Tell your musician friends to donate a song today on Songs For Life to help raise funds for multiple myeloma research! Dr. Sarah Holstein, MD, PhD, Roswell Park Cancer Institute Interview Date: September 19, 2014

 Dr. Sarah Holstein describes a very exciting new immunotherapy that will open in a Phase I/II clinical trial shortly. This new drug called ALT-803 by Altor Bioscience was listed as one of the most exciting immunotherapy choices according to the NCI. In experiments in mice, it changed the immune system to kill myeloma cells and then trained the immune system with a memory to continue attacking it, even when more myeloma cells were injected. Dr. Holstein shares the details of how this new therapy works. She also discusses her research to "choke" myeloma cells with their own product by leveraging the secretory nature of myeloma (the production of the M-spike). Additionally, she shares three strategies to overcome bortezomib resistance - 1) using HDAC inhibitors, 2)Using new heat shock proteins and 3) Manipulating the bone marrow microenvironment. There is much to learn in this excellent show. The live mPatient Myeloma Radio podcast with Dr. Sarah Holstein, MD, PhD,

Jenny: Welcome to today's episode of mPatient Myeloma Radio, a show that connects patients with myeloma researchers. I'm your host, Jenny Ahlstrom. If you like to receive a weekly email about past and upcoming interviews, you can subscribe to our mPatient Minute newsletter on the homepage or follow us there on Facebook or Twitter and please share these interviews with your myeloma friends. Before we get started with today's show, I'd like to tell you about a couple initiatives that are going on for myeloma. Dana Holmes, a myeloma patient, has launched a dance initiative for myeloma research called Mambo for Myeloma. So you can dance, take a video of your dance, upload it to the Mambo for Myeloma Facebook page, and then donate to any of the foundations supporting myeloma research. I also wanted to let you know about a new music contest that our organization has initiated, called the CrowdCare Foundation, it's called "Songs for Life", and it's a new way that we're raising funds for myeloma research. Artists donate their inspiring original cover songs on songsforlife.org website, they share your entry, and the top 20 are reviewed by a music judging panel that includes famous musicians like ThePianoGuys and Jessie Funk and some others. And then that will be turned into a Songs For Life 2015 album that will be sold and all proceeds will go to myeloma research. Now on to today's show. We are very fortunate to have with us today, a researcher and clinician who as Dr. McCarthy told us may be doing work to blow up myeloma cells and she will have to describe that in a little more detail but she has a lot of exciting things to tell us about. So welcome, Dr. Holstein, to today's show.

Dr. Holstein: Thank you very much.

Jenny: Let me give a little background on you for a minute. Sarah Holstein completed her medical school, graduate school, internal medicine residency and hematology-oncology fellowship at the University of Iowa. She joined the faculty in the Division of Hematology, Oncology, Blood and Marrow Transplantation at the University of Iowa in 2010. In 2014 she joined the Lymphoma/Myeloma division at Roswell Park Cancer Institute where she specializes in the treatment of multiple myeloma. Her basic, translational, and clinical research efforts are focused on myeloma. She has published over 25 peer-reviewed articles as well as multiple review articles and book chapters. Her laboratory is currently funded by the NCI and the American Society of Hematology and has previously received funding from the PhRMA Foundation and Carver Charitable Trust. She is a member of the Alliance Myeloma Committee. So welcome again, Dr. Holstein, and maybe we can start by just giving us a little bit of background of how you got interested in myeloma work.

Dr. Holstein: Sure! Well again, I really want to thank you for giving me this opportunity to speak with you today. I think my interest in myeloma began when I was a resident doing internal medicine and we were doing rotations and I got to meet a couple of patients with myeloma. And at that time, there were very few treatment options and I was really amazed by how much damage myeloma could do to a person. So I saw people in kidney failure and with broken bones and I was a little bit dismayed about the relative lack of treatment options. And then a few years later, when I actually went to my hematology-oncology fellowship, I was pleasantly surprised to learn that just in a few years, several drugs have been approved and that patients were doing much better. Given my background in Pharmacology for my graduate degree, I thought that this really seemed like a clinical field where there was a lot of room for pharmacology to improve things. And during my fellowship, I made sure that I focused on seeing as many myeloma patients as I could. I did a research fellowship as part of my clinical fellowship and during that time, I started my research project in the field of myeloma. And as I was finishing up my fellowship, it seemed clear to me that the most rewarding thing for me to do would be to continue to pursue both clinical treatment of myeloma and also basic research because I really think that seeing patients every day with myeloma reminds me how important the basic research is to improve their lives.

Jenny: And what a unique perspective it gives you to be doing both.

Dr. Holstein: Absolutely. I often tell people who are thinking about rotating in my lab that although they might not see me as much as some of my peers who are PhD only and get to be in the lab 100% of the time, that again, I think I bring a different perspective in seeing these patients and sometimes the somewhat petty annoyances in lab when things aren't going right become less important when, again, I think about the problems my patients are facing.

