Dr. Muzaffar Qazilbash, MD MD Anderson Cancer Center Interview Date: February 25, 2016 

 Immunotherapies are the "next big thing" in multiple myeloma care but it may be too early to have them replace effective treatments like autologous stem cell transplant, iMiDs and proteasome inhibitors. Dr. Muzaffar Qazilbash, MD of MD Anderson Cancer Center shares how the new treatments will be added to current therapies to make outcomes even better for patients with this aggressive cancer. Using the new tools available can potentially offer longer remission times to standard therapy without adding extra toxicity. Dr. Qazilbash shares his most recent study to use a personalized vaccine together with a T Cell treatment and stem cell transplant. The vaccine is personalized based on a patient's own type of myeloma. Additionally, the patient's T cells are removed, grown and expanded in the lab. Following a normal autologous stem cell transplant, the vaccine is administered and the expanded T Cells are given back. This is just one way in which the new immunotherapy approaches can boost the impact of tried and true treatments. 

 

Thanks to our Episode Sponsor, Takeda Oncology

Jenny: Welcome to today’s episode of Myeloma Crowd Radio, a show that connects patients with myeloma researchers. I'm your host, Jenny Ahlstrom. I would like to thank today’s episode sponsor, Takeda Oncology, for all they do for myeloma patients. Now, we have an announcement before we get started with today’s show. On Monday, in honor of March, which is Myeloma Awareness Month, we are starting a program called Muscles for Myeloma. This is a fitness challenge to get us all up and moving while raising money for a good cause, myeloma research. Now, at ASH in December in Florida, I heard many doctors talking about how they are segmenting patients into Fit, Unfit and Frail categories and tailoring treatment based on those categories rather than by age. So our ability to handle more difficult treatments or extended treatments, typically, will get us longer overall survival. So no matter what fitness level you are at - you can be just coming out of transplant or newly diagnosed or in maintenance therapy -  any exercise plan is a good plan for myeloma patients. So here is how it works. First, you can create your own page on the Myeloma Crowd site by clicking on the link at the top, and when you create your page, you can tell everyone how you plan to get fit between March and April of this year. You can even add a photo or a video if you’d like. You can join alone or you can create a team page and invite people to join your team. Then to add some accountability to it, you can ask your friends and family to sponsor you for each minute you exercise. It could be a cent per minute, ten cents per minute, a dollar a minute or more. It’s kind of like the elementary school walkathon. All proceeds will be donated to the Myeloma Crowd Research Initiative, which are two important immunotherapy projects that are dramatically changing myeloma care. And we’re also joining local races in several areas around the U.S. during March and April. So you can find a race that we’ve got planned so far on the right side bar which they include San Diego, Salt Lake City, Fernandina Beach, and we expect about eight to ten other locations coming in the next week. It’s an incredibly important initiative to get us all moving and get those endorphins flowing while making us more fit in the process. Please consult your doctor before starting any fitness program. Now, onto today’s show, our next Myeloma Crowd TV episode is on the use of vaccines in myeloma. And last year, we had a show with Dr. Larry Kwak about a vaccine in development in MD Anderson. This vaccine is now being used in a clinical trial which brings up a very important issue for all myeloma patients. As we start using the new drugs, will they be replacing standard treatments or will we be adding them together for our very best benefit? So here to talk with us today is Dr. Muzaffar Qazilbash at MD Anderson. We’re delighted that he’ll be helping us understand how to blend the old with the new combining well-accepted treatments like stem cell transplant with newer treatments like immunotherapies because it sounds like they might not be mutually exclusive. He is an expert in both stem cell transplant and immunotherapy, so he is really uniquely qualified to discuss this topic. So welcome, Dr. Qazilbash.

Dr. Qazilbash: Thank you very much for having me.

Jenny: Let me introduce you before we get started. Dr. Qazilbash is Professor of the Department of Stem Cell Transplantation in the Division of Cancer Medicine at the University of Texas at the MD Anderson Cancer Center. He also serves as Medical Director of the Transplant Inpatient Service and he’s Co-director of the Stem Cell Transplant Fellowship Program. His research interests include, of course, stem cell transplant in myeloma, but also cancer vaccines and immunotherapy approaches. He serves on several committees including the Myeloma Tissue Bank Steering Committee, Institutional Review Board, and Clinical Research Committee. And he has received awards including the Excellent Review Award, and the ASBMT Travel Grant for Tandem, ASBMT. Now, to put this in perspective, MD Anderson is the largest center in the United States that does transplants. And talking before the show, he let me know that they are doing 900 transplants per year and 300 of those are in myeloma. So has his hands full. Welcome again, Dr. Qazilbash. Dr. Qazilbash: Glad to be here, thank you. Jenny: So now at the recent ASH Conference, there were discussions about the continuing role of traditional therapies like stem cell transplant and the new drug development. And immunotherapy seemed to be bigger than ever, even the year prior. But are there two key messages here of blending of the old with the new to improve outcomes?

Dr. Qazilbash: Yes. I think there is always this linear progression where older treatments, proven treatments are combined with newer treatments to basically enhance and increase the benefit to improve the outcome. And it takes a long time to replace any of the current standard of care or treatment, especially when combining the two treatments offer you greater benefit. So unless the new treatment is uniquely effective, much less toxic and basically eliminates the need for the older treatment, the general approach is to combine the older and newer treatment and to combine them in the most effective way where you can maximize their benefit, and at the same time, minimize their toxicities.

