Dr. David Siegel, MD, PhD John Theurer Cancer Center Interview Date: April 15, 2016 

If multiple myeloma patients relapse or become refractory to existing medications, it doesn't mean the disease has won. Dr. David Siegel explains the difference between "relapsed" and "refractory" and shares a hopeful message that the new drug combinations give doctors and patients so many more tools to use. He tells us that just because one drug or even class of drugs (like proteasome inhibitors or iMiDs) have stopped working doesn't mean they won't work again when used in a different combination. Dr. Siegel says that no longer can patients be given a specific timeframe for survival because investigators are just at the beginning of understanding which combinations may be right for which patients. He shares pomalidomide as an example of a new, potent drug that is great for patients with kidney issues because it is not excreted through the kidneys. Pomalidomide also extends the effectiveness of other drugs. He uses the HDAC inhibitors as examples of drugs that do nothing by themselves, but can re-energize drugs that have stopped working. For example, patients who became refractory to Revlimid  used Vorinostat and the Revlimid started working again, even when the myeloma hadn't changed genetic features. Dr. Siegel mentions metabolomics, or taking advantage of a cancer cell's weaknesses with the body's metabolism. He concludes with recommendations to not exclude any therapy as an option and that different combinations can be used according to the NCCN guidelines off-label based on individualized patient needs.

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Jenny: Welcome to today's episode of Myeloma Crowd Radio, a show that connects patients with myeloma researchers. I'm your host, Jenny Ahlstrom. We'd like to thank today's episode sponsor Takeda Oncology for all I do for myeloma patients. Now, some announcements before we get started, we are well into our Muscles for Myeloma campaign which is a fitness challenge for myeloma patients. Our ability to handle more difficult treatments gives us longer overall survival and doctors are determining treatments based on fitness levels. Now as part of the challenge, we are raising funds for the two Myeloma Crowd Research Initiative immunotherapy projects, so you will be getting fit for a good cause. You can join us at a race that we are joining in Salt Lake City on the 30th of this month The Myeloma Crowd is also hosting day long patient meetings specifically for high risk and relapsed or refractory myeloma patients, called Myeloma Crowd Roundtables on High-Risk Disease. The first will be held on May 7th in Salt Lake City and the second will be held June 18th in Saint Louis. Several myeloma experts will be there to discuss topics like immunotherapies, high risk genetics and effective strategies for relapse refractory patients, which is what our show is about today. You can check the Myeloma Crowd website and learn more about these live patient meetings. We will have more meetings to follow in the coming year. Now onto today's show and we are waiting for Dr. Siegel to join us by phone. So I am going to go ahead and give an intro for him. Most myeloma patients will eventually relapse and so with newer drugs in a myeloma arsenal, what are investigators learning about the right order and combination of treatments to get the optimal responses especially for relapsed refractory patients? Today, joining us is Dr. David Siegel. Dr. Siegel is chief of the division of multiple myeloma at the John Theurer Cancer Center in Hackensack, New Jersey and has made the facility one of the premier myeloma academic centers in the country. Dr. Siegel is also clinical professor of medicine at the New York University Medical Center. Dr. Siegel's research has almost exclusively focused on multiple myeloma and has been published in many leading medical journals including Nature, The New England Journal of Medicine, Blood and Journal of Clinical Oncology. Dr. Siegel served as a lead investigator of a pivotal phase 2B study involving 30 cancer centers in North America that lead to the FDA fast-track approval of Kyprolis or carfilzomib for relapse multiple myeloma patients. Dr. Siegel is also one of the eleven investigators nationwide who brought the chemo agent Velcade to his patients through his clinical trials. Now Velcade as you know is an injectable drug that blocks some of the pathways associated with myeloma growth. He is also been involved in many clinical trials using Revlimid and carfilzomib. Dr. Siegel is a member of the MMRC which is the Multiple Myeloma Research Consortium Steering Committee. Dr. Siegel, I'm glad you joined us. Thank you so much for making the time.

Dr. Siegel: Thank you.

Jenny: Okay. So I have given an intro for you and we'll just jump right in into questions if that's okay with you.

Dr. Siegel: I'd be happy to.

Jenny:  One thing that I wanted to ask you about is how you create a myeloma academic center? I don't know where you started out from but I know that you worked at UAMS and then you came to Hackensack and created a myeloma academic center that's really one of the premier academic centers in the country. In doing this, how do you go about doing that and how do you create critical mass and myeloma specific expertise at a new facility?

Dr. Siegel: Well I don't know that my intention was to do that. I mean I came from Arkansas to New Jersey and was actually hired to start a breast cancer transplant program but at about the same time that I was hired to do that, people stopped doing bone marrow transplants for breast cancer. So my expertise was always in myeloma and I just started taking care of myeloma patients and I think more by word of mouth than by anything. There wasn't all lot of activity going on in this part of the country in terms of myeloma and patients started to come and we were fairly innovative. At least we tried to be innovative and we tried to participate in clinical trials. So we had some drugs that other people in this part of the country didn't have at a time when there weren't a whole lot of alternatives for the management of multiple myeloma, so I think that's what attracted patients.  I think now obviously some of it was the interpersonal part of it and I was fortunate enough to have the opportunity to work with some nurses and administrative people who were not just excellent but amazing and excellent. I think that that was a part of what made it feasible.