Jenny: That's a nice connection. Now I saw a video that you did where you were giving an overview of how we can overcome myeloma resistance. Would you like to start out by just talking in general about strategies that are being used right now to overcome myeloma resistance? And then we'll get into some more detailed studies.

Dr. Holstein: Sure. So myeloma resistance is an extraordinarily complex topic and problem. Myeloma cells are very smart and there are some inherent properties that make them resistant to drugs and then they figure out how to become resistant to drugs once you expose them to drugs. So right now there's a lot of basic science and also clinical research going on and there are a couple different approaches being taken. One is to try to understand the mechanisms by which myeloma cells become resistant to particular drugs. So for example, with the proteasome inhibitors, there appear to be changes that occur in cells which might be able to be combatted by other drugs such as the histone deacetylase inhibitors; so for example, the panobinostat combination with Velcade. There are other approaches that are being taken such as heat shock protein inhibitors. Those two classes of drugs are really meant to target proteasome inhibitor-mediated resistance. Globally, other approaches that are being used are meant to target the interaction between myeloma cells and the bone marrow microenvironment so myeloma cells are heavily dependent on the bone marrow microenvironment for cell growth. So these bone marrow cells secrete substances which help the myeloma cells grow and help protect them against drugs. The adherence of myeloma cells to the bone marrow microenvironment also protect the myeloma cells and so some of the things that are being investigated are ways to interfere with the ability of #1, myeloma cells to adhere to a bone marrow environment; or #2, the interaction based on factors between the bone marrow microenvironment and myeloma cells.

Jenny: Okay. It sounds like those are maybe two totally different ways of approaching it so maybe we start by talking about the proteasome inhibitor. So if someone becomes resistant to Velcade, you're saying that there are multiple ways of trying to overcome that Velcade resistance. So one is using the HDAC inhibitors, which we've heard about a little bit, and the other is the heat shock protein inhibitors. So can you explain what these heat shock protein inhibitors are and how they work and what they do.

Dr. Holstein: I will try. I think we probably don't understand all of it because as of all these inhibitors, they do many, many things in the cells. But I think the general gist with heat shock proteins is that first of all, these are chaperone proteins that are meant to help newly-synthesized proteins fold into the right shapes and, in some cases, get to where they need to be. The heat shock protein 90 or Hsp90 has been particularly targeted because it helps chaperone or fold some variety of important protein in the cells that have a lot of different properties, some of which have to do with cell growth or sensitivity to cell death pathways. And so there have been inhibitors developed which target this Hsp90 and they do induce cell death in myeloma cells. They've also been tested in some other cancers as well. There has been some very interesting preclinical work showing that you can improve cell killing induced by bortezomib if you add a heat shock protein inhibitor and also in some cases, you can overcome resistance to bortezomib by adding the heat shock protein inhibitor. There have subsequently been some initial clinical trials done with heat shock protein inhibitors and there seems to be some activity there. How exactly the heat shock protein inhibitors are reversing bortezomib resistance I don't think is completely understood at this point. In part, it's thought that one of the mechanisms or one of the actions that bortezomib does -- and I know this is a little bit counter-intuitive -- is that it actually increases the stability of sub-units of the proteasome. And so that even though you're inhibiting the proteasome with bortezomib, any sub-units that are out there are thought to be more likely to try to form an active proteasome and therefore try to prevent the toxic effect of bortezomib. This stability is thought to be, in part, mediated by the heat shock protein. And so if you block both the proteasome with bortezomib and then also block the ability of the newly-synthesized protein to fold properly, then you might make cells more sensitive to the proteasome inhibition.

Jenny: Okay, that makes sense. It's like a dual-strategy because one is only working partway.

Dr. Holstein: Correct. And that's just one hypothesis.

Jenny: Right. And how is this discovered?

Dr. Holstein: I can't claim any credit for it. This has been done in multiple labs and there has been a lot of interest in trying to figure out why people become resistant to bortezomib and there doesn't seem to be one straight answer. But really interesting: heat shock protein has probably been around for more than a decade now but how exactly we apply it to myeloma in specific and to oncology in general is still being developed.

Jenny: And you said it was in some early studies, is there a myeloma-specific study that's open right now looking at that?

Dr. Holstein: I don't know the answer to that. I know that one of the earlier generation heat shock protein inhibitors, an early phase study was completed with bortezomib. I have not gone on clinicaltrials.org recently to see if there are newer versions of the Hsp90 inhibitors available.

Jenny: Okay. And is this what Dr. McCarthy was talking about when he said you were working on blowing up myeloma cells?

Dr. Holstein: No, that gets more to what my more focus is in the laboratory which is -- although I have published some with looking at Hsp90 inhibitors in combination -- the major focus of my lab has to do with targeting a different pathway and I think that's what he was referring to with the comment about the blowing up the myeloma cells.

