Dr. Robert Z. Orlowski, MD, PhD MD Anderson Cancer Center Interview Date: January 9, 2015

Dr. Orlowski begins the new year by highlighting some of the most important myeloma therapies that will take us into 2015. He reminds us of the new International Myeloma Working Group guidelines that allow for earlier treatment in smoldering myeloma without waiting for CRAB features. He notes that MRIs will be a critical tool for smoldering myeloma patients to make this determination. He notes the important results of the ASPIRE study of carfilzomib/lenalidomide/dex, telling us that it gave progression-free survival for two years, even in the relapsed/refractory setting. To put that in perspective, this used to be only accomplished with transplant in the newly diagnosed setting. He describes how treatment is becoming more tailored and uses the example of how immunophenotyping can tell if the plasma cells in the bone marrow are normal or not post-treatment. He predicts that two new immunotherpaies (elotuzumab and daratumumab) may be approved in 2015. The appeal of these immunotherapies are that they target myeloma cells that are in virtually all patients, for maximum effect. He also shares the excitement around CAR T and CAR NK cell therapies in myeloma. He shares the development of new oral proteasome inhibitors to make treatment more convenient for patients and highlights two new inhibitors that are showing impact on their own that will be therapies to watch in the new year. The Myeloma Crowd Radio Show with Dr. Robert Z. Orlowski

Jenny: Welcome to today's episode of Myeloma Crowd Radio, formerly mPatient Myeloma Radio, a show that connects patients with myeloma researchers. We've run this show for the last year and a half as mPatient Myeloma Radio and started it because we want to encourage patients to consider clinical trials. Less than 5% of myeloma patients and adult cancer patients participate in clinical trials, and clinical trials are the way that we move research forward. We've spent quite a bit of time and interviewed quite a few researchers (over 42 researchers in myeloma) to learn about the very best clinical trials and the latest research. We will continue this show as Myeloma Crowd Radio and we think it's appropriate that Dr. Orlowski is joining us today because he helped us launch mPatient Myeloma Radio. Because I started the Myeloma Crowd website and we now have many others helping with that website, I thought it was time to do a little consolidation on the name.  We have brought over all of the past shows on to the MyelomaCrowd.org website and we'll be posting on new shows on the Myeloma Crowd website and we'll eventually phase out the mPatient site over time. Now, I'd like to give a shout-out to Dana Holmes and her mambo for myeloma program. She's helped spread worldwide awareness for myeloma. I think it's a great example of what patients can do, which leaves me to another announcement that the Myeloma Crowd just made us part of the ASH Conference. We are a division of the CrowdCare Foundation, which I also started, and we will be starting a crowd funding for myeloma research project in February. We'll be calling for proposals in February. We absolutely love what the other foundations are doing. We've personally donated to each of these foundations, so if you ask why we created our own initiative: We think it's important to give patients the opportunity to be involved as one of the key stakeholders in finding a solution for myeloma, so we will be selecting specific studies to fund. We'll be giving you a very transparent view of where the funds will go. Patients will be able to have a say. There are patients on the advisory board that will be helping to select projects, and this is really the first time that patients have had a key role in helping determine what research gets funded and how, so we encourage you to think about how you can get involved to make a difference. We'll have lots of ways that you will be able to get involved outside of just funding with dollars, so you'll be able to perform activities that will help. If you'd like to receive a weekly email about the past and upcoming interviews, you can subscribe to our Myeloma Crowd Newsletter on the homepage or follow us there on Facebook or Twitter, and please feel free to share these shows with your friends. We are very privileged to have with us today Dr. Robert Orlowski of the University of Texas MD Anderson Cancer Center. Dr. Orlowski is Professor of Medicine in the Department of Lymphoma and 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 and Myeloma. He's a member of the NCI Steering Committee, the Multiple Myeloma Tissue Bank Steering Committee, the Computerized Provider Order Entry Steering Committee, BMT Committee, and American Society for Biochemistry and Molecular Biology. He's the Chair of SWOG, which is one of the major research groups that compile different facilities together to run studies. It's called the Southwest Oncology Group and he's also on the Editorial Board of Hematology and the Journal of Clinical Oncology. He has received many awards over a number of years including the Leukemia & Lymphoma Society Scholar in Clinical Research, the Leukemia & Lymphoma Society's Man of the Year Award, Emil Frei III Award for Excellence in Translational Research from MD Anderson. He's completed many, many studies and is the recipient of a coveted SPORE grant from the NIH, which is the highest level of grant you can achieve. Dr. Orlowski is very aware of the need to communicate to the multiple stakeholders in the myeloma community and he has a daily newspaper that I highly recommend. I found it to be one of the most valuable resources around for myeloma. It's called a Paper.li paper. The title of it is "Multiple Myeloma Daily". If you search in Google on "Paper.li and Multiple Myeloma Daily", you'll find the link. He is also very active on Twitter and you can follow him at @myeloma_doc. I'm consistently amazed at the good work that he does to communicate the complexities of myeloma in such an elegant way and consistently educates the various stakeholders, like I said, in this myeloma community. He educates not only the others, his peers, but also patients. He completed a similar show about ASH yesterday, so you may want to look at that program as well.