Jenny: We always suggest that patients go and consult at least with some myeloma specialists even though they might get treatment locally because having a myeloma specialist in your corner is really, really critical. So I'm glad people sought you out to do that. I think with the newer treatments, it's more important now than ever and you have a lot of expertise bringing drugs, new drugs to the market. So you have a great perspective on this. You help bring both Velcade and carfilzomib to the clinic in these large scale clinical trials. Maybe you want to give us a broad overview of your opinion on last year's approvals and your thoughts just generally before we get into details on where myeloma treatment is headed next.

Dr. Siegel: Well for the recent approvals, obviously I think we are all very excited in myeloma. I want to take a step back and say that the first person to be treated with thalidomide was my patient, so I was involved in the development of thalidomide. We were one of the two sites that were most important in developing lenalidomide as well, Revlimid. Actually, every drug that has been approved for myeloma with the possible exception of Doxil, we have been key participants in their development - daratumumab perhaps not key participants but certainly participants. So I don't want to limit us to Velcade and carfilzomib, but the changes in the myeloma world over the last year have been dramatic and we finally have monoclonal antibodies that are active in myeloma, daratumumab and elotuzumab had been very important drugs. We were sort of left behind as the breast cancer world and the lymphoma world incorporated monoclonal antibodies into their therapy and now we finally have effective drugs and these drugs have activity in situations where we might not have expected to be able to salvage the situation. So I think that these have been a very, very important breakthroughs. We have a number of new proteasome inhibitors, ixazomib (Ninlaro) and carfilzomib I think are very important. I think that carlfizomib is probably the single most active drug that we have. We have the new iMiDs, so lenalidomide has been followed by pomalidomide which is clearly the backbone for many, many therapies including therapies that are not commercially available at this point. So we had some very, very fruitful years and to the point that I no longer can have conversations with patients: Always one of the first questions that patients ask is what does the future hold for me? How long do I have kind of questions and we have always been able to at least say “This is how myeloma patients do in general.” I think for a myeloma patient who walks in the door today, we can no longer say that. I mean we really don't know what the timeline is and that's incredibly exciting. And you said you asked the question about what does the future hold, I think I have always been fairly good at sort of identifying where myeloma was going, what were the new technologies that were going to be the most important ones and for the first time that is very, very cloudy that there is so much stuff going on in oncology in general but myeloma specifically that we really can't say that this is clearly the next big area. I mean I think many of us feel that immunotherapies but there are so many kinds of immunotherapies that are going on right now that it's almost self-serving to say well, immunotherapy is where the field is going. That's just too broad of a statement but which of the immunotherapies whether it's going to be CAR T-cells and or combinations based on the monoclonal antibodies or checkpoint inhibitors that we are very involved in all of those kinds of research - which of those is going to be the home run, I don't know. They are all going to move the field forward which is going to be the true breakthrough intervention. It's nice not knowing exactly because so many things are attractive.

Jenny: The possible combinations are just exploding. That's why I think you really have to have an expert in your corner because trying to figure out how do you time things and when do you time things and in which combination and then doctors are trying to make it a little more personalized and so many different options.

Dr. Siegel: I hope that there are things that we already have in our hands that once we learn to use them a little better will be potentially curative for patients. We don't necessarily need a huge breakthrough. We just need to identify the right combinations and the right patients to fit those combinations too and we may be close in some of those patients already.

Jenny: I believe that too. Now, I know that it seems like when you start -- when you do clinical trials especially the large scale trials, they are started with patients who are relapsed and refractory and then they kind of move to the frontline. So in just looking at your papers and things, you have great expensive experience especially for relapsed/refractory patients. Maybe you want to begin by explaining what is relapsed and refractor because some patients might not know the difference and then let's talk about some specifics that you are working on right now.

Dr. Siegel: Okay. So we tend to change the definitions that we use, but it's probably best just to speak in general terms. So refractory means that a patient is not responding to a particular drug. So if you are getting treated with the drug acts and the disease doesn't respond, you're a refractory to that drug. Relapse means that you got treated with the particular drug. You had a response and now the disease is returning. So that can be either on therapy or off of therapy. So if you had a stem cell transplant five years ago and your disease was doing very, very well and now your disease starts to come back, you are now relapsed. If you are getting treated with a particular drug and your disease progresses while you were on that drug, you are relapsed and refractory. So response followed by relapse off of therapy would be just relapsed. Response or lack of response followed by progression on therapy would be relapsed and refractory and then just refractory by itself means that you are not responding to a drug that is being administered to you.

