Full Show: Targeting High-Risk Myeloma with New Approaches - Dr. Saad Usmani, MD, Levine Cancer Institute
Learn about all myeloma happenings on the new Myeloma Crowd site: the first comprehensive site for myeloma patients and caregivers. Dr. Saad Usmani, MD Levine Cancer Institute Interview Date: June 27, 2014 Summary Dr. Saad Usmani is the new director of the Plasma Cell Disorder program and the director of Clinical Research in Hematology myeloma program at the Levine Cancer Institute. He shares three key lessons he learned through his work at UAMS: all myeloma is different and the effectivity of the most used drugs will vary from one patient to the next; about 10-15% of myeloma patients are high-risk and resistant to most of these therapies; there is a big disparity in clinical trial access especially for racial minorities. He defines "high-risk" by clarifying that high-risk smoldering myeloma is the risk to progression to active myeloma, while the risk for a newly diagnosed myeloma patient is the risk to relapse after treatment has been given. He defines the highest risk features as being deletion 17p, translocation (14;16), translocation (14;20), and amplification of chromosome 1q21. Although the 4;14 translocation has been known to be a high risk feature, he notes that if bortezomib is used in therapy, these patients can have similar outcomes to normal risk patients, so 4;14 can be an intermediate risk factor. He gave a very clear explanation of the GEP test and other tests needed to determine risk and relapse. He shared his experience at UAMS showing that many high-risk patients getting transplant and even double transplant relapse quickly, so he prefers to use clinical trials and newer drugs instead of a melphalan-based treatment because of toxicity issues. He shares the first ever clinical trial specifically designed for newly diagnosed high-risk myeloma patients with del17, 4;14 and 14;20 that has two arms - the first uses Revlimid-Velcade-dexamethasone and the second uses Revlimid-Velcade-dexamethasone with a newer monoclonal antibody that targets the CS1 protein called elotuzumab. He describes how and why the trial was constructed. This SWOG 1211 trial is available in the US and in Canada and is the first major trial to address the needs of high-risk patients. He now provides deep myeloma expertise in the Charlotte and surrounding area for an underserved patient population. The live mPatient Myeloma Radio podcast with Dr. Saad Usmani
Jenny: Welcome to today’s episode of mPatient Myeloma Radio, a show that connects patients with myeloma researchers. This series is in place to help you learn more about the latest research in myeloma so you can make your very best treatment decisions. It’s also to make you aware that if patients participate in clinical trials in greater numbers we can help with the bar. It’s very rewarding to get emails saying that patients have joined a clinical trial based on one of the interviews that they've heard. It makes this program worth the effort and its very fun for me to hear. Now, if you like to receive a weekly email about past and upcoming interviews you can subscribe to our mPatient Minute newsletter on the homepage or follow us there on Facebook or Twitter, and please share these interviews with your myeloma friends. We also have a site called myelomacrowd.org. This is a site with comprehensive information from all myeloma sources. We've posted several articles this week on the importance of patient advocates and the need to be an educated patient and if you look at the Life with Myeloma section, under that heading we have a section called "Becoming An Educated Patient." We list the variety of ways you can become more educated with the lots of resources there. We would love to have you contribute on this site what you were learning or a snapshot of your experience, and you can click on the "Become a Contributor" link in order to do that. Today we are very excited to have with us Dr. Saad Usmani of the Levine Cancer Institute. Dr. Usmani joined the Levine Cancer Institute as the director of the Plasma Cell Disorder program and the director of Clinical Research in Hematology in July of 2013. He's a specialist in hematology, medical oncology, and bone marrow transplantation. He holds an academic appointment as Clinical Associate Professor of medicine at the UNC-Chapel Hill School of Medicine. He received his medical education -- and Dr. Usmani, you're going to have to help me with the name of the school -- the Allama Iqbal Medical College in Pakistan, correct?
Dr. Usmani: You've done it.
Jenny: I did?
Dr. Usmani: Yes, ma’am.
Jenny: He completed a residency in internal medicine at Sinai-Grace Hospital/Wayne State University in Detroit, Michigan; and a fellowship in Hematology & Oncology at the University of Connecticut Health Center in Farmington, Connecticut. Before joining the Levine Cancer Institute, Dr. Usmani was an Assistant Professor of Medicine at the University of Arkansas for Medical Sciences in Little Rock where he served as the Director of Developmental Therapeutics at the Myeloma Institute for Research & Therapy, also known as MIRT. He is a member of the International Myeloma Working Group, the SWOG committee, the American Society of Hematology, ASCO, and the American Society of Bone Marrow Transplantation. He serves on the ASCO Scientific Committee on Lymphoma and Plasma Cell Disorders, the ASH Committee on Plasma Cell Neoplasia, and the NCI Myeloma Steering Committee. He is on the editorial review board of numerous medical journals, has authored and co-authored over 50 peer-reviewed manuscripts, and presented over 75 abstracts at international meetings and national meetings. Dr. Usmani has served as the Principal Investigator and Co-Principal Investigator for over 35 clinical trials in all phases. So, Dr. Usmani, welcome to the show. We're very, very happy to have you.
Dr. Usmani: I'm glad to be here. Thanks for giving me the opportunity to actually utilize this mode of social media to educate and advise patients. I'm thrilled to be here.
Jenny: Well, we're learning a lot. You were previously at UAMS, so that is considered a great center of excellence in myeloma care and maybe we would like to start the show by you telling us what you learned at UAMS.