Dr. Orlowski: Yes, Jenny, thanks very much for having me on your program and thank you for the very kind introduction.

Jenny: Oh, your timing is perfect! I know you had something right before this. Well, thank you so much for joining us. I feel like the timing is perfect. We are changing the name of the show to Myeloma Crowd Radio for some name consolidation, and you were our first interview on mPatient Myeloma Radio, so I feel that this is a fitting start to the New Year.

Dr. Orlowski: Thanks very much.

Jenny: The ASH Conference was held in December and there was so much content. It's hard to get your arms around it, but it seems that myeloma is really seeing its day. There was a major session where Dr. Jesus San Miguel spoke and you were the moderator for the main myeloma session with hundreds, if not thousands, of attendees. And so, maybe you can give us a broad overview and then dive into what you feel like are the most important subtopics, and then we'll get to your research at the end, if you don't mind.

Dr. Orlowski: Sure. Well, thanks again for the invitation, and you're right. Myeloma has gotten a lot of attention lately, all for good reasons, which is because all of the new drugs and advances and improvements in patient outcomes, so let me give you an overview of what I think were some of the highlights not only from ASH, but maybe some recent developments in the myeloma field that people should know about in general. One of these is in the area of what is smoldering myeloma versus what is active myeloma, and some of the listeners that you have on may know that there is what's called smoldering myeloma. It used to be called asymptomatic myeloma. This is a condition where patients have myeloma based on having at least 10% plasma cells in the bone marrow, but they don't have any of the so-called CRAB criteria, which used to be high calcium, which is the "C"; renal insufficiency, which is the "R"; anemia, which is the "A"; or bone lesions, which is the "B". The reason the CRAB criteria were important is that if patients had CRAB criteria, they usually were considered candidates for chemotherapy, whereas if they had myeloma without CRAB criteria, they usually were considered candidates for watchful waiting. The watchful waiting part of course is always frustrating because as a patient, the last thing that you want to hear after you're told that you have cancer is that your cancer doctor isn't going to do anything about it, and you can imagine from a physician perspective, we don't get into the field of treating myeloma patients and then say, "We're not going to treat." It turns out though that in the smoldering category, there are some people now that we can identify as being ultra-high risk and these are folks who have such a short time between diagnosis of smoldering myeloma and between the development of one of these CRAB criteria that now, the definition has been changed. And now, those patients are considered to have active myeloma. The three areas now that have been added, one is if on the bone marrow, patients have at least 60% involvement of their bone marrow with plasma cells, a second is if their free light chain ratio is a hundred or more, and a third is if there are at least one focal bone lesion on magnetic resonance imaging. So people who have any one or more of those who used to be considered smoldering are now considered active and therefore should be candidates for chemotherapy rather than watch and wait.

Jenny: I know that you posted this several times and feel that it's really critical, so maybe you can help us understand. For this group of people, it's very critical.

Dr. Orlowski: Definitely. It means the difference between treatment and no treatment, and again, the rationale for treating them is because we now understand that they're not going to stay asymptomatic for a long period of time, whereas the people that don't have these criteria, some of them have a chance of never becoming symptomatic and therefore maybe never needing chemotherapy.

Jenny: What else was part of that change that is so very critical?

Dr. Orlowski: Well, the other features of course are that there is still a high risk smoldering myeloma group. These are people who have within about five years of diagnosis. Anywhere from 50% to 70% of those people will progress to myeloma, and there are now many studies that are targeting those patients as a sort of, if you will, chemo prevention approach to try to reduce their risk of progression. One of them is a national trial, which is occurring through the ECOG folks. That's the Eastern Cooperative Oncology Group where people may get either lenalidomide or watchful waiting, and there are other studies underway as well, including with some of the monoclonal antibodies, which we'll hopefully talk about later. I think those are exciting because the antibodies are a way to make the myeloma cells more visible to each patient's own immune system and help their immune system to attack the cancer cells.

Jenny: Well, those are great approaches and we will talk about those in a little bit. If they have some of those features, obviously they could be treated, but can you remind us what constitutes ultra-high risk for those that don't know that?