Jenny: And then you can be double refractory too. Do you want to explain what that means?

Dr. Siegel: You can be double refractory. You can be triple refractory. Now those definitions get to be a little bit confusing. So the term double refractory was I guess coined mostly to mean that a patient had become refractory to both Velcade and Revlimid. So that became a key point because when Velcade and Revlimid were the two best drugs that we had, the likelihood of responding and being able to maintain a response once you became refractory to those two drugs was very, very low but you could also be refractory to those two drugs in combination. So you could be double refractory, but double refractory to the combination was even more ominous than being refractory to those two drugs independently. Well now, we have many more than two drugs that are important. So we started to use the term quadruple-refractory because we have Revlimid and Velcade, pomalidomide and carfilzomib as the dominant drugs. So not just in terms of conversation but even in terms of the FDA wants to know who is not responding to those four major drugs. So we now have daratumumab. We're going to talk about patients being five-fold refractory and we're going to have arguments about whether a patient who is refractory to carfilzomib should be considered proteasome inhibitor refractory or do you have to show refractoriness to both Velcade and carfilzomib before you are considered proteasome inhibitor refractory. So this gets the very, very complicated language as we have more and more drugs that are effective.

Jenny: And then sometimes using them in combination will bring it back into action or you might be refractory but you add something to it and then it works all the sudden.

Dr. Siegel: Yes, you can have patients who are independently refractory to steroids, to pomalidomide and to carfilzomib and you put those three drugs together and you get excellent responses and sometimes those responses can be quite durable.

Jenny: Well let's start broad and then go down to some specifics. What current strategies do you see as being particularly effective for relapse refractory patients?

Dr. Siegel: Well I don't know - first off, relapse refractory can mean so many different things and relapse refractory can be to your first try at very early drugs and act as obviously a completely different meaning than somebody who has seen six or seven drugs and multiple drug combinations. So the early relapse is something that we have now come to expect the patient not only to respond but to respond well and durably. This is a completely different world than it was five years ago. I think the relapsed/refractory that is problematic is the patient who has seen most of those major drugs. Now, we are fortunate that we have had daratumumab become available. We have Panobinostat, we have Vorinostat, we have a whole series of monoclonal antibodies. Elotuzumab is commercially available. Pembrolizumab was just one of the checkpoint inhibitors, is in clinical trials but the point being that we have a bunch of new drugs or drugs that are coming along that almost no patients have seen. So we are fortunate at this particular moment to have commercially available choices. Beyond that, centers such as ours that have a large numbers of some clinical trials going on, we even have reasonable drugs for those patients who have become refractory even to the newest of drugs that have been approved. So I think it is a very exciting time not just for those of us who care for patients which myeloma but those of us who have myeloma or care about patients with myeloma. So I think we have to be cognizant of what is available out there and that's part of why it's so important to have somebody who has particular expertise in myeloma as part of your care team because otherwise you lose the opportunity to participate in clinical trials with new drugs or even to consider combinations that your local doctor might not be aware of.

Jenny: All right. I completely agree and we -- I think I heard that at ASH a lot that if some of the myeloma specialists were saying, you know, it's going to take us some time to figure out what you said earlier - who these combos are best for when to use them, when to reserve them and when you to use them most effectively and for whom and I really can't stress that enough. I think myeloma is complex enough and now with a lot of the new treatment options which is a great problem to have, right, you have more options and so it might be a little confusing using them but you have more. It's a great blessing. So you really need somebody in your corner and I want patients to understand that there a lot of patients, many, many patients who do this. They go to an academic center. They get a care plan crafted by a myeloma specialists. They go back to their local center and then have that plan implemented and then as they get checked and they can do periodic checks with that myeloma specialist so they are up to date on their care where they're at and that's very common in myeloma. So I want patients to know that.

Dr. Siegel: It needs to be more common.

Jenny: Yeah, it does. It needs to be more common. I think so to because I think there are a large majority of patients that just go to their local oncologists and my guess is that there are two to three years behind all the published work and we had other doctors say, you know, every two years we would have the international meeting which would be okay but now everything is happening in six month increments or faster. So that's not really sufficient anymore.

Dr. Siegel: And this is not a criticism of your oncologist. 60% of the work that they do is breast cancer and local oncologists needs to be expert in the diseases that they see most frequently and after breast cancer comes a whole bunch of other diseases well before you get to myeloma just in terms of the numbers of patients, so even the best of local oncologists can't keep up with the details of diseases that are much more narrowly affecting the population. This is I think something that every myeloma patient should be aware that it's very, very hard to be an expert in everything.

Jenny: Right. And just as an example. I mean I went in to go get checked at my very first appointment and I asked this local oncologist how many myeloma patients he saw and he said five and then I went to an academic center that was still in my city and they had over 300, closer to the 400. So the difference in being able to treat those and see patterns, you are able to see a lot of things that they will never see and you understand the science and the art of it. So I highly suggest that patients do that. If you had to estimate how many patients in myeloma are seen by local oncologists versus a specialist, what would be your guess? I know it's hard to say but I'm kind of curious.