Dr. Usmani: Absolutely. I would probably backtrack a little bit and just highlight my trainings starting from fellowship when I started to get involved in myeloma research. This was around 2007 when I was starting up my fellowship training and a lot of exciting things were happening within the field of myeloma at that time. We were just starting to understand how myeloma is so unique amongst hematologic malignancies where there are actually many different clinical phenotypes or behaviors amongst myeloma patients. And then around the same time, a lot of newer drugs and therapies were being developed. So for a young person who was interested in hematologic malignancies, myeloma attracted my attention. But I was trained in a very classical way of approaching myeloma as an incurable disease, a disease that can be controlled for a brief period of time before we run out of therapeutic options. So as I was presenting some of my data from a myeloma-related lab project, I met with Dr. Barlogie at one of the scientific meetings and got invited to interview for a faculty position. I think that was probably the best decision that I ever made. I had several other options at academic constitutions, but going to the Myeloma Institute really provided me with a very well-rounded academic and biologic orientation about myeloma as a disease and developed the expertise in patient care and really looked at the bigger picture of what are the key issues and how to address or approach those specific research issues. So I’m truly appreciative of the kind of research mind that Dr. Barlogie has. And this is an exciting time for him because I think he's transitioning into a retirement or emeritus role today in Arkansas. He turned 70. And another very smart myeloma investigator from England, Dr. Gareth Morgan, will be joining that program to lead that program. But Dr. Barlogie was a wonderful mentor; he's one of the smartest people I know and truly the first translation researcher that the field of myeloma saw. So I’ve learned a great deal from him. The key things that I learned were as follows: Dr. Barlogie was the first one who wanted to approach myeloma with curability in mind, very much like how the treatment for leukemia was approached starting in the '50s and '60s and later on. So his philosophy for myeloma therapy was you have to combine all effective myeloma therapies in an upfront strategy if you are going to be able to cure a patient, and that philosophy holds true for all cancers. If you want to eradicate cancer, you have to pick your best drugs in an upfront strategy. And when he started his career, it was melphalan -- melphalan was the only effective myeloma drug at that time. So, over his career, he built his therapy around melphalan. And as he discovered thalidomide's efficacy, he added that on to his Total Therapy program. And then when bortezomib came along, that was incorporated. What was clear to see was that if you took a hundred myeloma patients and treated them the same way, not every myeloma patient behaves clinically and responds in the same way. So the first lesson that I learned from that whole experience was that you can probably group myeloma patients into specific clinical behaving phenotypes and that correlates with the disease biology at the gene level as well. So the "total therapy" or the most effective drugs for any given myeloma patient will likely be very different from one group of patients to the other. Even when you combine all these effective therapies in the Total Therapy program, not every patient goes into a deep remission or a long-lasting remission. So you really have to tailor therapy for any given patient. The second most important lesson that we learned that even by combining all of these effective drugs together in an upfront strategy, there is a 10% to 15% group of newly diagnosed patient who will be at high risk of relapse. So even though you’re combining all these drugs together, all the effective drugs together, there is a subset of patients where we still don’t have a good answer. And they’re going to have a quick relapse of progression in spite of all our best efforts. So we do need new drugs. We do need to understand the disease better. We do need newer drug classes. We probably need better combinations of therapies in a different platform. And so those are the areas of research from a therapeutic standpoint that are important to understand and move forward. The third very important thing that I learned was the fact that there is a big disparity when it comes to access to clinical trials across the United States, especially when it comes to trial participation of ethnic or racial minorities. So the fact that this disease is two and a half times more common in the African American population and still those patients make up less than 5% or 10% of clinical trial patients being enrolled on of these trials is an underwhelming fact. And so as I was transitioning out into my new role here in Charlotte, I wanted to take these lessons with me and build my program around it. Charlotte is one of the top 20 metropolitan areas by population in the US, but did not have an academic cancer program up until four years ago when the Carolinas HealthCare System decided to invest funds along with the Levine family and they were lucky. They were able to actually recruit one of the top cancer center directors in the country, Dr. Derek Raghavan, who was heading up the Cleveland Clinic Cancer Institute at that time, to come and build a truly world-class cancer institute. So Dr. Raghavan came here with a mandate to not only build a broad virtual cancer center across the Carolinas, but also to standardize the state-of-the-art care for each disease subset, and also to bring the novel clinical trials to this region. Carolinas HealthCare System, being the second largest non-for-profit healthcare system in the US -- outside of the VA system actually -- you know, this was a very unique opportunity and a very unique mandate and model that Dr. Raghavan wanted to execute. So actually, when I came to interview here I wasn’t anticipating the kind of infrastructure and resources that have been committed to this endeavor. So for me it was kind of a no-brainer to actually come to this institute and build a program here. There’s a big patient population. The greater Charlotte area has a population of about three and a half or four million without any academic or clinical research program. And because of its ethnic diversity, that also made me choose this particular institute as an option because again, going by those three lessons that I shared with you, I would have the opportunity to build my program around those three lines in a very short period of time.
Jenny: And I think you need all the support. You need the clinical side and you need the research side and you need the patient population in order to successfully investigate and then try it out it seems.