Dr. Orlowski: Well, ultra-high risk would now be considered people with at least 10% plasma cells in the bone marrow. Usually, they have a higher level, not always, but usually a higher level of the monoclonal protein, meaning at least three grams per deciliter. If they have again one of these three criteria, either 60% or more plasma cells in the bone marrow, or a free light chain ratio of a hundred or more, or if on MRI, for example of the spine, they have one or more focal bone lesions, that means they're ultra high risk and therefore, they should be treated. The immediate implications are that you need to probably have MRI of your spine in particular even if you're not having any back pain. If you're considered to be in the smoldering group, to know whether you're ultra-high risk or just plain old high or intermediate or low risk, the MRI I think is going to be critical. We think in the future that probably PET scanning will be important as well. What this means is that if you don't have symptoms, we still have to look even harder to make sure that you're not at high risk for developing symptoms even within a few months.

Jenny: And the sensitivity of all these tests is improved, so --

Dr. Orlowski: Yes. Definitely the MRI and the PET scan are much more sensitive than just the plain bone survey by X-ray, which used to be the standard of care.

Jenny: Yes. From what I understood, that only catches it at a later stage.

Dr. Orlowski: Correct.

Jenny: But for ultra-high risk, you're not looking at genetic features, right? You're not looking at deletions or additions of specific genes for ultra-high risk. It's just more of those presentations.

Dr. Orlowski: Right now, they are clinical presentations, but you're bringing up an excellent question. We do know from a number of studies, including from the folks at Arkansas, as well as from SWOG trials that if you have high risk cytogenetic abnormalities or a high risk gene expression signature, for example, if you have a deletion 17p by FISH and you have smoldering asymptomatic myeloma, that high risk chromosome feature does put you at a higher risk of progression. We still don't advocate treating those people, but what I use that information for is to determine how frequently I should follow people. If they have intermediate or low risk smoldering myeloma with normal chromosomes, normal FISH, and a low risk gene expression profile, then I don't need to see them as often. But if they have for example deletion 17p by FISH or a high risk GEP, then I feel that I need to see them more often because you want to make sure that you catch the disease early if it's going to progress and start treatment early.

Jenny: Right. Well, I think that speaks to a point that patients need to be aware of what kind of myeloma they have, whether it's smoldering, and they need to be asking their doctor about their different features so they can be more aware of their own care and I think it's critical.

Dr. Orlowski: I totally agree with you. The other thing is to make sure that you have involvement with a myeloma specialist in your care because myeloma is not the most frequent cancer out there. There are probably about 24,000 new cases of myeloma diagnosed each year in the United States, and if you're being taken care of by a private practice physician, he or she may not have a large patient population with myeloma. I would definitely recommend that you at least as a patient get a second opinion with an expert and then hopefully that expert and your local physician can work together to make sure that you're getting the best quality of care.

Jenny: Well, I think that's a great strategy. I think there's no question that a myeloma specialist is absolutely critical to have. There are many, many, many patients who do that. They go to a myeloma specialist. They get the proper diagnosis. They get the direction of care that they need that's the latest because you and these other specialists are up to speed on the absolute latest therapies, and then they can get a lot of the treatment back home or at a different care facility.

Dr. Orlowski: Definitely.

Jenny: I agree. Well, would you like to start in with what you thought was the most important topic of ASH, or topics?

Dr. Orlowski: Yes, sure. There were a lot of, I think, exciting developments. One of them is that we saw data from the ASPIRE study, and this was a phase three randomized trial for patients with relapsed or refractory myeloma, and they got either lenalidomide and dexamethasone, or they got carfilzomib, lenalidomide, and dexamethasone. Some of you probably know that carfilzomib is already approved, but only for relapsed and refractory myeloma, and that was as a single agent. This study looked at the combination. It was very exciting because the three-drug combination had a progression-free survival of more than two years. It used to be that only stem cell transplant in the newly diagnosed setting was able to give us that kind of progression-free survival, and yet here, we were getting similar numbers for patients with relapsed disease, which was usually more resistant to treatment. Hopefully, this will lead to an approval for carfilzomib in this combination for earlier patient treatment in the second line or later setting. Also, I think the other thing this trial showed us is really the power of continuing treatment. In the past, the way we treated myeloma was we gave a certain number of cycles of treatment and then we stopped. Stopping can be good because of course, people often feel better when they're not on chemotherapy, but the flip side is that if it causes the myeloma to come back sooner because you're not on treatment, that can be a problem. In this particular study, the carfilzomib was actually continued for 18 months. Now, that's a lot of going back and forth to the doctor to get the IV carfilzomib and granted that can be challenging, but it was interesting from the study that most of the progressions on the carfilzomib arm happened after the 18-month period when carfilzomib was already stopped. I think this analysis, along with many other data sets from other trials, really show that the longer you're able to stay on therapy, the longer the disease is going to stay away and that's ultimately what we want. We want people to be disease-free and to live longer, so I think that was an important lesson from that study.