Dr. Siegel: Well I mean you said something about the number of patients. I mean we between my colleagues here at Hackensack and myself, we're seeing 200 to 300 consults a year. I think an extraordinarily busy local oncologist might see two or three myeloma patients a year. To give a guess as to how many patients in the United States have a "myeloma specialist" involved in their care, I would guess it's 50% of them, maybe even less than that. It's just geographically -- it's impossible for some people and that's why people such as yourself and some of the patient advocacy groups are so important and why patients should take the opportunity to listen when information is made available by you or when one of these patient directed seminars comes to their neighborhood. It's an important thing and sometimes patients have to force their local oncologist to pay attention to some of the newer information just because it's impossible for them to keep up with a disease where they only have one patient.

Jenny: Right. Well you don't want to be having them going back to Google things while they are taking care of you. I think they have to do that sometimes because they are just overwhelmed by breast cancer prostate, lung or whatever else they're treating.

Dr. Siegel: Yes, or they need to have their myeloma expert that they can call and say I just saw a patient who has this, this and this going on what do you think?

Jenny: Yes, now let's talk about some specifics. You have talked earlier a little bit about pomalidomide and there is thalidomide and lenalidomide and pomalidomide. When you are looking at relapsed/refractory, how do you use pomalidomide and when do you choose to use it and how do you incorporate it into treatment for these patients?

Dr. Siegel: Well I think pomalidomide is an exciting drug. It has certainly advantages and disadvantages. By the far the most important advantage of it is that it's the most potent of the innate drugs between thalidomide, lenalidomide and pomalidomide. The way it was approved by the FDA, it can't be used very early on. It's only reserved for patients who have relapsed disease or relapsed/refractory disease but as I said the most potent, the most active patients whose disease has progressed on Revlimid will still respond to pomalidomide. Pomalidomide has allowed us to do a lot of things. It's easy to use because it's not excreted thru the kidney. So for all those myeloma patients that have poor kidney function and whom we have to worry about the dose of lenalidomide, that's not a worry with pomalidomide. So not only is it more active but we can use it easily in situations where we can't necessarily use lenalidomide with as much freedom. So I think it adds both response and flexibility and that I think is particularly important when inexperienced people are using the drugs. So when a local oncologist is trying to put together a combination there might be a little bit less trepidation in using pomalidomide. But I think pomalidomide extended the use of many drugs. So we have patients whose disease has progressed despite being on multi-drug combinations and when we include pomalidomide in those combinations sometimes were able salvage responses that are quite durable. So it has been an exceptionally exciting drug and it works in combinations with the same degree of ease that lenalidomide does. So I think people who have acquired experience with lenalidomide will find very similar experiences with pomalidomide. It's not as perhaps scary by the patient or the practitioner because of those similarities to lenalidomide.

Jenny: If somebody has kidney failure right at the get-go when they are diagnosed. When will something like pomalidomide be available if it's only available now for relapsed/refractory patients or approved that way? How long does it take to get approved for an earlier state?

Dr. Siegel: I don't know that it will ever get approved for the frontline patient in myeloma. As far as I know there are no clinical trials going on with that. I think that there are perhaps even newer drugs in development that may supplant pomalidomide in that regard but the way that the drug is approved right now, there is no opportunity to use it in the newly diagnosed patient. It doesn't mean that it can't be used very early on for that patient who gets the combination as part of their initial therapy that doesn't work to move on to a pomalidomide-based regimen fairly quickly is certainly reasonable but the way that the guidelines are written is that patients has to have seen lenalidomide previously.

Jenny: Now let's move on a little bit because I know you are doing a clinical trial with Vorinostat which is an HDAC inhibitor. Maybe you want to explain what that trial is all about and why Vorinostat over I think it's Panobinostat is it? That's another HDAC inhibitor.

Dr. Siegel: Vorinostat I wouldn't say over Panobinostat. Vorinostat has been around longer. It was approved for the treatment of cutaneous T-cell lymphomas. It was never approved for the treatment of myeloma and yes, we had developed a lot of experience and it's a very, very effective drug and used in the right circumstances can sort of re-sensitize a patient to drugs that they had seen previously. These histone deacetylase inhibitors - I’ll talk about Vorinostat first and then Panobinostat second. These histone deacetylase inhibitors have no activity by themselves. The patients do not respond to the single agent. Yet, we can take a patient who had been getting Revlimid but had progressed on the Revlimid and add the Vorinostat and all of a sudden the patient responds again and sometimes those responses can be quite durable. Merck never managed to get Vorinostat approved for the treatment of myeloma although it does now have NCCN guideline-based approval. While the drug can't be advertised in myeloma, it is sometimes possible to get the drug approved. Well, fortunately Novartis got a very similar drug called Panobinostat approved. It was approved in a very specific circumstance but again Panobinostat very similarly to Vorinostat can be combined with a number of drugs and the response re-cquired. So I think these histone deacetylase inhibitors are very important drugs and there are patients in whom you would project that nothing was going to work and we use these combinations including histone deacetylase inhibitor and lo and behold, we see responses that are both surprising but well maintained. These are drugs that when used carefully and in the right circumstances and combinations can be very well tolerated. So I think it's very exciting and there are other histone deacetylase inhibitors being explored both pre-clinically and in early clinical trials. So I think we have a reason to be hopeful that this class of drugs will continue to be part of our armamentarium. But Panobinostat is approved in myeloma and I think is a very effective drug when used in the right combinations at the right times and that's part of the feel that one needs to get.

