Andrzej Jakubowiak, MD, PhD University of Chicago Interview Date: October 19, 2016 

Newly diagnosed multiple myeloma is the most sensitive to treatment, so picking the best up-front treatment is key to getting long-term optimal outcomes. Dr. Andrzej Jakubowiak, MD, PhD shares his experience for newly diagnosed patients. He highly suggests triple combinations before stem cell transplants vs. doublet combinations. He is impressed with the Kyprolis, Revlimid, dex triple combination, especially for patients without heart conditions. He also likes the Velcade, Revlimid, dex triple combination for patients without peripheral neuropathy. With more significant disease reduction and patient responses, Dr. Jakubowiak shares that we can now use more sensitive testing (minimal residual disease testing) to help identify which treatments are and are not working at earlier phases of clinical trials. He also suggests that they may become end points worth measuring during these studies. He notes that patients with minimal disease negativity do typically have longer lasting outcomes, but patients with some minimal residual disease can still have good outcomes. To further test the impact of MRD status, he is running a unique trial post transplant that compares Revlimid alone to Ixazomib, Revlimid and dexamethasone (an all oral combination). He stresses that good risk patients benefit from more aggressive myeloma treatment up front and says that this theme is moving its way into the clinic for high-risk smoldering myeloma patients. Dr. Jakubowiak shares a variety of strategies that can be used at relapse, depending on the kind of relapse and options previously used.

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Jenny: Thank you for you joining us on today show on Myeloma Crowd Radio. I’m your host, Jenny Ahlstrom. We’d like to thank Takeda Oncology for their sponsorship of this program. Now with us today is one of the foremost myeloma experts who leads cutting-edge myeloma research efforts internationally, Dr. Adrzej Jakubowiak. So, welcome Dr. Jakubowiak, We’re so happy you’re here.

Dr. Jakubowiak: Good morning. I’m so honored to be part of this effort and this broadcast and I’m happy to talk to you and it is always my favorite to share my views and opinions with patients, which I understand is our audience.

Jenny: Yes, we are thrilled to have you. This is an opportunity for us to understand what’s happening and what’s the very latest in research from experts, exactly what they’re working on but patient-friendly language. So we really appreciate your time out of your busy schedule. Let me give an introduction for you before we get started. Dr. Adrzej Jakubowiak is a professor of Medicine and Director of Multiple Myeloma Program at the University of Chicago. As well as a member of executive committee in the section of Hematology/Oncology and other Clinical Trial Review Committee at his facility. He’s co-lead in a Hematological Myeloma working group also at the University of Chicago. He is a member of the Multiple Myeloma Research Consortium, Project review committee and steering committee as well as member of the Alliance which is CALGB which designs Myeloma Clinical Trials and the International Myeloma working group which helps define myeloma standards globally. Dr. Jakubowiak reviews articles and publications such as the British Journal of Hematology, Leukemia Lymphoma, Blood, and the Journal of Clinical Oncology. He’s received many awards including the MMRF Myeloma Accelerator Award and Myeloma Center of the Year award in 2008 and 2010. He is the first honorary member of the Polish Myeloma Group and was recognized as one of the best teachers in Hematology/Oncology by medical fellows. He’s received distinguished honors from his home country, Poland in recognition of the major contribution he has made not only to myeloma in Poland but in the world. Dr. Jakubowiak’s primary research focus is the development of new drugs for the treatment of multiple myeloma. He’s the lead investigator on a number of multi-site clinical trial for patients who are newly diagnosed, have relapsed or had become refractory and so we were thrilled that you’re here. You are, I I believe, one of the foremost experts and we have a lot to talk about but maybe we want to talk about first about newly diagnosed myeloma and kind of work our way through different stages of the disease. You have been working considerably to find out what the optimal induction therapy is for myeloma patients, so maybe we want to start with that.

Dr. Jakubowiak: And its one of those probably most important, emotionally charged moments and questions which come to every patient with the diagnosis and the physician talking to them. I have to maybe narrow it down by sharing few points of research which has been done in years giving, us some guidance on what we should be using in initial treatment of myeloma. The first important point is that at this stage, even if disease may create some problems including some organ dysfunctions, the disease is most sensitive to any therapy and we have now therapies which are essentially 100% successful in reducing the disease by 50%. This is great news to patients and for all of us. We have at least 4 or 5 very good choices potentially equivalent, as we cannot really say with certainty, which one is better from the other, but I think I would like to maybe point out what I think we all agree to right now. Number one, that initial treatment with a 3-drug combination has been consistently shown to produce superior outcome than a 2-drug combination. That’s number one. The most successful combinations were combinations was proteasome inhibitor and immunomodulatory drugs, and in United States the most commonly used combination with the longest track record in this regard and first to hit 100% response rate was a combination known as RVd also sometimes called VRd for Revlimid, Velcade and dexamethasone and actually brand names or generic names lenalidomide, bortezomib, dex. That is by no means (if I would discuss it with my patients) one of the top choices currently in newly diagnosed myeloma. My research evolved from that particular combination and power and the ability to achieve excellent responses and deep responses by making minor changes together with my colleagues to the combination and replacing bortezomib/Velcade with carfilzomib/Kyprolis and this combination usually known as CRd know renamed as KRd for Kyprolis. We found that it is highly powerful and highly effective. We predicted that it may potentially produce deeper responses and while a parallel study comparing KRd to RVd have not been done - they’re in progress or being planned. Direct comparison seems to favor KRd and that’s something which eventually led in my center and in a number of centers to selecting KRd vs RVd as the top choice with reservations that we do not have enough data and there is a need for discussion about risks and benefits, peripheral neuropathy in RVd is very common but on the other hand concern for cardiovascular and pulmonary toxicity which are much less common in RVd are associated with KRd. But then in the end we have outstanding results with KRd and the tolerability of the regimen for most patients is very good with only mild to at most moderate toxicities and for my patient population as far as we discussed with the exception of very frail patients, that’s my top choice. On occasion, alternative choices like CyborD or VTD (Velcade, Thalidomide, dex) in Europe are reasonable, but now in direct comparison at least CyBorD is inferior than a construct with immunomodulatory drugs and proteasome inhibitor like VDT.