Jenny: Okay. Well, maybe you want to talk about that next.

Dr. Holstein: Sure, always happy to do that. So my interest for quite some time has been in a pathway that all cells have and it's called the isoprenoid biosynthetic pathway but most people know about it because it's also referred to as the cholesterol biosynthetic pathway. So it's how cells make cholesterol and sterols. But that's really only part of the pathway. This pathway also makes isoprenoids which are carbon chains and these are important for a variety of reasons but at least with respect to what I do, they're important because some proteins get modified by these isoprenoid chains. So some proteins actually become labeled with these chains of carbons at the tail-end of the protein and this little chain of carbons actually makes the proteins go to the right place in the cells and behave properly. And so this modification is called prenylation and more specifically, there's two major types: farnesylation and geranylgeranylation. I know the latter is a mouthful to say. There are a particular type of prenylated proteins that I have interest in and those proteins are called the Rab proteins. They play very important roles in helping cells mediate vesicle trafficking. So within the cell, there's trafficking between organelles and all of that is mediated by this Rab proteins. In order for these Rab proteins to be functional, they have to have that carbon chain attached to them. So if you block the enzyme that attaches that carbon chain to the Rab proteins, they no longer are functional. My idea was that since myeloma cells depend so much on protein synthesis and secretion of protein, namely the antibodies that myeloma cells make, that we could target these Rab proteins and essentially shut down secretion of the antibodies or the monoclonal protein and essentially choke the myeloma cells with their own product. And so I think when Dr. McCarthy was talking about blowing up the cells, he was talking about the fact that what we're attempting to do is really shut off the secretion process and what happens is that this protein keeps building up and building up within the cell and leads to cell death.

Jenny: That makes sense. Now where are you in this process?

Dr. Holstein: So what we've done so far is look at a variety of different ways to target these proteins using drugs and kind of prove our hypothesis. So we've shown that using drugs which target the isoprenoid pathway at several points, that we disrupt the Rabs, that we do increase this antibody or this monoclonal protein within the myeloma cells that this induces something called ER stress where the cell becomes stressed and that in fact, this induces cell death. So we've kind of proven each step of our model there. And then at the same time, I am collaborating with a chemist from the University of Iowa and we are trying to come up with new compounds that specifically target the Rabs with the thought that perhaps one day, these will be able to be used in the clinic. So right now we're working on trying to fine-tune the chemical structures and trying to figure out which chemical structures yield the best activity in the myeloma cells.

Jenny: And is there anything that exists today that you can draw from or you're creating with this chemist brand new compounds?

Dr. Holstein: We're creating brand new compounds. So it turns out that the enzyme that adds this carbon chain to the Rab proteins is a little bit more complex than the other enzymes that are in the family. And instead of using strategies to make inhibitors that look like the protein substrate, we have to make inhibitors that look like the carbon chain substrate. And this is really an approach that hasn't been used before to target this enzyme in general. There hasn't been a whole lot of interest in targeting this particular enzyme for clinical purposes so there's really not much out there in the literature. There are a few examples of some compounds that have been made but so far none of those compounds are probably specific or potent enough yet to be taken into the clinic. So our hope is to rationally design compounds using computer modeling in part to come up with drugs that could potentially be used to treat myeloma.

Jenny: Well, it sounds like you're working on essentially a brand new idea.

Dr. Holstein: Certainly targeting this enzyme is a brand new idea and we're very excited about it. Just like the proteasome inhibitors, it takes advantage of the myeloma cells' natural function, which is that they're highly-secretory. So one of the reasons that the proteasome inhibitors work so well in myeloma is because, again, these cells produce so much protein that they need to be able to get rid of abnormal protein. And so just like with the idea with the proteasome inhibitors, we're really trying to target a process in myeloma that's completely intrinsic to the myeloma cells. They are plasma cells at heart but we're just doing it in a completely new way.

Jenny: And it sounds like it might be a really effective way to use it against itself basically.

Dr. Holstein: That's what we hope. We're certainly nowhere close, unfortunately, to be able to give it to a patient yet but we're working as hard as we can to come up with new compounds and at the same time, to continue to try to figure out in addition to affecting just the protein secretion, what other pathways are affected by these drugs. So some of our preliminary data suggests that not only might these drugs be effective because they're blocking the secretion of this protein but they might also be doing other things. For example, they appear to block the ability of the myeloma cells to adhere to bone marrow stromal cells so that could be another important mechanism of action for them because, again, it's so important for the myeloma cells to stick to the bone marrow stromal cells.

Jenny: And just a general question about innovation. When you have ideas like this, how long does it typically take to create something in the lab, this brand new idea that hasn't existed before, or maybe some small research has been done on it, and take it where you have a drug? I know that's a very loaded question.