Dr. Usmani: That’s true. At the same time you also have to study the disease. One of the things that I learned from Arkansas was how important translational research, research on patient samples is, because that gives you the ultimate answer. How does the disease behave under the effect of different therapies? One of the things that I do want to highlight is a clinical trial that I wrote as a member of the SWOG Myeloma Committee when I was still in Arkansas, and this was the SWOG trial for newly diagnosed high-risk patients who are either transplant ineligible or they are deferring their transplant. This actually a good opportunity for me to bring up this particular point. We talk about the risk a lot within myeloma. You know, we talk about high-risk smoldering myeloma, we talk about high-risk in newly diagnosed active myelomas, then we sometimes talk about high-risk and the relapse affecting myeloma patients; and it’s extremely important to distinguish all of these risks. I’m going to try to highlight one particular thing about the high-risk smoldering patients. So the risk, when we talk about risk in the smoldering patients, the risk pertains to the progression of that smoldering patient from a state of no organ damage to a state of organ damage requiring treatment. So that risk is different than the risk of relapse that we talk about in active myeloma patients. And Jennifer, please feel free to ask me any questions if you want me to elaborate further. But when we are talking about risk in smoldering myeloma, it’s the risk for that patient to turn to an active patient with active disease. Whereas, when we’re talking about high risk in a newly diagnosed active myeloma patient, we’re talking about that particular patient receiving their initial therapy and then being at a high risk of relapsing very quickly. So what makes high-risk myeloma or high-risk active myeloma high risk is the risk of relapse. The same risk holds true for the relapsed/refractory setting, but it’s not as well-defined as it is in the active myeloma subgroup. There are several different clinical high-risk features in an active myeloma patient. When I say clinical features, the patients who have primary plasma cell leukemia at the time of their diagnosis, they are clinically high risk of relapse very quickly regardless of the therapies that we’re giving to them. The patients who have extramedullary disease, so myeloma that decides to leave the bone marrow and go to other tissues like liver or skin or pleura or soft tissue, those patients may be at a high risk of relapse very quickly after their initial therapy. Patients who have very high serum LDH levels are at high-risk of early relapse. And many times elevated or high serum LDH levels and extramedullary disease go hand in hand. So those clinical features, when people are presenting with those clinical features, those patients are at high risk of disease coming back sooner after they’ve had their initial treatment. Then there are certain biologic features by cytogenetics and FISH analysis on the bone marrow biopsy at the time of diagnosis. So features such as deletion 17p, translocation (14;16), translocation (14;20), amplification of chromosome 1q21. And if we’re talking about myeloma on a global scale, translocation (4;14) is also an intermediate to high-risk factor. Now, I'm making a special comment about translocation (4;14) when I say talking about this particular disease subset in the global landscape because we do have evidence that if you are using or utilizing a bortezomib-based regimen for the translocation (4;14) patients, they actually have better outcomes. And in some clinical trials, they’ve been shown to actually be as good as standard-risk patients. And then there are some next generation technologies like gene expression profiling that have been utilized by the Arkansas group to identify a high-risk gene signature that can distinguish about 13% to15% of newly diagnosed myeloma patients who are at high risk of relapse, early relapse; and a similar signature has been developed by the HOVON group, the Netherlands group, which can identify similar number of high-risk patients. Both these gene signatures are commercially available. The first one is called MyPRS; that’s the Arkansas one. The second I believe is called SKY-92. So those gene expression signatures are available commercially now. And I know that the MyPRS is reimbursed by Medicare and other insurances. And to my knowledge, SKY-92 was working in that direction. I’m not sure whether they’ve achieved that yet or not. But these are the broad categories of what we define as high-risk newly diagnosed myeloma.
Jenny: So can I ask a question about the GEP for a minute? Beyond the definition of, let’s say, your (14;16) or (14;20) that might picked up on the GEP, what else is that providing to you that shows high-risk? What else would you be looking at?
Dr. Usmani: So the gene expression profiling is actually a different test than cytogenetics and GEP. So when we’re doing conventional cytogenetics, actually what we’re doing is -- you know, this is a very old technique, and I’m going to try to simplify and explain this to the best of my abilities. So what conventional cytogenetics or usual cytogenetic testing does is we take a bone marrow aspirate from the patient and we take that sample, separate the cellular components, and put them, say, in a test tube with some growth factors, some special growth factors, that make the cells divide or go through cell division. And then at a certain time point, say, three or four hours after exposing those cells to growth factors, we take those cells and make special slides. We are picking that time point because we are assuming that after a certain period of time those blood cells will be in cell division. So if you were to look at a cell under the microscope, the nuclear material is very crumpled and you cannot see the chromosomes until the cell is in cell division and those chromosomes are lining up in the center of the cell. So that’s why with conventional cytogenetics you take those cells, put them in the test tube, give them certain growth factors to push them towards cell cycle, and then take a look at those chromosomes under the microscope. And so the issue with the technique is you’re relying on the dividing cells and you’re looking at chromosome abnormalities specifically in those dividing cells. So that’s one technique through which we look at chromosome abnormality. The second technique is FISH or Fluorescent in Situ Hybridization. With FISH technique, we have special probes that can tag a specific gene on a chromosome and usually for a certain gene each of the cells has two copies. So if you are missing a copy inside a cell, you will only have one probe light up in that cell. If you have more than two copies, you're going to have three or four probes light up in that cell under the microscope. So that's how these two techniques of looking at chromosome abnormalities differ from each other. So FISH would tell us the percentage of cells who may have a certain abnormality. What gene expression profiling does is very different. So there are 30,000 genes in each of the human cells, and these genes are present on the 46 chromosomes that they have in each of the cells. What gene expression profiling does is it measures that expression of each of those 30,000 genes and the step is run on a special chip that has almost 54,000 probes for those genes. So some of those genes have multiple probes and by measuring these gene expression levels, one can determine which genes are active in the cancer cell and which are inactive in the cancer cell. So these techniques are very different. The gene expression profiling provides a more global picture of what's going on in all those myeloma cells that have been collected and can tell us a lot of information about the cancer than can the cytogenetics and FISH. Gene expression profiling can be utilized to group patients into molecular subtypes based on clinical behavior. So the Arkansas group discovered -- this was that 2007 paper I was telling you about. By gene expression profiling, the Arkansas group discovered that there were seven different subtypes of myeloma patients that behaved very different clinically. So there was a group called low bone or LB where you had a lot of myeloma activity, but those patients did not have a lot of bone damage, for example. Specific clinical behaviors that correlated with those gene expression profiling and then the Netherland, the HOVON group, went on to discover that there were three additional molecular subgroups on top of those seven subgroups, and they published this work about a year and a half or so ago. So there's a lot of heterogeneity within myeloma patients, and GEP can be very helpful in distinguishing those. It can also help in modeling signatures to predict drug response to therapy or its relapse. Longwinded explanation but I hope that this helps.
Jenny: I want to ask you a little bit more about the drug response to therapy. Just as an example, when my cytogenetics and my FISH were done, it didn't pick up my (14;20) translocation, but when I had my GEP done, it did pick up the (14;20). So, I only learned that because I had that extra test done. So two questions I guess, will you be doing the GEP at your new center? And then, can you talk more about drug response to therapy based on the different groups or subtypes?