Jenny: And so, when you’re talking about  induction therapy this is either transplant eligible or someone who may not be getting a transplant the same? And then how many cycles are you saying is typically used for induction therapy

Dr. Jakubowiak: So, In general, we divide patients into transplant candidates and non-transplant candidates and that’s how it is across the world, probably less so in the United States which is our audience. I don’t really see a dramatic difference in selecting the regimen for transplant candidate vs non-transplant candidates. KRd and VRd will still be my top choices with the exception of maybe frail patients, so that’s very general comment. There is no question that the data for transplant is part of the initial strategy which has been generated in late 90s is still very strong and in fact last year brought a number of important developments further supporting transplant as an initial strategy. There was a presentation at the last ASH (American Society of Hematology meeting) in which French investigators showed that RVd with transplant produced longer remissions than RVd without transplant in only transplant candidates. That was done with a relatively short course of RVd,  with transplant 5 cycles and without transplant 8 cycles. But equivalency of exposure to treatment was comparable and the transplant group won. In a way it showed many of us that novel era with even as a powerful regimen as RVd, transplant seems to be adding value in achieving longer remission. There was no difference in survival between those two groups at the time when it was presented, but at least we have seen longer remission, which I think for every patient, is important.  So, how maybe, to answer your important other question very quickly? How long to treat for those who go on transplant? I typically would use 3 to 4 cycles and that’s what most of us would use. It’s a balancing act to achieve good remission. We know the deeper the response before the transplant, the better the ultimate outcome, and to limit toxicities from induction which may potentially carry over into our strategy in the post transplant setting. So, that’s for the transplant group and for this particular French study, there was induction with 3 cycles. Most of us probably prefer 4 cycles and depending on what we use that may potentially impact what we do later and for how long. I want to comment because your question also included how long to treat altogether. In transplant candidates, the field is completely in an evolving stage I would say. Most studies and centers will use induction for 4 cycles then transplant and then maintenance with a single agent. The most popular in United States is lenalidomide, or Revlimid. However, a number of studies including our KRd with transplant study seemed to be indicating that extended treatment even in transplant patients including the post-transplant period is important. I am using this comment supported by data of non-transplant patients. It was two years ago at ASH and now a published effort by again French investigators which showed that Revlimid /dex or lenalidomide/dex used for 18 months (not  a short period) and then every patient stopped treatment vs. extended treatment until progression showed no difference until 18 months. But at the time when those patients who were in the 18 month treatment group stopped treatment, their duration of response dramatically dropped. It was much shorter compared to those who continued Rd. Providing as a proof of principle, which I think is an important phrase to use, is that (at least in the context of this regimen) extended treatment unto progression is better than further treatment. The survival benefit was marginal only for this group but it was emerging and I think there could be an argument to be made not necessarily to continue treatment, but on the other hand, there was such a dramtic statistical significance in remission, that many of us adopted extended treatment as a new principle of therapy. At this point I will summarize: try to use as good a drug regimen as possible (a 3 drug regimen) with or without transplant. That would be my summary of this segment of my commentary about initial treatment.

Jenny: Let me see if I can summarize for patients who might not be fully up to date on the different things. So, you’re saying typically induction therapy is with Revlimid/Velcade/dex and now you’ve used Kyprolis, Revlimid, dex and you’re finding that to be more powerful. So the RVd , if you have neuropathy issues, that may not be something that you want to do, but if you have cardiovascular issue, heart condition or things like that, you may want to exercise caution using the Kyprolis/Revlimid/dex. So you take that all into balance when you consider using your induction therapy and then you are saying that transplant is still critical for patient and you give 3 to 4 cycles of induction and then either go to transplant or if they are not eligible for transplant you keep that going, and then you’ve learned over time that maintenance therapy until progression is probably a good idea. Is that an accurate summary?

Dr. Jakubowiak: Yes. Those with cardiovascular concerns should not use Kyprolis and those who have neuropathy should not use bortezomib, just to make sure. Yes. And it is something of importance to stress. I want to say why I use a more powerful “KRd as preferred regimen” vs. RVd, which is an outstanding regimen, and potentially alternative choices despite some risks.

