Four Experts Debate Aggressive Treatment Approaches and the Goal of Complete Response Recorded on April 19, 2014

Transcription

1 Patient Power Knowledge. Confidence. Hope. Toward a Cure for Multiple Myeloma: Four Experts Debate Aggressive Treatment Approaches and the Goal of Complete Response Recorded on April 19, 2014 Gareth Morgan, MD, PhD Director, Myeloma Institute for Research and Therapy University of Arkansas for Medical Sciences Jesús San Miguel, MD, PhD Head, Hematology Department Hospital Universitario de Salamanca Philippe Moreau, MD Head, Hematology Department University Hospital of Nantes Rafael Fonseca, MD Site Director, Hematological Malignancies Mayo Clinic Arizona Please remember the opinions expressed on Patient Power are not necessarily the views of our sponsors, contributors, partners or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That s how you ll get care that s most appropriate for you. Andrew Schorr: Hello and welcome to Patient Power. I m Andrew Schorr. Recently, world experts in myeloma gathered in Boston for a medical meeting called Myeloma And we were on the scene. We got four of the world experts together for a roundtable discussion to hear the latest for clinicians and for patients. Here s our host, Dr. Gareth Morgan. My name is Sir Gareth Morgan. I'd like to welcome you here to Boston at the 2014 myeloma meeting, where I'm joined by three of my internationally esteemed colleagues, Professor San Miguel from Pamplona, Philippe Moreau from Nantes. Nantes. France.

2 And Rafael from Arizona. So, gentlemen, if you don't mind me asking you a few questions, so what are the new treatments that are really there for use in patients in the clinic now? When you talk about new treatments I think it's important just to discriminate between the newly diagnosed patients and the relapsed patients because I think most of the innovation nowadays are in the relapsed setting, but they're moving very fast to the newly diagnosed. And if I would think in something really that could be something that would change the treatment of myeloma, I think we should talk about monoclonal antibodies. Elotuzumab plus the anti-cd38 monoclonal antibodies are showing clear efficacy. The first one in combination with lenalidomide (Revlimid), dexamethasone (Decadron), while the second one, anti-cd38 daratumumab and the SAR from Sanofi, are showing clear efficacy 40 percent of relapsed patients as a single agent. On top of these we have the second- and third-generation imids and the second- and third-generation proteasome inhibitors, where particularly pomalidomide (Pomalyst) is showing efficacy in relapsed/refractory patients. Also a new proteasome inhibitor, carfilzomib (Kyprolis) and ixazomib, another proteasome inhibitor, are showing clear efficacy in the relapsed setting, but at the same time they are also being tested in the newly diagnosed patients. And finally there is another class of drugs that I think is of clear interest are the HDAC inhibitors, particularly panobinostat that has shown efficacy in combination with bortezomib (Velcade), dexamethasone in a Phase III randomized trial. The data is going to be presented, positive data is going to be presented at the next ASCO meeting and the EHA meeting. So, Philippe, Jesús has clearly told us there's a range of drugs, but when are we going to be able to access them for our patients? Well, this is an issue in Europe because the drugs are quickly approved in U.S., for example, pomalidomide and carfilzomib are already approved in U.S. Pomalidomide is recently, very recently approved in Europe, but we have to stick to the labeling of the approval. And it was mentioned that the drugs are used in combinations very often, and I think that a single drug is approved in the relapsed setting, but we want immediately to combine this drug with other agents to increase the efficacy. So I think that very soon we will have carfilzomib in Europe, maybe next year. Pomalidomide is already available, and I think that we have to wait for these molecular antibodies because elotuzumab won't be available before two years probably in Europe and daratumumab, the anti-cd38 monoclonal antibody, not before three years from now. So we have the results of ongoing Phase II, Phase III trials that are positive, but we have to wait a little while to have access to these drugs. And this is a problem for us in Europe. So Rafael, what do you think about these monoclonal antibodies? Well, I think as Jesus was saying, it's incredibly exciting that they have single agent activity, but as we always do in myeloma we are always thinking about combinations. The nice thing about monoclonals, I'm going to venture to say, is it's going to be very easy to quickly move them up front. We have to go for the myeloma equivalent of an R-CHOP. So maybe it's going to be a R-KRD and R-CyBorD or something of the like followed by some other treatments perhaps--i think still for some time we're going to be using transplant but perhaps at some point in lieu of the transplant itself. And we talked about monoclonals, and it's exciting to cite our colleague, Sagar Lonial. This is the only disease that produces a monoclonal antibody for which there is not a monoclonal therapeutic antibody, but now we have them. That's perfect. So one of the things we're learning about here is this personalized medicine strategy. So, Jesús, how do you consider personalized medicine for the myeloma patient?