Jenny: Do you want to talk a little bit about your clinical trial that is using Vorinostat?

Dr. Siegel: We had a number of clinical trials, the one that we are actually just putting the manuscript together now, we took a bunch of patients in whom the drug Revlimid had either not worked or had worked and then failed and took those patients, many of directly progressing on Revlimid and dexamethasone or Revlimid and dexamethasone in combination with other drugs and went directly to add Vorinostat and these patients again responded. So the data that was actually, for us very exciting - response rates that were in the 20s or 25% range in a population in whom you would have certainly not expected that have to be the case. We also had a clinical trial we called our quad trial in which we used the combination of carfilzomib, lenalidomide, Vorinostat and dexamethasone. So a four drug combination and this was actually extremely well tolerated and the response rates were quite robust. I think while the response rates were certainly much, much higher,  the clinical I just spoke of  was perhaps more exciting because it proved a scientific point I think more so than our quad trial because it took drugs that were failed and by adding the Vorinostat, we were able to resensitize them to these therapies that were no long effective or had never been effective. I think as a class of drugs, very, very exciting and now we have Panobinostat which is more available and we now use sort of interchangeably in those circumstances that we had learned from our quad trial and from our Vorinostat salvage trial. So I think that the data was impressive and now we have the opportunity to expand on that.

Jenny: Well it's a huge blessing. It's like a “make it work again” strategy to bring possibilities back to patients.

Dr. Siegel: Yes, and I think hopefully will teach us something about how these drugs that are so important to us stop working and why they stop working and if we can understand what it is about the histone deacetylase inhibitor that re-sensitizes patients may give us opportunities to develop new drugs or new strategies that can be effective in even more patients.

Jenny: When you are looking at some of the reasons why these drugs stop working, do you think it's because the clone is changing? Because I know the clones can evolve over time and then stops working and this does something -- I don't know if this affects the clone.

Dr. Siegel: So we have this notion of clonal tides in which there are multiple populations in the myeloma that we select for and we select for a clone that is resistant to one drug and then we switch drugs and we then are able to kill that clone that had become dominant but now a new clone evolves. So what I think is particularly exciting about the work that we did with Vorinostat was that it wasn't the case. We took a patient who was clearly resistant to Revlimid. So the clone that was the dominant one was resistant and we add the Vorinostat and all of a sudden that clone becomes sensitive again. So the notion that it is a tide back and forth of different sub populations of the disease that explains this, clearly isn't the case here. I think that makes it even more exciting.

Jenny: Yeah, that's very good information. Amazing. Well I think I want to come back to this four drug combination idea in a minute but I do want to talk a little bit about what you were talking about earlier and people becoming refractory to drugs and then trying different combinations. So let's say somebody becomes refractory to a Velcade is a proteasome inhibitor you mentioned carfilzomib still an effective option can you swap these things out and have them still work?

Dr. Siegel: Absolutely. I think that's the exciting part about these drugs is even drugs that hit the same targets can be effective in patients who have become resistant to that target and what is the explanation? I mean part of it is just that you can get higher concentrations of a drug and therefore it overcomes some level of resistance but part of it is well beyond that. I think that we need to be cognizant of the fact that all proteasome inhibitors are not created equal, all iMiDs are not created equal and that the notion that we have to switch classes and we have to jump to other strategies isn't always the case. I mean we are lucky that we have the opportunity to do that now. We have more categories. So the ability to transition from one category to another is now much easier for us but the fact that one becomes refractory to Velcade doesn't prove that one is going to be refractory to Kyprolis or carfilzomib.

Jenny: Well that's important for patients to know. And I know about ixazomib which is a new oral proteasome inhibitor. Can it be used in the same way like if patients are refractory to Velcade or carfilzomib, can they use that instead because what you're saying is all proteasome inhibitors aren't the same?