Jenny: Okay

Dr. Jakubowiak: I think because of the increased sensitivity of disease in the initial phase of the therapy, we are observing with KRd especially with KRd and transplant, high and in fact never seen before even with any other strategies - rates of disease elimination to no detectability. It is called complete response by our traditional criteria, no evidence of any measurable myeloma protein in urine and serum and normalization of free light chains that is achieved now with this treatment strategy in over 50% of patients without transplant. Based on the last update in over 70% patients with transplant and KRd, which are really giving us a sense that we are making breakthrough progress by using this strategy and potentially justifying some risks related to this approach. In addition to this traditional measure of elimination of disease by naming it complete response, we have measured in most of our patients status of MRD or minimal residual disease using two methods: Flow cytometry: We are now using very close to Spanish techniques with very high sensitivity for flow and our center and as well as next gene sequencing method which was previously done by Sequenta and now by Adaptive. That is more sensitive based on the reports and these patients who are treated with this strategy achieved ultimately close to 60 and more at last update and we will present it again at ASH in a couple of months, MRD negative disease with stringent complete response and the negative imaging study. So, imagine how great an achievement it is for these patients. They and I and patients who are treated by other physicians can potentially open the door to hope that maybe potentially in some of these patients' disease was permanently eliminated. So, I’m arguing that this strategy is a step towards finding a cure to myeloma and of course, we need to wait longer and validate this data in bigger studies, but I think this is emerging as potentially heading in this direction. So, to summarize why I have this comment about this KRd and the results: I think that if we are having disease which is traditionally considered non-curable (that’s how its written in all books and how we should probably still approach it, because we don’t have evidence of curability) but if we know that a proportion of patients in those prior studies have achieved permanent elimination of disease and compatible with cure,  if we then correlate that cure with an increasing proportion of patients with this outcome with initial therapy achieving complete response with minimal residual disease, then this increases the probability that a larger number of patients may potentially be achieving elimination of disease. We all see those patients in follow ups and in multiple publications you see these patients are truly eventually achieving such a good responses and durable ultimate response.

Jenny: So, what I hear you saying is that because of the results you’re seeing, you think that this different combination of upfront therapy and how deeply it’s kicking the disease, you are very hopeful. What you are saying is the better you do upfront, the better you’re going to do overall typically. Maybe you can stop for minute and explain a little bit about minimal residual disease testing, because I have seen graphics where it’s like an iceberg. So, you see the myeloma at the top of the iceberg and that testing to date brought it down. Can you get very good partial response? Or are you getting an M-spike and it is not showing upon your immunoelectrophoresis test but then minimal residual disease is even deeper and you mentioned that you can do it by flow cytometry or next generation sequencing? Can you elaborate on the importance of the deeper testing and finding fewer myeloma cells in this minimal residual disease testing compared to someone who says “well, I have a stringent complete response” or complete response? Then one other question that I have is when are doing that MRD testing? Is that after induction? Is that after the transplant? When are you seeing those great results? Because those are fabulous results.

Dr. Jakubowiak: This is a very important question. I think again it’s an evolving story and evolving sense of understanding it as well as we can. Let me tackle it and maybe putting as backdrop information that not that long ago in the mid-2000s decade we have in most strategies not more that 5% of patients achieving complete response and that has increased to about 30% in the majority of the currently used strategies. I mentioned the levels which we are seeing in KRd with or without transplant. That brought an absolute need to trying to see whether there is a difference between one patient with CR and another person with CR. We know that achieving complete response or CR is not a guarantee of elimination of the disease. The disease might possibly relapse even from complete response. So, how to detect better any residual disease and assess better what we have accomplished is left to more sensitive methods which are now becoming essentially standard of care. These are, as you mentioned, flow-based minimal residual disease evaluation which was developed by Spanish investigators and based on gene sequencing methodology developed here in the United States. What these methods are doing is by aspirating the bone marrow they are able to detect abnormal clones of malignant cells by flow in 1 to 100,000 cells. In other words, if we aspirate bone marrow and 1 in a 100,000 cells and a cell is malignant, that would indicate that there is still some residual disease even if immunofixation and protein electrophoresis does not show any product of this cell, or there’s no M-spike. That’s why it was found to be helpful because we noted that if we applied this technique we can pick up patients who are seemingly in complete response but still have some residual disease. The concern was that this is not good enough. That’s why effort has been taken and is still in progress to go deeper. At least in theory and by some data, next gene sequencing methodology seems to have sensitivity in picking up one in a million cells, which is positive for a malignant phenotype and that is eventually our current threshold. But you mentioned iceberg, the iceberg slide which has been shown by many of us. I show it in my talk.

Jenny: I like that slide. 