Jenny: Are most specialists now recommending longer term therapy or a continuous maintenance therapy?

Dr. Orlowski: It depends a little bit on the setting. There's no one right answer for each individual, but I think in general, the answer to your question is yes, both for people who have had a stem cell transplant as part of their frontline therapy, as well as for people who have not. We are recommending longer durations of treatment. Oftentimes, this kind of maintenance therapy involves either fewer drugs or fewer doses of the drug or a lower dose of the drug than what is used when the myeloma burden is greater. That means that it's easier. You don't have to come as often for treatment. When the doses are lower, people usually tolerate therapy better, but it seems that keeping people on treatment longer, even though I know people love to be off of chemotherapy, but longer treatment duration does produce better time in remission and better survival.

Jenny: So you're trying to keep quality of life up by manipulating the dosage and the frequency, but yet keep it at bay as long as possible.

Dr. Orlowski: Exactly, and we have data now that by doing that kind of either consolidation or maintenance therapy or both after the initial or so-called induction therapy, people do live longer and that's of course what we all want.

Jenny: Absolutely. When a drug like carfilzomib is going through that process and they have FDA approval to be used in the relapsed or refractory setting, is there a typical time frame that it takes to be used in the upfront setting?

Dr. Orlowski: Well, carfilzomib is being studied in newly diagnosed patients in the upfront setting. There's a large cooperative group study, which is for newly diagnosed patients comparing bortezomib, lenalidomide, and dexamethasone to carfilzomib, lenalidomide, and dexamethasone. Carfilzomib isn't yet FDA-approved for newly diagnosed patients, but it has been listed as one of the potentially recommended therapies by the NCCN, which is the National Comprehensive Cancer Network. I do think that in some settings, a combination like carfilzomib with lenalidomide and dexamethasone is appropriate as an initial therapy for newly diagnosed patients.

Jenny: That study is not complete yet, so you don't know which is better so far, bortezomib or carfilzomib, right?

Dr. Orlowski: That study is still ongoing. Actually, I would encourage for any of those of your listeners, who may be eligible, to enroll. It is a randomized study, so you will only have a 50-50 chance of going on one arm or the other, but one of the important things other than having a myeloma specialist involved in your care is we need to try to increase enrollment to clinical trials because we all want to know the answers to these questions and improve everybody's outcomes as quickly as possible. One of the best ways of doing that is by enrolling these trials more quickly, which gets us to the answer to the studies more quickly.

Jenny: Absolutely. Well, we absolutely believe that because that's why I started this show.

Dr. Orlowski: Exactly.

Jenny: I think one of the questions that I had from ASH that maybe you can speak to because you moderated that session is kind of to that point about clinical trials. Because there's no cure, obviously you need new answers, so when you have therapies that work for some people but not long-term, obviously you need to try new things. How do you balance the use of newer therapies while leveraging the existing therapies that are working in the best way -- for example, transplant -- and then using these new approaches like carfilzomib or the monoclonal antibodies that we'll talk about? How do you best do that as a researcher and a myeloma specialist?

Dr. Orlowski: Well, one of the debates at the educational session that you referred to was whether transplant is still important in myeloma or not. Of course, the reason there was a debate would suggest that we don't know the answer. There is a large trial currently ongoing in the United States, which is led by the folks at the Dana-Farber and MD Anderson is part of it, as well as many other places, which is comparing treatment with transplant either as part of initial therapy or not doing transplant upfront and waiting until the time that the patient's myeloma relapses. The debate at ASH, I think, was between Philippe Moreau, who was in favor of upfront transplant, and Paul Richardson, who argued that not all patients necessarily need to do transplant. My perspective is that a lot depends on your particular disease and how well it responds to therapy. In some cases, if you have myeloma and it responds very nicely to the initial chemotherapy, you get into a complete remission especially one that can be proven to be complete by one of the newer methods of detecting disease. This is in the category of MRD or minimal residual disease. One of the methods that's now available at many places, including MD Anderson, is to do what's called flow immunophenotyping. What that means is that you get a bone marrow. In that bone marrow, we look at the plasma cells. In the past, it was considered that you were in complete remission if you had less than 5% plasma cells in the bone marrow, but 4% plasma cells that are cancer cells is not a good situation. What the immunophenotyping allows us to do is essentially a fingerprint of the myeloma cells. It tells us if the plasma cells in your bone marrow are normal. In which case, that's a great result, or if the plasma cells in the bone marrow are myeloma cells. I would suggest, although we don't yet have the proof of this, but I would suggest that if you're in a complete remission and you have, by flow, no detectable minimal residual disease, I would still collect stem cells in that kind of a patient and hopefully store them for later use, but you could consider in that kind of patient doing maintenance therapy and not necessarily going right to transplant, whereas if your myeloma responds well to treatment but you don't achieve MRD negativity, then I think adding the transplant is very reasonable. Also, I think if you have high risk disease, I still think that stem cell transplant is important. Remember, these are to some extent just my opinions and we still need to do the trials to prove that these are in fact the case. As I mentioned earlier, there's no one-size-fits-all. Myeloma is different in each individual, so don't necessarily take the recommendations or the suggestions that I gave for applying to everybody.

