Full Show: The Excitement Around Checkpoint Inhibitors in Myeloma with Dr. Don Benson, MD, PhD, Ohio State University
Dr. Don Benson, MD, PhD Ohio State University Interview Date: June 10, 2016 Summary Ten years ago the first checkpoint inhibitor was used in metastatic melanoma, with amazing results. Now, an abundance of testing is done for this new class of drugs that allows the immune system to do its job in multiple myeloma. According to Dr. Benson, the immune system regulates when to attack and when to back off. For example, in infections, we want the immune system to fight the infection but not spin out of control and attack healthy tissue. In myeloma patients, the immune system is handicapped and brakes have been put on it so that it can't operate properly. Dr. Benson explains the various checkpoint inhibitors that are being used in clinical trials. He tells us that the amount of research and the number of clinical trials is awe-inspiring. These inhibitors can be used with Revlimid, dexamethasone and are being tested in a wide variety of other combinations. Adding these inhibitors can also bring non-working drugs that patients have become refractory to back to life. To find clinical trials using checkpoint inhibitors, click on the links below: Nivolumab Clinical Trials Pembrolizumab Clinical Trials Dr. Don Benson on Myeloma Crowd Radio Full Transcript Jenny: Welcome to today's episode of Myeloma Crowd Radio, a show that connects patients with Myeloma researchers. I'm your host Jenny Ahlstrom. Now before we get started with today's show, I'd like to mention that we have two patient doctor meetings coming up in June. Now you listen to this program because you want answers from Myeloma experts and we recently launched an additional way to get answers from experts. We call them Myeloma Crowd Round Tables. We recently held our first round table in Salt Lake City and invited three Myeloma experts to join. The Round Tables covered new treatment options and hot topics like immunotherapies, but also focus on relapsed and high risk disease because these patients need help the very most. Our next Round Tables will be held June 18th in Saint Louis and another on June 25th in Boston, because we all need to plan ahead for our best Myeloma Care. These meetings are really for all patients. You can register through the links on the menu of the Myeloma Crowd website. Now onto today's show, the ASCO Conference has just concluded; this is a global cancer conference where doctors can present their research to their peers. There were papers presented there on Myeloma and one of the important topics covered were checkpoint inhibitors. You may have heard of these but you will likely by hearing a great amount more about them. So joining us today is myeloma and immunotherapy expert Dr. Don Benson who has been researching these inhibitors for a number of years. So welcome, Dr. Benson. Dr. Benson: Thanks, Jenny. It's great to be back. Jenny: We're happy to have you again. Let me give you a quick introduction for those who don't know you before we get started. Dr. Don Benson is Associate Professor of Medicine and Coordinator of Education in the division of Hematology at Ohio State University. He's a member of the ASCO committee for the Oncology Training Program, a member of the Ohio State Residency Training Program, Core Competency Review Committee member, and Fellowship Candidate Selection Committee member. His recent awards include the Henry Kunkel Society for Immunology, Champion of Family Medicine Award, Gold Humanism Honor Society, Excellence in Teaching Award, the Courage to Teach Award, Professor of the Year and the ASCO Merit Award to name a few. Now Dr. Benson's research emphasis is specifically in immunotherapy for cancer and in particular multiple myeloma, and other blood cancers. His lab performs research looking to enhance the normal immune system functions as a means to eliminate cancer using a variety of methods, like cytokines, antibodies, immunomodulatory agents and new small molecule targeted therapies. Again Dr. Benson, welcome. Dr. Benson: Thank you. Jenny: Weve had you on the show before and ASCO just concluded. So we know we have a lot to talk about. But for those who don't know what checkpoint inhibitors are, maybe you can give us just a general overview of what they are and how they work. Dr. Benson: So I think it's important just to talk to a little bit just a couple of minutes on the basic biology of this idea, and some of the historywhere these concepts were first described. When we think about the immune system in general how it was designed, how we evolved, your immune system is charged with keeping you healthy. These are cells in the body that help to fight off infections, viruses and bacteria and so forth. Going back more than a hundred years there has been a lot of interest and a lot of thinking around if and how the immune system can help to fight cancer too. So in that context looking back over the decades, the attempts to harness the immune system as a cancer treatment have been related by this fundamental idea that the immune system needs to be invigorated or it needs to be incited into action, that some sort of stimulus needs to be added to tweak it or to tip it over the edge or to press the gas pedal if you will. And that reallythat goes back over a hundred years to some of the earliest documented attempts of immune therapy in our country. And then even up through the very recent present even in the last ten years or so, we have done a lot of work in cytokines, which are hormones that are meant to stimulate the immune the system. For example, there have been antibodies developed that are little proteins that stick to cancer cells and act as flags for the immune system to mark these cells for destruction. Tumor vaccines are another way to try to teach the immune system what they should be killing. Even donor transplants, donor stem cell transplants could be viewed in that lens as wellthat these are all historic attempts to try to stimulate the immune system into action. It's as ifby analogyit's in an idle mode and all that needs to be done is you need to step on the gas. Checkpoint inhibitors come in really in the relative recent history. So it wasn't until the 1990's that the idea of balance of the immune system was first recognized or even proposedmaybe a little earlier than that. But in the 1990's, that's where we got our first demonstration that there are proteins in the immune system. There are mechanisms in the immune system that act as checks and balances. In other words, your immune system had a gas pedal but it also has a brake pedal. The first demonstration of that was a protein called CTLA4, and it was a gene that had been discovered just a few years prior. And a group of researchers developed a mouse in which they knocked that gene out. So they were able to remove the CTLA4 gene to see what would happen. What they found was that these mice developed severe inflammation. It was as if their immune systems were on overdrive; all of their lymphocytes, all their immune cells expanded and caused a lot of autoimmunity. In other words, these cells were starting to attack the host tissue and not just the viruses or bacteria what have you but it was like they were going out of control and they didn't know when to stop and what was friend and what was foe. As that line of studies progressed, people realized more and more that the CTLA4 protein acts as a checkpoint; it acts as a brake for the immune system, and it was a really revolutionary idea. It kind of makes sense if you think about it that if you get an infection, you want to take care of that infection but you don't want the immune system to spin out of control. You don't want it attacking healthy tissues and normal tissues. And in that context, we also learned a lot about autoimmune diseases like Lupus or Type I Diabetes or what have you, where the immune system attacks normal tissues by accident or in a misdirected way, if you will. So CTLA4 was the first and then TD1 came along and this was another protein that was characterized in a similar way. The researchers knocked it out, took that gene out of the mouseand what they found was an interesting result. It was similar to when they knocked CTLA4 out but not as dramatic; it took more time for the mice to develop autoimmune symptoms and rampant inflammation. It