Dr. Jakubowiak: Is showing in a very easy to comprehend way what we are talking about. The  top of the iceberg is what we see over the water is maybe what we shave off when we achieve disease through absence of any monoclonal spike in in the urine and serum, but we know that if we apply immunofixation techniques then we pick up some spikes which have not been seen without that technique. So that goes under the water, which is the first layer. And then when we go with the flow technique, we can go even lower under the water, but there is still part of the iceberg which we are not seeing despite the flow technique being better and then we think when we go with gene sequencing we can go even lower and do we know whether we go to the bottom or not, we don’t. But I think that’s the effort that we need to make and I would say and maybe link it back with my earlier comment, I am among those treating myeloma and myeloma researchers who believe that we are at the doorsteps of finding the cure for some patients with myeloma - I hope for the majority of myeloma patients. I think that we need to refine and make this technique as good as possible that we can use this technique with the highest sensitivity level to eventually be able to say that there is no detectible disease. And there’s number of studies which have done this technique and are following the patients now for many years from that point on. We may be able to say in two or three years from now that if patients achieve this level of response and meet some other characteristics like for example, negative CT-PET along with MRD negativity and sustained MRD for a certain period of time, that these patients may achieve the ultimate goal compatible with curing the disease. Maybe we can advise some these patients in the near future (which we are not ready yet) to stop extended treatment and stop maintenance therapy. That’s an important effort from the ultimate perspective in finding the cure. MRD also has an absolutely critical value prognostically if it’s applied in a systemic way. It may, based on the studies which have already been done or are in progress, help us early in the course of the treatment in clinical trials and make predictions as to  what will be the progression free survival or medium time to progression for the average patient treatment strategy based on MRD instead of waiting for 5 or 6 or 7 years as we do nowadays at 1 or 2 year landmark. For that reason, to answer your question, in my place we measure MRD at the time when the patient achieves CR but also at landmark time points: at the end of induction, at the end of transplant, at the end of consolidation post-transplant.

Jenny: So, you’re doing it multiple times and because you are looking at that as really a primary indicator. So, let me ask you some follow up questions about that and you mentioned it already. But what you’re saying is this dramatically shifts the way you run clinical trials. Right now in clinical trials you’re looking at either progression free survival (or how long does it take patients’ myeloma to progress) or overall survival? And with the better drugs,  that could be a long time, right? So, you’re trying to create these studies around these certain end points. Now, what you saying is you might be able to use minimal residual disease testings now that it is such a sensitive test as a different end point for your clinical trial to say “Okay, we’re going to look at patients who achived MRD negativity at what time and then that gives us an indication on how they’ll progress and how long they’ll live. Is that correct?

Dr. Jakubowiak: Absolutely correct and absolutely important point to make to ourselves and to those who approve clinical trials including the FDA. It’s work in progress. I know that many of us has worked on that end point to being now considered as a valid end point. The FDA and those who have a critical look at what we have achieved so far and are giving us feedback at this point. We still have rather limited data on the correlation between MRD and outcome. I think this data is already emerging to the level that I am very optimistic. In fact,  one of the next studies which are on drawing board right now and being discussed by the FDA will use MRD as at least a co-primary end point, which may need to be validated. This is understood by progression free survival later on to validate that this was in fact, what we were planning to accomplish and could be used as surrogate endpoint soon. I can translate it to a more easily understood concept: if at the end of two years, one study gives, say 80% of patients stringent complete response and MRD negative status and another study or treatment in a different arm gives, say 60% or 50%. That’s only the response rate at this point and we know that from both groups patients might still be relapsing. But we can connect those two values with historical data - how patients achieving that level of response have done over time. We can plot statistically what the curve of progression free survival will look like for those two groups and we can propose to regulators or those who approve those studies that this is very solid data which can predict the high probability nowadays  and in three or four years we can use it. Now, we will of course, continue follow these patients to make sure that these assumptions are confirmed with ultimate outcome. This is an extremely important effort which we are making right now.

Jenny: Well, that makes sense. Now that minimal residual disease testing is out and that is with a company called Adaptive. So, if patients haven’t had that, they can ask for doctor about getting that test but how many patients would you guess or percentage of patients are using this MRD test? And then another question, can you have low minimal residual disease and never end up progressing. What have you seen now that you’ve been doing this MRD test for a while?

Dr. Jakubowiak: I will answer maybe in two steps. Number one, it depends which center. In my center, every patient has MRD evaluation and they are on clinical trials. We are approaching patients who are not in clinical trial in a very similar way. The test is pre-approved. There is different availablity in different institutions of this test and I’m not going into technicalities. It’s still not completely reimbursed and approved and I think that could be a potential reimbursement issue if the hospital does not have mechanism of agreement with Adaptive or the insurance companies will not accept it. Flow-based MRD is done for all our patients without any concerns for reimbursements and that’s very important information. Its very close in sensitivity to what Adaptive technique does so In between those two tests we have more information. So, that’s first part. The second part of the question is extremely important and I will link it to what I have discussed earlier. Achieving MRD disease has prognostic value. It can potentially predict elimination of the disease status if we find that sustainability of MRD are different in period of time can be linked to that outcome. So, that’s one part, but I want to stress to all the patients who have heard about MRD and are unable to get to MRD negative status, that elimination of disease to MRD negativity is statistically predicting better outcomes, but for a given patient having residual disease does not mean an ultimately bad outcome. There is an increased probability of relapsing earlier with MRD positive status than without, but I have a lot of my patients whom I treated earlier in Michigan who continue to follow up with me so they are 14 -15 years later who never achieved complete response and MRD negative status. They may have received a few lines of therapy but their survival is outstanding. Their outcome is probably as good as those patients who have stopped treatment in MRD negative status. So that’s an important distinction which you made by asking and framing this question. It is good to have MRD negative status for our studies to have because we know that it can serve as surrogate endpoint we discussed, maybe potentially give us guidance on how to get the curing the disease. But I think that should not be ultimately a guide yet to achieving it in patients whom despite best efforts are not in MRD negative status. Their outcome can still possibly be quite good.