3 Okay. When you get in front of a patient, always you are thinking in a personalized attitude with a patient, but sometimes we have no--the tools just to identify difference between one patients and the other. And in this context, what I think is personalized medicine can also be called optimized medicine or optimized treatment, in other words to offer the best possible treatment for the patient until we have the tools just to dissect genetic deletions that will benefit from any specific treatment, targeted treatment. Philippe, what do you understand about personalized medicine? What does it mean for you? We have to always take into account the heterogeneity of the disease. We know that there is only one--there is not one unique multiple myeloma, but we have different types of disease. And we know that there are different sub groups of patients, patients with, let's say, good risk and on the contrary, on the opposite, patients with very high risk. What we are trying to do now all of us with biomarkers, with biological tests, we are trying to identify specific test for specific group of patients and try to provide specific treatment with a specific target. We are not ready yet for this personalized medicine. We are working hard, and today enjoying this myeloma workshop in Boston we've heard about incredible results. And we are doing a lot of progress, but that's too early to, my opinion. Rafael, high-risk myeloma, could you explain that concept to us, and how do you deal with high-risk myeloma? Sure. No, I'll be happy to do that, and we get a lot of questions about this from patients. Really, high-risk just means that there is a way that we could identify those patients that we think are at greater risk of experiencing an earlier relapse, and we've traditionally done that through a number of genetic markers, the translocations as well as deletion of 17, but we now know there's multiple ways in which one can go back determining who has high-risk disease or not. It isn't perfect. We cannot tell 100 percent for sure in every single case who has high-risk disease, but this provides us with an alert of someone we should be thinking perhaps about more intense combination therapies, longer duration of therapy, first and foremost clinical trials. And I think for patients watching us out there, they should know that a big part of our discussion this morning was how do we focus our efforts so we can provide yet better options for patients who have high-risk disease given that there's tremendous progress for the non high-risk population. And still we have significant room for improvement. So how do you think these new agents we've heard about are going to be used in that sub-group of patients? So good discussion this morning. I think we've heard a number of strategies, first of all, trying to do things like combinations, getting smart about combinations, perhaps combine them with some of the targeted therapeutics that will attack those known mutations or other genetic abnormalities. People talk about maybe using these novel agents which are not so new anymore but we have for the clinic with immunotherapy strategies. So I think it's going to a multi-prong approach in how we approach high-risk disease. Jesús, so combinations of drugs, kind of sequencing drugs, single agents, perhaps you could explain your thoughts on how we should best go forward with that in the clinic. Okay. Since myeloma is, as already has been mentioned, is not a single disease and is a quite complex disease in the way that you have several subclasses, I think combination therapy is required. Single-agent treatment is more appropriate for the diseases that have a single genetic lesion like CML that you can target or acute myelocytic leukemia that you can target the genetic code by a chemical marker in that context. By contrast, in multiple myeloma, I think patients usually benefit from multi-target therapies.

4 So, Philippe, you work in the IFM, and you've been pioneers in kind of the treatment of myeloma. Perhaps you could just explain about induction, consolidation, maintenance and where you see those different concepts are going to be used to improve outcomes. Yes, that's a very, very important part of our protocols, ongoing and future protocols, especially in young patients. We want to improve the quality of the response at each step of a therapeutic strategy. And in young patients, we are using induction to reduce the tumor burden and then an autologous stem cell transplantation and then consolidation to further increase the response and maintenance, short-term maintenance in France to have a long duration of response. So at each step we are trying to find the best combination. Up front we are used to triple combinations, three drugs, and in the future we are going to randomized three drugs plus or minus monoclonal an antibody daratumumab because we want to increase the response. We are also trying to find of best conditioning regimen prior to stem cell transplantation, and then we are going to do a randomized study comparing melphalan 200 (Alkeran) that is the standard of care versus melphalan 200 plus bortezomib in order also to increase the response rate if possible. And we are also trying to find the best approaches following stem cell transplantation to increase the quality, the depth of the response with consolidation, and we are working on this. So we have to optimize all the steps of a strategy to reach many more residual disease negativity, so we are not able to detect any tumor cells within the bone marrow. That is the optimal goal for cure for sure. So we heard this morning that if you survive to 10 years that the kind of survival curve becomes flat suggesting those patients are cured, and you alluded to just then that the achievement of a complete response is pretty much an essential prerequisite for cure. So, Rafael, do you think we should aim to get everybody into a complete response, or are there ways of personalizing your approach? You know, I as think as a global strategy it makes perfect sense to go for a complete response, so when I think about how we're going to treat our patients and we do so in the clinic say outside of the context of a clinical trial, for me that's an important goal. It doesn't mean you necessarily have to adjust the goal as you go forward in the sense that for instance if you have a patient who doesn't really achieve a complete response with induction should you necessarily change to a different regimen, we don't know that. But I think the results are very exciting. We've seen that from the data that was presented from Little Rock. We certainly had that very strong paper presented by Jesús and colleagues in the Spanish group back in 2011 that shows 30 percent of patients who reach a CR will be without evidence of disease recurrence at the median follow-up of 20 years. I don't think if we can't call that a cure we're just being just incredibly conservative. I think those patients are really cured. Now, the interesting part of that study, there are some patients who don't have a complete response and yet maintain well control in the long-term. We acknowledge that. We don't really have enough wisdom to know exactly what that means for each one of those sub-groups. So we hear that myeloma is always preceded by a MGUS phase, that could either be a clinical phase or even sub-clinical so you couldn't detect it. So do you think there's any kind of likelihood that you could put people back to a MGUS phase where they don't have damage, and they just remain? I think that's a good goal. It's a highly achievable goal, but we might be able to cure the MGUS, and the precedent for this is when we treat patients with light chain amyloidosis. Many of them have a pathologic state of an MGUS, just happen to have a bad protein, a protein that gets deposited in the body, and those patients can have eradication of their monoclonal proteins. Admittedly we haven't gone in and checked in deeply say like with molecular flow cytometry as much as has been done in myeloma. But I think the answer is yes. If one has to live with an MGUS, you know it's a very good outcome for our therapy.