Dr. Holstein: I think on average at least ten years and I think most people working in academics would say that it's very difficult to truly go completely from bench to patient by themselves. I think what happens most of the time with… so if we identify a compound that truly has activity, the quickest way to get it to patients at some point will be to partner with somebody in pharma. But if I were to try to personally take this from my bench to patients, the timeline would be even longer.

Jenny: Now we talked a little bit with Dr. Bradner about that process and it doesn't sound like an easy one.

Dr. Holstein: No, it's an uphill battle and I'm sure you've heard the statistics about how few drugs make it through the pipeline but I guess all we can do is to continue to try.

Jenny:  Well, keep going. We'd love that. Okay. So let's go back a little bit and talk about the bone marrow microenvironment because I know we want to talk about an immunotherapy as well and I want to be able to get to everything. But the bone marrow microenvironment seems to be a really interesting target now. People are understanding it more so could you give us an overview or your thoughts on how you're working to shut that down?

Dr. Holstein: So again, as a brief overview, the bone marrow microenvironment is incredibly complex so there are multiple different cell types that the myeloma cells interact with. And again, in some cases, the bone marrow is actually providing a niche which fosters the myeloma cell growth. In other cases, the myeloma cell is altering. So for example, in the case of bone remodeling, the myeloma cells directly altering how bone cells work. Some of our currently available drugs, namely the IMiDs -- so thalidomide, lenalidomide, pomalidomide -- are thought to disrupt in a variety of ways the interaction of the myeloma cell with other immune cells and with other cells in the bone marrow. But there are currently a variety of other strategies under investigation, some of which have to do with targeting some of the secreted factors that the bone marrow makes which helps the myeloma cells grow. So for example, in clinical trials, there's been an interest in an antibody which targets IL-6 which is a very important growth factor which is secreted by the stromal cells which helps the myeloma cells grow. In other cases, there's been interest in trying to target the adhesion process and again, more immunology-based is simply ways to try to increase the ability of the immune system to fight off the myeloma cells to recognize the myeloma cells as foreign and kill them. So there's really multiple different ways that are being studied right now.

Jenny: And where is your focus mostly?

Dr. Holstein: I would say that my primary focus right now is still myeloma cell-based. My personal laboratory work is less immunology-based and more myeloma cell- and pharmacology-based right now. But my clinical interest does encompass the immunology-based and one of the things that I've done since I've moved to Roswell Park is worked to open a clinical trial which involves a new drug which really is immunology-based. And I thought this would be a really good fit for Roswell Park because Roswell Park has such a strong immunology program, in fact, headed by our other myeloma physician, Dr. Kelvin Lee. I didn't know if you want to talk about the…

Jenny: Let's go ahead and you can describe what that is. So let me just give a little set up, because when you mentioned it that we might want to talk about it today, I started doing a little bit of research. And this is the ALT-803, right, that we're going to talk about?

Dr. Holstein: Yes, ALT-803.

Jenny: ALT-803. So in the NCI review, they said they listed it as THE most promising product candidate among 12 immunotherapy drugs. So everyone should perk up to listen to what you have to say about this. So can you explain what it is and how it works and what your plan is?

Dr. Holstein: So this particular study will be the first one done in patients with myeloma and this is a pharma-sponsored study. But basically, ALT-803 is a brand new drug which is based on Il-15. So IL-15 is a substance that our body makes and it's part of our normal immune system and it helps to activate both our effector and memory T-cells and also our NK cells. And so this is thought to be one of the mechanisms by which the immune system is protective against cancer cells. And the idea is if we could really ramp up the activity of the IL-15, we could really increase the activity of our own immune cells to recognize and kill the myeloma cells. So what this company has done is they have modified this IL-15 and basically I refer to it sometimes as a super agonist so they've made this IL-15 more active than the normal IL-15 and they've done some things to also modify its half-life so that you can give it as a drug and it can stick around in your system for a while and actually do some good. So ALT-803 is a modified version of IL-15. The preclinical work that has been done with this drug, I think is extraordinarily exciting and that's in part why I really wanted to see what it can do in our myeloma patient population. So in a mouse model of myeloma where they take mice and essentially infect them with myeloma cells and then they develop myeloma; just one dose alone killed off about 90% of the myeloma cells after four days, so that's a very impressive cell killing. And then when they took mice and gave them just two doses spaced a week apart, they found that more than 80% of the mice were still alive 190 days out as opposed to if the mice have been injected with the myeloma cells and didn't get the drug, all the mice were dead by basically 28 days. So this is a very impressive result. I think the most impressive bit of pre-clinical data is the fact that they took the surviving mice who had gotten the drugs and who had lived and three months later, they reinjected the cancer cells but they didn't give them any more drug. And just reinjecting the cancer cells alone, these mice, even though they didn't have any more drug, were able to fight off the cancer cells and they were still alive after six months. And again, if you just take mice who had never gotten the drug and inject them with cells, they'd be essentially dead within about a month. So why this is so exciting is that it means that this drug has changed the immune system and essentially given the immune system a memory so that even in the absence of giving more drug, this immune system has now learned to recognize the myeloma cells as bad and to kill them. So we're really, really excited to try to see if this drug is effective in patients with myeloma. And so the study that will be conducted at both our site and a few other sites across the country will be a traditional Phase 1 study where we figure out what the dose is and then a Phase 2 portion where we treat more patients with the dose that was determined in the Phase 1 portion. And in addition to looking at the usual things like what the response rate is and how long our patients live before they progress, the study is also doing a number of blood samples where they're going to look to see how effective this drug is in changing the immune system so they’ll be looking at levels in the blood that relate to activation of the immune system.