Jenny: I’ve heard some doctors say that you still might have MRD positive status but it might be like an MGUS-like state. Is that true? Can we address that at all? Is that, How do you differentiate?

Dr. Jakubowiak: Yes. It’s a concept which many of us have discussed exactly how you put it. This M-spike .1 or .2 maybe distressing patients and doctors because there is still evidence of residual disease especially if it’s the original M-spike, but this may not behave like residual myeloma but like MGUS which we know may for years may not progress. I have again with my years of working with myeloma patients (quite a good number of patients) having that MGUS-like behavior with or without maintenance never really moving up and staying at this .1 .2 and behaving like MGUS. It’s true. Again, for individual patients at this time we don’t have data to really change our approach based on MRD status. I’m actually treating both groups of patients in a very similar way for an extended time. It may change but at the moment, that’s how it is and this one part of my comment. The second part is that not achieving MRD negative status does not necessarily mean that this patient may not fare quite well and might not require another round of treatment for the rest of his or her life.

Jenny: So, you can still have MRD positive status and be hopeful that you can have good outcomes.

Dr. Jakubowiak: Right. Absolutely.

Jenny: So, before we move on to relapse, what do to at relapse, because I do want to cover that briefly. You mentioned that, the two different inductions that have been compared. When you look at standard risk vs high risk do you see any difference when you look at the high risk genetic features or high risk types myeloma? And then for high-risk patients, do you change your number of cycles at all, to shorten it up to get them to transplant faster. Those are two totally separate topics. So sorry I joined those questions together,

Dr. Jakubowiak: It’s an important topic and potentially controversial. So as everything, what I say today is my opinion and my commentary and all I know about the subject. High-risk disease is present in approximately 15 to 20 % of patients. What this means until recently a number of investigators and modes of treatments have proposed the following approach that patients who have low-risk or standard-risk disease could be treated less aggressively. Their disease tends to behave with quick or earlier relapses and stays longer in remission. Saving better drugs or better regimens for later has been part of the recommendations for examples from the mSmart algorithment and some others. Many at that time would reserve those more aggressive regimens like RVd and now KRd only for high-risk patient preferentially. And that’s something which I think is changing now. First, we have seen that there is indeed a difference in outcome between good risk or standard patient and high-risk patients in the context of any therapy. I cannot really discuss results yet here but we will present KRd in newly diagnosed patients based on risk factors at this ASH meeting. In short, all prior studies seem to be indicating that regardless of how powerful a regimen we use, if you separate patients with high-risk for a given regimen, their outcome would be somehow inferior to those who are good risk disease. So, that evolved to a next step of data and the next step of an approach. We have realized that high risk patients indeed need better regimens because with a less aggressive regimen their outcome has been truly, highly inferior. They do need better regimens for high-risk for sure. So, no question about the high-risk patients and needing good regimens to treat them. What we’ve learned is that good risk patient benefit at least equally from more aggressive regimens. The difference between those groups remain, but those high-risk and low-risk patients both benefit from a better strategy. It has been shown in relapse setting in the ASPIRE trial, which was KRd vs Rd, there was superior outcome for KRd in this regimen in the relapsed setting but when they did a subset analysis based on risk they noted the benefit of about 10 plus months was seen for more or less the same amount of months improvement in high-risk and low-risk patients. This provided as a proof of principal argument that we should be treating also good-risk patients in a more aggressive way because they can benefit more. I’ll say for patients with good risk and potentially are exploring what to do, if I were the patient and I would be told, with a  high-risk strategy, my life expectancy will be 10 years with the more aggressive strategy and say 7 years with less aggressive strategy, based on old data I would be interested in extending my life by 3 years. I’m using those numbers just to illustrate my point. I think we in fact, probably, relatively increase life expectancy more for low-risk patients than for high-risk patients. That improvement is even more visible. So, in short, to answer your question, I think that we still don’t have the best strategy for high-risk patients, but we all agree that whatever we think is at the moment the best we should use for high risk patients. Most of use also agree (and if there are no contraindications for more active regimen) that also good risk patients should achieve that better strategy and that’s how I approach it in my center.

Jenny: That’s great. Now, when you’re talking about minimal residual disease testing, you also have a clinical trial that I want to have you mention. so, you’re using Ixazomib, lenalidomide and dex vs lenalidomide alone. Do you want to talk about what that trial is?