Jenny: At ASH I was listening to one of the sessions and one of the doctors was talking about transplant and he said, “There’s still no single agent that’s as powerful as melphalan is,” which is what’s used in stem cell transplant. With your background with both stem cell transplant and vaccines and immunotherapies, is there a difference in kind of power behind some of these new treatments?

Dr. Qazilbash: Sure. So there are basically different ways to look at the big picture. The basic goal is to get rid of myeloma, to kill and eliminate and eradicate those cancer cells. And there are different pathways. There are different mechanisms, different approaches to get to that point. One is what we call the conventional treatments or standard treatments as we have seen in the last two decades, and especially in the last few years, tremendous progress. We have understood many different pathways. So we have immunomodulatory agents, we have proteasome inhibitors, we have HDAC inhibitors like panobinostat, so that’s one way of targeting the cancer cell. Then we have these old alkylating agents like melphalan which we know that if given in very high-doses can completely eradicate myeloma cells even for a short period of time but they are very effective. So that’s another way of attacking and targeting those cancer cells. And then there are other novel approaches which is to harness the power of the immune system, the indigenous immune system, hence, the development and growth of immunotherapies. And then there are other pathways as we understand the biology of the cancers and what molecules are playing a role in that and how to target them. So the bottom line is that to achieve that goal, we have got all these different tools, all these different pathways that we can use to kill cancer cells. So this is where all this growth and development is taking place, and which is of course good news for our patients and good to basically target that disease and achieve improvements and everything.

Jenny: It’s been no surprise that typically, combination therapies have been used in myeloma treatment, a proteasome inhibitor and an iMiD and something else. So following what you just said, it’s not that unlikely to just say, “Well, let’s start adding immunotherapies into that next and see what happens.”

Dr. Qazilbash: Sure, absolutely. So as we have seen and since you had referred to ASH or as we have all heard that with the have the availability of agents like proteasome inhibitors and immunomodulatory agents, there is this general discussion that they have replaced stem cell transplant or high-dose melphalan. But as you rightly pointed out that these are two very effective approaches, and if you combine them, you can get additional benefit. You can get additive benefit, and they are not mutually exclusively, and that’s one of the major trials from the IFM group which compared the newer agents with stem cell transplant upfront versus the same agents but delayed stem cell transplant. And they showed that if you use all these things together early on in the course, you can prolong the duration of remission and prolong the progression free survival. So using the same paradigm, if we can safely and tactfully incorporate immunotherapies and immunotherapies are on their own at showing the benefit, we anticipate that we are going to further improve the outcome and enhance the benefit.

Jenny: Can I ask you just your personal opinion, because there are a lot of different opinions in how myeloma is treated even among experts. And there’s one philosophy that kind of says, “Hit it hard upfront,” which is what you referred to with the IFM, the French study. And then there is another approach that says, “Well, we might be close to a cure soon, so maybe we don’t hit you hard upfront with everything, we just kind of see how it goes.” Do you have a preference when you look at a newly diagnosed patient who’s just coming into it?

Dr. Qazilbash: Very good question. So yes, you know, there are people who talk about two different philosophies, cure or control or that this is not a sprint, this is a marathon. And in selected patients, yes, one can discuss both approaches and there are clinical trials and data to support both. Since you asked my personal opinion and my interpretation of existing data, here is what I think that so far the only way we have treated cancer, especially blood cancers is by attacking them hard early in the course and eradicating it. This is the approach we have used in curing acute myeloid leukemia. This is the approach we have used in curing acute lymphoblastic leukemia, non-Hodgkin’s lymphoma or Hodgkin’s disease that had the time of diagnosis. Use a combination of agents that have additional or multiplied benefits with minimal or as little toxicity as possible and try to eradicate the disease upfront, try to achieve a complete remission, and that’s the first step to achieving a cure. We have not cured any cancer by treating it gently and waiting for it to relapse and then hitting it hard. As you know with the current data in multiple myeloma, with each relapse, the duration of remission goes down. So the best time to go for the cure is early in the course of the disease.

Jenny: That’s interesting. I know that was my doctor’s philosophy, but I know everyone is so different. It’s very hard for a newly diagnosed patient to decide because sometimes it just depends on who you go to. So when it comes to research, you have training in both stem cell  transplant research, and also immunotherapy research. Are there differences in the thinking or approaches between research looking at those two different approaches? Are there different paradigms, I would say, between those two or are there similarities?

Dr. Qazilbash: Sure. There are great similarities. So again, no matter what type of research we are doing, especially since people like myself are also physicians who are taking care of patients and treating physicians, our ultimate goal is to understand a particular disease treat it as effectively as possible and go for the cure. So the general principles are the same, whether it is an immunotherapy drug or whether it is a targeted molecular drug or whether it is an immunomodulatory drug. First, you want to study it in the laboratory or in animal models to see how it works, what kind of toxicities to anticipate, how to manage those. And then you start out in clinical trials. In terms of how different drugs work and different approaches work, sure, there are differences. You know, one of the oldest immunotherapeutic approaches is stem cell transplant from a donor. So that’s obviously not a personalized form of immunotherapy but that is immunotherapy. The reason we cure patients with allogeneic or donor transplant is primarily because we utilize the donor immune system which goes after patient’s disease, whether it’s the leukemia cells or myeloma cells. But the drawback is that that same immune system can go after their normal organs. So that’s the oldest way of using immunotherapy. But there are other approaches as well which have been used in drug development and simple chemotherapy trials. And same approaches can be used in immunotherapy trials seeing that patients have been treated in phase 1 and phase 2 studies. So there are some differences but there are great similarities as well.