Jenny: Well, I think it's interesting that you can get to that level of sensitivity. You're looking at so many different aspects that it just proves the point that you really need to be treated by someone who knows what they're doing because to get that level of sensitivity and to know that that you need to check those things and you could craft your treatment based on all of that information, and you're really working with the latest technologies to do that.

Dr. Orlowski: Definitely.

Jenny: It's just a more sensitive approach. Well, would you like to talk about the monoclonal antibodies?

Dr. Orlowski: I would love to. We're very hopeful that sometime this year in 2015, probably towards the second half of the year, we may get two monoclonal antibodies approved. One of them is elotuzumab, which recognizes a protein on the surface of myeloma cells called SLAMF7, and the second is daratumumab, which is an antibody that recognizes a different protein called CD38. One of the problems with myeloma is that it figures out a way to avoid being detected by each patient's immune system. Otherwise, it wouldn't be there to begin with. What the antibodies do is they often will bind to a protein on the myeloma cell surface and act as sort of like a flag and tell the immune system that, "Here's the cell you need to pay attention to and come and destroy." What we hope to have later this year are data from a study where elotuzumab with lenalidomide and dexamethasone was compared to lenalidomide and dexamethasone. There were data presented at ASH from the phase two study looking at just the three drug combination, and that had around the 90% response rate in the relapse setting.

Jenny: Wow.

Dr. Orlowski: Yes, it was really great and the progression free survival was again over two years, similar to what was seen with the carfilzomib, lenalidomide, and dexamethasone combination. I think we're excited about that and hopefully the data will be available this year and the drug will be approved. The second drug, which is daratumumab, that hopefully will be approved this year as a single agent. It has activity by itself. The response rate has been in the 30% to 40% range, but the data at ASH that were presented were in combination with lenalidomide and dexamethasone. And in combination, the response rate is in the 70% to 80% range and we don't yet know the progression free survival, but there is a phase three trial ongoing comparing daratumumab, len- and dex-, with just len- and dexamethasone. The exciting thing about that trial is because of all the excitement around daratumumab, it's actually accruing more rapidly than was anticipated. We're thinking that we will reach the needed enrollment either in March or April, so if any of your listeners are potentially eligible, they should try to enroll sooner rather than later. Again, the benefit of more rapid enrollment is that we get to the answer more quickly. Other antibodies that I think are exciting, there's a different anti-CD38 antibody called SAR650984. It doesn't yet have a name, but that showed very good also 70% to 80% response rates in combination with lenalidomide and dexamethasone, and by the way, we're planning on a study with that antibody by itself in high risk smoldering myeloma hoping that this kind of immunotherapy approach will be something that could prevent progression. The other great part about these antibodies is the problem with small drugs, small molecules, so these are things like dexamethasone, lenalidomide, bortezomib, carfilzomib, pomalidomide. When you take those medications, because they're so small, they to some extent get into almost every cell in the body. When they get into a myeloma cell, that's good because hopefully they get killed, but they can also get into some normal cells and cause side effects. The antibodies are much more targeted. They bind to myeloma cells and usually not many other cells, and what that means is that it's much more targeted. In general, we hope that the side effect profile will be much better, although I should say harkening back to the study we mentioned earlier with the carfilzomib, lenalidomide, and dexamethasone ASPIRE trial, the other exciting thing about that other than the great results were that the addition of the carfilzomib really did not significantly increase side effects, so we're now getting to the point where even some of the small molecules that we have, have only minimal additional side effects.

Jenny: Some follow-up questions about that because I'm curious about what you're saying. With the elotuzumab and len-dex, you were seeing a 90% response rate for relapse, and for the daratumumab and the SAR, you were seeing 70% to 80% response rate, but elotuzumab doesn't necessarily work by itself, so it has to be used in combination, and the others are better in combination, it sounds like, but they can be used by themselves. I guess I'm curious as to why that's the case. Is it just the target that it's hitting? Anyway, I'm not a researcher, so maybe I don't really know the question I'm trying to ask, but --

Dr. Orlowski: You're asking a good question.