Dr. Jakubowiak: Yes. So, just a brief background. We generally treat enrolled patients when they are newly diagnosed or if they relapse. This trial is a novel trial in a way because we are enrolling in this trial patients who completed transplant. Eligibility is presence of minimal residual disease and then patients are randomized to what is considered as "standard", which is Revlimid maintenance for one group of patients with minimal residual disease and another group of patients receive Ixazomib, Revlimid, and dex. Ixazomib is an oral agent (called Ninlaro) convenient for maintenance therapy called a protesome inhibitor, therefore similar to bortezomib. It has shown activity in those relapsed and front line settings which randomize study showing superiority of we call this regimen IRD vs RD looking at progression free survival with modest improvement of that benchmark. In newly diagnosed patients, the regimens has been shown also very active. It can be potentially considered in newly diagnosed patients based on two studies with two different schedules with a randomized study comparing it to RD in progress. So, that’s why we use IRD because it does produce good responses and extended responses for this trial. It’s convenient because it’s all-oral, it’s proven to be active, it’s proven to be well tolerated. There was no major difference in toxicity between those two arms. So in a way, for patients who are craving convenience it is a very good approach. All oral and not (at least based on the data which we have) increasing risk. What we are looking for in this study is to see whether at the end of one year of treatment with either IRD or Revlimid there will be a difference in MRD negative disease. We anticipate that even Revlimid patients will have some conversions to MRD negative status. This is could be the effect of Revlimid or ongoing effect of transplant . We anticipate that the IRD group will have more of these MRD negative patients at the end of 12 months. That is pilot phase II randomized study which will give us some new information whether that strategy actually is valid and is important that will provide us some guidance for potentially intensifying treatment for those who have MRD positive status. If we find that this could be beneficial so, right now, earlier discussion which I had with you was we really don’t know what to do with these patients. We should be hopeful because many of them will do well. That study will give us information whether this search for the elimination of the disease using this  particular strategy will be beneficial. We of course, will look at progression free survival down the road and some other end points.

Jenny: And what I hear are saying overall throughout the show is that your goal is to load all these different treatments potentially and that’s what this trial is like – after transplant. What can we do to prevent relapse? We’ll talk about relapse briefly in a second, but that’s what I hear you saying. Lets get the most effective drugs upfront but still keep the transplant because its still showing to be more effective and deeper response and then after we finish transplant, continue what even a triple therapy instead of just one. With the goal of preventing relapse because myeloma is the most sensitive at the beginning of the disease

Dr. Jakubowiak: Right. The argument can be made if you use all of the good drugs in the beginning you maybe left out with nothing to use and that is a valid argument. I challenge this argument and I use always example when I was having difficulty getting patients on Thalidomide-based triplets 10 years ago and the argument was made “well why don’t we use Thalidomide later and at the moment let’s start with VAD and see what happens.” You know, patients which I treated more aggressively have been in remission for 6, 7, 8 years and even if they relapse, time of Thalidomide past and we have many more choices right now. I think the race for finding new drugs is generally helpful because we are getting new drugs and we’ve been absolutely super fortunate in last few years that we keep getting new and promising drugs.  As you know, four drugs were approved in 2015 and some of them extremely promising. We talked already about Ninlaro. We didn’t talk about Elotuzumab, the anti-CS1 antobidy, based on the ELOQUENT data, panobinostat earlier and I think what excites many of us probably most is the anti-CD38 antibody daratumumab (Darzalex), which is a game changer in a way. So I think that we didn’t talk about this in a front line setting. I’m sure it’ll come to the front line setting, but in the relapsed setting, we are achieving remissions like in combination with RD in the POLLUX trial approaching 40 to 50 months. I would like to give as a back drop of information that in most of the studies which have matured enough, the median time to progression in the newly diagnosed patients has been between two and three years. So, we are now in the relapsed setting achieving 4 to 5 even 6 years remissions by just having new agents.

Jenny: Great

Dr. Jakubowiak: I would say, ok, we maybe don't necessarily have super choices if the disease relapses early but for the most part, lets push the field. Let’s make sure that progress is made and if I am unfortunate to relapse 7 years later who knows what’s gonna be happening in 7 years later lets get to 7 years and then worry about that later.

Jenny: Great. That’s fantastic. Well, in the last few minutes, I want to just leave it up to you. You have many open clinical trials that you could talk about and we could also talk about what patients should do at relapse because that’s kind of what I talked to patients about that we would cover in this show and I want to make sure you address it a little bit. When patients relapse, what do you suggest and then which clinical trials would you like to share with us that are the most interesting for you.

Dr. Jakubowiak: So, it depends on when the relapse happens and  we always look at prior history; how quickly relapse happens, how aggressive is the relapse, is there high-risk disease or extramedullary disease? These direct us in a variety of choices. We are fortunate to have a lot of choices. In general, we can always try the original regimen at the relapse if it worked and had sustained remission for extended period of time, I generally apply a rule of making two changes versus what has been used most recently. For example, somebody progressing on Revlimid maintenance, If there’s relapse we have number of choices and as you know number of triplets has been approved. For example in my center, our priority regimen for these patients especially who already had a proteasome inhibitor, to make a change to a more effective proteasome inhibitor like Kyprolis and its combination, the minimum is dexamethasone or maybe with Pomalyst. That’s one of our studies which is evaluating activity of Kyprolis, Pomalyst and dexamethasone. We presented it at ASCO and its still an ongoing study, which is still to be published, but it has very powerful effect. Nowadays, with Darzalex not yet approved for more than single agent but with some insurance already accepting it, reasonable alternatives would be daratumumab-based combinations with for example with RD if there was no refractory status to Revlimid and Dexamethasone or with proteasome inhibitors as we had data with Velcade/dex. Other combinations are coming anytime and I think that will be potentially first, second, third relapse which I will be using. Triplets in general work better than doublets in this type of setting. We have one very powerful doublet which was Kyprolix/dex which was superior to Rev/dex but whenever we can, probably triplets will give us more efficacy and longer remission. That’s how I eventually approach and then every step the disease needs re-treatment is becoming more complicated and more sophisticated always requiring review of prior treatment strategy. That’s why I use clinical trials and what we use here. For example, one study which I would like to bring to people’s attention which we have in multiple sites including the University of Chicago is the  combination of Kyprolis, Dexamethasone with Selinexor, a new class of agent, which is used in our study in those patients who are progressing on the Kyprolis combination. Most of these patients have exhausted all possible combinations before and what we found and we presented it prior meetings and we will have oral sessions from updated resulted at this ASH is that majority of patients progressing on Kyprolis combinations will respond to this combination because of Selinexor was found to be able to overcome resistance to Kyprolis in pre-clinical and now in clinical settings. So, this example, a number of other studies in our center include new agents like Venetoclax, a  new antibody from Abbvie which we have we are also moving toward CAR Ts. These are strategies which are at our disposal.

