloma cells and there's a lot of the protein inside them and also often on their surface. The way this study is done is we take blood from the patient before they have a stem cell transplant and we purify this M-protein in the laboratory. Then just before the patient has the transplant, we give them an injection of this protein along with other material to help the immune system recognize it better. And again, just before the transplant, we collect T-cells from the patient's blood, which are then grown in the laboratory and these are T-cells which recognize the myeloma. Then after the transplant, these T-cells are infused back in the patient's own cells and they get additional injections of the M-protein as a vaccine. So again, this is a way to try to train the immune system. And after transplant, you're basically developing a totally new immune system. And the thought is that by exposing it to this myeloma protein, the immune system will be much stronger in recognizing cells that make this protein, which are basically the myeloma cells. We hope that that will be a good approach to improve upon the benefits of stem cell transplantation because we know that people still have myeloma after transplant unfortunately, and many of them go on maintenance therapy, but a vaccine would be even better because it would avoid some of the chemotherapy drugs that are used. And just briefly, I'll put in a plug for an upcoming study that we're going to do, which is using elotuzumab as maintenance after transplant, again, trying to avoid chemotherapy drugs.

Jenny: Well, especially because a lot of people have been talking about long-term maintenance therapy with lenalidomide and other approaches. That's always great if it keeps the myeloma away, but also kind of a concern. So having a monoclonal antibody, if you needed to use it long-term, would seem to be a better or a nice approach.

Dr. Orlowski: Definitely. We know that even with lenalidomide as maintenance, it unfortunately does not cure most people. It does prolong the time that they are in remission, which is great, but most people still have myeloma cells left over and we'd like to attack those. And some of the approaches I've mentioned, including with vaccines as well as antibodies, are really trying to get rid of those last few myeloma cells left over, which I think will get us closer to curing some folks with myeloma.

Jenny: And it looks like these approaches are more broad, so you take what's most common across all myeloma patients and try to develop a therapy around that versus trying to look at a specific, like a (4;14) or a (14;16) translocation or del(17p) and then trying to develop a therapy for that. Is that right?

Dr. Orlowski: Well, we're actually doing both. You're asking a great question. One of the things we're trying to do is also develop specific therapies for types of myeloma. You mentioned del(17p). We have a laboratory-based project, which has been funded by the Leukemia & Lymphoma Society, which is trying to identify what are the best targets in del(17p) myeloma that will be helpful in the clinic. And if we can successfully navigate that project, we're going to try to do the same for some of these other molecular subtypes, but until we know what is best for each individual subtype, it's I think wise to take advantage of the fact that there are some targets that are common across everybody's myeloma because then the cost of therapy will be cheaper and we'll be able to help more people than, for example, a drug only against (4;14), but we're really trying to do everything.

Jenny: And once you start a project like that in the lab, how long does it take to get to the point of clinical trials?

Dr. Orlowski: Great question. It's very variable and of course, it depends on how exciting and how quickly the results come, but I'll give you one example. We published recently some studies that identify the mechanisms of resistance to lenalidomide and we found that at least in the laboratory, we were able to overcome that resistance with a drug called ATRA, which is all trans retinoic acid, and this is a drug which is already used in, for example, patients with certain types of leukemias, so we knew the right dose and what side effects. The paper was published earlier this year and we already have a clinical trial with lenalidomide, dexamethasone, and ATRA, which is open and enrolling patients. So in some cases, we're able to get these ideas from the lab to the clinic very, very quickly. Where it slows down a little bit is if you're looking at a new drug that hasn't been in people before because then you have to go back to phase one studies to make sure that the drug is safe before you can look at efficacy, although usually phase one studies look at both.

Jenny: And that's kind of similar to PD-1. Maybe you can give us a little more explanation about that study that you mentioned because Dr. Benson just months ago mentioned PD-1 and said it had been used in melanoma.

Dr. Orlowski: Correct. PD-1 is a very hot target in other cancers because as you can imagine, myeloma isn't the only cancer that is able to survive by suppressing the patient's immune system. Many cancers do the same thing and this PD-1 -- and there's also something called PD-L1 or PD-1 ligand which binds PD-1. Many cancers use this approach and the first studies that really showed that blocking PD-1 was very exciting were in melanoma, but there are studies now looking at other cancer types. For example, there have been nice data in lung cancer and we're hoping to be able to show the same thing in myeloma. Although this is not a myeloma-specific therapy because it's seen in other cancers, as I mentioned earlier, because most cancers use these mechanisms to suppress the immune system, we're still hopeful that it will help myeloma patients as well.