Jenny: And the process sounds like it’s pretty similar.

Dr. Qazilbash: That is correct. In terms of testing a drug, taking it to the next level, yes, that process or doing the clinical trials, but where the difference has come, and I’m sure maybe a caller or you may have more questions about that, the difference has come on how to manage different agents whether it’s antibodies or cellular therapies, and there, of course they have their own specific mechanisms of action, their own particular type of pharmacology and one has to have some basic understanding of those processes.

Jenny: I know you’re saying that immunotherapy really started, I mean the allo transplant or the donor transplant is an immunotherapy. So could you explain your training, I guess, or your background in transplantation and then how you did vaccines, immunotherapies at the same time, because I think that’s kind of fascinating?

Dr. Qazilbash: Sure, absolutely. As I mentioned that anyone whose trained in a stem cell transplantation, at some level is also trained in immunotherapy because allogeneic stem cell transplantation is a form of immunotherapy. So you have to have some basic understanding of immunology, and a lot of things that happen are mediated by T lymphocytes that can cause so-called graft versus tumor effects and can also cause graft-versus-host disease. So we are trained in handling those type of complications. Of course we are taught to understand those mechanisms. So that’s one thing that is part of the training of stem cell transplant, which of course in the bigger picture is incorporated in the training of hematologist and oncologist. And then my personal interest or how all these things developed, I’ve been working at MD Anderson for the last 14 years, and before that, I did my training at the National Institutes of Health, and both these places of courese research emphasis is great. And here at MD Anderson in my department, we have a lab of transplantation immunology. We also have Cancer Immunology Treatment Center and there are a number of pioneers of immunotherapy who work here. So I’ve been working and collaborating with several of those colleagues. So when I came here, I started working on a vaccine that was developed for the treatment of acute myeloid leukemia and chronic myeloid leukemia. I initiated that trial. I worked on developing trials using T-cells to treat leukemia and then working with Dr. Kwak whom you mentioned who was in one of your previous shows. We worked on developing this myeloma vaccine and then vaccine specific T-cells. So this was another immunotherapy approach that we utilize. It’s a combination of stem cell transplant, that training and background, and working with people and researchers who are coming from the immunology side and how to bring those treatments in the realm of stem cell transplant and bringing them to the clinic that my career sort of developed this way.

Jenny: Well, let’s move on to what you just mentioned and maybe break it apart piece by piece. You’re working on a vaccine that Dr. Kwak was also working on. And maybe you can give us a quick refresher of what that is, but maybe you can also explain just in general the use of vaccines in myeloma, when and how they’re best used and how do they work and things like that.

Dr. Qazilbash: Absolutely. This is something that I try to discuss with my students, with my residents and fellows. So when we talk about immunotherapy, what do we mean in very simple terms? Essentially, what we are trying to do here is using the power of the patients’ own immune system, and we know the immune system is powerful because if someone transplants a kidney or a liver, the immune system can go after it and literally melt away that organ. So that’s the power of immune system. So somehow, the goal is how one can harness that power and use that to go after and attack cancer cells. Two very basic ways of using immunotherapy; one is what we can call the active immunotherapy, and second would be the passive form of immunotherapy. Active immunotherapy would be vaccines, just like an influenza vaccine that you give a little piece of either the germ or in this case a little particle or a molecule or a protein derived from the cancer cell so that the body can see that as a cancer cell and mounts an immune response. This is active immunization. This is what we can see with a vaccine. The second type of immunotherapy is passive or adoptive immunotherapy. Here, we are not stimulating the immune system with a vaccine but we are giving cells like T-cells, and those T-cells can be genetically modified like CAR T-cells or somehow just stimulated with different cytokines like the T-cells that I am using. So this is the second way of delivering or approaching immunotherapy, which is the passive immunization or T-cells or antibodies, which are also part of the immune system that you give that protein that can detect the target. So vaccination is one way of giving immunotherapy, antibodies, and T-cells is another way of giving immunotherapy. And now, you are seeing a third approach of augmenting the immune response or revving up the immune system, which is the checkpoint inhibitors and you will hear a lot about those as well. That’s been on the horizon for the last few years and made  tremendous progress in the treatment of kidney cancers and melanomas. And we saw a presentation at ASH of their effectiveness in multiple myeloma where you basically remove brakes from the immune system along to go after the cancer cells. So these are the different approaches that we use as immunotherapy to target myeloma. So now to answer your next question, what are the different types of vaccines that are being used in myeloma? Again, there are a number of those. I think the most common ones that you have heard about or you may have seen the papers, one is the idiotype type vaccine, which is what Dr. Kwak developed and which is what we are using in our clinical trial. So idiotype protein is basically a little piece from the M spike. So this is a piece from the protein taken from myeloma cells of the patients. Any myeloma patient is familiar with M-protein or M-spike or paraprotein. So this idiotype is basically a little piece derived from the M protein. That’s the most commonly used and the best understood myeloma vaccine. But there have been other vaccines that have been used. Some of them have used dendritic cells which are the antigen presenting cells in the body, some of them have used other proteins that may be present on the surface of myeloma cells like NY-ESO or survivi-. So these are the different types of peptide vaccines or dendritic cell vaccines that have been used in myeloma.