happened, it developed, but it suggested that there was some complimentary pathway that was involved, or in other words, gosh it looked like there is multiple checkpoints in the immune systemthe immune system has multiple breaks just like there are multiple gas pedals. So this really revolutionized how we think about immunity, and then immediately, what can we do with this information to help people? What can we do to help people with autoimmune diseases and what can we do to help people with cancer? And if you are still with me, if I haven't put anyone to sleep yet, the really interesting thing is if you sit back and just reflect on everything I just said, you come to this point where you start to realize that things that might be helpful to treat autoimmune conditions, might actually be harmful in cancer, and vice versathat things that might be helpful in cancer, might be harmful in autoimmune conditions. So in other words, there are situations, there are diseases where you want to take the brakes off. For instance, in developing a double negative, a checkpoint inhibitor. And there are other places where you want to dampen down the immune system, and that has launched this complimentary field and how we manage everything, from psoriasis, to rheumatoid arthritis, to Crohn's disease and so forth. In parallel, there was another class of checkpoints called KIRs, K-I-R, which are expressed on another subset of immune cells. And it turns out, there is probably dozens of these brake pedals in the immune system that all act in a similar way on a global level, but each have their own intricacies and each have their own specific settings where they might be important. In this context, the first drug that was developed and brought into clinical trials was an antibody that targets CTLA4, and this drug was called Ipilimumab. The study that really knocked all the walls down in terms of even what's conceivable, not much less what's possible, but even what's conceivable, even what we could dare to dream was a study of Ipilimumab in patients that had metastatic melanoma. This was published now, not quite ten years ago the study was done. But this was a study where people had this form of skin cancer that have metastasized, it had spread throughout their body. A group of these patients were randomized in the trail to receive Ipilimumab. And what they found was something like a 20 or 25% response rate which doesn't sound like a lot. But as time went by, that group of people when into remission and many of them didn't relapse. Many of them didn't have a relapse after months and even after years. The reason that's so dramatic, the reason that was such a watershed event is that at the time there had never been a drug that was shown to have a survival benefit in metastatic melanoma. The median survival at the time was around three months or 12 weeks. And here was an antibody treatment, not a chemotherapy not a radiation, not a surgery but an antibody treatment that didn't even do anything with the tumor that the antibody actually stuck to your immune cell, and worked in effect by taking the brakes off of your immune system. And so Ipilimumab was FDA approved in 2011 as the first checkpoint inhibitor for any cancer. And there has been multiple long-term follow-up reports from those studies, and dozens of trials have followed it to show that in patients with metastatic melanoma, this drug can inducein some of these patientsvery durable remissions. That's where the floodgates opened; that's where this whole field began to take off, this idea that maybe stepping on the gas isn't the only thing we could do. Maybe we could try to take our foot off the brakes of the immune system as well. And that's where checkpoint inhibitors as a field have come into cancer therapy. Jenny: How did you get involved in studying this? Dr. Benson: I got involvedI guess my first exposure as a medical student, I was training at the national cancer institute and was involved in some of the trials in the late 1990's with patients with metastatic melanoma actually. At the time we were using some of these cytokines that I had mentioned earlier, some of the tumor vaccines I mentioned earlier, and I was captivated. We were taking care of these folks who had come from all over the country for these experimental immune treatments and nothing had worked for them. And I'll never forget a patient there who whose care I was involved in. He had gotten one of the experimental immune therapies, and had come back for his CAT scans, and every deposit of tumor was gone, to the point where people were questioning if they had the wrong name on themthis is back in the day where we used to print out the CAT Scans and hang them up; we didnt have computers yet. But people were staring at these scans in bewilderment, that there is no way this could be the same person, that there is no way that these tumors could be gone from the bones, and the liver, and the lungs. That really got me interested in immune-based therapies. Then when I came to Ohio State, I got into a group of folks who work in specific area of immunology called innate immunity. Around that time in 2002, there were several studies that were published in Leukemia that were highlighting this role of a postulated checkpoint that modulates the innate immune system. A group of researchers from Europe had shown that if you intentionally mismatched these receptors when you do donor transplants in patients with leukemia, a significant number of these patients were cured of their diseaseeven if it's chemotherapy refractory, even if they have exhausted everything else that you cure refraction in these patients, simply by mismatching these checkpoints in the donor and the recipient. We began working with another group in France who were developing an antibody to target that checkpoint. That was a cure checkpoint, and then we did the first trial in patients with myeloma with a cure checkpoint inhibitor. Gosh, that was almost ten years ago now. Jenny: So this is not something thats new to you. Dr. Benson: It was one of those perfect storms of things happening, and discoveries being made, and very rapid translation happening, and lots of collaboration in multiple countries. This entire field has just literally exploded. I was doing some reading last night on some of the background, and I found a statistic that between 2011 and 2015 there have been over 40 new patents on checkpoint inhibitors that have been filed. This area is just burgeoning, and it's hard to keep upI mean there are so many drugs and so many targets, and so many combinations, and so many possibilities that it's truly hard to keep up, even if this is what you do every day. Jenny: Well we are thrilled that you joined to take time to explain it to us, because I think this is something that patients need to understand. So you mentioned melanoma. Are there other solid tumors where it was used and has been used? Dr. Benson: There are now three checkpoint inhibitors that have FDA approvals to treat patients with solid tumors. So Ipilimumab was the first and that's marketed as Yervoy and it's approved for metastatic melanoma. There are two more checkpoint inhibitors that have been FDA approved. One is called Nivolumab and its marketed as OPDIVO, and its approved for Melanoma either the single agent or in combination with Epi. Nivolumab is also approved for a specific type of lung cancer, non-small cell lung cancer, its approved use in kidney cancer, renal cell carcinoma and its most recent approval is actually in Hodgkin's disease. And then there is another one called Pembrolizumab or Keytruda and its FDA approved for Melanoma as well as non-small cell lung cancer. So there are a number of these that are actually out on the market already and many of these, I'm sure you know, have even made their way into the lay press with patients who truly had unspeakably horrible situations where they have gotten great benefit and durable remissions. Even with metastatic non-small cell lung cell cancer, which at least in my opinion, Jenny, would not have even been on our radar 10 or 15 years ago. And these are approved drugs now. These are out there and people are getting them. Jenny: Well that's great because you can take potentially something that's already been approved and maybe apply it. I don't want to interrupt what you were saying but that would be my next