5 If I can expand a bit on this, this type of patient is a small fraction who we detected a diagnosis of approximately 8 percent of the myeloma population that present with a myeloma with lytic lesion clear picture of multiple myeloma that they have, and MGUS clone, and you detect this MGUS clone by flow cytometry because you have a quite high number of residual polyclonal plasma cell diagnosis that is something that is present in MGUS. When you treat these patients in multiple myeloma including transplantation you are able to eradicate the big bulk of the disease, but you remain with this small clone that was present at diagnosis. These are the only fraction in which I will be conservative. For the rest of the patients I think you need to try to eradicate the disease as Philippe has already mentioned. Otherwise, the patient will relapse, and we want to cure these patients. So I think we're all sensible doctors, and we have strategies based on you know trying to achieve CRs, but what about the kind of frail, older patient? How do we personalize our strategies for them? That's a very, very important issue, and we've heard for example that at the last ASH meeting, the meeting of the American Society of Hematology, and very interesting and good presentation from the Italian group. And we have to adopt in patients that are considered as the elderly population of patients, we have to adopt a strategy and the treatment according to the stages, to co-morbidities. A patient can be fit, and he has to receive the best treatment options with combinations including novel agents. But we do have patients that are frail or are not fit to receive intensive treatment, and we have to consider and to evaluate this performance status immediately at the time of diagnosis. That's really important. So I kind of think one of the things that's important as well is how we monitor patients. So what do you think the ideal frequency for monitoring is, Rafael, and how do you think we should monitor patients? You know, it's a great question because we really don't have a lot of data. While patients are under active treatment, we really monitor them on a monthly basis. Perhaps being an academic institution, we might do a little bit of extra testing, so we monitor everything as we collect our data basis. But for the most part, obviously, following the monoclonal protein, we do the free light chain routinely. I think as patients do well then it becomes problematic because then should you do that every two or three months? There's very little data to support either practice. The one thing I know is every time I test the patient there's a great deal of anxiety that goes into how am I relapsed, what are my results? Now, the patient can get those results the same day, that short a time, but sometimes they have to wait for a week. So if I do it every three months, you know, is that good enough? Probably is good enough for most of my purposes. Maybe I decrease a few of those visits for my patients. What if they're CR and they're 10 years out, like one of those patients in the Spanish group? Maybe they could be tested every six months, every year. We don't really know. So there's a lot of finesse in the art of medicine that is still practiced when we monitor our patients. So one of the really important questions for patients are are we getting to a stage where we may be able to cure them, and when will we know if they're cured? So if I ask you each at a time to give me your opinion, what the meeting's conclusions are about that. So, Jesús. Okay. I think we should not be so optimistic about talking for cure in a high fraction of patients. I think at this point we're curing in a small fraction of patients, but the good news for the patients is that we are moving very fast in the myeloma treatment. Until year 2000, there was only melphalan (Alkeran). From year 2000 to here, we have more than five drugs, and there are we have talking about other agents that are coming. Then I think cure is going to be a reality in the near future for myeloma patients. And then the best news for them is that they have the new drugs and each year that they are able to continue under the treatment or in control of the disease are more hopes for them.

6 Philippe? Well, I think that myeloma is probably the disease for where the most important progress is over the last decade. Probably the overall survival has doubled for our patients over the last decade, but we are not ready to speak about curing a patient when we are seeing a symptomatic patient for the first time. We cannot tell this patient, well, we are going to cure you. That's too early to my opinion, unfortunately. Rafael? I guess I would define if I see a patient that would be 10 years out which we don't do this right now, but 10 years out who has received optimal therapy, be that with modern induction now would be a transplant, some form of an maintenance strategy, and I can see that the patient is MRD negative maybe 10, maybe 15 years out, I'd be hard pressed not to say that patient is cured. But as Jesús said, unfortunately, we still are talking about a small minority of patients. The proof of principle is there, but we want that percentage to be much greater. So on that optimistic news that we're now really considering cures for myeloma patients where in the past we didn't really consider cure at all, I'd like to thank my colleagues for giving such erudite discussions and sign off. Thank you very much. Andrew Schorr: Thanks to Gareth Morgan and all of our other experts for sitting down with us and their dedication to patients, around the world, living with multiple myeloma. Remember to be signed up for alerts on our website, so we can let you know whenever we post something new. I m Andrew Schorr. Thanks for joining us. Remember, knowledge can be the best medicine of all. Please remember the opinions expressed on Patient Power are not necessarily the views of our sponsors, contributors, partners or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That s how you ll get care that s most appropriate for you.