Jenny: Okay. Great. So one piece of your clinical trial that you’re going to talk about, hopefully, is this vaccine, this idiotype vaccine. So you take a part of a patient’s own M-spike and then you’re creating a vaccine that’s very personalized.

Dr. Qazilbash: That is correct. I’ll give you a little summary of this trial. So this trial, the hypothesis is that if we inject this little piece of M protein to the patient, the patient will be able to mount an immune response against their own myeloma. Normally, the immune system is suppressed but the way we process this protein, this piece of protein that we basically conjugated, we bind it to an immune adjuvant, the kind of things that is used in the vaccines in general, and we give it with another growth factor that can boost immune response called GM-CSF. We give this vaccines to the patient. So in this clinical trial, which is a control trial in the sense that half the patients were supposed to get their vaccine treatment, vaccine stimulated T-cells and the other half were supposed to get control vaccine which means that they were not getting the idiotype. They were just getting that non-specific immune stimulator and combine with again, the T-cells, which was supposed to be activated or amped up by this vaccine. And this whole treatment is done in the setting of high-dose melphalan and autologous stem cell transplant. So this is how we did it. So every patient who was enrolled in the trial would either go to the control arm or go to the idiotype arm. If you go to the idiotype vaccine arm, you get a vaccination, and about two weeks later, we will collect your T-cells. These are the cells of the immune system that are supposed to be activated by the vaccine, and then we would collect those T-cells and we will activate them in the laboratory. This approach has been used by University of Pennsylvania and has been published a few times in the context of other vaccinations like influenza and pneumonia vaccine. So we use that to basically activate T-cells against myeloma. Then patients had their high-dose melphalan and autologous transplant. And then two days after transplant, they got their T-cells, which were activated. Then they got two more booster vaccinations. If they were in the idiotype vaccine arm, they got two additional idiotype vaccines -  one month and three months after transplant. If they were in the control arm  same schedule - you get the vaccine, we collect your T-cells, you do the transplant and then we give you T-cells back, and then two booster vaccinations. So it sounds complex but everyone gets three vaccinations: vaccine, primed, or stimulated T-cells in the setting of an autologous transplant. And our hypothesis was that patients who will get the idiotype vaccine will have a more robust myeloma-specific response, myeloma-specific immune response which will translate into better overall response and a longer duration of remission.

Jenny: Okay. I think that’s terrific, and I think I want to ask some more questions about that. I don’t think I understand the difference between the two arms because you’re vaccinating people on both sides, right?

Dr. Qazilbash: Yes. Good question. So in order to show that we are getting a myeloma specific response, one group of patients are getting the idiotype which is taken from their myeloma protein, the other group of patients, the other half, the control half is not getting the idiotype. They are just getting a non-specific immune stimulator called KLH. It’s used but it’s a flu vaccine or whether it is a pneumonia vaccine or anthrax vaccine. So it’s a part of a number of vaccinations. So it’s just a non-specific stimulator of the immune system. It can activate anything but it won’t be a myeloma specific immune response. So we want to see the difference. If we do idiotype vaccine, we are going to see specifically anti-myeloma T-cells going up versus non-specifically all the cells going up but not particular enrichment of anti-myeloma T-cells.

Jenny: And now vaccine has been actually personalized for you as an individual patient.

Dr. Qazilbash: That is correct, and that’s its strength as well as weakness. Strength because it is personalized therapy. This is taken from patients own myeloma protein from their unique M spike, but the disadvantage is that it takes time to make that vaccine. So we have to collect it from each patient and then it takes two to three weeks to develop the vaccine and then it has to go through all the release testing to make sure that it fulfills all the criteria that yes, it is safe to be given to a patient.

Jenny: So if you have really fast-growing myeloma, is that going to be a problem?

Dr. Qazilbash: Yes. So in those type of situations, it may be, except that the way this particular trial was set up that patients were already getting their induction treatment while we were prepairing for the vaccine. So a newly diagnosed patient comes to us and let’s say this patient is receiving induction treatment with bortezomib, lenalidomide and dexamethasone, and we have collected there because this patient has to have an M spike for us to make the vaccine. So we would see them early. We would collect their blood to make their vaccine while the patients are getting the treatment. So we did not run into that problem. So when the patient has completed three cycles, the vaccine has already been made, and then they basically go and get the vaccine. But yes, in those rare situations where if you need to treat someone right away on this trial but the disease is progressing, then obviously, you would not want to wait just to make the vaccine. You would then go on and treat with something that can be given right away.

Jenny: But that’s probably going to be a pretty small portion if you already have patients that are starting in some kind of treatment already.

Dr. Qazilbash: Absolutely.

Jenny: So as part of the T-cell portion of this, I read that it was a CAR T-cell. Is that true? Because we’ve done other shows on CAR T-cells, and if so I have other questions for you about that.