question; how do you apply this to hematological cancers? Dr. Benson: Yes. This is where it gets really interesting. There are dozens if not hundreds of trials going on in cancer now with various checkpoint inhibitors. I tried to go back and count up all the checkpoint inhibitors that are in trials now and I cantevery time I turn a page or look at another paper, there is another one. But these are being tested in everything from brain tumors, to pancreas cancers, to childhood malignancies, to blood cancers. There have been some data in myeloma with many of these. We published the first trial of a cure antibody as a single agent in relapsed myeloma, and then we have since published a combination trial of that antibody with Revlimid with no Dexamethasone, actually, in patients with relapsed and refractory myeloma. And there was also a study published with a cure antibody in patients with smoldering myeloma now, too -the CTLA4 checkpoint inhibitors and the PD-1 checkpoint inhibitors. I'm not sure there is any published data yet but there is an awful lot of data that has been presented, for instance at the ASCO meeting you mentioned, or at the ASH meeting. We know some of these early resultswe did get final results on one of the trials at ASCO just earlier this week. We have some data that we can talk about even though it's not been published yet. So where should we start? How about with Nivolumab? Jenny: Okay. Dr. Benson: So NivolumabI think that this one was the first PD1 antibody with data that was presented in myeloma. Nivolumab was studied across a number of B-cell malignancies in lymphoma, and T-cell lymphomas, and then Hodgkin's disease as well as myeloma. This was one of these big phase-one trials where patientsany patient that had a B-cell related form of blood cancer could be eligible for the trial, and ended up enrolling almost 30 patients with myeloma. I think they had 27 total patients with myeloma in the study. Nivolumab as single agent didn't perform as well in myeloma as it did in the other cancers. They had really astonishing responses in Hodgkin's Lymphoma, which led to its approval very quickly in that blood cancer. In the myeloma cohort, almost 2/3 of the patients had stable disease with the Nivolumab antibody, and they did have one response that I think was a complete remission, ultimately. But at least compared to the other settings, they didn't see as much efficacy with Nivolumab as they did in the other B-cell lymphomas. But still some evidences signal that if you can block one checkpoint and show that you can stabilize progressive myeloma with a single antibody, that was significant; that was an exciting finding. The other PD-1 antibody called Pembrolizumab has some more data that's been presented now in combinations. So Pembrolizumab or Keytruda has been studied in combination with Revlimid and Dexamethasone as well as in combination with Pomalidomide and Dexamethasone, and we have some results from those trials. So the study with Pembro and Revlimid and Dexamethasone, the final efficacy data were presented at ASCO just a few days ago. And in this combination study, I think the first thing to say is that these folks who had had a lot of treatment already. These were patients who had to have had at least two lines of prior treatment; they had to have had an immunomodulatory drug, and a proteasome inhibitor to be eligible for the study. Almost all of the patients that had Revlimid, 96% of the patients have had Revlimid, 98% have had Velcade. A big fraction of it has already had Carlfilzomib and Pomalidomide. Almost half had Thalidomide, over 80% have had stem cell transplants. What was interesting was 75% of the patients had myeloma which was considered to be refractory to Revlimid which is an important point when we talk about the results here. About a third of them were considered to have double refractory diseaseso refractory to Revlimid and a Proteasome Inhibitor, for example. About 2/3 of the patients had disease refractory to Velcade when they came into the study. In total on this trial, 88% of the patients saw their monoclonal protein go down on a combination of the PD-1 inhibitor with Revlimid and Dexamethasone. If you look at objective responses, so complete responses, very good partial responses, partial responses, the overall formal response rate was 50%, and in the patients who had myeloma that was refractory to Revlimid, almost 40% of those patients had an objective response. If you look at those people and then add in the people who had stable disease, who had disease control at least, 98% of the patients showed response in those four conditions. Even the patients who didn't meet the objective criteria, still had some disease stabilization. At the time these data were presented, the median duration of response was over 11 months. And this is now the subject of a randomized trial. There is a randomized phase three trial of Revlimid and Dexamethasone, with or without Pembrolizumab that's already open to accrual. And then there is similar data with Pomalidomide and Dexamethasone and Pembrolizumab, and that combination is also in a phase three trial now as well. So things are moving ridiculously fast. Jenny: And where are those trials? Dr. Benson: Let me see. The trial with Pembrolizumab with Revlimid and Dexamethasone is called KEYNOTE-185. And I think that this is an international study. It's open at sites around the world. And then the other with Pomalyst and Pembrolizumab and Dexamethasone is called KEYNOTE-183, and I think this is also an international trial as well. Jenny: Okay. Well we can add a link to our show we'll look them up. Dr. Benson: The last time I counted, at least 18 open trials with PD-1 inhibitors in Myeloma. And that ranges from the smoldering setting through trials around transplant to NIVO combinations to single agents to relapsed refractory setting. So it's literally this concept being applied across the board. Jenny: Yes, a lot of the doctors that I have interviewed, they always this is what you need to watch for because it's super exciting that you can put it with something else. So let's talk about using it alone versus using it with some of the other drugs like the Revlimid or a Revlimid Dex or Pomalidomide and Dex. What's the rationale? Why does it work with Revlimid? You're taking patients, just from what you said, that were resistant or refractory to Revlimid, and then having a combination work again. That's super exciting for patients. Dr. Benson: Isnt that incredible? We have seen that with other antibodies too that not necessarily checkpoint inhibitors, but some of the other antibodies in development. It's almost as if you can recover the activity of that drug that would have been lost otherwise, and squeeze benefit out of the combination. This is where the fieldthis is where I think a lot of the emphasis is right now. By analogy, I like to talk about this relative to myeloma. So ten years ago, 20 years ago for sure, there was a time where we didn't realize that myeloma was more than one disease. All the cells looked the same under the microscope, its myeloma, and the X-rays look the same, and they all have monoclonal antibodies; it was all sort lumped together as one cancer. We know that's not true now. We know that genetically, that molecularly, myeloma clearly is more than one disease. That's something that you and I have talked about before, and it's a commonly accepted idea now, that there are multiple subtypes of myeloma. We talk about high-risk, we talk about subtypes that are characterized by what mutations they have and so on. That concept now, we need to apply in the immune system. When you say it, it makes sense that all people don't have the same immune system, that all of us have different immune systems. When I teach in the medical school, I tell the students, it's like back when you were in grade school there was a kid who was always sick and he was always missing school and he was always late because he's in the doctor's office, but on the other end of that bell shaped curve, theres people who never get sick. There is people who never get poison ivy; they could roll in it and never get sick. The immune system has differences too. And there are connections between myeloma and the immune system. For instance, there are studies that show that if people have a mutation in the CTLA4 protein that I mentioned, then that