Nikoletta Lendvai, MD, PhD Memorial Sloan Kettering Cancer Center Interview Date: October 28, 2016 

 Why should patients participate in clinical trials and is it ever too late to join one? Dr. Lendvai tells us that every stage is a good time to consider clinical trials, but when you've run out of options isn't one of them. She shares insight into the details of joining clinical trials (like who pays) and discusses the new drug in clinical trial - selinexor - as an example. This drugs is now being used to help patients who have become refractory to proteasome inhibitors like Velcade and iMiDs like Revlimid. In early studies, it looks like this drug can make many patients sensitive again to these prior treatment options. Dr. Lendvai shares clinical trials open at MSKCC for newly diagnosed patients, smoldering myeloma patients, clinical trials for transplants and for relapsed/refractory patients. It is very clear that going to an academic myeloma center gives patients a large number of options to take advantage of newer treatments that have not yet been approved.

Thanks to our episode sponsor

Jenny: Thank you for joining us on today’s show on Myeloma Crowd Radio. I’m your host, Jenny Ahlstrom. I would like to thank our episode sponsor, Takeda Oncology, for their support and making this program possible. Today’s show is all about an important way that patients can help researchers get to a cure faster. Our show is on the ins and out of clinical trials, why are they important, what kind of care can we expect, and why it’s in our best interest to keep them in mind at every stage of our disease. This is so important for us to understand, and as a topic, it’s really near and dear to my heart. With us today is myeloma expert, Dr. Nikoletta Lendvai from Memorial Sloan Kettering Cancer Center in New York. Welcome, Dr. Lendvai.

Dr. Lendvai: Thank you, Jenny, for having me on today.

Jenny: Well, before we get started with this show, let me give a brief introduction for you. Dr. Nikoletta Lendvai studied neuroscience before earning both her MD and her PhD at Albert Einstein College of Medicine. She’s Assistant Professor of Medicine at Weill Cornell Medical College, as well as Assistant Member of the Memorial Sloan Kettering Cancer Center. She started as Clinical Director of the inpatient lymphoma and myeloma service, and serves both patients in inpatient and outpatient service. She concentrated her time in New York and has taught at NYU, Weill Cornell Medical College, and Memorial Sloan Kettering while also treating patients previously at the John Theurer Cancer Center. Her research interests are in immunotherapies, determining how to use immunotherapy to prevent and treat myeloma relapse. And also, a development of new therapies for relapsed/refractory myeloma combining new combinations with each other and with currently approved myeloma therapies and with immunotherapies. And as a researcher, she spent significant time on the creation of clinical trials and executing those clinical trials. Again, we are so happy you joined us today.

Dr. Lendvai: Thank you.

Jenny: Well, maybe we want to just start with some of the basics. So, what are myeloma clinical trials? Maybe we just want to start there.

Dr. Lendvai: Clinical trials are really a framework, if you will, a way of evaluating new therapies or new approaches, in this case, for the treatment of myeloma. They can occur at any stage of therapy. Most clinical trials will be interventional. They will involve some sort of treatment.

Jenny: This is a topic that’s near and dear to my heart, I guess, because after I was diagnosed and got treated, after my initial treatment was finished, I went on www.clinicaltrials.gov, which is a website where all the clinical trials are listed. I found over 450 open myeloma clinical trials. So there is a lot of work being done by different facilities around the world. If you want to talk about how clinical trials are created; like a pharmaceutical company will decide they’re going to study something. And then an investigator like yourself will say, “I’m curious about trying this new drug in this particular combination.” So, do you want to try to talk about how they’re constructed, basically, or how an investigator decides to open a clinical trial?

Dr. Lendvai: Absolutely. But let me just step back. Before we even talk about how clinical trials are constructed, let me just address a few misconceptions that people have about clinical trials. One common misconception is that clinical trials will have a placebo arm, if you will, so that patients may not be getting actual treatment, which turns out not to be the case in the vast majority of clinical trials. The other important thing to have everybody understand about clinical trials is that participation is always voluntary. And even after people do join, they always have the option of coming off of the study for any reason. It's also important to understand that if a patient’s disease is not responding the way that we would hope, in other words, someone is not responding to treatment on a clinical trial, then they would be automatically taken off of the study. As you mentioned Jenny there are several different kinds of clinical trials. There are early phase clinical trials that may be looking at a new drug and may be focusing on finding the right dose of a drug. Later stage clinical trials where there’s a dose already identified might be looking at the efficacy, how many patients respond to that particular dose. And then, yet later stage studies will be comparing a newer combination or the addition of a newer drug to standard of care. Certainly, these larger studies that will involve hundreds of patients are typically run by either, or sponsored rather by pharmaceutical companies, given the funds that are necessary to get a trial of that size done while smaller studies testing new drugs, new concepts, new approaches may be initiated by an investigator and may involve a single center or a smaller number of centers participating.