Dr. Qazilbash: Right. No, a good question. No, these were not CAR T-cells. So the CAR T-cell that’s -- you have done the program. So those are genetically modified. Those are genetically engineered cells where through those manipulations, those cells are made to express a certain protein on their surface so they can go and bind to their target and kill them. These cells are not genetically modified. So these cells were collected from the patients after the patient has received the vaccination. So they’re supposed to be stimulated by that vaccine but they were not genetically modified. But they were manipulated in the laboratory, which is what approach that was developed by Dr. Carl June’s team that we would grow them in the presence of these beads which would activate them. They would grow and multiply and then we would give them back to the patient. So these were not CAR T-cells. These are antigen-specific or idiotype antigens restricted T-cells. They were not genetically modified, so they were not CAR T-cells.

Jenny: And the reason for using the T-cells is that T-cells from just what I’ve learned, and you can correct me, is that T-cells help kill things that are not supposed to be in your body. A lot of times, myeloma patients have a very weakened immune system. So by taking these T-cells out and expanding them, growing them up and then giving them back, you’re helping to reset what the patient may already have had before the myeloma, the stronger immune system, basically.

Dr. Qazilbash: Absolutely. So as you rightly pointed out, that vaccination itself -- so idiotype vaccine, although it’s personalized and patient-specific and it has been around for many years, but because of the inherant immunosuppression, patients are not able to mount an effective immune response. So this is basically a double whammy of combining two effective approaches that a vaccine stimulates their own immune system. And then when you take T cells which are part of that immune system and grow them to a very, very high number and activate them, then you give those back to the patients with these combined approach of immunization with a vaccine. And then giving these mega-doses of T-cells, you can effectively kill myeloma cells in a shorter period of time, and obviously, in a much higher number. So that is the whole idea of combining the two approaches so you can get a much higher cell kill in a much shorter period of time.

Jenny: Well, that’s a very nice strategy because I’ve heard other doctors talk about using vaccines in myeloma and they normally say, “Gosh, you can use vaccines but you have to have a pretty low tumor burden to have the vaccine work on its own.” It sounds like what you’re doing is combining it with something else and then doing transplant and giving it again.

Dr. Qazilbash: Absolutely. So we have like our first question that combining what we know and what works with some of the newer approaches because obviously, we’re still not curing most of our patients. So whatever we can get, whatever effective strategy that we can rationally combine them and get the maximum benefit, the better it is.

Jenny: I guess I want to just make a comment because I think a patient could go through a standard stem cell transplant and then they could go on to the standard drugs. But after you complete something like this, you can do that anyway. So I look at things like this and I’d say, “Why wouldn’t you join something like this to give yourself a step-up from what the traditional or the standard treatment therapy is?” I just think using some of the newer stuff in addition to what we know already works is kind of a no-brainer.

Dr. Qazilbash: Yes, and I think you are seeing that more and more people are encouraged to participate in clinical trials. Hence, you see these great publications telling us that ixazomib works or daratumumab works or elotuzumab works or the SAR antibody works. It’s because we know that there are all these things that can be incorporated in the existing treatment. As long as they are done safely and in a scientific way, we can learn from it and we will all come out as winners because we’ll have another effective treatment to improve the outcome.

Jenny: I agree. So why don’t you talk a little bit more about the trial? Is it currently open and is yours the only facility that’s doing it and how many patients are you looking for and who’s this trial for?

Dr. Qazilbash: Sure. So this particular trial, we just recently completed enrollment. So the trial was open at two facilities - MD Anderson and University of Pennsylvania. We treated 40 patients in total at the two centers, 30 of them at MD Anderson and 10 at University of Pennsylvania. All 40 patients have now completely their transplants as well as T-cells and vaccinations. In terms of who was eligible for the trial, it actually had a pretty open enrollment. So as long as someone had multiple myeloma up to age 70, they had to have an IgG monoclonal protein because this idiotype vaccine, the way the technology works is currently made from an IgG monoclonal protein. So if someone had IgA or IgM, they were not eligible. And also, because we are making vaccines from the idiotype or from the M-spike, so patients had to have an M-spike of at least 0.2 grams. So not very high but at least 0.2 grams for us to obtain enough protein to make the vaccine. So almost all newly diagnosed myeloma patient who had an IgG monoclonal spike and who are otherwise considered transplant-eligible up to 70 years of age were eligible for this trial.

Jenny: And now that it’s completed or the enrollment is completed, how long does it take for you to complete the study and then get the results and publish the results and create your next study?

Dr. Qazilbash: Absolutely. So we are actually in the process of gathering all the data both in terms of immune response, clinical response. And again, after treating 40 patients, we did not see any unexpected toxicity, unexpected in the sense nothing that you would see outside of high-dose melphalan. We did not see any immunological reactions or patients going to the intensive care unit because of the cell therapy toxicity. So no unexpected toxicities, no treatment-related deaths. In terms of responses because our follow-up is short but up to 90 to 180 days, we are seeing the degree of complete responses or the number of complete responses that one would expect. And again, with caution because the follow-up is short, we saw more complete responses in the idiotype arm than in the control arm. But again, after a short follow-up, also because patients also got high-dose melphalan, one cannot read too much into it. But my goal is, my hope is that by this year’s ASH, we would have the data to at least present it at the meeting and then put together a manuscript.

Jenny: And if someone says, “Gosh, it sounds really interesting. I want to join a trial similar to this or like this,” what would you recommend for them?