might be connected to a susceptibility to developing myeloma, actually. We're at a point now where we need to work together across, not only across different types of cancer, where myeloma experts need to sit down with lung cancer experts and melanoma experts and kidney cancer experts, but we need to sit down with immunologist too who don't know anything about cancer but know a whole about the immune system. And that's where the answer to your question is going to come from. In other words, where would use a single agent and where would we use combinations? It would depend in part not only on the type of myeloma somebody has but on the type of immune system they have. Does that make sense? Jenny: Yes it does; you mentioned this in the last show, and I have been thinking about it since the last show. So when you say everyone's immune system is different, and you look at these checkpoint inhibitors and one of the comments you made in the past show wasyou know, we need to figure out who these are working for because when they work, they work almost permanently. Who are these people? Because we all want to be one of those people; how do you assess the immune system, and what kind of research has been done to look at the immune system like that, like what you're saying needs to be done. Dr. Benson: Yes. This is just starting to come out now in a fleshed-out way. One of my favorite papers to at least give us a framework about how to think about this was published in Science last month. The title of the paper is, The Cancer Immunogram. The author is trying to say okay, look, we know that there is some people out there where we can use NIVO as a single agent or we could use Pembro as a single agent, and we can induce really incredible responses and remissions. But like you said, that doesn't happen for everybody. And the reason is that the interface between the tumor and the immune system is multifaceted. Not only across tumors, but even in a specific cancer, and I would even say even in a specific patient there may be windows of opportunity where one of these would work great, and then in the same patient, windows where it's not going to work at all. The reason for that is that, not to anthropomorphize cancer too much, but the reason for that is cancer learns. Cancer can learn how the immune system is trying to survey it, trying to attack it, and actually generate immunoevasive strategies and defense strategies to keep the immune system at bay. Anyway, in this immunogram paper, these authors describe seven different parameters through which at least T-cells interact with the immune system. And so one of the concepts is, how foreign is the tumor, and what that means is that many cancers including myeloma will explicitly put up on their surface, proteins that identify them as belonging there. In other words, these are proteins that are self-proteins, that the immune system comes in and says are you friend or foe, or, do you belong here or don't you belong here? I think of them as fake IDs you know, when the cops go into the bar and the 19 year-old is in there, he's got his fake ID and that patron is passed over and not recognized as being foreign, as not belonging there. But this concept of tumor foreignness is very interesting, because it could mediate whether the immune system could even recognize the cancer as being abnormal or not, and cancer cells have strategies to make themselves appear less foreign. There is another parameter called the general immune status, or how inflamed is the immune system? So in other words, is the gas pedal pressed down, but the tires are spinning? would be a good way to think about that. Some of these are interrelated; so in some tumors, they can take a biopsy and the cancer is enriched with immune cells. In other words, the immune cells are in the room and they are looking around and they know something is wrong, they just can't figure it out. And then there are other tumors where you take biopsy and there are no immune cells at all; it's as if they came in and looked around and said everything is okay and moved on. There is another parameter called soluble factors. We have some data there were about to publish now in myeloma specifically, but this has been shown in other cancers too, that cancer cells can secrete hormones and cytokines to let the immune system know everything is okay here, there is nothing to see. There is a really interesting paper that was published in myeloma, that the ligand for PD-1 can be measured in the bloodstream, and this actually has prognostic significanceso you can test how much PD-1 is in circulation at diagnosis in myeloma. And that carries some implications about statistics for survival, even at the time of diagnosis. We have already been talking a lot about the expression of checkpoints. There are cancers, including myeloma, that actually upregulate the expression of the ligands for those receptors. They will put up signals to make sure the immune system keeps the brakes on. Even if the immune system is revved up and trying to do its job, it's getting a continuous signal to keep its brakes on and keep the reins on, and not unleash its full power. So at any rate, what the authors do in this paperit's only like a three-page paper in Science and they have a really neat figureit looks like a spider web. But the concept is really important, that on an individual basis, we need to characterize the tumor but we also need to characterize the status of the immune system. And then with that information, you might be able to predict which immune therapy might work best. So in the supplement for this paper, they have some case study examples where you could say, well this patient might need a PD-1 inhibitor but this patient might need a CAR cell. This is a patient where this approach might not work but this ishere is a patient where a combination might work exceedingly well, whereas either one by itself might not work at all. You could knock all the dominos down by hitting two at once. So this is where we need to go though. We have to, in parallel, be characterizing the tumor but also characterizing the status of the immune system, realizing that as an easy example, the immune system of someone who is 80 years old might be different than the immune system of someone who is 40 years old, as just one example. The immune systems might be different for someone who lived in an urban environment their whole life versus someone who lived in the country their whole life. And those are sort of easy examples. Jenny: Yes. And I wonderI know they talk about myeloma being more prevalent with obesity and things like that. I just wonder if that's inflammation related. There are just bigger predispositions because you have more body inflammation. Dr. Benson: This is where we need to go. You are exactly right, because there is this line of data that the idea of a monoclonal protein or clonal plasma population could be raised against an antigen that has to do with adipocytes, or with a particular lipid protein expression for it. I'm trying not to use any medical terms, but you get the idea that there might actually bethere is a biologic link there and the right setting is a little bit of inflammation, then Jenny: Right. It just makes you more susceptible. Are there any tests that are being formally run right now where you can go and you could say I want to know the status of my immune system. Can I get some tests run, or how would I do that? Dr. Benson: Outside of clinical trials, I'm not aware of any. When we do complete blood counts on people, we measure what kind ofwe measure the quantity of how many neutrophils, how many lymphocytes, how many eosinophils, how many macrophages do they have? In clinical trials, a lot of correlative data looks specifically at immune cell function thatwell this person has natural killer cells. Do they work? And we can do that as a correlative study to a trial. One of the hang-ups that has been realized recently, is that you can draw peripheral bloodyou can draw blood out of the vein of an arm and do extensive studies and learn a whole lot about that blood, and it means absolutely nothing because the myeloma is in the bone marrow and those are the cells we need to studywhat they call the tumor infiltrating lymphocytes or the marrow infiltrating lymphocytes are the ones that are more important because that's where the action