Dr. Siegel: Yes. So structurally, ixazomib, Ninlaro is very, very similar to Velcade, to bortezomib but we know that patients who are refractory to bortezomib can respond to ixazomib, to Ninlaro. We have less information about being refractory to carfilzomib and then responding to Ninlaro, but we have certainly seen patients who have failed carfilzomib based combinations who have responded to Ninlaro based combination. So it's very confusing, but a pleasantly confusing field and whether it's that it's a slightly different combination or that the mechanisms of resistance are different enough to allow for continued responses. I think we still need to figure out some of that stuff.

Jenny: Now, you were talking about combinations and the HDAC inhibitors are a perfect example of bringing people back to getting it to work. Are there other combinations that can overcome let's say being refractory to a single agent like either a proteasome inhibitor or an iMiD?

Dr. Siegel: Yes. I think that we see that all the time. Back in 1997 when we treated the very first patient with thalidomide, we started off using it as a single agent and we were amazed. It was perhaps the most important pharmacological breakthrough in myeloma and all of the patients who got put on thalidomide were refractory to corticosteroids but we added corticosteroids to thalidomide and low and behold, the patient started to respond again and sometimes those responses were very, very deep and very, very durable and I think that was sort of a revelation for me but it is something that everybody needs to be aware with almost all of these drugs that we used. The fact that Velcade failed us the first time around, it doesn't mean that Velcade is going to fail us in the next combination or the third combination and we see that not just with Velcade but with corticosteroids and IMiDs and the fact that we fail once doesn't mean that that drug is crossed off the list and I think that that is perhaps the most important principle to understand is that to be enough respectful or our inability to understand  why these things happen that we need to be very, very comprehensive in terms of understanding how many different ways we can use these drugs. And if we use carfilzomib once and it doesn't work as carfilzomib and dexamethasone, that it may very well work as carfilzomib, Revlimid and dexamethasone or carfilzomib, pomalidomide and dexamethasone even though the patient had gotten Revlimid before and failed or had gotten pomalidiomde before and failed - that these combinations still need to be explored because we will get good responses over and over again even though it's the same drugs.

Jenny: So what you're saying is be flexible and maybe don't take no for an answer when something is not working.

Dr. Siegel: Yes. Don't acknowledge that the disease has won because it hasn't and as we add more drugs, those algorithms becomes so much more complex when you had two drugs it was really -- You could use thalidomide by itself. You could use dexamethasone by itself or you could thalidomide and dexamethasone. Once you add dexamethasone, Revlimid and Velcade, the number of combinations becomes exponentially greater. And when you have 10 drugs the way that we do now, the number of combinations becomes almost infinite and I'm not saying that every patient needs to get all hundred potential combinations, that's clearly not the case but there are so many combinations that we should be very, very leery of giving up too early.

Jenny: I agree. Now let's go back to the four drug combination idea. I know that typically these combinations have to be tested in clinical trials as you have run and how do you do this rapidly? And then we have so many different combinations. How do you do some I guess rapid fire clinical trials to get to these conclusions faster in your opinion?

Dr. Siegel: Well first off, in the United States and this is perhaps not true in most and of the rest of the world, it's not 100% true that you have to have a clinical trial that proves the exact thing that you are trying at that moment. In the United States, we used drugs off label all the time and so the need to have a large clinical trial that proves that a particular combination is justified, is not always the case. Now don't misunderstand what I'm saying. I think we need to do clinical trials to establish the safety and role of different drugs but I think the individual institution needs to say okay, this is a combination we're trying and then do the pilot study and publish the data from that pilot study to show that a combination is effective in a particular population and can be done safely. We have tried to become very, very centralized in how we do clinical trials. When we do that and we only do large trials, we miss out on the opportunity for the smaller combination to be tested quickly and I think we need to make sure that we have the interest and the liberty to do those kinds of trials. The problem is that very often these drugs are in the hands of the pharmaceutical companies and it requires the cooperation and collaboration between the number of companies that each own the individual drugs. I think we're very fortunate in the myeloma world that there are a number of drug companies that are willing to do that, I mean Celgene with its series of iMiDs has been very, very happy to say, yeah, you get Amgen to provide the carfilzomib or whatever the next new drug is and we will be supportive of a clinical trial using our drug as well. So it's a difficult environment sometimes but I think we have managed to do most of the things that we need to do.

Jenny: Well wonderful. I know we're running out of time. I am going to keep you over if that's okay with you because I have another question -- Dr. Siegel: I have a patient waiting but I'm glad to talk.

Jenny: Oh, you do? Okay. It won't take too long. Now you are doing a clinical trial using glutaminase inhibitor, BB839.

Dr. Siegel: Glutaminase inhibitors.

Jenny: Yes, glutaminase. Okay, so can you explain what this is and how it's used? I want you to be able to cover that.