Dr. Qazilbash: Right. So the next generation of the study we are working on and what we may want to do is refine our vaccine, what we are working on is something that can be developed commercially, and there are a number of those approaches that we are working on with Dr. Kwak’s lab and others because as you heard, it takes a while to generate vaccine from each individual patient. So are there ways where you can get myeloma-specific proteins and they can be available at a very short notice? So if we have to modify it, we would do that and then combining it with the T-cell approaches. But there are a number of immunotherapy approaches that are available at different centers, like I said, that you’ve heard about the CAR T-cells, I’m sure you’ve heard from Dr. Borrello who will be featured on your program, the marrow-infiltrating lymphocytes. And then we, at MD Anderson, have our own CAR T-cell program both directed against CD19 as well as some other targets on myeloma and lymphoma cells. We have a program where we are using natural killer cells also part of the immune system which we are targeting against myeloma. So there are a number of different immunotherapy approaches that are available at major centers to treat myeloma and other blood cancers.

Jenny: Actually, we started the Myeloma Crowd Research Initiative, and I don’t know if you’re familiar with that, but we are actually helping to fund the research by Dr. Borrello, and also some CAR T-cell research in Germany of going after CS1 and BCMA.

Dr. Qazilbash: Of course we have always looked for funding. As you know research is expensive and very competitive. No, this is actually a great avenue and we’ll be exploring that as well.

Jenny: I guess with all these newly approved drugs and the list of things that are going on is just incredible. So how do you recommend the patients best understand their treatment choices? And how do they go about navigating the possibilities when there are so many different combinations?

Dr. Qazilbash: Sure, and this is obviously an important issue as you know and we, physicians, also know that it is, especially when you read so many things and there are news items and how do you filter what is important and where does this particular therapy fit. I think if possible, given the complexity of treatments and the wealth of options that are available, which is great, but how do I utilize them? Which one works best for me? Or where do I fit in this scheme of things? If possible, I think it would be important for everyone to see someone who specializes in treating myeloma because again, that’s not that we have some greater intelligence or endowment. It’s just that you spend more time in studying a disease or treating a group of patients. As a result, you are trained, you read, you learn, you interact more about that, so you get to develop a perspective. So if possible, see a myeloma specialist at cancer center that is closest to you. Even if you do not continue treatment there for obvious reasons of too far or you have to travel, but you do get some perspective, and most of us work with our colleagues in local cancer centers or clinics. And it’s a very good relationship which helps both ways. So that would be one thing if possible. Number two, of course, and I tell my patients and I give them all this information. There are great resources available like your site, and you know that there are a number of other websites or literature or support groups where patients can get to meet very well-informed and knowledgeable people who can provide very well-authenticated information that is very useful for the patients to navigate and negotiate. So I think these are a couple of important things, seeing a myeloma specialist where possible earlier in the course is good. And number two, to communicate or get information from authentic websites or resources and connect with a support group. I find them very helpful and very encouraging for my patients.

Jenny: Great. I completely agree when you talk about having a myeloma specialist in your corner. And for those who are listening that don’t have one, most patients or a lot of patients go to a myeloma specialist and they help kind of craft their treatment plan and then they go back to their local oncologist and get their local care. So they’re not traveling all the time but you get the benefit of having someone who truly understand this disease. And I just think it’s so incredibly complicated that there’s no way that their local oncologist can be as up-to-date as a myeloma specialist. I just don’t think it’s possible.

Dr. Qazilbash: Sure. And just to give you an example, here at MD Anderson, about half of my patients are from outside of Texas. We get patients from as far as Kuwait and Dubai and Saudi Arabia or Portugal or Venezuela to Wyoming or Oregon, and we work with our colleagues and all those settings and patients are completing their cycles and some of them come here for transplants, some don’t even do that but they work with their local oncologist. It’s a long-term relationship that we have and it works out very well. So yes, I think it would be really invaluable to have a myeloma specialist that you go to. And the earlier you go to the better it is because then you can basically jot out the plan.

Jenny: I agree. So now before we open it up to caller questions, which I would like to do, I would like to also ask you about kind of unrelated topic, but I guess related. You have an allo transplant and an ixazomib trial which is the new oral proteasome inhibitor for high-risk myeloma patients. So when are allo transplant strategies warranted for patients? And why ixazomib?