Jenny: When you just talked about shorter development times, if you have a drug that already exists and is being used somewhere else, how do you -- it's tricky because it seems like to really understand myeloma, you have to have this deep knowledge of the disease, which is why most patient advocates advocate going to a myeloma specialist, but yet it seems like some of these discoveries come maybe across certain kind of cancers, that the disease is not necessarily, let's say, localized. So how do you construct, or as a researcher, how do you take all that into consideration to find new targets?

Dr. Orlowski: Well, you're right. It's sort of very confusing at times with all the number of targets, but it's also exciting in a way because we're not yet at the point where we have enough targets in myeloma and we need to identify new ones. I would say it's a combination approach. First of all, although we know a lot more about myeloma biology than we used to, we still don't know as much as we would like to know. For example, we don't even know the basics of why some people develop myeloma and others do not. Some of you on air may know that African-Americans have twice the risk of developing myeloma compared to Caucasian Americans, and yet we don't really know why. Maybe if we did, it would help us to treat the disease better or maybe even prevent it. We're actually doing a study to try to understand that, which is being led by some folks at the University of Southern California. Also, we're trying to identify new myeloma targets, but you mentioned other cancers and I think we all have to be open to learning from other cancer researchers in other fields because there are some pathways that are shared between cancers. And so, we have to be open to the possibility that something which is learned in melanoma or colon cancer will also be applicable to myeloma.

Jenny: And it would seem that it's a lot to stay up-to-date on if you have a busy practice.

Dr. Orlowski: Well, it's true, but that's why it's important to have a large team because no one person can be an expert in any of these fields, or I should say, in all of the fields. You can be an expert in two or three of them, but it's difficult to cover all, which is why it's great to go to an academic center with a myeloma program because you'll have some people who are experts, for example, in small molecules or drugs. You'll have other people who are experts in antibodies. You'll have still other people who are experts in transplant. And then when your case is discussed in a large forum like this, you get not just the opinion ultimately of one doctor, but you get the opinion of 10 or even 20 doctors together and that's like seeing 20 doctors individually even though you're only seeing one in the clinic on the particular day that you visit with them. I think that's the power of some of the myeloma programs that are out there.

Jenny: Can you tell us about the MD Anderson group?

Dr. Orlowski: Well, we have a number of folks both on the laboratory side, as well as on the clinical side. As of April 1^st we're going to have six people who see multiple myeloma patients including -- we have a new doctor coming from the National Cancer Institute. Her name is Dr. Elisabet Manasanch and we have doctors that are focused on laboratory research in myeloma. On the laboratory side, for example, Dr. Larry Kwak, who's the department chair, is a big vaccine and immunotherapist who does lots of work in the myeloma space. I have a laboratory group and we're interested in new, small molecules, as well as understanding the biology of myeloma and developing biomarkers. We also, for example, have a physician in the laboratory, Dr. Jing Yang and her expertise is in myeloma bone disease. That just gives you a flavor for the variety of people and therefore, the variety of input that people could get into their cases. This is not just at MD Anderson. I don't want to shamelessly plug only our center. There are many excellent myeloma centers out there that have this kind of approach where you have both different types of clinicians, as well as different types of laboratory-based researchers, all of whom work together to try to push the field forward.

Jenny: Well we are appreciative for what you're doing. So you've talked about immunotherapies and maybe there's more you want to say, but I know you had a few themes you wanted to talk about, so I don't want to prevent you from doing that.

Dr. Orlowski: No, not at all. Thank you. Actually, we covered the second theme that I wanted to mention already, which were new approaches to try to make stem cell transplant work better. I think the last thing I would talk about is new, small molecules because as I mentioned earlier, we still need to have new drugs, as well as new drug classes that will work against myeloma. And just briefly, I'll mention some of the things we're doing. We have a couple of trials with oral proteasome inhibitors. The current drugs, which are bortezomib and carfilzomib, have to be given by injection, but there are new oral proteasome inhibitors available, which we're now using both in newly diagnosed patients, as well as in the relapse setting on clinical trials. The advantage is that for example, one of the studies we have for newly diagnosed patients is with the combination of oprozomib, lenalidomide, and dexamethasone, oprozomib is one of the oral proteasome inhibitors and what that means is that people can get initial therapy for their disease with a regimen which is all oral. They don't have to get any injectable chemotherapy, and that's exciting because that means they spend less time coming back and forth to the clinic or the hospital to get their treatments, and therefore hopefully have a better quality of life.

Jenny: That's big on quality of life.