Jenny: Okay. And a little more detail about that trial, so who will be invited to join that phase 1 trial?

Dr. Holstein: So the inclusion criteria are basically anybody who has active myeloma who's had at least two prior treatments. I think they do count induction transplant as one treatment or it can be just two separate treatments. And so that's also another nice thing about the study. Sometimes with our relapsed refractory trials, we restrict the trials to patients who have been very heavily pre-treated -- 4, 5, 6 prior treatments. Here, you can have had a relatively few number of treatments and still have access to this drug.

Jenny: That's very exciting. And then how many patients? I know phase 1 trials are typically small so how many patients will you be looking for in these four different sites and at Roswell Park?

Dr. Holstein: At Roswell Park, I think we hope -- so certainly as many patients as I can get, I think. I promised our institution that we would get at least two patients within the first year. The number of patients in the phase 1 portion will really depend on how many dose levels are needed. So in general, 3 to 6 patients per dose level with the understanding that if you got a couple dose levels in and suddenly there was toxicity that you won't go above that dose level. I think the phase 2 portion then, about 19 more patients then will be enrolled during the phase 2 portion.

Jenny: And then when do you expect it to be open?

Dr. Holstein: At Roswell Park, we are doing our site initiation visit in just about two weeks from now and my hope would be that then about 2 to 4 weeks after that, we could open it. My understanding is that we might be the first center to have the study open. Again, I think it's going to be conducted in about 4 or 5 different sites across the county. So this drug has been tested in humans. Our study won't be the first in human but it will be the first in myeloma. But there is also a study going on right now not at our institution but looking at this drug for patients with a variety of hematological cancers who have relapsed after an allogeneic transplant. Again, since this drug is affecting the immune system, I think it's going to have activity in not only myeloma but in other immune-based malignancies.

Jenny: So what other cancers has it been used in? Leukemias, lymphomas, both or just one?

Dr. Holstein: So again, this is a very new drug so the only clinical in-human patient experience right now is the study that's being conducted in the post-allogeneic setting. And because it's not being conducted at my center, I can't really give you specifics about whether it's been leukemia or lymphoma patients who have been enrolled.

Jenny: And as immunotherapies, I think the hope for patients is that immunotherapies will be… I guess not free of side effects but significantly-reduced side effects. So has there been anything published about any side effect it might have, because this sounds like a really exciting opportunity.

Dr. Holstein: So what we know is there is a bit of a reaction when you first get the drug. But that unlike some other drugs, so for example, IL-2 which is used in some other cancers. When you give it, the patients have fevers, they can drop their blood pressure, they can get very sick because the immune system gets so ramped up. The experience with ALT-803 so far is that it's a much less severe reaction. They do, as part of their protocol, administer some pre-medications to kind of quiet down the immune system a little bit. But what I've been told so far is that it's very tolerable and that once you get past the initial 24 hours, that patients are not really reporting side effects. But again, it's still very, very early in clinical development at this point.

Jenny: And it's probably too early to ask this question but I know that immunotherapies like daratumumab and the new SAR Sanofi drug are coming out. How does this compare to those, and as a more complicated question or to muddy the waters, I guess, once you test for safety and all that and you see it working -- could you ever combine like an anti-CD38 immunotherapy with something like this? Will they be able to do that?

Dr. Holstein: I think that's a great question. I think that absolutely there's reason to think about drug combination with this type of approach. I think what we've learned about myeloma is that there is no magic bullet and that we need to combat the disease by many different routes and that combination therapy is almost always better than single agent therapy. So which particular agent to pair with this new drug, I can't say. I know that there is interest in pre-clinical data to support the thought of using a combination of an IMiD with this new drug but certainly I think it would also be very reasonable to think about using it in combination with a monoclonal antibody.

Jenny: And then just a question. I know in talking to some myeloma specialists, especially about vaccines, they just say that vaccines are best used when the tumor burden is really low. So if your study is for relapsed/refractory patients, do you look at tumor burden at all? You're just going to try it in everyone and was there a difference when you tested it in the mice with the level of tumor? Or just it worked with everybody, it worked with all of them?