Jenny: So there are different stages of clinical trials is what you’re saying, right? The phase 1 is -- for example, we did a show just recently on daratumumab, and those studies started like in 2007. So if you look at the course of a drug being tested in the clinic, it takes a while for it to get through this process. Those phase 1 trials are testing out a drug and seeing how big of a dose you can give and how safe that dose is, right?

Dr. Lendvai: That’s correct. Yes, in a phase 1 study, you’re looking at a relatively smaller number of patients making sure that there are no toxicities, which we call unacceptable toxicities associated with the drug, and you’re trying to identify the dose. That would be most appropriate to test in a larger group of patients.

Jenny: But also, phase 1 studies can also be where you’re trying a drug that hasn’t been used in a particular combination before, right?

Dr. Lendvai: Yeah, that’s absolutely right, exactly. Case in point, the study that I think we’ll get to later on that I am currently conducting at Sloan Kettering is the phase 1 study that involves a combination of three drugs. Only one of which is a new drug. The other ones are known drugs with efficacy in myeloma. So absolutely, a phase 1 study may be building on the backbone of known therapies as well. In the case of a study like that, we are looking for the dose that would be the most advantageous to combine with the existing therapies. Notice that I didn’t say maximally tolerate this dose because very often, we will choose a dose that’s actually not as high as you could potentially go in terms of toxicity while we’ll see less toxicity with enough efficacy to move forward.

Jenny: So the dose might go up over time in future trials, is what you’re saying. But you’re just trying to make that initial determination in that phase 1. I know the phase 1 trials are like officially looking at safety and the dose and everything, but I know you’re also looking to see if it’s working. And I know a lot of times -- in myeloma clinical trials, I know that patients need to understand that by the time a drug is entering a clinical trial, especially in myeloma because we have so many new drugs now, that it’s already passed a lot of vetting. It’s not like, “Hey, we’re going to throw this out there and hope that something good happens with it.” There’s a lot of research that goes into it even before it gets to clinical trials, right?

Dr. Lendvai: It depends on the particular study. Again, to go back to the example of the study that we are doing. With selinexor, because it’s a combination, even though it’s phase 1, there’s a lot of preexisting data on the use of these drugs by itself and combined with other drugs. In some cases, you will have studies that are even at an earlier stage, if you will. These are referred to as first-in-human studies where you may be one of the first people getting this drug. The important thing to remember is that all of the drugs that we use today, be that pomalidomide, be that daratumumab were first given to someone. We never know if this is the next daratumumab that you’re getting. But the vast, vast majority of phase 1 studies, just like you said, will have a significant amount of data on them, on the particular drug already coming from earlier trials, whether it is in a different cancer or a different setting.

Jenny: And then in phase 2 trials, what’s the average number of patients would you guess that are involved in phase 2 studies, which is like how well is this drug working?

Dr. Lendvai: What is the average number, is that what you’re asking?

Jenny: Yes. Just in general.

Dr. Lendvai: Yes. You can have a relatively small phase 2 study of 20 to 40 patients, depending on the design. Some phase 2 studies will be randomized. Then we’ll be testing, in a smaller way than phase 3 studies will, the difference between what is considered standard of care therapy in one arm and the addition of the studied drug to standard of care therapy in the other arm.

Jenny: And then phase 3 studies, is what you talked about earlier when people really run a large scale, hundreds of patients, trials at multiple sites. And there are a lot of myeloma trials that are like that. And then they’re comparing, typically, the standard of care, which you would be getting in the clinic, anyway, versus the standard of care usually plus something else, right?

Dr. Lendvai: That they are comparing standard of cares versus the studied drugs or the study of combination to the standard of care.

Jenny: Right. So, when should patients consider joining a clinical trial? Let’s talk about that for a little bit.