Dr. Qazilbash:. Great question. So as you know, allogeneic transplant has been used in myeloma for -- as long as myeloma has been treated with transplant for about 30 years or so. And as we know today, if there is one treatment that is potentially curative in myeloma, it is allogeneic transplant. There have been studies that have shown that after 10 years or 15 years or 20 years that patients were alive and disease-free without any treatment. So this is the positive side of the allogeneic transplant. But why it’s not being used? Why is it not so commonly used? Why aren’t more patients doing allogeneic transplant? Well, it’s because of its toxicity, because as opposed to an autologous transplant with melphalan, after an allogeneic transplant, unfortunately, 10% to 15% of patients can die in the first year not because of their disease but because of the complications from transplant, which is a significant number and those complications are graft-versus-host disease or serious infections because of immunocompromised or immunosuppression. So we have not been able to overcome those complications. So a number of trials have been done comparing allogeneic transplant with autologous transplant. And the bottom line is that although you see more relapses after autologous transplant, but because of high early death rate, the overall outcome remains the same. So because of that, allogeneic transplant is not considered a standard approach. It should only be used in the setting of a clinical trial, and this is whether you go to the NCCN guidelines or you listen to any myeloma expert they say that it may have a role but it’s not a well-defined role. It has to be done only in the setting of a clinical trial. So this trial is actually a national study. It’s a bone marrow transplant clinical trials network, and I think about 40 to 50 centers all over the United States are already enrolling patients on this study. So this trial is only for patients with high-risk myeloma based on cytogenetics and FISH study 17p deletion, 4;14, 14;16 plasma cell leukemia or patients who have an early relapse after their primary treatment, less than 18-month remission. So they, by all definition, are defined as high-risk patients with their overall survival of only two to three years. So it is designed for patients who are known high-risk, who have known to have, based on statistics, short survival. And if those patients have a donor, either a fully matched sibling or an unrelated donor in the registry, they are eligible. The hypothesis is that even in these patients with such high-risk disease, allogeneic transplant can potentially cure. And that’s what this trial is all about. Ixazomib or Ninlaro is incorporated in this because of two reasons. After the transplant, a percentage of patients still relapse. So what we are doing here is that for one year after allogeneic transplant, patients will continue to get ixazomib. It will be randomized. Half of them will get ixazomib, the other half won’t, and the hypothesis is that the ones who will get ixazomib will have a longer duration of remission and better overall outcome. The second thing about ixazomib is that it also, this group of drugs, also reduce the risk of graft-versus-host disease which is an immediate complication of allogeneic transplant. This has been shown with bortezomib. So again, extrapolating that to ixazomib, that’s the second potential benefit that it may also reduce graft-versus-host disease. So that in a nutshell is what this trial is. For high-risk patients with short-life expectancy will be eligible for this trial.

Jenny: Interesting. As I understand, I heard from another doctor that the proteasome inhibitors might be great for induction and maintenance therapy for Deletion 17, specifically. So that’s a nice addition.

Dr. Qazilbash: At this point, for high-risk patients, the only treatment that has made a difference is a proteasome inhibitor and the study from the Hovon group from the Dutch-Belgian group where they used bortezomib as maintenance showed that their patients with 17p deletion had similar outcome as the ones without that. But again, we need more data and more trials to show that and confirm that.

Jenny: Well, that’s great to hear. Well, I do want to open it up for some caller questions. So if you have a question for Dr. Qazilbash, please call 347-637-2631 and press 1 on your keypad. We will start with our first caller, go ahead with your question.

Caller: Hi, good afternoon, doctor. We follow each other on Twitter, so it’s by the way nice to actually meet and speak to you.

Dr. Qazilbash: Yes, my pleasure.

Caller: Yes. Thank you, sir. I have a question. I understand myeloma patients don’t typically have robust responses to the traditional vaccines like the flu or the pneumonia vaccines. So I think that means that they don’t elicit an antibody response, which I guess would be a B-cell response. Is my understanding that the vaccine that you’re using doesn’t rely upon that B-cell response, that antibody response. It’s looking to elicit a T-cell response? Would it really matter if myeloma patients actually have that limited response to traditional vaccines?

Dr. Qazilbash: Right. Very good question. Yes, this vaccine should elicit both B and T-cell response but since we know that cancer patients, in general, and myeloma patients, in particular because after all B-cells or plasma cells are part of the immune system, are unable to mount that robust immune response. So yes, we do expect some immune response but that’s why we are also using these T-cells which are derived from these patients and activating them, growing them, making them more powerful by stimulating them in the laboratory and giving them back. So we are not just relying on the vaccine for this exact reason that patient themselves are unable to mount a robust immune response.

Caller: Okay. That was very good to hear because even I myself, I’m a smoldering myeloma patient and already I’m not seeing much of a response to the annual flu or the pneumonia vaccine. So I’m interested in listening to what you have to say. That’s great that you guys are working around the limitations that myeloma presents the patients. I appreciate that. I know that these trials are for newly diagnosed myeloma patients, and you did state that you felt it was best to really approach the disease as early as possible. And I realize again, this is in the realm of the newly diagnosed myeloma patients. But doctor, what about as early as smoldering patients? Can we have hope down the road that something like this will come along for us? And again, I realize we’re talking stem cell transplants and that’s certainly not something that many of you or your colleagues would introduce in the smoldering population, but what do you see in store for us along these lines?

Dr. Qazilbash: It’s an excellent question. As you know, there have been a great interest in treating smoldering patients because in the beginning, I said that if one has to cure cancer, and we take the example of breast cancer or ovarian cancer, you hear that early detection is the way to achieve a cure. You diagnose them early and treat them aggressively and get the best possible outcome. So using that paradigm, people are looking at treating smoldering myeloma. So here at MD Anderson, we had a trial for smoldering myeloma patients with vaccination. In fact, this is one of the areas where vaccination approaches exist. As I see the role of vaccine per se without T-cells or without CAR T-cells, the best places where one can use the vaccine is when you have a very low volume of disease where you allow the immune system to grow and go after the tumor and there is no overwhelming disease burden to overcome. So smoldering myeloma post-treatment in the maintenance setting, those are the kind of settings where vaccines and immunotherapies can play a big role. So yes, there are centers that are already doing vaccination approaches for smoldering myeloma. On that, there are many places and many of you, since you’re also knowledgeable and well-informed, are probably aware that there are many centers that are doing clinical trials for high-risk smoldering myeloma and some of them of course in other smoldering myeloma patients as well. Again, trying to achieve a cure at the earliest possible disease manifestation.