might be. In trials, especially in the solid tumors, people have worked tirelessly to look for biomarkers. So the serum lactate dehydrogenase level (LDH), for example, could be a marker of how much anaerobic metabolism there is. In other words, how much cells are relying on other means to generate energy besides oxygen, that these tumors are hypoxic. The bone marrow is hypoxic and so they need other strategies to make energy. Jenny: And LDH levels are an indicator of high risk myeloma too, right? Dr. Benson: So it all comes back doesn't it? You can start to connect these dots together that the CRP or even the beta2 microglobulin or the LDH could be markers of an inflammatory state that could give us clues to what an immune therapy might be particularly effective. And then characterizing the tumor toodoes the tumor have ligands for PD-1? Does it have ligands for KIR? Does it have ligands for CTLA4 that are overexpressed, or what's floating around in the bloodstream? Are there ligands for these out there are causing distractions or misleading the immune system into some kind of task at approval of the cancer? The number of groups and the number of people working on all these biomarkers is incredible. It's actually really humbling to go through the literature and see how much work is going on. In our projects ten years ago, again, this wasn't on the radar. Now it's a matter of just an incredible investment of people, and time, and resources, and energy, and with the goal that down the road maybe well have a blueprint where you could do that. You could get a blood test or a bone marrow sample. We had talked about this in the past, with drugs that target the myeloma directly. Now, we are talking about this idea of matching an immune therapy for its effectiveness and durability based on a patient, with their myeloma, with their immune system. It's truly breathtaking. We recently, a group of us, authored a paper together across diseases. It wasn't a myeloma-exclusive group of authors, but people who work in many diseases came together and wrote a paper and said, these are the immune tests and the immune studies that we should be looking at in natural killer cells and T-cells and monocytes and macrophages and myeloid derived suppressor cells, and regulatory T-cells. It was a really neat effort to have so many people around the table who are really good at the one thing they do, and produce something that truly couldn't have come out any other way. Those sorts of projects are ongoing, and there is going to be more of those sorts of ideas coming out to try to formalize this process in clinical trials, to inform decision making to say, well, we have antibodies that target PD-1. Well, we also have antibodies now that target the ligand PD-L1, and maybe one would work for somebody and the other one wouldn't. At least we'll have a blueprint now as to even how to begin to think about this. Jenny: I have a lot of questions. You look at the timing too, like you said, there are windows of opportunity. Is this something that you think would be appropriate to use with transplant, before transplant, after transplant? Would that make any difference? Has anybody tried that with transplant? Dr. Benson: All of that is going on now. There are trials of all of these drugs in the autologous transplant setting and even the allogeneic transplant, donor transplant setting. We're giving themwell when do you do it? Do you do it during the phase of immune reconstitution? Do you do it two weeks after or did you do it three months after? All of those are actually the subject of ongoing trials now. There are studies in smoldering myeloma. There are studies in relapsed refractory myeloma. One of the really interesting things, one of the really interesting concepts that has come out of the solid tumor literature is the mutational burden of the cancer. In other words, how many mutations does the cancer cell have, and does that relate to the efficacy of a checkpoint inhibitor? And the reason being that the more mutations there are, the more neo antigens there are. In other words, the more mutations the cancer cell has, the more abnormal proteins it makes and the more likely it is to present one of those to one of the patrolling immune policemen. If all of those things happen, then one of these checkpoint inhibitors could have exquisite anti-tumor activity. And there have been charts published of the mutational burden of different types of cancer, and myeloma falls right in the middle. It's one that certainly has a lot of mutations but not as many as melanoma, for example, or not as many as non-small cell lung cancer. But having said that, again it goes back to individual variability. There may be people with very high mutational burdens where these drugs might have exceptional activity, and then other conditions where there aren't a lot of mutations, if that theory is true, where one of this might not be effective. Jenny: So you're saying it's better if you have fewer mutational mutations, because the higher your mutational burden, the less likely it would be to work just because there is lessthere is more policing it has to do or you are saying the opposite? Dr. Benson: The opposite. The more mutations there are, the more likely the cancer cell is to tip its hand to the immune system, and the more likely it is that the immune police will recognize it and respond to it. Jenny: Oh, I see. That makes a lot of sense. Well that's great news for people who are later into their therapy because that's when they start developing more mutations, as they start relapsing these different treatments. Dr. Benson: That's what is so interesting. I have got the slides up on my computer here as we're speaking from the Pembrolizumab, Revlimid, Dex presentation at ASCO and they have a couple of patient case reports that they presented, and one of these folks had double refractor disease, with extramedullary myeloma and got two cycles of this therapy and has had a strict CR ongoing for a year now. Jenny: Wow. That's shocking. Dr. Benson: Yes. Who had gotten Revlimid before Velcade before transplant, had gotten an anthracycline before, had gotten oral Melphalan, and in the fourth line got Pembrolizumab with Rev Dex and now has this durable response. Jenny: Yes. Oh, shocking and wonderful. Why Revlimid do you think? Dr. Benson: Yeah. That's a good question. In fact, people were asking. Well could we use Revlimid in other cancers to, not for its direct anticancer effect necessarily, but for its ability to modulate the immune system somehow. I think that the answer to that is still unknown. We have seen that with other antibodies. We had my group presented a study at ASCO with the new anti CD38 antibody called Isatuximab. I think that allif not all, most all of the patients in that study have had Revlimid before, and a good number of them had disease that was refractory to Revlimid. Even in that study, we saw significant responses in the Revlimid refractory group. It argues that, or at least it suggests that there is something more about Revlimid. There is something more about IMiDs than just killing myeloma cells directly, that they have these immunomodulatory properties that maybe in a simple way, it's nothing more than a way to step on the gas and then take your foot off the brake at the same time. Jenny: That's what I've heard that they stimulate the immune system. Whereas something like Dex kind of suppresses the immune system. Dr. Benson: Yes. So that's why we did our study. When we published our KIR checkpoint inhibitor with Revlimid, we purposefully left Dex out of that, and these studies we have been talking about all include Dexamethasone. And that's always made me wonder, could Dex be playing a role in the immune dysfunction? So not only killing immune cells but rendering them senescent, rendering them exhausted or energic, or just incapable of doing their job and maybe the Pembro rescues that, or maybe the checkpoint inhibitor whichever one it is, can overcome that and the sum is greater than the parts in the end. Jenny: Interesting. Because I would think, well maybe I would want to find a clinical trial that didn't use the Dex but maybe not. Dr. Benson: Thats what we thought when we designed ours Jenny: I hate Dex. Everyone hates Dex so I was like wow, something that gets rid of Dex, awesome! Dr. Benson: I mean we were excited about ours