Dr. Usmani: Sure. So when I came here, one of my goals was again to standardize the care of myeloma patients across the network. So we were able to develop myeloma specific pathways for newly diagnosed patients who are either transplant eligible or ineligible to have standardized battery of testing when they're diagnosed to better biologically and define their disease and appropriate disease burn assessment. Because I was coming from an academic setting, trying to bring that mindset into this particular healthcare setting, there is always a lag period between what's going on in academia and how it translates into clinical practice. We started to do both cytogenetics, FISH as well as gene expression profiling at my program as soon as I got here. So we have been utilizing gene expression profiling since July of last year. It's one of the standard tests that are done at my center. One of the motivations is again, to identify the high-risk patients so they can be channeled toward clinical trials sooner. And the second is to really determine how the disease of a particular patient will behave knowing what we already know about the disease by having done gene expression profiling for over a decade now within the academic world. In terms of identifying or choosing therapies based on the gene expression profiling result, I don’t think that we are there yet. The only thing that I'm a little vociferous about is reserving high-dose melphalan transplants for the high-risk patients. I do not tend to become a strong proponent of using high-dose melphalan or stem cell transplants for high-risk patients in an upfront setting because having seen how patients relapse quickly even after tandem transplants in Arkansas within this high-risk category, I'm a little hesitant in recommending that kind of toxic therapy for the high-risk patients. I would rather utilize the upfront strategies that we have right now and if the patients do progress, channel them towards the myeloma trials with new drug classes, things that the myeloma cells have not seen before. I don't think we are there yet in terms choosing therapies based on gene expression profiling. We will likely get there in the coming years. We are certainly not there yet. The subgroup, the translocation (4;14) group, I preferentially utilize it for proteasome inhibitor-based regimen for those patients. But outside of that, we don't have a lot of evidence to support therapies in certain subset of patients. Having said that, the gene expression profiling in these days are being generated to help facilitate that.
Jenny: So if somebody comes into your clinic and they have, let's say, deletion 17 or (14;16) or something like that and you want to shy away from doing the high-dose melphalan up front, what do you choose instead?
Dr. Usmani: I would be enrolling them on the SWOG study, the SWOG 1211 clinical trial, which is comparing RVD induction and maintenance or RVD elotuzumab induction and maintenance. The idea here is you are essentially picking one of the forefront standard of care regimens and you are continuing that therapy until relapse or progression in a given patient. The standard arm on this trial receives eight cycles of induction followed by a dose-attenuated maintenance with those three drugs until the patient has relapsed or progressed, compared with the experimental arm where the patients are getting elotuzumab in combination with RVD or Revlimid, Velcade, Dexamethasone. Elotuzumab, as you probably may know, is a monoclonal antibody that targets the protein called CS1 that is present on the surface of myeloma cells and elotuzumab has been in clinical trials for relapsed/refractory patients as well as in upfront patients in a randomized Phase III in combination with Revlimid and dexamethasone. But this high-risk trial is the first one that's combining a three-drug regimen with elotuzumab as monoclonal antibody therapy. Even with stem cell transplants in the upfront setting, more than half of the patients who have high-risk myeloma will be relapsing within two years. And I sincerely feel, having seen so many high-risk patients relapse after a singular or double transplant, that it's not worth the toxicity for that subgroup of patients. I'd rather be utilizing more novel therapies developing newer clinical trials to include better proteasome inhibitors or better monoclonal antibodies together in combination with other drugs for these patients in clinical trials and trying to find a different answer. The approaches that we have for high-risk myeloma right now for that 15% patient population is not helping majority of the high-risk patients.
Jenny: So now a question about that is that I know lots of people are excited about elotuzumab and daratumumab and these monoclonal antibodies. How did you come to construct this trial using elotuzumab over, let's say, a daratumumab or something else? How did you pick that? Is there something special about that that applies to (14;16) patients and (14;20) patients that other drugs like maybe an HDAC inhibitor or an AKT inhibitor or there are lots of different new classes of myeloma drugs? How did you come to that conclusion?
Dr. Usmani: This trial was developed in early 2011. The landscape for therapeutic agents at that time was very different. We had early data that at least in the relapsed/refractory setting, the combination of elotuzumab with Revlimid and dexamethasone worked as well for patients with high-risk features as well as it did for standard-risk patients, and it did not have any side effects. That was the other important aspect of choosing elotuzumab. If you are improving the efficacy of your treatment strategy without adding toxicity, that would be a very attractive feature of a clinical trial. Daratumumab wasn't in clinical trials up until 2013. Within the cooperative group setting, it takes about 18 months or so for a clinical trial to actually be conceived, constructed, and then go through the necessary regulatory rigmarole before it gets activated. The trial was designed in early 2011, at which point RVD was the most commonly used induction chemotherapy regimen across the academic as well as community institutions and elo was just making its way into the relapsed/refractory setting. A newly diagnosed trial for elo had not been conceived at that time. Based on some of the early efficacy data that we find in the relapsed/refractory setting, as well as the side-effect profile, made us pick this particular drug.
Jenny: Can you show a little more about the results in the relapsed/refractory setting? Because I know typically new drugs or drug combinations will start in the relapsed/refractory setting and one day work, then you move them to the newly diagnosed setting which is what you've done here, it looks like. So what did you find and why are you excited to try that?
Dr. Usmani: Sure. The combination of elotuzumab along with Revlimid, dexamethasone was tried in the relapsed and relapsed/refractory myeloma patients yielding an overall response rate of a little north of 80% which was a pretty significant overall response rate for a two-drug combination. A similar combination of elotuzumab with Velcade and dexamethasone yielded a response rate of about 47% or 48%. So these data were just emerging and being presented at ASH and ASCO at that time. So even though elo as a single agent does not have a lot of appreciable clinical activity in combination with other drugs was showing clinical activity beyond what those single agents would have done in that setting. And specifically, looking at the elo, Rev/dex data, there weren’t any differences in the responses or the durability of responses between the patients who had specific cytogenetic abnormalities versus those who did not.