Dr. Holstein: Because all these preclinical testing was done not by me but by the drug company that's sponsoring the trial so I don't think I can answer that question. It's certainly an excellent question. I think that you certainly do need the presence of tumors and that is certainly one of the criteria. You need to have evidence of active disease so we aren't going to take somebody who's in remission and then use this drug. So I do agree that it's similar to a vaccine -- you do need to have some disease present. Having said that, though, I think unlike a vaccine, I think this compound is going to be more likely to be able to handle a larger amount of tumor. Again, with the mice studies, they injected a fairly good amount of cells and this drug didn't have any problem handling those cells.

Jenny: Well, I think what's really so exciting about that is what you said before: not only is it affecting the myeloma to kill the myeloma, then it's affecting it from ever coming back again which is so exciting.

Dr. Holstein: You're right. Again, I think they are extraordinarily exciting preclinical. Whether it translates to humans, I will keep my fingers crossed. But I think it's one of the few approaches that I've seen so far which might truly be changing our immune system and allowing long-lasting activity and it might potentially mean that we don't need to keep re-dosing this drug which I think would be really exciting.

Jenny: Yeah, very exciting to think you are actually cancer-free. You know when Dr. Palumbo was doing his interview, he made a comment that even if you're MRD negative, you still have residual disease. So when we're talking earlier about outsmarting myeloma resistance, what other ways are you looking at to completely eliminate it so there's no trace left, it's not hiding anywhere.

Dr. Holstein: I think that's an excellent question and probably one of the key questions because, as you just said, no matter what we do, whether it's autologous stem cell transplant with great drugs before and after, even when we are MRD negative, we know the disease is still lurking there somewhere. I'm not sure that I'm smart enough to figure that out on my own but what I'm trying to do is just learn as much as possible about the disease and about what everybody else is doing with the disease to try to figure out what the best approach will be.

Jenny: Well, I've seen a lot of collaboration between the myeloma specialists. It seems to be a really nice community of doctors that work really well together.

Dr. Holstein: Yes, you're absolutely right. It truly has to be a collaborative effort and the more each of us knows, the more the group knows. And again, at the end of the day, what we really care about is coming up with new treatment strategies for our patients and the only way we're going to do that is as a group.

Jenny: Well, I agree, and hopefully, with patient support. We would like to help you do what you need to do.

Dr. Holstein: That would be fantastic.

Jenny: Are there any other trials that you would like to talk about at Roswell Park in myeloma?

Dr. Holstein: Yeah, so I can just briefly highlight what we have. So we are taking part in the DETERMINATION trial which is being led by the Dana-Farber in conjunction with the IFM in France and I think this is a critically-important trial. So very briefly, this trial is asking the question for the newly-diagnosed transplant-eligible patients whether you need to do the transplant upfront, meaning after a few rounds of chemotherapy, or whether it's just as good in terms of long-term outcome to do the transplant after you first relapse. And so we're very excited to be taking part in the study because this is a question that every single one of my transplant-eligible patients asks me about. They want to know, "Do I really need to do the transplant right now?" And I think the study is really going to help us answer that question. The other study that we have open right now is a study for the transplant-ineligible population. And so this is a study for older patients with newly-diagnosed disease and it is looking at the combination of Lenalidomide and Dexamethasone with or without Ixazomib which is the oral proteasome inhibitor. And so it's a placebo-controlled trial and I think this is very exciting trial because based on the first trial which was just published a week or so ago in the New England Journal, I think many of us think that Lenalidomide and Dexamethasone is one of the standards of care for newly-diagnosed older patients and whether or not we could add an oral proteasome inhibitor and improve things even more, I think is a very important question. So we are also looking for patients for that study. And then although not yet open, we will be participating in the Alliance study which is looking at the combination of Pomalidomide and Dexamethasone with or without Ixazomib and so this is in relapsed refractory patients and again I think this is going to be a very exciting option for patients with relapsed disease. It's another all-oral regimen which is clearly very convenient for patients. So that's currently what we have in our lineup and I'm always looking for new and exciting studies.

Jenny: And the Alliance study will be Phase 2?

Dr. Holstein: Right. So the Phase 1 portion is going on right now but that portion is just being done at a few centers and then once that portion is complete and the dose has been established, then the Phase 2 study will open in more centers and Roswell Park will be one of those centers.

Jenny: And it seems like it's a challenge to figure out which drug combinations work. I know there are a lot of trials going on with all the different types and bringing in new drugs seems to be a challenge because then you have to start all over again.

Dr. Holstein: Yes, and then how you sequence those combinations. So it's getting incredibly complex. It's great that we're starting to have more and more options but at the same time, we now have more and more questions about the best way we should be doing things.