Dr. Orlowski: Yeah, definitely. I mean, we hope to be able to cure people, but we also want to maximize their quality of life, and certainly spending less time traveling back and forth to see us or to get treatment is a big part of that, not to mention that it's somewhat expensive to come back and forth. If we could save people a few bucks while improving their myelomas and quality of life, that's a win-win for everybody. We also have some studies with new drugs coming in the relapsed and refractory setting. One of the drugs we're especially excited about is what's called filanesib. The older name was ARRY-520. This is a so-called kinesin spindle protein inhibitor, which is a new drug class in myeloma. It has shown nice activity in relapsed and refractory myeloma in the phase one setting, and we will have phase two and phase three trials available. And then the last -- I promise -- molecule I'll talk about is a drug called ACY-1215. People may know that there was a press release at last year's ASH meeting about positive data from a study with panobinostat in combination with bortezomib and dexamethasone. Panobinostat is a so-called deacetylase inhibitor. Basically, what that drug does is it changes which genes are expressed in myeloma to make the myeloma cells more sensitive. I think based on that press release, people are anticipating that the drug will be approved. ACY-1215 is another drug in that same class, but is more targeted. It only hits a certain subtype of deacetylases, which means we hope that it will be as effective, but much better tolerated with fewer side effects. And so far, that's what we're seeing. I think that's another theme, which is that as we learn more and more about the drugs and the targets, we're able to develop agents that are much more specific, that retain activity, but that show much less in the way of side effects. And less side effects, as we mentioned earlier, are great because people have fewer complications. They feel better and their quality of life is better.

Jenny: You're saying that the ACY-1215 is in the same class as panobinostat, and panobinostat is more broad and then the other is more targeted?

Dr. Orlowski: Correct.

Jenny: I think that's interesting that you can take two drugs that are in the same class and then combine them together because you would just think you would need one or the other, but I've seen it now a few different places.

Dr. Orlowski: Well, right now, we're not yet combining panobinostat with the ACY-1215, but you're right. Actually, we did a study and we're hopefully about to publish this where we combined lenalidomide and thalidomide together. What we found is it seemed that the combination was better than either drug alone, so it is sometimes possible to combine two drugs in the same class and get better outcomes because the drugs are not always identical. They are different and that sometimes can be taken advantage of in the clinic.

Jenny: Well, is there another area you'd like to talk about before we open it up for caller questions?

Dr. Orlowski: Well, I think I've probably gone off long enough. Maybe we can take some questions from the folks at home and get them answered.

Jenny: Well, we'd like to open it up for caller questions, so if you have a question for Dr. Orlowski, you can call 347-637-2631 and press 1 on your keypad, and while we're waiting for someone to become brave to do that, I have several questions that have been emailed in. I have one from Dana who says, "Back in July, you spoke of a possible trial for those with smoldering myeloma using the anti-PD-1 antibody." She says, "Long story short, I know they didn't receive FDA approval to try it in smoldering myeloma. Are you planning any others with immunotherapies in particular…" and you talked about PD-1 a little bit, "… as opposed to the CRd and the Rd novel anti-myeloma agents already in trials?"

Dr. Orlowski: Great question. I've mentioned that we have the PD-1 antibody in combination with lenalidomide and dexamethasone. What the FDA said about the study in smoldering myeloma, which I think is very reasonable, is that they wanted a little bit of data about efficacy and safety in myeloma before using it in the smoldering setting, and we therefore are still planning on doing that study, but what we hope is that maybe later this year when we have some data from the combination, we can submit that to the FDA and if they find that the data are supportive of activity and safety, we hope that they'll approve the single agent study in the smoldering setting.

Jenny: And then her second question, she just wrote a post actually on the Myeloma Crowd about smoldering myeloma patients being needed to be evaluated to make sure they don't actually have active myeloma, so she asks, "Can you also give us your best opinion on how  those smoldering myeloma should be evaluated in order to exclude active myeloma?"

Dr. Orlowski: Well, definitely that's an important thing to do because if you have active myeloma, you need treatment. The way we look at these patients is, of course, we do the plain bone survey and the bone marrows and the urine tests and the blood tests, but if those are all negative, we usually will also get a PET scan, and in some cases, either or both an MRI and a PET scan. The reason is that the plain X-rays sometimes don't detect bone damage at a low level that can be detected by the MRI or the PET scan. And if there is bone damage ongoing, you want to try to catch it as early as possible. If there is bone damage on the MRI or the PET, then we treat them like an active myeloma.

Jenny: Great. Well, that answers her question. Okay, so we have a caller who I would like to open it up for. Okay, go ahead with your question.

Caller: Aloha, Jenny! Is it true you're on your vacation in Hawaii? What are you doing on a radio show?

Jenny: Well, it's important that we're doing this today. :)

Caller: A question I have is around a trial that I heard about at the University of Utah. It's a phase one trial from a drug company called Sanofi. I don't remember the name of the drug, but it seems to be -- the news that's leaking out is it's pretty interesting and it's phase one trial. Could you tell me more about what's going on there or I'm just making this up and heard incorrectly? Do you know what the name of that drug is and what the class of that drug is?

Dr. Orlowski: Well, there is a Sanofi drug which doesn't yet have a name. It's called SAR650984. Does that ring a bell?