Jenny: And then you also have an elotuzumab, lenadidomide, dexamethasone study for high-risk smoldering, right?

Dr. Jakubowiak: Right. And it is one of the important efforts led by Dr. Ghobrial from Dana Farber. We joined that effort; it is an approach which comes from two observations. Number one, which I mentioned the earlier the disease, the more sensitive to treatment it is. Number two, the ELOQUENT study showed that RD and elotuzumab is superior compared to RD. And the next observation which was the basis and rationale for this study, Spanish investigators published the results of their study in smoldering Myeloma high-risk in which they showed that patient treated in this stage of disease with Revlimid/dex had superior control of the disease but also superior survival compared to those who are observed. This was a placebo study which we won’t do anymore, but that information is available so we are building up on the Spanish information and study and kind of escalating intensity of smoldering myeloma as a target of more effective therapy And I have to say that this is the first step in the direction which I’m hearing and seeing a lot around. There is a study being in development in fact KRd with or without transplant in high-risk smoldering Myeloma which we will likely participate as well which comes with this concept. “Okay, this is a good regimen and worked well in newly diagnosed Myeloma.” Dr. Landgren showed the data with outstanding results and in fact, smoldering subsets of his KRd treated patients. So, it’s a good probability that we can achieve even better result with very aggressive therapy in this segment of the disease. It has to be with important caution which I want to make – that it is done in the context of a clinical trial because there is a potential that many of these patients may not need therapy for the years to come and we don’t want to be entering into this haphazardly without any evidence that this in fact better strategy than wait and watch.

Jenny: Okay, so that sounded great for KRd and smoldering myeloma and it’s exciting to know that there’s more progress they made right now in both newly diagnosed myeloma and earlier stages. I think it’s really really exciting. We talked a little bit earlier in the show about relapse and I just wonder from a patient’s perspective, how can patients be best prepare to consider their options either one newly diagnosed and everything is so new and different to them or at relapse because they usually make decisions quickly. As an expert in myeloma, What is your opinion about that?

Dr. Jakubowiak: Well I think they need to, first of all, have a physician with expertise in this field level which potentially gives them and anybody a sense that their physician can navigate very difficult decision making process and guide the patient. Most oncologists are very qualified to make that decision but there is no question on the advantages of working with key myeloma specialists in key centers like Mayo or Memorial or our center. These are physicians who are not only qualified but absolutely 100% focused on myeloma. So, with that in mind they may potentially have the newest information, maybe even a very promising clinical trial with treatment which is not available as a standard of care. At a minimum, they may potentially provide a good second opinion reinforcing the plan implemented by primary oncologists or maybe potentially providing additional guidance. That can be usually arranged with most of us very quickly. If we hear something like that we took as an our place, I can patients next day within a week for sure and others in my group can help and that is typical for other patients as well, I think that’s important. It’s very difficult moment, I agree with that and that’s why getting this extra opinion is important. If they overdo it on the other hand, that may potentially be creating a lot of uncertainty what to do because unfortunately, at any crossroad, even key opinion leaders may not always 100% agree and that maybe potentially more complicated. But if it comes to this point, between two or three experts, the patient is usually very well advised, that’s my experience, by listening to not only what is on the paper for any physician talking to them, whether they feel that they have somebody whom can they really fully trust in their opinion and the way of presenting what needs to be done and then go with that either directly under care of this physician or having him or her involve in the decision making process.

Jenny: And my final question I think, is that I have one writing question that I’d like to ask is, you talked earlier also about later relapse. You said it depends on the type of relapse and how long It has been and things like that. So, you hear about patients who relapse multiple times and then they add a different combination and they’re still alive. I have friends that are still alive 17 – 20 years later, which is incredibly amazing and wonderful but and then I have other friends who struggle with it and their myeloma is more aggressive. How do you differentiate as a clinician and researcher to know which strategy, at which point in time. Maybe the MRD testing that you talked about earlier would give us some clues.