Jenny: Okay. Okay, that’s great. Well what else would you like to share about this trial?
Dr. Usmani: So yes, so the SWOG 1211 trial when through a Phase 1 portion in which regardless of the patient’s risk category we enrolled a certain number of patients. We plan to enroll six patients for what’s called a run-in phase where we’re treating patients with that regimen and seeing if there are any side effects or we need to adjust doses. We did not notice any severe adverse event with the addition of elotuzumab. It was very well tolerated. And the Phase 2 portion opened up in October of last year. This is an NCI high-priority trial. ECOG institutions as well ALLIANCE or CALGB institutions are also participating in this study in the Phase 2 portion. And so this is accruing across all national clinical trials network sites. Some sites are still lagging behind in opening this, but many sites across the United States are already open. The trial will actually also be opening in Canada, so across the NCIC network sites as well.
Jenny: That's very nice.
Dr. Usmani: So the idea is this the small subset of patients. So we are trying to make sure that we have this trial accessible to as many places as possible.
Jenny: And I have a question, so if you consider deletion 17, (14;16), (14;20) high risk, which they are, why is (4;14) not included in this group? Because it’s not considered as high-risk as the others?
Dr. Usmani: Right. No, that’s a very good question. So at the time that that this trial was being designed, the patients with (4;14) -- within the US market we have a proteasome inhibitor that's available and is utilized in the upfront strategy for newly diagnosed patients. And when we looked at some of the clinical trials coming again from the Netherlands group and Arkansas, patients who were receiving bortezomib as part of their induction chemotherapy and later as a maintenance strategy, patients with (4;14) were doing as well as the patients who have standard risk disease. So it was thought that translocation (4;14) can probably be considered an intermediate, if not, a high-risk feature. If you look at the relapsing patients, if you look at the Kyprolis or carfilzomib Phase 2 trial that led to that drug’s approval, if you look at cytogenetic abnormalities, even in the relapsed/refractory setting, the patients on the trial who had translocation (4;14) did as well as patients who had standard risk features, whereas the patients with deletion 17p did poorly. So the point I’m trying to make is there is something about proteasome inhibitors benefiting the translocation (4;14) patients. We have data with Velcade and we have data with Kyprolis; with Velcade and the upfront setting with Kyprolis and relapsed/refractory setting. So I think that proteasome inhibitor-based regimen for that subgroup of patients is extremely important. And my personal preference in my practice based on these data and observations, my translocation (4;14) patients do remain on a proteasome inhibitor-based maintenance therapy as well after they have had their initial chemotherapy.
Jenny: And do you think the new oral versions are going to be just as effective? Are they showing to be just as effective as the infusions or the injections?
Dr. Usmani: The head-to-head trials have not been done. I don’t think that they will be done. Bortezomib is going to become generic in 2017 so I don’t think that there will be a head-to-head trial like that, but that is what we anticipate. There is more data coming with ixazomib and I do not anticipate that we’ll see anything different. Oprozomib is a little behind in terms of its clinical development at this point in time, but we are keenly anticipating those results. But from a translational research standpoint and intuition, I would think that proteasome inhibitors, regardless of whether they are oral or IV, will continue to benefit that subgroup of patients.
Jenny: Well, is there anything else you’d like to share or talk about, other clinical trials that you have planned for your center?
Dr. Usmani: Absolutely. After joining here, we did engage and participate in several trials within the relapsed/refractory patients, recognizing the fact that once the patients have progressed with their second or third line of therapy, the options for therapy become very limited. And if the patients here in the greater Charlotte area wanted to seek out a clinical trial, they had to travel to either Duke or Chapel Hill or to Emory. So there was nothing in almost a 200-mile radius for these patients. So the first set of trials that actually opened in the relapsed/refractory setting included daratumumab and filanesib. We are about to open the oprozomib/pom/dex Phase 1 study. We do have a Kyprolis/ibrutinib Phase 1 study that’s open. There are some daratumumab-based upfront as well as relapsed/refractory trials that are coming down the pike. There are three other relapsed/refractory trials in the works. There are certain investigator-sponsored trials that have been approved that will be opening at my center over the next six months including studies with a very exciting oral exportin-1 inhibitor called Selinexor. There are several upfront as well as relapsed/refractory trial options that are available at our center. What we are trying to do is to be very selective in the kind of trials that we’re picking that actually cater the needs for our patient population. What my mentor, Dr. Barlogie, has taught me is that the trials are for the patient; it’s not the other way around. I'm big on access to care for my patients and that’s how we’re picking our trials. We are participating in some Multiple Myeloma Research Foundation initiatives and we'll be partnering with the MMRC in the coming months on clinical trial initiatives as well. We are also doing pre-clinical translational work. We have the capability to do cell line as well as primary myeloma cell research. We are engaged in next generation genomic testing-based projects relevant to racial disparities. We are also initiating on the minimal residual disease testing by the EuroFlow method in July in a specific research protocol, and we will also be including the DNA sequence-based MRD testing in our clinical trials as well as clinical practice here at my center in specific projects. All of those initiatives are underway. I do also want to highlight the fact that we have a second myeloma-specific investigator joining the program in about three months from now, Dr. Manisha Bhutani, who was one of Dr. Ola Landgren's protégés will be joining the program here in Charlotte and she will be leading efforts in the newly diagnosed patients as well as the high-risk smoldering myeloma patients. We've seen a lot of growth in a very short period of time. Our program is very patient-centered, and we're trying to pick the research questions that are most relevant to our patient population because that's what one has to recognize. All that we're doing within the field right now is relevant to how we can serve the patients the best way.
Jenny: Well, they're lucky to have you in Charlotte and the surrounding area. It's always better if you go see a specialist, especially one that has access to both patient care and research. So Charlotte is very fortunate to have you.
Dr. Usmani: Thank you.