because we had no Dexamethasone in the trial and we had a 24-month median PFS with Revlimid and a cure inhibitor. So we thought that was pretty exciting, with no Dexamethasone involved. So the overall response rate was only 33% but we had an MR, and then we had six more patients with disease stabilization, but we thought it's not a homerun. But again it's one of those little clues that maybe we can do this without Dexamethasone. Jenny: Now with what you have talked about already, which findings did you present at ASCO or just a few days ago or have you talked about that already? Dr. Benson: At ASCO, we didn't have any of our checkpoint data. We had our CD38, and we have been working with a new CD38 antibody called Isatuximab, and we had some data there from new cohorts in combination with Revlimid and Dexamethasone. Jenny: For patients, that's similar to Daratumumab. It's the same target but a different drug. Dr. Benson: Same idea. Yes, there are at least three of these now that are Daratumumab obviously approved. And the data there at ASCO were mind boggling, and there is going to be more mind boggling Dara data that are coming at EHA. But Isatuximab is another CD38 antibody, and then there is at least another one that's already in clinical trial. Jenny: And EHA is the European Hematology meeting, right? Dr. Benson: Correct, yes. Jenny: With this, some of these drugs already being FDA approved, which is so thrilling because you don't have to wait for that process and they are in clinical trials, what happens from here? How quickly can they be tested and tried and then moved to the clinic? Or do you think just the number of clinical will first increase, and well try these different variations, and then people decide oh, it works best with this or this or not this. How do see things happening? Dr. Benson: So Pembrolizumab is in phase three trials now. That one seems to be out on the forefront with the nearest point of potential. So there are phase three trials of Pembrolizumab with RevDex and then there are phase three trials with PomDex for Pembrolizumab. So I think that if one of this is approve forif one of the checkpoint inhibitors approved for myeloma, that's probably the one that's in the lead right now. Theres literally at least a dozen new checkpoints that have antibodies in development that we haven't even talked about yet, but LAG-3 and TIM-3 are two of this that are in clinical trials now. There is Vista and Oxford, theres a host of these that are similar in their mechanism, that they keep the brakes on the immune system, but they have their own subtleties in how they work. So I think that the answer is both that we need more trials and more evaluations, and then to keep pushing these that are out front to get into clinical use, or at least to a decision where we can say with confidence that this is something that needs to be approved. Jenny: And then when you think about it as thisit seems to be that everyone is really excited about this as the add-on, the hot add-on, and I love that. At one point do you decide, I know sometimes with proven myeloma therapies but they are not curing myeloma, that people are adding sometriplets are better than doublets and maybe potentially a monoclonal antibody or some kind of immunotherapy could be added as a quad kind of therapy. At one point can you start peeling things off, or is that ever possible, or myeloma just so complexall these different drugs are doing different things? I know that's probably an answer just by clinical trials but I'm just curious about your gut feeling on that. Dr. Benson: Well these trials are going on now where they are using VRD upfront with Daratumumab for example or with Elotuzumab for example. So this Holy Grail, we have talked about this for a long time that, could we get to a CHOP-like regimen for myeloma. So CHOP is an acronym for a four drug regimen that was shown to be curative for some forms of lymphoma. And they added an antibody called Rituxan for that. That same concept has been used in myeloma - we had the EVOLUTION study a few years ago. We published a trial with Revlimid, Velcade, Dexamethasone and Doxiland this idea that is their sweet spot, where you can now come with another drug, with a completely separate mechanism of action like a monoclonal antibody with the intention of curing the disease. Those trials are going on now. Whether that antibody is going to be tumor directed like Daratumumab, or whether it's better to use an immune directed antibody like Lirilumab or Pembrolizumab or Nivolumab, I think is something that gets settled in trials ultimately. But the question is there now thatand it's being addressed now, and the studies are on their way. It's hard to put into words how exciting it is. Jenny: Yeah, I know. They always use the word promising, but sometimes you want to just get up and shout. This is more than promising, yeah. Dr. Benson: They are doing trials now. We have been participating in these trials with combination antibodies too, with Elotuzumab and Lirilumab for example, or Elotuzumab and Urelumab. This idea that you can start to tinker with the immune system and multiple axes at once, and is there a way to simplifyis there a way to step on the gas, to target the tumor, and release the breaks and deliver a tumor-directed immune signal that's going to eradicate the disease, and spare the host too, and not cause autoimmunity. That's something we haven't touched on yet, but is there a way to do this in a safe way that directs the entire emphasis of the therapy towards the cancer and not cause any collateral damage? Jenny: Yes, that would be great. I think every patient would love to see just immunotherapy types of combinations particular if they were as effective and as doing things like a transplant or being on one of the other ones. That would be fantastic. Are those in clinical trials right now orand do you have any insight as to how that works yet? Dr. Benson: They are. So these combination antibody trials are in clinical trials now and then peoplewhat I love about this field is how creative people are but they are talking about combining antibodies with CAR cells for example. I mean it sounds sort of straightforward to use Revlimid with one of these, but that's a combinatorial immunologic therapy and they are seeing activity with that alone. So could you build on that? Could you use Revlimid with a checkpoint inhibitor and a tumor directed antibody? How far can you push it and not impair the safety? I think this is something that is a big concern. But it's exciting because they are doing it. I mean we are doing it. We are doing combination antibody trials. People are talking about combining CAR cells and antibodies. It's justI promised you I wasn't going to say promising but it's really invigorating to think that, gosh, the solution seems like it's right here now, and the trials are underway. Jenny: Well it's fantastic. We only have a few minutes left. But I want to leave some time for caller questions. So if you have a question for Dr. Benson, you can call 347-637-2631 and press 1 on your keypad. And we'll start with our first caller question. Go ahead with your question. Caller: Hi. Good afternoon, Dr. Benson and Jenny. Dr. Benson, I listened in on your second show with Jenny back in August of 2013, and you put PD-1 in my vocabulary almost three years ago, and I have been trying to keep informed about it ever since, especially since it's that time we had for the smoldering community about one or two trials available at that point, clinical trials. Fast forward obviously three years, and we have many more trials now on our offering plate which is awesome but it also causes more confusion as to which ones to actually consider. I recently learned and you also mentioned earlier in this discussion that I struggle with the real names of these drugs. So I prefer to use the trade names because they are a little bit easier for me to remember. But I recently learned that Keytruda and OPDIVO target PD-1. And then there is another drug. It doesn't have a real name yet. It's Atezolizumab which targets PD-L1. So Yale and MD Anderson are both doing high risk smoldering trials using checkpoint inhibitors, single agents. MDA is going to be using Keytruda and Yale is going to bethey actually opened and they are accruing from what I understand the Atezolizumab trial. So which oneI mean one is