Dr. Lendvai: In my view, patients would consider joining a clinical trial at all stages of their treatment. Now, clearly, the kind of clinical trial that one would consider will be different at different stages of the treatment. For example, a lot of our research at Sloan Kettering currently involves looking at precursor conditions, such as asymptomatic multiple myeloma, and looking to see what can be done to decrease the risk of developing active myeloma. So in a situation like that, in terms of the possible interventions, you may consider participating in a clinical trial. The clinical trials that we and others have had for this situation are with drugs that are very well studied and almost always, or in fact, I should say already FDA approved for multiple myeloma. If you have, for example, newly diagnosed myeloma, we have therapies for newly diagnosed myeloma that have upwards of 90% response rates. Obviously, it would not be ethical for the myeloma community to offer a clinical trial where you either get standard of care therapy, which again, will carry a 90% plus chance of response versus a first-in-human study or a phase 1 study where we know very little of the efficacy of the drug. A study for newly diagnosed myeloma patients would offer standard of care therapy, plus, some additional drug or approach that’s aimed at improving those response rates and the duration of response over the already existing 90 plus percent. But as if somebody had myeloma that has relapsed five, six, seven times when the standard of care approaches have mostly been tried, then that patient and that patient’s doctor may be willing to take more risks in terms of trying drugs that are at earlier stages of development.

Jenny: You’re saying that you can consider a trial if you’re newly diagnosed or even if you’re -- like you were saying, you have a lot of expertise in the smoldering myeloma or early precursor conditions at Memorial Sloan Kettering. At every step, whether you just relapsed or have multiple relapses, you’re looking at how to carefully craft these trials to get optimal outcomes for your patients and just build on what’s already available.

Dr. Lendvai: That’s exactly right.

Jenny: You have to have pretty great combinations -- so when patients think about joining a clinical trial, I heard some doctors say that your care, actually, during the trial can be really outstanding. Do you want to cover that a little bit? What kind of care could you expect to receive in the clinical trial?

Dr. Lendvai: I think it’s fair to say that in the vast majority of clinical trials, you should expect to receive the care that you would receive otherwise and more. If anything, most clinical trials will have closer monitoring, more testing than you would otherwise because of course we’re looking for additional information that we may or may not expect when we deliver standard of care. So patients get, in my experience, get really -- they get excellent care when they are receiving care at the myeloma center, the standard of care. But when they are in a linical trial, they tend to have even more eyes watching them even more closely.

Jenny: They can do so much monitoring that needs to happen.

Dr. Lendvai: Exactly.

Jenny: Yes. I’ve had patients say, “My care was fabulous because they’re watching everything.” So, are there other benefits to joining a clinical trial that you can share with patients?

Dr. Lendvai: Well, I think in addition to the very close monitoring, the access to new drugs, like you mentioned. Even though this process has sped up very significantly over the last decade or two, it still takes years for drugs to go from initial studies to FDA approval. So early access to drugs is a huge part of this. In general, I think probably everyone who is listening knows that in spite of the huge advances that have been made in myeloma, we are not where we want to be, whether that is a new drug or a new approach involved. Certainly, improving on what we can do with current standard of care is important, and is the goal of most clinical trials. Of course, it’s also important to remember that we wouldn’t have any of the drugs that we have today if it wouldn’t have been for others participating. I think most physicians and researchers will acknowledge that many clinical trials place somewhat greater burden on the patients than they would have. Otherwise, they might have a few more visits, they might even have a few more scans or biopsies, more blood tests almost certainly. This is what other patients had to go through for us to be able to say that we have what we have with standard of care today. I think we recognize and very much appreciate it when patients are willing to take that extra burden on. I certainly think that it’s a two-way street. I think that most patients benefit from participating on clinical trials. But we recognize that it’s not always easy to do so.

Jenny: Yes because you might have mor visits. Well, let me just weigh in for a second because from a patient perspective, I look at this and I say, “Wow. That’s great. We have four new drugs last year.” And just to repeat what you said, we’re doing better and outcomes are longer, but I still have friends dying of myeloma, and I don’t want to see that happen. I don’t want to die of myeloma. I don’t want anyone listening to die of myeloma. So, what do we need to do to help push toward the cure? When you look at adult cancers in general, and I think myeloma is very typical, 3% to 5% of myeloma patients are joining clinical trials. So if as patients, we want to tighten up that window to the development of new drugs (and some clinical trials have shut down because they can’t get patients recruited for them), if we want to help researchers help us find a cure faster, this is something that’s really critical for us to participate in and to just be aware. You know, not every trial I think might be right, and you can comment better on this than I can for us. Like you said earlier, we can opt out if necessary.