Jenny: We have some caller questions so I would like to open it up for caller questions. And then I have some emailed in questions that I'd like to ask, so we might keep you over our hour time, but I hope that's ok with you, just for a few minutes.
Dr. Usmani: Sure.
Jenny: If you have a question for Dr. Usmani, please dial 347-637-2631 and press 1 on your keypad.
Caller: Yes. Dr. Usmani, how are you? This is Dana Holmes. It's a great pleasure to speak to you. How are you?
Dr. Usmani: Good, Dana.
Caller: Oh, good, I have a couple of questions for you, doctor. Of course, I'm going to sidetrack it a little bit and steer towards smoldering because that's my area of interest. I know that you recently attended the IMWG Summit in Milan, and I was curious if there was a consensus reached to reclassify smoldering into both high risk and ultra high risk categories. And if there was, can you share the criteria with us, which criteria actually needs to be met under each of those labels?
Dr. Usmani: All right. Now that's a very pertinent question. And I will just backtrack a little bit just to give you an explanation. The idea to identify the ultra high-risk smoldering myeloma patient population is based on the fact that the myeloma cancer-related changes have already taken place in those malignant plasma cells. And it's only a matter of time that that particular subset of patients will progress with an end organ damage. And the point that we're trying to make is why do we need to wait until that patient presents with a bone event or anemia or kidney problems? Why cannot we presume that they are a very early stage myeloma and they are going to have some problems? Why don't we mitigate that problem and go ahead and treat the patient? So that has been a challenge because from the perspective of clinical features, the clinical parameters that we have right now do not consistently help us identify those patients. Anecdotally, we've utilized a lot of different things, certain features, percentage of plasma cells, and the base with which the M-spike or the light chain ratio is changing over time. But really when we look at a population of patients then try to tease out through statistical methods, we’re not finding the right clinical parameters that can identify 100% of patients who are going to have that feature that will lead to turning into active myeloma. There has been a lot of debate around how to reclassify the ultra high-risk myeloma or a smoldering myeloma patient population and then graduate them into active myeloma. What I can share with you is there has been a consensus; the consensus has been reached. We have a manuscript that is in preparation for submission to a distinguished medical journal, and you will be hearing about this very shortly as soon as this comes out. Then I can probably inbox you some details about this.
Caller: Wonderful! I would look forward to that.
Dr. Usmani: But we have selected out three features that will help us identify that ultra high-risk smoldering myeloma patient and reclassify them as active myeloma.
Caller: Very good. Dr. Usmani, which imaging diagnostics are really critical to have for a patient that you suspect smoldering to really reach an accurate diagnosis? We’re confused as to which test works best or do they each work differently, therefore collectively being necessary? Should we get the PET-CT? Should we also get the MRIs? Should we get the skeletal survey? Should we have the full complement to make certain that we’ve truly been evaluated the right way?
Dr. Usmani: I would suggest getting all three. All three tell us a different story. The skeletal survey tells you the damage that was done perhaps 12 or 18 months ago. It takes about 70% of the bone to decalcify before a lesion shows up on X-rays. So there’s always a time lag between the damage that has been done and what shows up on X-rays. The MRIs tell you collection of myeloma cells that may be sitting in the spine or in the skull without having caused any bone damage, so you actually see focal lesions not lytic lesions. Lytic lesion is bone damage. You can actually see collections of myeloma cells or focal lesions sitting inside the vertebral spine using the MRI technique. The PET-CT gives you a more detailed bone picture, and the PET part gives you any areas of increased abnormal uptake of sugar which can signify myeloma activity. A lot of times if you do identify a big enough MRI or a PET lesion, you would seek an FNA to confirm the activity and presence of myeloma cells there. If you see that, then I would go on and treat that patient like a real myeloma patient.
Caller: Great. Now I realized that a whole body MRI would be optimal, but I don’t think many centers offer that. So would an MRI of the full spine be sufficient at least?
Dr. Usmani: Yes.
Caller: Okay. And what about the cytogenetic testing, the conventional, the FISH, and the GEP test, should asymptomatic smoldering patients try to get that as well? Can GEP identify risks to progression in this population?
Dr. Usmani: So the SWOG 0120 trial looked at gene expression profiling to see if the same 70-gene model can be utilized to predict patients who may progress to active disease, and that 70-gene model showed that with the different reading cutoff, you can identify patients who are at risk for progression. But that test is not commercially available, and I’m not sure about its applicability because it has not been validated. We have a hypothesis generating dataset but we haven’t validated those findings nor have they been commercialized because they haven’t been validated in independent datasets. So we do have some evidence that the GEP may be helpful but it’s not ready for primetime. Within the smoldering myeloma patients, we do know from the French data and the Spanish data, the patients who have deletion 17p or translocation (4;14) may have more proliferative -- or rather they may have a higher risk of progression from smoldering to active myeloma, if those findings are identified in a smoldering myeloma patient.
Dr. Usmani: So they may have to be watched quickly. They may have to be watched closely.
Caller: More closely.
Dr. Usmani: Yes. But that risk of progression still does not reach that critical cut-off that the myeloma experts are using right now. So we --
Caller: For the ultra-high risk. Okay.
Dr. Usmani: Yes. So for ultra-high risk, we’re defining that by picking the features which will identify patients who have an 80% chance of progression to active myeloma within two years.
Caller: Within two years and then, the high risk is less. What is the high risk within like a two to five-year period? Is that the theory?
Dr. Usmani: I didn’t get that question. Caller: Not the ultra-high risk group but the group below that, what we’re referring to as the high-risk smoldering, what’s their risk of progression? Is it within a two to five-year period?
Dr. Usmani: Yes.
Caller: Two to five-year period. And lastly, do you have any plans to develop any clinical trials for the high-risk smoldering group in your clinic?
Dr. Usmani: Our plan is to collaborate. So Ola Lundgren has done some of the early work at NCI. He’s just moved to Memorial Sloan and having Dr. Menisha Bhutani join from his team, that’s one of our goals, to actually start clinical investigations within that subgroup of patients in collaboration with Ola’s team. Yes. So that is one on our to-do list for sure.