Caller: I don't know.

Dr. Orlowski: Not quite, okay.

Caller: Jenny, do you know what this is?

Jenny: I think that might be it.

Dr. Orlowski: So the Sanofi drug that I just mentioned is also a CD38 antibody -- okay, there we go, so it has some similarities to daratumumab because it really binds the same target, but there are also differences because it binds in a different location, and you're right, that so far the data seem to say that it is a very active drug by itself like daratumumab. If you are interested, I think that that's a good drug. We've also talked with the Sanofi people and hopefully there will be a nationwide study of that drug very, very soon because it's another one that we'd like to get into people to help with myeloma.

Caller: For drugs like this with early indicators that are leaking out are pretty interesting. Can this be fast tracked into patients or are we still years out from having that available? Because as I understand, this was available for other cancers and it's been approved for other cancers. Can it be used, off-label use, for a patient that might be refractory to other treatments?

Dr. Orlowski: This particular drug has not been approved for other cancers, so I don't think that you're talking about the same one. When you're asking about whether a drug approved for cancer D can be used in myeloma, the answer is that your oncology or hematology doctor has the discretion to use a drug that is approved for an off-label indication. The problem that sometimes you run into is that insurance companies are becoming more careful about what they approve and don't approve. And sometimes, if a drug is not approved in myeloma, you may not be able to get coverage for the cost of treatment, but this particular drug of the anti-CD38 antibody has not yet been approved. Certainly, we're hoping that it will get this fast-tracked, or as I've mentioned earlier, it's now called breakthrough therapy designation, which will mean that it will go through the approval process much more quickly, but I still think that we're a couple of years away from the approval of that drug because it still is in a phase one study, which means a relatively small trial, and that's not really enough basis upon which to be able to get an approval.

Caller: All right, yeah, so this one was used for skin cancer. Maybe it wasn't approved for skin cancer, but that was the original target, and then there are -

Dr. Orlowski: We might be talking about a different drug then.

Jenny: Yeah. I think that one was actually used in lymphoma, wasn't it, or maybe not?

Caller: Okay.

Dr. Orlowski: If you want to email me, my address is rorlowski@mdanderson.org. Just give me the name of the drug, if you can look it up, and I'll let you know what I think by email.

Caller: We'll do that. We'll run it down and quit rearranging my ignorance here. All right. Thank you very much.

Dr. Orlowski: My pleasure.

Jenny: Okay, and just to comment about that, too. I know the use of new drugs in -- I've heard a lot of researchers say the use of new drugs is by far the best within a clinical trial environment because then we can measure results instead of somebody getting a drug in a one-off kind of situation. What's your opinion on that.

Dr. Orlowski: Well, I definitely agree. The benefit of a clinical trial is that the data are collected very carefully and then put together. One patient responding to a new drug for myeloma is certainly good news, but we do sometimes see that drugs will have only one or two responses and if you treat 10 or 20 patients, then you don't see any additional benefit. So I think that helps to have a larger experience because we want drugs that help more than just one patient on average, although really any patient who benefits, of course, that's great.

Jenny: Okay. One more question from Michelle. She says, "Can you explain your work at MD Anderson in lymphoma with brentuximab targeting CD30 and does that relate to myeloma?

Dr. Orlowski: Good question. Brentuximab is a monoclonal antibody. It's a little bit different than the drugs that we've mentioned earlier because the other antibodies right now for myeloma that we talked about are so-called naked antibodies, which means it's just the antibody by itself, whereas brentuximab is a conjugated antibody, meaning that it has a drug molecule attached to it. It does recognize a protein called CD30 and after it attaches, the antibody plus the attached drug is taken up inside the cell. Then the drug, which is the drug called vedotin and it has an antimicrotubule effect, is released and that's what does the job of killing, in this case, the lymphoma cells. Unfortunately, CD30 is not very commonly expressed on myeloma cells, so I don't think brentuximab is going to have a big role to play, plus one of the side effects can be neuropathy, and the last thing we need is another drug in myeloma that causes neuropathy.

Jenny: So you haven't used it a lot in -- or you haven't used it with myeloma?

Dr. Orlowski: Now, most myelomas do not express the CD30 protein, which is what the antibody recognizes.

Jenny: Well, that was her question. Well, we are out of time. Thank you so much, Dr. Orlowski, for joining us today. As always, you're excellent at explaining everything we need to know. We hope that you will just keep going in your research. Thank you for your research to take care of myeloma patients and your discoveries will help find a cure for this disease. We're so grateful for you outstanding work.

Dr. Orlowski: Well, it's my pleasure and thank you very much for having me.

Jenny: Oh, thank you for participating. We are really grateful. 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 cure for myeloma by joining clinical trials.