Jenny: I'm just curious about the result.

Dr. Orlowski: You're right that the elotuzumab is not active by itself in the relapse setting, whereas daratumumab and the SAR antibody are. I don't think we fully understand why they are not active when elotuzumab works by itself -- or I should say we don't fully understand why elotuzumab does not work as a single agent and daratumumab and the SAR compounds do. Part of it may have to do with how they activate the immune system, but we don't fully understand that it's the bottom line.

Jenny: Have you seen anything so far because I know that you haven't been out for very long, but they've been in some early clinical trials. Have you seen any differentiation with patients that they work well for or patients that they don't work for in terms of genetic profiling in general? I know that's a difficult question to answer.

Dr. Orlowski: Well, that's a very good question. What we know is that the targets, for example, for elotuzumab, for daratumumab, and also for the SAR antibody, the targets are expressed on virtually all myeloma cells, so that's great because that means that the maximum number of patients out there could benefit. We're not yet at the point where we can predict which patients will respond for example to daratumumab by itself and which patients will not. I think that because the combinations work so much better than the single agents that we probably should just go ahead and work with the combinations. The other thing we hope is that there is what's called high risk disease and we talked about that a little bit earlier based on the gene expression profiling and also based on some of the chromosome studies. We actually hope that these antibodies will help to overcome high risk disease because the antibodies really should only care about whether the protein is expressed on the surface, not what chromosome changes are present inside the cell. We don't know yet if they do overcome high risk disease for sure, but there are some early indications that they might, and that would really be a game-changer because high risk disease is one of the major causes for unfortunately patients dying of multiple myeloma.

Jenny: Right. Well, it will be fantastic to get these in and used and as part of the common treatment plan for myeloma. I'm just curious. When these studies are run, when the early studies are run and you say it's not working for 30% and it's working for the 70% or 80%, do you retrospectively look at this and say, "What kind of profile did that 20% have versus the 80% have?" and try to look at that later?

Dr. Orlowski: Definitely. One of the things we're doing now, for example, at MD Anderson -- and I know other places are doing this as well, so I'm not just trying to wave our flag, but we are collecting samples on patients before they go on treatment. Once we know whose disease has responded and whose has not, we try to go back and look at the characteristics of their myeloma. We try also to look at the characteristics of their normal bone marrow cells, and what we hope by doing this kind of analysis is to understand exactly what you're asking and figure out if we can find a biomarker that would predict who will and who will not have responsive disease because nobody likes to put someone on a treatment that turns out not to work, that wastes time, it risks side effects, and also wastes money. I don't think we're quite yet at the point where we can predict exactly what is the best treatment for everybody, but we're certainly getting a lot closer.

Jenny: A question about this anti-CD38, I heard someone -- I don't know if it's at ASH or somewhere else -- that says some mutations might have a negative CD38 presentation like daratumumab or SAR might not work for them. Do you test? How do you test for that?

Dr. Orlowski: One of the good things about CD38 is it's actually used by the pathology doctors when they look at bone marrow samples to identify whether myeloma is present or not. What that means is that most patients with myeloma will already have had a test looking at whether CD38 is expressed or not. So far, it seems that the number of people with CD38 negative myeloma is pretty darn small, so I don't think right now that we would need to do that testing in advance, but it is possible that we may need to think about that in the future.

Jenny: Well, it seems sort of a small issue out there a little bit, but I was just curious about that. Now, you mentioned minimal residual disease (MRD) earlier in the show. I think for the first time, there were a lot of poster sessions about MRD. Is that something that you found was important about ASH or just something that we'll continue doing in the world of myeloma?

Dr. Orlowski: Well, I think it's important to look at MRD because it's a more sensitive measure of how much myeloma each patient has. What we don't yet know for sure is whether if someone has MRD positive disease, do we really need to continue to treat that patient to make them have MRD negative status or in some people, is it okay to have just a few myeloma cells left over? In general, what the studies that have been done so far show that MRD negative patients generally do better than MRD positive patients, but that's logical because less myeloma is always going to be better than more myeloma. However, we know that there are people with MRD positive myeloma who nonetheless have very, very good outcomes. I think that points to the fact that we still don't understand everything about myeloma and the way it interacts with each patient's bone marrow and immune system, and we need to prove that treating an MRD-positive patient results in a benefit, and that we still have not yet done in a randomized trial, but studies like that are now being designed, so I do think we'll have that information in the future.

Jenny: You mentioned the impact of the bone marrow microenvironment. Is that something that you felt was interesting or important that was presented at ASH?