Dr. Jakubowiak: Well, We didn’t talk much about it, but the disease is heterogeneous so there is at least good to understand there are two major categories: good-risk vs high-risk features. High-risk are in fact are supported by course of the disease until this point and that typically is associated with short lasting responses, difficulty achieving care MRD negative status, even with the best therapies always with a  recurring pattern of relapse. These patients are in highest need to provide them the best possible next option. Highest on list of the things which should be considered for these patients will be new agents, either recently approved or those which can potentially work in this high risk setting or a new approach using clinical trials. The patient you mentioned 17 plus years, and there’s a lot of them like that even with multiple relapses but each after 4, 5 or 6 years or something like that, there are options are generally bigger and easier to make. They are usually able to respond to prior therapy so you can make an history of treatment  assessment and then pick up based on those prior histories and how agents which have been used in the past worked for the next best regimen. As I mentioned that earlier, I generally have a rule that I try to make at least one or preferentially two changes vs the prior therapy. I’m trying to follow the rule of using multiple agents and in general this is three for the time being worked better than two. We try to achieve as likely high rate of response and deep responses as we can. Unfortunately, no guidance from the biology of the sample with few exceptions. There may be some emerging substance of myeloma which we may treat preferentially with one or the other agents but that is still work which we need to do as researcher so we pick up empirically new regimens. Fortunately, was all of the combinations which we have you can imagine that those types of relapsed patients, any of the four newly approved drugs can be part of a treatment that will usually work very well for them.

Jenny: That’s perfect. Well, we’re excited that there’s so much more in the clinic. And I have a write-in question and then I’ll let you summarize what we talked about today but Wendy asked “There’s a lot clinical trials that are doublets vs triplets and like you mentioned earlier we’re pretty much convinced that triplets are a better choice. So, is there better way of running those trials to test different combinations?”

Dr. Jakubowiak: I’m sure there is. It’s a very complicated question; I very much appreciate person who sent it. Those trials are very important for us to establish new standards of care. They are designed at the time of their design when we truly do not know whether tested triplet vs doublet would work better. That’s by any IRB committee required test point which we need to pass and the same FDA level. So, that’s in the background, but there is no question that the hypothesis before this trial is that the triplet will work better than doublet. And for the most part, that’s what happened in us. There are few years maybe with the exception of one or two studies where those differences were so small or minimal that eventually  did not end up  achieving any progress significant clinical progress. How to better design these studies to make some of these advances? I have some ideas. I think that, I think we should be looking at typical end points in those studies like progression free survival and difference in toxicity in both arms of treatment and ultimately overall survival but usually end posts are distant. As we discussed earlier, putting surrogate end points early into the study may potentially limit the size of the studies and create the data which can be interpreted sooner with lesser cost. This is, to some extent also driven by the need to provide evidence of a probability of a drug combination for a given indication and these are very hard and difficult discussions which we have internally before we propose to study to the  FDA or other regularity agencies in Europe and eventually to our colleagues and to our patients. I’m realizing that I’m not giving really answer how to make this better but I think that, with some efforts to, not to allow certain studies which have obvious written on the wall answers, would be one thing I probably would consider. And number two, maybe limit those evaluations to providing the arm of treatment for example, three vs two in a way that prior historical data does not provide high probability of success of one of these arms. It’s not easy subject to tackle.

Jenny: Yes.

Dr. Jakubowiak: And I know that I’m not helping but I think this is probably the best I can comment at this time.

Jenny: Well, it’s complicated. That’s what you’re saying. Because you have a lot of factors to consider.

Dr. Jakubowiak: Right.

Jenny: Is there something that you’d like to add just in conclusion? We’re so thankful that you’re joining us today.

Dr. Jakubowiak: Well, Again, I want to thank you and I will thank you those who are listening for staying until the end and listening to me and my opinions. It’s really a great pleasure, I think that you can hear me throughout this interview and my comments that I’m excited about where we are in myeloma. My excitement maybe very much related to the fact that in particularly in newly diagnosed myeloma, we’ve made tremendous progress. For those newly diagnosed patients requiring treatment and in smoldering myeloma which can be high-risk and is now treated in some clinical trials, high level of success elimination of the disease are high rates never seen before and eventually, are increasing hope that many of these patients may be cured as some of the data emerging from these seems to be showing. I think this is the area where we need to make the biggest effort as disease in this stage is easiest to achieve response and easiest to eliminate. I think that the direction within the context of clinical trials to apply some of these best strategies even in smoldering myeloma is something I very much like and would like to see continuing. We didn’t talk much about it but I think some of the agents which are currently in the relapsed disease setting are ready to evaluated in newly diagnosed myeloma - anti-bodies like daratumumab and elotozumab mentioned earlier. I think that some of the more promising newer agents at the moment being evaluated in relapsed disease can make a difference. Then eventually, we didn’t talk much about it but back to your earlier question: In the era when we know that the disease is heterogeneous we’ve got to figure out how to pick KRd and RVd or  CyBord or one of these regimens based on the biology of the disease in certain characteristics rather than by our preference or our experiences or comparing against historical data. That needs to be done and as well as targeting a more difficult aspect of precision medicine, some of the abnormalities which we are seeing in the biology of disease and patient’s genotype of malignant cells and those efforts are in progress. I’m proud to be part of MMRF and MMRC and other organizations are joining including yours that are tackling those issues in the context of clinical trials. I’m sure that in the next even month and a half after ASH we will be wiser and more educated about what to do. Every meeting now in this era brings new information and brings new hope and further improvement, which I have, no doubt will continue. Thank you so much.

Jenny: Well, thank you so much and we just appreciate all you’re doing for myeloma patients, all you’re doing to drive research forward and we’re just thrilled. So, Thank you for joining us today and taking time out of your very busy schedule and we just wish you the best.

Dr. Jakubowiak: Thank you so much and very much appreciated being invited and speaking to all of you.

Jenny: Thank you so much.Thanks for listening to an other episode of Myeloma Crowd Radio.