obviously targeting PD-1 and the other is targeting PD-L1. PD-1 targets the immune cells, correct the T-cells and PD-L1 is found on the tumor cells. So do we know yet which is the best of the two to target? Can you combine both of these drugs and hit them both? Dr. Benson: Thanks for calling. This is great. You are talking about cutting edge science because the answer is we don't know. We don't know the answer. Atezolizumab is a PD-L1 antibody. Caller: Oh, is that how you say it? You say it so easily. Dr. Benson: Well you did it great. You did it great. There is another one called Divolumab that's in clinical trials now that's a PD-L1 targeting agent. I think the answer is we don't know and that's why these trials are going on now. Whether one is better than the other, whether one would in a place where the other wouldn't, whether you could give both together and get a synergistic effect, are all questions that will hopefully be answered with these trials, you're absolutely right. The combination of a PD-1 and a PD-L1 together, I don't know. I don't think that that is an active trial yet. People have chosen to combine different axes rather than to target the same with two drugs. So for instance actually OPDIVO and Yervoy are FDA approved to be given together in melanoma. So to target CTLA4 and PD-1 together is an FDA approved combination in melanoma now. The idea of targeting multiple breaking systems in parallel seems to be more attractive than targeting the same one with multiple agents. But whether one is going to have more efficacy, whether one would have more side-effects and truly honestly, not to just go on and on but there are patients and there are immune systems where one would make more sense and one wouldn't. Maybe there are tumors. We are targeting PD-L1would carry more efficacy and there are other situations where an immune system would derive more benefit from blocking PD-1. PD-1, for example, has multiple ligands. There is PD-L1 and PD-L2, for example. So you could envision that blocking PD-L1 might not help in that setting but blocking PD-1 would, just hypothetically. Caller: Oh, I see. So is the Atezolizumab just blocking the PD-L1? Dr. Benson: Correct. Caller: I haven't learned about PD-L2 yet. I'm going to have to look it up and expand my knowledge. Do any of these trials have ways built into these protocols to test the patient's cells even in a petri dish to see if they would respond to the investigational therapy? Dr. Benson: Most of these do. Most of these trials have correlates where they are assaying for the expression of PD-L1 and PD-1 and CTLA4 and KIRs, and they are doing these in real time as the trial progresses. I don't know if any of it have it as eligibility criteria though; I think that's what you're asking. Now there are CAR cell trials where that's an eligibility criterion. In other words, they'll screen the bone marrow to look for the target at a CAR cell before they let a patient on that study. But I'm not aware of any checkpoint inhibitor studies where that's a condition of eligibility. It's correlative science that's being done in parallel as the study goes on. Truthfully, part of that could be because the biomarkers aren't established yet. There are situations where someone might respond to a PD-1 antibody for example and the tumor doesn't have a lot of PD-L1 on it. And maybe the action is in a lymph node or maybe it happens in the micro environment indirectly. Caller: Really these are the early stages. We are stillwe still have a long way to go before they have a lot of answers for myeloma patients and smoldering patients because I would imagine to have to really work first in multiple myeloma patients before it moves into our cohort. Dr. Benson: So I think two things. I think I don't know how long we have to go, but I would say we have a lot of work to do. I think that it's a subtle difference but I think the speed and the scope is much greater now than it was before. So things are being done with more urgency and rapidity now, and discoveries are being translated faster. As far as drugs being tested in different settings, I think this is purely my opinion I should say that first. But I think this is a concept that came from our paradigm of how we used to test cytotoxics. In other words, if you had a drug that was cytotoxic that worked by poisoning the cell if it was an alkylating agent or what have you, it was tested in the relapsed refractory setting first and then moved up into earlier, earlier stages mainly out of safety. First and foremost, out of safety. With the immune system works, there may be a rationale to test it in someone in a first relapse because they have a more immune competency. They haven't had a lot of Dexamethasone yet. They haven't had a lot of radiation yet. So I think that we need to be creative as a field, again going back to how do you marry the disease to the immune system, and maybe PD-L1 antibodiesmaybe this would work best in the relapsed refractory setting where there is so much immune disarray that blocking the signal would have significant benefit. But I think this is alreadythis is already in real time too that these are all like you mentioned, there are trials across the board for patients and all. Caller: Yes, really exciting for the smoldering community to really see these trials popping up. It's like I said you'd go to clinicaltrials.gov three years ago and two or three popped up and one of them was an observation trial. So it's really neat to kind of be part of this now. You know what, I sat and I wondered because after seeing and hearing what you mentioned about Dr. Mateo's ASCO presentations where she spoke of Pembro and it showed better outcomes when combined with Revlimid. I'm wondering if that would translate also then into the smoldering population because obviously these two trials are just I guess, phase one or maybe even pilot studies just trying to efficacy or safety I guess, safety and the dosing for smoldering patients. So I'm wondering if something like this couldI don't know. I don't know if this is something to kind ofthat needs that little bump as well maybe from Revlimid for the smoldering people as well. And I guess that there is still a lot of different answers, questions that need to be answered. So you actually even said that you could envision a combination of let's say a monoclonal antibody whether it'd be Dara or the Isatuximab combined with a checkpoint inhibitor and perhaps even Revlimid. And again I just wanted to clarify because I think I captured that. With something like this, would a combination like this, the potential, the side effect profile might include an autoimmune disease outcome unintended. Did I capture that right? Dr. Benson: Right. So that's the big concern with this whole approach is that it could work too well. And I think the best example would be to look by analogy at the setting of donor stem cell transplant, where you could cure the cancer but at the same time the patient could die from what they call graft versus host disease, where the immune system came in and realized that this tumor needs to be taken care of and it does that and at the same time, the immune system from the donor realizes that these aren't my lungs; this isn't my liver, this isn't my heart, those aren't my eyes. So a lot of these drugs have autoimmune side effects. They have pneumonitis for example where people get inflammation in their lungs from the PD-1 antibodies or colitis, inflammation in the colon. Caller: Are these outcomes long lasting or do they result after you stopped the drug. Dr. Benson: Well they can improve. They can resolve with stopping the drug and then actually treating them with immune suppression, treating them with steroids, treating them with drugs that you would use to treat autoimmune disease. Now I think at ASCO, if I'm not mistaken, there was an abstract presented that patients have been re-challenged with PD-1 antibodies and developed pneumonitis again. So that would be an example of the collateral damage that we had mentioned earlier. Now there are trials where they are using Pomalidomide with Elotuzumab and Nivolumab. I mean these trials, these triplet immune-based trials are just getting off the ground now. From a safety standpoint, we have gotten past the grave concerns that you can't do three immune therapies at once. These trials are, in combinatorial