Dr. Orlowski: Well, we've known for many years that the myeloma cells really rely very heavily on support and nourishment from the bone marrow microenvironment for their growth, for their survival, and also for resistance to treatment. In fact, if we do a bone marrow and take out the myeloma cells and put them in a dish where they sit there by themselves, most of the time, even if we feed them with sugar and proteins and other nutrients in the laboratory, they usually die within three or four days. It's only because they have help from other cells in the bone marrow that they have such a much better life span in patients. Many of the drugs that we have available work in part by changing either the interaction between the myeloma cell and the microenvironment or by changing the microenvironment itself. One example is the immunomodulatory drugs. One of their mechanisms of action is by changing the immune microenvironment to make it less nice for the myeloma cell. Proteasome inhibitors do that as well. All of these make the environment more hostile to myeloma, which is a good thing. We still do need to learn more though about how especially to harness the patient's immune system and we hope that with these antibodies, that will be part of the equation. Also, a lot of excitement has been focused on these so-called CAR T or CAR NK cells where you can take the patient's own T-cells. What we do at MD Anderson is we're using natural killer or NK cells and you can train them in the laboratory to recognize myeloma cells, put those cells back in the patient so that they find the myeloma and start to kill it. I think those are also very interesting approaches, which are being tested in many places.

Jenny: Absolutely. I guess that's my follow-up question. I want to leave some time for caller questions, and it's surprising how fast the time goes. What do you see as the most exciting work that will be happening in 2015 and also that you'll be doing that you would like to share with us?

Dr. Orlowski: I think we've touched on a few of the really exciting areas. Just to summarize, I think that we have the monoclonal antibodies coming. I think these other immunologic approaches such as with the CAR T and CAR NK cells are very good. There are some vaccines that look very promising in myeloma. We should not forget that there are oral proteasome inhibitors coming. There's a drug called ixazomib, which is in the same family as bortezomib, and there's a drug called oprozomib, which is in the same family as carfilzomib. Both of those are oral proteasome inhibitors and there were very nice presentations at ASH showing that those drugs are active both in newly diagnosed myeloma and in relapsed myeloma. The advantage, of course, is that right now, bortezomib and carfilzomib are both given by injection. So if you were able to take these drugs in a pill form, that would be I think much better for patient satisfaction and quality of life, and not have to schlep back and forth to see the doctor or the clinic where you would get your injection. Also, there were other drugs I think that were very interesting at ASH that were presented in myeloma. There's one new drug, which is a PIM kinase inhibitor. The drug doesn't have a name yet, but the designation is LGH447. This drug had about by itself 25% response rate and two-thirds of patients had stable disease or better where they previously had disease that was progressing. I think that tells you this is really an interesting and exciting new drug that we're looking at now in combination.

Jenny: Do you have a study open at MD Anderson with that? I thought you did.

Dr. Orlowski: We do both by itself as well as in combination. It's an oral drug, which is another plus. I think a third drug to mention is a drug called filanesib or ARRY-520, which is a kinese spindle protein inhibitor. It is IV, so a little bit less convenient, but no neuropathy associated with it. In some patient populations, it has a 30% response rate even when people have myeloma that no longer responds to bortezomib to lenalidomide and to other drugs. There is a registration study ongoing right now open at many centers in the US, and if the data were similar with that kind of response rate, that could lead to an FDA approval. So I think it's an exciting time for new treatments of myeloma. As you know probably, survival has doubled in the past ten years and I think that was before pomalidomide and carfilzomib and of course the antibodies are very exciting, and I think we'll continue that trend. Finally, you probably remember hearing a little bit about panobinostat in myeloma in combination with bortezomib and dexamethasone. The data from a large study of that drug are still being evaluated by the FDA. I think it's fair to say that there certainly were patients who benefitted from that drug and I think there is still hope that that could be approved.

Jenny: Okay. Well, that's terrific. It's so exciting to be in a medical area, or at least have a disease in the medical area that there is a lot going on. What do you credit that to the most?

Dr. Orlowski: I think the excitement is of course those of us in the academic community, we become focused on research because we want to improve patient outcomes and it's exciting when you can be part of a trial that sets a new standard of care, which improves survival. What that allows us to do is you can therefore help more patients both in the United States and worldwide than you would ever be able to just by seeing all of them in person, so that's the exciting thing. By being part of a new drug that comes to the FDA approval stage, we can help thousands literally and tens of thousands of patients with myeloma.

Jenny: It's fantastic. Well, we thank you for all you do for this disease and for us as patients. Thank you so much. I'd like to open it up because we have several caller questions and I want to make sure we get to everything, if that's okay, so I will start with our first caller.