Caller: Very good. Congratulations with Dr. Bhutani. She is on all of the NIH smoldering documents and articles, and they turned out a lot of helpful information for our population. Dr. Usmani, thank you so much for what you do, for your support, and for taking all of my questions. Very much appreciate it. It was a pleasure.
Dr. Usmani: You’re welcome, Dana.
Caller: Hi, Dr. Usmani. I’m just wondering about how I would go about joining your trial. Dr. Usmani: Where are your located?
Caller: In California.
Dr. Usmani: I see. Perhaps, if you can kindly email me, I can give you my email address right now. I can see if I can direct you to a place that’s close. The other option is, if you go to clinicaltrials.gov, I think that might actually be a better option. If you go to clinicaltrials.gov and type in SWOG 1211 clinical trial, the clinical trial will pop up and my contact information and the study coordinator contact information will show up there. You can just use that contact info to get a hold of me and I can help direct.
Caller: Great. Thank you so much.
Dr. Usmani: You’re welcome.
Jenny: Okay. We have some emails and questions also. Two by Suzierose. She says, "How do you treat high-risk myeloma patients differently? Do you use different agents for induction, consolidation and maintenance or do you extend induction in the cycles beyond four before high-dose melphalan and extend maintenance?
Dr. Usmani: As I mentioned, I have a educated discussion with my patients about the role of high-dose melphalan and knowing that majority of myeloma patients who have high-risk features are going to relapse fairly quickly after having undergone high-dose melphalan either once or twice. So my usual choice for high-risk patients is the RVD induction regimen. If they are deferring transplant, we go on to give them eight cycles of induction before going to a dose attenuated of RVD maintenance until relapse or progression. If they opt for a high-dose melphalan, the patients get anywhere from four to six cycles of induction and we stop the induction when the response has plateaued or when you’re at best depth of response with that regimen, collect the stem cells, give the melphalan transplant, and then once their counts have recovered, usually by day 60, we start them back on Velcade-Revlamid-Dexamethasone-based maintenance strategy and then keep them on it until a time of relapse or progression or if they cannot tolerate the treatment.
Jenny: Okay, great. And her second question was did TP53, which I think is deletion 17, is it?
Jenny: …patients achieve minimal residual disease with the VT-PACE induction therapy and when you were in Arkansas.
Dr. Usmani: So in Arkansas we did not start using MRD testing until January of 2013, and the results were fairly preliminary. At that point in time, I’ve had discussions with some of the investigators there. The MRD testing analyses are still preliminary so we cannot make far-reaching conclusions from that. What we do know about high-risk patients, including p53 patients, in general, is regardless of the depth of response, even if those patients go into stringent CR, they do relapse back fairly quickly. And we did see patients who were "MRD negative" who were also relapsing. So again, these were small numbers and only prelim data without having a lot of numbers and proper analysis done.
Jenny: Well, a question from Jason. It's actually a good follow-up then for that. What do you recommend for relapsed/refractory high-risk patients?
Dr. Usmani: Clinical trial. A clinical trial with a combination of drugs that their myeloma has not seen before. I truly encourage clinical trial participation for all the patients. It took that leap of faith for a myeloma patient to go on a Velcade trial so that you could benefit, that future patients could benefit from Velcade or Revlimide or thalidomide or carfilzomib or pomalidomide. I’m a very staunch advocate for clinical trial participation. And honestly, barring all the host of things that can exclude patients from going on a clinical trial like performance status and other health-related issues, I sincerely encourage myeloma patients to seek out clinical trials and participate in them.
Jenny: Well, that’s why we’re doing this series is to promote awareness about it because unless we have a cure we need something new.
Dr. Usmani: Agree. Yes. There are several exciting drug classes. I mean daratumumab is probably just the beginning of immunotherapy revolution.
Jenny: Yes, I completely agree. And Dr. Kuehl said immunotherapy is seeing its day basically. Okay, our final question is by Liz and then she says, "Dr. Barlogie mentioned that there are a small percentage of patients who could be considered to be cured, maybe in the 5% range." She says, "Are there any high-risk patients in this 'cured group'?"
Dr. Usmani: The short answer is no, but there are some high-risk patients who can benefit from therapy beyond the usual two or three-year mark that we quote for them. So we have seen high-risk patients going out four, five, six or seven years with the advances in therapies that we’ve made. But I would not consider high-risk myeloma in the cured category. We’re not there yet. I mean that’s one of our goals, but we just don’t have the right drugs.
Jenny: And it looks like -- I mean in this clinical trial, I think it’s one of the few that’s unusual in that it’s targeting only high-risk patients. I don’t think that’s really been done much before. Would you agree or is that not true?
Dr. Usmani: I’m sorry. There was some interference on my end. Can you kindly repeat the question?
Jenny: The question is, it seems like the SWOG trial is one of the few that targets a particular patient sub-population of myeloma patients, and I think that would be nice to see that more in the future. So is that true that it’s one of the few? And then do you expect --
Dr. Usmani: That is true.
Jenny: -- more in the future?
Dr. Usmani: It’s the only national trial and it’s the only North American trial that’s focused on high-risk patients. As a single-center study, the Arkansas Total Therapy 5 study was probably the first prospective high-risk Phase 2 trial. I served as the PI of that trial while I was in Arkansas, but that was a single-center study. The SWOG study is a truly North American multi-institutional high-risk study, the first of its kind, but with many more to come.
Jenny: Yeah, that would be terrific. It looks like we have two more caller questions, if you don’t mind hanging on.
Caller: Yes. Thank you for taking my question. My question is about access to clinical trials for high-risk patients. In fact, in answer to one of the earlier questions, you said that for newly diagnosed high-risk patients, you would recommend RVD induction and perhaps high-dose melphalan with the transplant. But if the patient has gone through that process and maybe is on some maintenance for perhaps a year or so and has not yet progressed but nevertheless was at diagnosis identified as high-risk, it seems to me that that patient is not eligible for any clinical trials. It’s necessary to wait until progression. What do you suggest in that case? I consider it a problem and I wonder if you agree, that for patients that are intermediate, they’re neither newly diagnosed nor relapsed/refractory, clinical trials are not available even though they were found to be high risk.