doublets, are active and ongoing. Caller: Oh, I see. So Elo and with either Rev and Dex or Pom and Dex is considered a triplet immuneoh, okay. Dr. Benson: So Elotuzumab with Pom and Dex and Nivo and Nivolumab. Caller: Okay. Oh, I hadn't realized that that one was out there because I spoketried to just focus on the smoldering one. So I guess I missed that. Dr. Benson: It's easy to miss, trust me Caller: I know, there is so much. I understand that monoclonal antibodies need to be taken long-term in order to continue the efficacy and if the answer to that is yes, do checkpoint inhibitors also need to be taken long term as well or are those questions are unanswered yet, either? Dr. Benson: They are not answered for sure. My supposition would be that they would need to be administered long-term but that's completely without any data to support it. Just arguing aboutarguing from the standpoint of a drug like Herceptin works in breast cancer. Herceptin is a monoclonal antibody for breast cancer where people can have these very dramatic durable responses with long-term or Rituxan and Lymphoma as another example of itof an antibody that's been around for a long time that's revolutionized how lymphomas are treated and you can get to a point where the maintenance administration isyou get an infusion every few months, for example, or every three months or what have you. It's not every week or every other week orbut I think that that's the understanding currently that these would be administered long-term to maintain durability or remission or maintain suppression of the malignancy. But the real answer is nobody knows. Caller: Well do you have any early data on the smoldering Dara trials? Has anyone come out with any early data about the efficacy, the response rates whether one arm is looking better than the others? Dr. Benson: Yes. I don't know. I'm laughing because we participate in that trial here at Ohio State, and I'm not aware that any data has been presented yet with single agent there and smoldering. Ola Landgren, when he was at the NCI did a trial with the KIR checkpoint inhibitor in smoldering, and that's published now. But as far as Dara and Pembro and NIVO and Durvalumab and the rest of these, I'm not aware of any data that's out there yet. Caller: Okay. So we're still winging it. I mean I have a smoldering myeloma Facebook group and we have a really nice representation in there of patients who are in a lot of the different clinical trials for smoldering myeloma. So it's really neat to have them share their experiences with other members and it helps each of us really learn a bit more about it and we have a few members from Dr. Landgren's trial down at the NIH, the Carlfizomib, Rev and Dex and each of them are maintaining their MRD negative status for two or more yearsactually one of them I think is going on the third year. So that's exciting and the Dara people are seeing responses but it's the long-term data that everybody sits and wonders about. Dr. Benson: Yes. I hesitate to name names because I'll leave people out but Olas work and Irene Ghobrials work in smoldering is justits magnificent. Just how we even conceive of the disease today compared to five or ten years ago and how much that's influenced practice already even. I think thatit's just that thethe conception how we even think about the disease now just fundamentally is very different than it was just in the recent past. Caller: Absolutely. And Dr. Ghobrial's clinical trial that she is running, it's more of a perspective trial. It's called PCrowd study. Many of our members are also contributing to that because that's such an easy trial. You just kind of donate your serum samples every time you go and have your blood drawn and then them on up to her lab and we're happy as a patient cohort to be able to do that. You don't need to actually travel up there to donateto give the sample. You can actually do it through the mail. So it just makes such sense to be able to really expand on that to our patient cohort and a lot of us are willing to do it. Because if we can't help you brilliant scientists with our samples, then what are we sitting around waiting to get us answers for? We really have to jump in and help out. Dr. Benson, thank you so, so much for your call. I appreciate it very much. Jenny: Thank you. Thanks for your questions. Dr. Benson: Thanks for your call. Caller: Yeah, great. Have a great day guys. Dr. Benson: Take care. Caller: Yeah, hi. You may have alluded to it briefly earlier. But clinically for patients who are in a remission or close to one, at what point is it advisable to try one of thethese checkpoint inhibitor based clinical trials? Dr. Benson: Okay, good. In other words, are there trials open if somebody is in remission and looking for a maintenance treatment? Caller: Or is it even advisable to do so or it's something you should only try in relapse? Dr. Benson: Well so the Spanish group had published a paper a year or two ago that showed in patients with MRD positivity that it appears that PD-L1 was over-expressed in that particular setting. So some of these trials that are using the antibodies after a transplant for example are looking at whether that could be an effective setting. I don't know. Although I will confess, I have no firm grasp on the sheer number of trials out there. It's mind-boggling how many there are. I'm not aware of any of it that are looking at the drugs in the maintenance setting, out of the context of a platform of a transplant. But it seems like at least this one data set would suggest that that's a potential target and a patient who is in remission but has MRD detectable. Caller: Is there any data on how they complement the transplant? Whether transplant by cell versus transplantthese experimental treatments are better? Dr. Benson: No. I don't think any of the data has been reported from those yet. Caller: Okay, thanks. Jenny: Okay. Thanks so much for your great question. Next caller, go ahead with your question. Caller: Yes. Thank you both very much, Jenny and Dr. Benson. With all of these singular agent drugs now that are effective as a single agent, all the trials, all the combos that seem to have been used up to now, just sort of automatically routinely include Dex. And I'm wondering if with all the negativity about these steroids, what they doare we at the point where we can do a double or triplet without including a steroid to still have the efficacy. Dr. Benson: Yes. That's a great question. The trial that we published last year had no Dexamethasone in it and I think that that was the first of its kind. At least hypothetically what we were thinking was that the Dex would undermine the favorable immunologic effects we were trying to achieve with two immune agents given together. So the patients who I take care of here every day would say the same thing that in the panoply of drugs that we use and the treatments they receive, that the Dexamethasone is the toughest one. I think that we have patients here in our practice who were getting Daratumumab for example that we have been able to get off of Dexamethasone after a few infusions. But I think that certainly from a clinical point of view, a practice point of view, if we could develop an effective steroid-free regimen, that would be one of the Holy Grails in the practice. So I think we are moving toward that as we learn more about how the immune system works, and learn more about which immune combinations could have synergies with them, that well be able to move past Dex. But I think our study was the first one that had no Dex in it and showed activity. Caller: Great. Thanks very much. Jenny: Okay, thank you so much. Okay Dr. Benson, thank you so much for joining us today. We're just thrilled that you did. We are so grateful for your wonderful research and your efforts for myeloma patients and we are so thankful for all that you do for us. Dr. Benson: Thank you, Jenny. Thank you for all that you do as well. I am very grateful for all of your hard work. Jenny: Well we are looking forward to seeing more about checkpoint inhibitors. And you just gave us an outstanding overview of what they are and how they work. So thank you so much. Dr. Benson: You're welcome. Jenny: Thank you for listening to another episode of Myeloma Crowd Radio. Join us for future shows to learn more about the latest in myeloma research and what it means for you.