Caller: Your colleague, Dr. Orlowski, when Jenny interviewed him a bit ago, I asked him what his dream trial would be for a smoldering myeloma patient taking into account, the available drugs right now, in other words, the monoclonal antibodies and things of that nature. He indicated that he, down the road, would love to see a monoclonal antibody cocktail of sorts - mixing and matching all of the ones that are out there. Obviously, the smoldering myeloma patient community gets excited when we hear things of this nature, and he did mention that he was going to be -- or actually, MD Anderson, was going to be working with the CD38 antibody by Sanofi, the Isatuximab, because I know that there are many centers that are involved in the daratumumab. But from what I’m learning and understanding is that each of these antibodies, although they go after the CD38 I guess protein or the antibody on the actual myeloma cells, they’re actually still different in the way that they are, I guess killing the myeloma cell. So the whole idea of an antibody cocktail sounds really intriguing, and I’m just delighted to know that you and your colleagues just really take such an interest in the myeloma community and are really looking for curative approaches. It gives us a lot of hope.

Dr. Qazilbash: Thank you. It’s of course an exciting time because we have so many tools available. I mean there are of course people who have been trying to do that for years, many of our mentors, but it’s just we did not have those medications. And when I review for publication purposes, some of our historic patients, it’s just sad that we had just the three or four chemotherapy drugs and you would just modify them and try a different combination and knowing fully well that we reached that point where not much is going to happen. So compared to that, yes, we have now so many different options and so many different things to explore and combine them together and use them in sequence. So yes, this is a great time to be treating myeloma.

Caller: And from a patient’s standpoint, when I first started trying to learn about this disease, I came across a lot of old of course videos and interviews and articles that indicated that the cure is right around the corner, and I think, “Gee. Well, they’re saying that from ten years ago.” And it worries me to hear that the cure is right around the corner now, but I’m thinking that I should have more hope in believing that statement is actually attainable with all of the changes now.

Dr. Qazilbash: No, I totally agree that you can just look at the statistics of life expectancy. So when I was a fellow in the early 1990s doing my hematology oncology fellowship, you could pick up any textbook of hematology oncology and it would say that multiple myeloma, an incurable disease with overall survival is about three years, patients are treated with melphalan and prednisone. About 40% patients respond, less than 10% achieve a complete remission, and as I said, life expectancy was about three years. Today, although no one is talking about cure but if you take an average myeloma patient with standard risk disease, before this advent of four new drugs in the last three months or so, the general consensus based on the available data is that the life expectancy for a standard risk myeloma patient is close to a decade and only to get better. So yes, we are making great progress maybe because we have better understanding of the disease, availability of so many different treatments and in a creative, intelligent way combining and utilizing them through the maximum benefit.

Caller: Well, that’s terrific. We support clinical trials within our own Facebook groups. We have them for every stage. We have them for MGUS patients and smoldering patients and we encourage people to get involved. We’re encouraging within those groups for patients to become involved in Dr. Ghobrial’s P-Crowd study where she’s doing the perspective study of just serum samples and bone marrow samples. Patients can actually just mail them to her and this opened up a whole new avenue for patients to really start becoming excited about joining these clinical trials, because it’s an observational trial but it’s still a trial. So if we could kind of generate the interest at that level, it’s really a terrific thing to really have people just become excited about it.

Dr. Qazilbash: Absolutely.

Caller: It was really a pleasure speaking to you today, sir, and thank you so very, very much for your time. And Jenny, thanks for taking my call.

Jenny: Oh, thank you very much for your questions. We have another caller. Go ahead with your question.

Caller: Hi. Thanks for taking my call, doctor. I just wanted to know if vaccines work for high-risk myeloma patients.

Dr. Qazilbash: Sure. Thank you, ma’am. Good question. So one of the things about immunotherapy, again, we will find out as more and more clinical trial data come out. But one thing about immunotherapy, and you will be hearing this term a lot that whether it is antibodies, whether it’s vaccines or T-cells, they say that these are risk-agnostic. Meaning that when you’re using immunotherapy, they are not going after any particular gene or protein where some cells are more resistant, the ones which have high-risk chromosomal abnormalities like 17p deletion or something. When you’re using the immune system, the immune system does not differentiate between the cell with high-risk abnormality and the cell with low-risk abnormality. So based on that, the general impression is that with immunotherapy, we may be able to overcome this resistance of high-risk myeloma. So that’s my hope and that’s the hypothesis, and we will find out. But yes, the simple answer is that we see a lot of promise in immunotherapeutic approaches in overcoming these high-risk features.

Caller: Thank you. Thanks so much.

Jenny: Thank you so much for your question. Dr. Qazilbash, we’re so grateful. We’re over our time but we’re still thankful that you joined us today. We’re so appreciative for your wonderful research and efforts for myeloma patients and we look forward to your next trial opening about this immunotherapy/transplant approaches, and we’re just grateful for all you do.

Dr. Qazilbash: Thank you very much. I really enjoyed it and I really appreciate this opportunity.

Jenny: Well, keep going, keeping those transplant patients doing great and continue your work in immunotherapy area. We’re excited to see what you’ll come up with.

Dr. Qazilbash: Sure. Thank you very much for your encouragement and have a good evening.

Jenny: All right. Okay, thank you so much. Thank you for listening to another episode of “Innovation in Myeloma”. We believe that myeloma patients can become involved to learn more and help drive to a cure.