Jenny: So with that in mind, how do you go about consolidating efforts and maximizing efficiency? I guess as a myeloma community at large.

Dr. Holstein: So my experience as far on the Alliance Myeloma Committee is that #1, there's a lot of effort to develop protocols as a committee so that everybody has a say on whether or not they think that a strategy is a good one. And at the same time, there's also a lot of collaboration between the myeloma committee and pharma. This is where the drugs are coming from and we want to try to make sure that the studies that pharma is performing are ones that we think will be helpful. So I think there is a lot of communication back and forth between pharma and the academicians who are on the collaborative group committees.

Jenny: Okay, great. Well, we look to support that work and appreciate everything you're doing.

Dr. Holstein: Thank you.

Jenny: Before we run out of time, I would really like to open it up for caller questions so if you have a question for Dr. Holstein, please call 347-637-2631 and press 1 on your keypad. And I think we'll go ahead and open it up unless there's another topic that you want to review before we do that?

Dr. Holstein: I'd be happy to take any questions.

Jenny: We’ll start with our first caller. Caller: Yeah. I was trying to get the name of the drug that you were referring to that had the superior results and that you re-dosed? And I think then you went on to talk about it. Was that ATI?

Dr. Holstein: It's ALT-803. So because it's so new, it doesn't have a real name yet and again, the results that I was talking about were the results that the company did involving mice.

Caller: Right. And what is it, a PDL-1 blocker?

Dr. Holstein: It's totally new, it's an IL-15 super agonist. So they took IL-15 and modified it a bit to be even more active than normal IL-15.

Caller: Very interesting. Okay, that's the first thing I've heard about IL-15. Second question. There's some trials and this is a little bit off what you're talking about but there are some trials going as you know about using PDL-1 blockers which is just recently approved for melanoma and myeloma. You're familiar with those, right?

Dr. Holstein: Yes.

Caller: My question is is there a particular mutation that that it requires in order to work? Are those onlyBRAF mutations, where you would expect those to be of benefit or is it…?

Dr. Holstein: That's an excellent question. With Ipilimumab, I would not predict that there is going to be a particular mutation -- that's important and that's different than with the BRAF inhibitors and there is interest with BRAF inhibitors in myeloma. So although they've shown activity in melanoma, there's also reason to believe that they might be of interest in myeloma for patients who have mutations in BRAF.

Caller: So the first that you mentioned is the one that is newly approved, not the one that's already licensed? The non-BRAF drug is the one that was just approved for melanoma.

Dr. Holstein: I'd have to be reminded of the name to make sure that I'm giving you the precise information.

Caller: The one that you mentioned starts with an "I"?

Dr. Holstein: the Ipilimumab? Yeah, so that works differently. That really does target your immune system as opposed to being a BRAF inhibitor. And I think there is some clinical data actually… I think somebody is looking at this for myeloma. I can't remember which center in the country here was doing it, but I think this is being studied in myeloma right now. I just don't have any personal experiences.

Caller: Sloan Kettering is doing it. I think MD Anderson is doing it and I can't wait to see it soon enough. But thank you very much for your comments. Appreciate it.

Dr. Holstein: Oh, thank you!

Jenny: And thank you for your question, appreciate it. Okay, we'll take our next caller.

Caller: Good afternoon, Dr. Holstein. Hi Jenny. What an interesting interview. Thank you so much for providing all these information. I'm a smoldering multiple myeloma patient so I'm interested in learning as much as I can at my stage. So I'd like to try to understand and put this into perspective for myself as far as the immunotherapy trials. As a smoldering patient, how do I do that, how do I put this into perspective? Do I wait to be able to access something like this down the road or do I pursue one of the clinical trials available to high-risk smolderers now which are trying to cut back, so to speak, on the tumor burden at a lower rate hoping to perhaps offer a cure, even to certain myeloma disease types. I'm referencing Dr. Durie's comment today on his blog on the IMF website about the CRD trial that they did at the NIH which is holding such promise. How does someone like myself really approach this? What would I do if I were your patient saying, "Dr. Holstein, help me, what do I do?"

Dr. Holstein: I think it's an incredibly difficult question. We really don't know yet what to do with smoldering myeloma in part because we're only starting to realize that smoldering myeloma represents more than just one group of people. It's really not one disease. It's really probably multiple groups of people. As I'm sure you're well aware, there's really not -- at this point in time -- true consensus about who's high-risk smoldering and who's not which makes interpretation of trials a little bit difficult.

Caller: Painfully aware of that, absolutely painfully aware of that.

Dr. Holstein: I'm not sure I have any brilliant words of wisdom for you except to say that I think the studies need to be done. I think that it's a very personal decision about whether one goes on a clinical trial or not, particularly in the smoldering context. But as a field, the studies absolutely need to be done so that we can, with confidence, counsel patients like yourself.

Caller: Do you have any smoldering trials at Roswell?