Caller: Happy New Year to you, Jenny and Dr. Orlowski! Thanks so much for taking the call. Dr. Orlowski, I have been a fan of Jenny's radio interview show from the day she started and I just really want to thank you for continuing to participate because it's become such a valuable resource for the myeloma community to be able to not only listen in on Jenny's questions, but she gives us the platform to call in as well, so thank you both for continuing this series. Dr. Orlowski, if you had a new patient who came to you with a questionable MGUS smoldering diagnosis via serum test only, no prior imaging or bone marrow biopsy performed, what specific steps would you take to evaluate this patient?

Dr. Orlowski: Well, thanks for your call, Dana, and for your kind wishes, and Happy New Year to you and anybody who's listening. I certainly agree. I think Jenny's show is great and she brings a very, of course, unique perspective to this as a myeloma patient herself. As to your question about what tests should be done, other than the tests that are fairly routine at this point, we talked earlier about how imaging is becoming more and more important, and I think that magnetic resonance imaging and in many cases, positron emission tomography, should be considered as important parts of the evaluation because if there is evidence of bone disease either by MRI or by PET scan, it makes it much more likely that there is a clinically relevant myeloma present, and if that's the case, then considerations should be given to doing a bone marrow. If however a patient comes to me with what looks like MGUS and their MRI and/or PET scan looks normal and they have normal or not very elevated free light chain levels, it may be reasonable in some of those patients to consider not doing a bone marrow for diagnostic purposes, so that's one way that I think we've been able to change some of the evaluations that we do.

Caller: Dr. Orlowski, if you were to perform the bone marrow biopsy, what tests would you typically perform on these samples? Would you obviously do flow cytometry? Would you employ FISH, gene expression profiling? How extensive is the test?

Dr. Orlowski: I think definitely the FISH testing, which stands for fluorescence in situ hybridization is important. The cytogenetic testing is important. There are more and more data about gene expression profiling showing that that is important. I do think that the flow cytometry is important as well. For example, in the high risk smoldering population, we know that one of the definitions of high risk smoldering myeloma is if there are at least 95% plasma cells that are abnormal by flow cytometry. That gives a much higher risk of progression than if you have plasma cells, but let's say 20% of them are abnormal. So if given the option, I would do all of those tests. Unfortunately, that means that sometimes we have to take a little bit more bone marrow because to do the additional testing, we need more plasma cells, but I think the additional information that we gain from that is really important. And by the way, more and more places are doing sequencing of myeloma cells, which is different than gene expression profiling. It looks at whether there are certain mutations in some of the genes in myeloma and I think we're close to the point that we're going to be able to decide on which drugs to use based on that kind of sequencing.

Caller: Would you employ the sequencing for someone with an MGUS who are smoldering? If you obviously have a sample to test, would you employ that at that stage or do you need a specific amount of plasma cells in order to test for that?

Dr. Orlowski: Right now, the sequencing I think would from a clinical perspective be likely to be more valuable in the relapsed setting because it might identify certain mutations that could allow us to pick good drugs. I don't think we're yet at the point in the newly diagnosed setting where sequencing is routine for clinical care, but I would definitely recommend doing it anyway if only for research because the chances are if you have a clone with a certain gene mutation, even if it's a small population, the chances are that that clone will probably be present later or at least that it will appear at some point even if it disappears in between. There was actually a study just published today in the Journal of Leukemia that shows that the major clone of myeloma cells present at diagnosis often will be present throughout the course of the patient's myeloma. I also want to quickly say -- because I know we're getting a little close to the top of the hour and I have to run for an 11:00 meeting here Central Time -- I wanted to give people my email address. It's rorlowski@mdanderson.org. Please feel free to email me your questions and I will try to do the best I can to get back to you either today or over the weekend with answers.

Caller: Thank you, Dr. Orlowski. I don't want to take up anymore of your time. Thank you for your support. Jenny, you too, have a great day.

Jenny: Okay. Thank you so much. We have more caller questions, but Dr. Orlowski, you said you need to run, so should we take the questions or just let you go?

Dr. Orlowski: Unfortunately, I have a call with the Southwest Oncology Group Myeloma Committee to plan some of our future trials, but please by all means, all of you, please email me and I will get back to you with answers to your questions by email.

Jenny: Well, thank you so much for joining us today. We hope you continue with your research and communicating to myeloma patients. We're just so grateful for your outstanding work.

Dr. Orlowski: Thank you very much and take care, everyone.

Jenny: Thank you so much. Thank you for listening to another episode of Myeloma Crowd Radio. Join us next week for our next interview as we learn more about how we, as patients, can help drive to a cure by joining clinical trials.