Dr. Siegel: Well I don't know that we should spend an enormous of time on it because I'm not sure if that's a drug that is going to be a breakthrough drug in myeloma but I think that that field in general of what we call “metabolomics”. So we tend to think that there are sort of individual pathways that are critically important in a particular disease but one of the things that's funny about cancer, we think that they are cancer cells or big bullies and are impervious to things but part of what it is to be a cancer is that a lot of your physiology becomes very, very delicate and these cells aren't as smooth running as the normal cells in our body. So things that sort of general physiologies, the sort of normal background processes that go on in cells sometimes make the myeloma cell and cancer cells in general more susceptible to these kinds of disturbances than you might expect. You would instinctively say no, the cancer cell is much tougher than the normal cell, but in fact that's not the case. So these cells that these drugs that interfere with the kind of metabolism that is normal metabolism sometimes kills the cancer cells much more easily than they kill normal cells. So metabolomics I think is an important area of investigation and there are lots of drugs and lots of kinds of areas out there that need to be explored and we are not quite at the point of being able to say well this is clearly a drug that is going to work in myeloma and we are still to some extent at the trial and error stage in terms of the kind of clinical trials that we do.

Jenny: The last question will be and then we'll move to caller questions. I know there was newly updated NCCN guidelines for the treatment of multiple myeloma and there was also a recent international myeloma working group paper on a high risk disease. So what stands out to you from these two things and what are issues patients need to think about as they relapse like when to consider a clinical  trial or how to best keep their options open, things like that.

Dr. Siegel: Well I think that the NCCN guidelines are very important, not as an absolute blueprint for everything that is available but particularly oncologists who don't do a lot of myeloma care as part of their practice. They tend to say well, this drug is approved in this situation but the NCCN guidelines will very often have combinations that aren't on label that can justify the health insurers of participation in supporting a strategy. So example that I will use is that the NCCN guidelines have what is called a 2A designation for the combination of carfilzomib, Revlimid and dexamethasone in a newly diagnosed myeloma patient. Well if you look at the package insert, that doesn't exist. But if you had a patient who for instance you didn't feel that Velcade was an appropriate drug for that newly diagnosed patient because they had a horrible pre-existing peripheral neuropathy as an example. Well you could use carfilzomib in that patient based on the NCCN guidelines and I think the overwhelming majority of practitioners out there have no idea that that's the case. So having those guidelines in front of you can sometimes allow you to do things that are right for a particular patient that you might not normally understand is available.

Jenny: You may have not thought about like that before.

Dr. Siegel: Yes, so you have that diabetic patient who comes in with horrible pre-existing peripheral neuropathy. Well you know what, you have a good choice that if you just look at the NCCN guidelines, you might not otherwise know and that could be true for any number of combinations. The spectrum of choices is not just what the FDA has approved. And in terms of the position paper on high risk myeloma obviously we have done pretty well, not well enough but pretty well in patients with standard risk disease and fully expect those patients to live not years but decades but for the high risk patient that unfortunately is not the case. And I think the most important point that this position paper makes is that we need to do clinical trials to allow us to understand what works in high risk patients. It's not so much a roadmap as to how to treat a high risk myeloma patient but more to give a notion as to what is available and how important it is to have those kinds of patients participate in clinical trials so that we actually can expose those patients to newer therapies and hopefully intelligently thought out therapies but also to allow us to learn so that the next generation of high risk patients can be treated in a more sophisticated fashion. We all have sort of our bias about what we should do in a high-risk patient, for instance, here at Hackensack, in young high-risk patients we do allogeneic transplants in a lot of them. But if we don't do it in the context of a clinical trial, then it almost doesn't matter that we will look at our patients and say wow, look how amazing our high risk patients who have been allo transplanted are doing because we haven't done it in the right fashion so that we can transmit that data to our colleagues. I think that that's the most important take home message from the position  paper is to say let's do our work carefully so that when we think we’ve learned things, we actually have learned them and that we have learned them in a context that is supportable and that we can transmit to our colleagues, and to the patient most importantly.

Jenny: Even if you do a retrospective study, at least you have a data to back it up.

Dr. Siegel: Yes, we all talk amongst ourselves, oh, I think we should do this and I think we should do that. Well at some level that's irresponsible if we don't gather information in a way that moves the field forward.

Jenny: That's very, very helpful. Well I want to open it up for just a few caller questions.

Caller: Thanks very much. I just had one question, have you and your colleagues at your center doctor, have you pretty well moved away from the idea of second and third transplants now that we have all these new drug combinations? I know a lot of people are still wondering if they should get another autologous transplant after relapse to reset their disease.

Dr. Siegel: Well I mean I think that that has to be an individualized answer. I think that right now, we sort of put transplant in a separate category and I don't think that we should. If we had a patient who had a great response to a carfilzomib based regimen and then for whatever reason stopped therapy and the patient stayed in remission for a year, for two years for three years and then relapse would say wow, that patient had a great response to carfilzomib. Let's use the carfilzomib-based regimen again. Well, why do we place a transplant in a different category? If I have a patient that in fact we have a patient who is coming up on her 20th anniversary of her stem cell transplant. If I had a patient who had a ten year remission after a transplant and now is relapsing for the first time, well the first thing that is going to come to my mind is a transplant. If I had a patient who had a ten month of remission after a transplant probably the last thing that would come to my mind would be a stem cell transplant. But transplants are number one, very effective. When we have a patient in whom it has been effective, we should be certainly be thinking about it again. Transplants have very, very little in the way of long-term toxicities whereas almost all the other drugs that we use have cumulative toxicities and in an environment where the cost of care is of greater and greater concern. Transplants are one of the cheapest things that we do. So I don't think we are ready to cross transplants off the list yet.