Dr. Usmani: Right. But remember, the high-risk category, if you’re already diagnosed, transplanted and a year out from into your maintenance, you’ve already beaten your odds of early relapse and the two-year mark because you’re probably beyond the two-year mark right now. So I don’t know what the remission status would be. But the overall overarching theme in medicine is to not try to fix something that isn’t broken. If you’re benefitting from the current therapy and knowing that there are some high-risk patients who can have long-term control of their disease, it wouldn’t be a good idea to intervene when there are no problems.
Caller: If I can just quote you a little bit, that the high-risk population is, as you say, not curable so as far as we know and the relapse will occur. If it hasn’t occurred yet, it will probably occur soon. If you wait until trying a couple more lines of therapy that don’t work and then for the relapse, by the time that such people can get or else go for the clinical trials, it’s sort of too late. The response to clinical trials is -- well, it’s pretty good in the later studies. There’s still a lot of people who don’t respond because their disease is too far advanced, and so it would be nice to be able to get the latest therapies earlier.
Dr. Usmani: Right. I totally agree with that and there are trials that allow patients to go on study at their time of first relapse and beyond. But you have to appreciate that how will you judge success of a clinical trial if you are already in complete remission and now -- what’s our baseline? How are we judging success?
Caller: It’s a specific case. It's my wife’s. She’s never achieved complete remission but has achieved stable disease, but there’s active myeloma still, has always been in spite of high-dose melphalan transplant, that the transplant had no effect.
Dr. Usmani: Okay. So she’s never had anything better than stable disease?
Caller: Well, she had a considerable improvement from induction therapy, a good partial response from induction therapy, no effect to the stem cell transplant but stable since then and on maintenance.
Dr. Usmani: So very good partial response after the primary therapy?
Dr. Usmani: Or 90% decrease in the myeloma markers?
Caller: Just about 90%, maybe 85%, something like that, but very definite high-risk markers by FISH both before and after transplant.
Dr. Usmani: All right. I don’t know the particulars of this case, but if she’s maintaining response after her induction therapy and transplant right now, I wouldn’t do anything differently.
Caller: I see. Okay.
Dr. Usmani: I mean clinically --
Caller: Thank you very much.
Dr. Usmani: You’re welcome.
Jenny: I think that’s a question because I’m sort of in the same position. When you’re on that middle road, let’s say you’re on stringent remission and I think as these new developments come out like immunotherapies or the vaccines, maybe there’s a possibility to create clinical trials for the group that is in the remission stage to see if those newer therapies that have no side effects can extend the remission time. That would be interesting.
Dr. Usmani: Right. A similar trial design idea or trial design was proposed to some drug companies, which shall remain unnamed, by Dr. Siegel and myself for this specific patient population. So exactly the gentleman who just called, his wife, they belong to this category of doing a consolidation after their transplant for the high-risk patients with some of the novel drugs and that did not get approved. But I hope that, that kind of a therapeutic strategy may get approved in the future as a pilot study. I didn’t want to bring this up, but one of the many issues that were raised when we proposed this study was how will you measure success? Well, you can measure success by delaying PFS (progression free survival), but you may not get a good idea from just looking at the response simply because if the patient already achieved a VGPR (very good partial remission) or a CR (complete remission) after the transplant, it will be very difficult to measure protein because you already are at that CR starting point.
Jenny: Right. Okay. We have one more quick question and we have a hard stop in just a few minutes, so we’ll have to keep it short.
Caller: Okay. I am one of those patients that were diagnosed with primary plasma cell leukemia. I was wondering if all this information is something that would apply to me as well as all the high-risk multiple myeloma or if there’s something different that would be considered.
Dr. Usmani: The primary plasma cell leukemia is considered a high-risk feature. So the high-risk information pertains to you as well. And honestly, for young high-risk patients, one of the modalities that we do recommend especially if they’re not having -- if they have had a good response to early therapy is to even potentially consider an allogeneic stem cell transplant. And primary plasma cell leukemias would fall under that category.
Caller: I had no matches. I had no donors because my transplant hospital wanted to do a donor transplant from the beginning but had no donors at that time. So I had my own transplant and have been in a complete remission for 16 months. So I don’t know. I’m just hoping for the best, I guess.
Dr. Usmani: No, that is fantastic and highly unusual but I am very happy for you. I can tell you that within -- when we were in Arkansas, we looked into primary plasma cell leukemia patients, and the average time that the patients would be disease-free was just nine months. This is wonderful. And I sincerely hope and pray that you remain in this remission.
Caller: Thank you.
Jenny: Okay, thank you so much. And Dr. Usmani, I heard your pager go off, so you probably need to go.
Dr. Usmani: Yes.
Jenny: And you stayed away overtime. So we just thank you so much for joining us today. We wish you well at your new center. We will do all we can to support you there and hope you create a wiledysuccessful myeloma program.
Dr. Usmani: Thank you so much. I just want to make sure that I acknowledge my whole team here including Tam Yunker, Brian Kirby, and the big myeloma support group that we have here. I especially want to acknowledge Sandy Hirsch who was a warrior of a myeloma patient. She passed away recently, and was the sole warrior for all myeloma patients here in the greater Charlotte area. She led a support group here, survived high-risk myeloma for nearly five years before passing away earlier this summer. Thank you so much for giving me the opportunity to come out and speak to you.
Jenny: We really appreciate you taking the time to talk with us. So, thank you very much.
Dr. Usmani: All right. Bye.
Jenny: Thank you for listening to other episode of Innovation in Myeloma. Join us next week for our next mPatient Radio interview as we learn more about how we as patients can help drive to a cure by joining clinical trials.