Dr. Holstein: We do not at this time. It's one of the things that we'd like to open but we don't currently.

Caller: Would you open something unique or would you look to open one of the trials that exist right now to any of your smoldering patients?

Dr. Holstein: I think probably we're hoping to either get in on a cooperative group trial which has a new idea. I would also be certainly open to something which is unique and open to a smaller number of centers. I think right now we haven't really been interested in opening the studies which are currently under way just because it's a little bit harder. By the time we finally get it open and then the study closes, it's a little bit hard to get patients on. So what we hope to do is get in on the front end of a smoldering trial.

Caller: Okay. Because I'm actually looking at the smoldering trials that they're hoping to perhaps bring to fruition using the anti-PD1 antibody perhaps coupled with Revlimid. I know Dr. Siegel is the principal investigator for that. And then also looking at the vaccine trial out of Dana-Farber, also they've just coupled that with Revlimid. So I'm more keen on these immunotherapy trials as well. I think as a smolderer, I think they just hold such promise. But I thank you for your time.

Dr. Holstein: I absolutely agree. Thank you.

Caller: Yeah. Thank you for your time and thank you for your insights. Appreciate it.

Jenny: Okay. Thank you so much. Our next caller, please go ahead.

Caller: Hi, I am currently in remission. I went through two or a tandem stem cell transplant. And as I hear you've described some of the trials that are coming up, some of them sound really exciting and potentially even curative. And at least from my perspective, what is most frustrating is that we have these wonderful things that are happening and then it's ten years away or we don't hear anything else. So we hear some of these studies and then it just drops off. And so the patient is wondering, well, there are someof these great drugs potentially or great treatments coming up and it takes so long. So is there any way that we can follow some of these studies and is there anything that we patients can do to move them along and try to make them available faster for the patient?

Dr. Holstein: Oh, that's an excellent question. I think part of it is just helping spread the word that these trials are available and also helping encourage patients that clinical trials are a good thing to participate in. I know, after having many conversations with my patients, that many of them come in with perhaps some feelings that a clinical trial would never be for them for a variety of reasons and I think the more we can spread amongst the myeloma patient community that these clinical trials are absolutely critical to help our myeloma patients, the better. In terms of the timelines of getting trials open, that's a lot of times institutional things and in terms of timeline of getting trials completed, that actually falls back again to how quickly we can accrue to the trials, so sometime some of the reasons that trials linger on is because we just aren’t accruing to them. So anything we can do to help spread the words that these trials are really meant to help myeloma patients as a whole would help these trials get finished.

Caller: Okay. And do you feel that some of these trials or some of the drugs that are coming or treatments are potentially curative? I mean if you were to -- I know this is kind of a loaded question -- estimate when we can cure myeloma or treat it better, I guess.

Dr. Holstein: Oh, gosh. Certainly as a myeloma physician I would be thrilled to be able to counsel my patients that I can treat them with curative intent. I just can't offer you a timeline. Clearly in the last decade, remarkable advances have been made. My hope would be that in the upcoming decade that we will get to that point where we truly have 20, 30-year remissions which are  close to cure. But I don't feel like I know enough to be able to promise that to you.

Caller: I have one more follow up question, I hope we have time. So I'm in remission and the big question is to stay on permanent maintenance therapy. Do you believe that if a patient were to say "I'm in permanent maintenance therapy" that it might leave those that do that, less able to participate in new trials or be receptive to new therapies. Do you think that would eventually not be such a good thing if we're around in ten years?

Dr. Holstein: I don't think so. There are certainly philosophical debates about whether maintenance therapy might be long term creating resistant disease but we really have not seen any clinical data to support that. So at this time, I do recommend to my patients that as long as they're tolerating it well and as long as they're in remission, that they stay in their maintenance therapy. I think by the time that many of these patients do eventually relapse, we'll have so many new treatments that have nothing to do with for example, lenalidomide if you're on that for maintenance, that it really won't matter. So I don't think you're harming yourself in the long term.

Caller: Okay, very good. I appreciate it, thank you.

Dr. Holstein: Thank you.

Jenny: Thanks for your question. Well, Dr. Holstein, the whole purpose of this series is to help encourage patients to learn more about clinical trials so that they can really make educated decisions about their care and it's tough to navigate. So thank you so much for joining us today. Thank you so much for describing this ALT-803 so we can better understand it. I think we'll have to do some follow up posting about this too when this trial opens to let people know what it is and how it works. We're just so very thankful for what you're doing in your research and in the clinic to move the field forward as fast as possible.

Dr. Holstein: Thank you so much. It's been a privilege to speak with you today.

Jenny: Well, thank you so much for joining us. We appreciate it. Thank you for listening to another episode of Innovation in Myeloma. Join us for our next mPatient radio interview as we learn more about how we, as patients, can help drive to a cure for myeloma by joining