Caller: Thank you very much.

Jenny: Thank you so much for your question. Okay, our second caller, go ahead and answer your question.

Caller: Hey, Dr. Siegel. Thank you for being very generous with your time this morning.

Dr. Siegel: My pleasure.

Caller: It’s very helpful and very hopeful especially in the area of high risk. It seems that all patients eventually becomes high risk and this information sharing about, between doctors and strategies seems to be an important component to increase the pulse of learning. A couple of questions. It's amazing what has happened in the field of myeloma over the past few years, what do you think are the factors that caused the explosion of the development in myeloma?

Dr. Siegel: I think a big part of it is just luck that we managed to have enough drugs being tested at one time that we hit a couple of homeruns but I think that if the myeloma community and I think this is patients as much as physicians has become extraordinarily well organized that myeloma patients communicate incredibly quickly with one another and with the health care providers that they have and the myeloma patient's willingness to participate in clinical trials has made it a very exciting area for the pharmaceutical industry to come to and I think that it's as much a credit to groups like the MMRF that have organized patients and made myeloma attractive to the pharmaceutical industry that is responsible for this as much as anything. A decade ago, we had to beg the pharmaceutical Industry to let us have their drugs and now they are like banging down the door saying please will you do our clinical trial?

Caller: There has been an explosion of the patient's community with IMF and MMRF and now the Myeloma Crowd that have created a rate of community that have taken on different niches to support research and patient involvement and so that's interesting that it has a quite interesting role in it and I appreciate all the work that the Myeloma Crowd is doing. I’ve been  looking forward to your interview.

Dr. Siegel: Yeah. I mean I think that this is exactly why we've had the success that we had is because myeloma patients become aware that stuff is going on faster than anybody and this is because it's such a close knit community.

Caller: All right. Well thank you for your time this morning. That's all I have.

Jenny: Okay. Thank you so much. We have one more caller and I'll just ask you to keep your question quick.

Caller: Yes, thank you Dr. Siegel. Is any evidence that four drug combinations are more efficient than three drug combinations and you mentioned how many permutations there are in choosing those four drugs. Is there any way to know a priori which are more likely to succeed either by genome profiling or any other type of before the treatment assessment of the patient?

Dr. Siegel: I mean that's an extraordinarily good, astute question. I mean unfortunately not one that I really have a good answer to. So when we say four drug combinations, it's almost the meaningless term that it's right for a drug combination exactly as you were implying and there are three drug combinations that are better than four drug combinations. It's just the matter of which drugs and which patient. So we are at the verge of understanding what drugs are going to be best for what patients. But this is really in its infancy and we can't even do that well for single drugs. I mean there are certain profiles that we think a patient is more likely to respond to Velcade or less likely to respond to Velcade. But even talking about a single drug like that, you would never not give a patient Velcade because they don't quite fit the profile and you would never choose to not move on to another drug quickly because a profile seemed to imply that Velcade was the best drug. Unfortunately, we are still much more at the empiric stage than the informed stage and that's when we talk about single drug in terms of having tools that will say okay, this is the best four drug combination for this particular patient, no. We are not there. I will tell you that you that here at Hackensack, we have a group. We have a close relationship with a big bioengineering group and one of the scientists who works with us has developed a three-dimensional device that can propagate primary myeloma tissues. Well one of the interesting uses for that is going to be to take a patient's myeloma cells, put them in the device and see what can kill them. I mean at the most basic level, that's a way to answer the kind of question that you are asking but I hope one day, gene expression profiling, whole genome sequencing, epigenetic analysis of tumor cells will allow us to have a really quick, easy answer to that but I still think we're certainly years and perhaps even longer than that away from being able to virtually test drugs.

Caller: Right. Thank you.

Dr. Siegel: Welcome.

Jenny: Thank you so much, excellent question. Dr. Siegel, we are so grateful that you joined us today. We're going to let you get back to your patients but this has just been an outstanding show. We are so thankful for your work that you work every day on behalf of us as myeloma patients and we're just so thankful for all you do. This show has been extremely hopful with some great takeaway messages.

Dr. Siegel: I had fun – I like talking about myeloma.

Jenny: Thank you so much. I appreciate it.

Dr. Siegel: Thank you so much.

Jenny: Thank you for listening to another episode of Myeloma Crowd Radio. Join us for future shows to learn more about the latest in myeloma research and what it means for you.