Dr. Lendvai: Exactly. I completely agree. As you say, if that 3% to 5% participation would go to 50%, that would go a very long way towards accelerating the development of the drugs that are in the pipeline, and there are many, many new drugs in the pipeline with different mechanisms that people want to be able to benefit from. And the way to do it is really for everyone to participate. Again, I think the people listening to this are probably those who realize the importance of getting their myeloma treated at a myeloma center. And what I always tell people is that the reason to get treated at the myeloma center is not only because we do this day and night and know the side effects of the drugs and know what to do when we see them, but because it gives people access to clinical trials. So certainly, I think increasing clinical trial participation would benefit the myeloma community, the patients immensely, and that benefit could be seen very quickly.

Jenny: I agree. That’s why we started this radio show to tell patients about clinical trials straight from the researcher in a patient friendly sort of way. Earlier, you talked about placebo where people might think, “Well, I might get this sugar pill or no actual treatment.” But what you’re saying is that you’re actually getting either standard of care or standard of care plus something else. And then you addressed what happens with so many progresses on the trial. They can either get off the trial. But I heard also that sometimes in a two-arm trial where they’re testing two different things, either standard of care or standard of care plus something, that if they start progressing, they could maybe throw them into the other arm of that trial. Does that happen frequently?

Dr. Lendvai: Yes. These are actually important questions to ask your doctor. Some studies where there is more than one arm, let’s say a two-arms study that’s testing standard of care in one arm and standard of care plus the studied drug in the other arm, the study will allow for what’s called crossover. And this is very important, obviously, because it gives the patients access to the studied drug even if they were not originally randomized or selected for that group. Some studies will allow for that and others -- so it’s important for the patients to know whether that opportunity is there.

Jenny: You’re in a center in a major city, I mean New York City is huge, and Memorial Sloan Kettering has a lot of clinical trials open, and we’re going to talk about some of your trials a little later. But can you address traveling to join a clinical trial? Because I’m sure you have patients that come to your facility that don’t live in the area.

Dr. Lendvai: Absolutely. We have a number of patients who travel to us for care, be that on a trial or not. When patients participate on a clinical trial, very often, I would say more often than not, we have a budget to reimburse people for some of the travel cost. That’s certainly something that you should ask about. It doesn’t mean that we can cover all costs for the entire duration, but depending on the travel burden, how often you need to come, how long you need to stay, there will almost always be some financial support that will allow us to reimburse you for at least part of your expenses. And we do have a number of patients who travel to us for this particular purpose.

Jenny: As a follow-up to that, who pays for a clinical trial? So if a patient wants to join -- I know it varies, so maybe you can talk about the different types of trials.

Dr. Lendvai: The way this works in the majority of studies is that when you participate on a clinical trial, you will have some testing and some treatment that is standard of care. Let’s say coming in for a blood test to see what your myeloma numbers are before starting treatment and after each cycle there would be something that we do for you, whether you are in a clinical trial or not. So that’s called standard of care procedure, and that would be something that the patient or the insurance company is responsible for us. The studied drug is most often, if not always, provided by the sponsor of the study. So the pharmaceutical company that’s involved. And then there are additional procedures. Those may be blood draws or scans which if they are not things that we would normally do for our patients, then those tend to be covered by the sponsor of the study as well. So you, the patient, are not responsible for that. Now, in terms of having your standard of care costs covered by insurance, that varies, depending on your insurance company. I’m certainly not an expert in this but for the most part, commercial insurance, as well as straight Medicare and Medicaid, from what I understand, are obliged to cover the standard of care cost of a clinical trial as long as you are in your network. This is also something that you can and should reach out your insurance provider for. But I would say that because of the existing federal laws, this is usually not an issue. The insurance company will pay for the standard of care cost while you’re on study.

Jenny: Just to give an example, like if somebody is on Revlimid, Velcade, and dex as a triple combination. The study is RVD plus a new drug. Their insurance company would pay for the RVD part, and then whoever is running the study on the new drug would be providing that new drug for free.

Dr. Lendvai: Well, that, I am talking more about the procedures and blood tests. You know, whether or not drugs that are already FDA approved are provided on a study, by the study, it really depends on the particular study. But yes, I would say that probably, if you’re in a study where you are getting Revlimid, Velcade, with study drug X then the Revlimid and Velcade would probably be covered by your insurance rather than the study. But again, some studies will provide the drug or the drug that’s FDA approved. That’s really study dependent.

Jenny: In your opinion, I know we want to get to your selinexor study and some other studies that you’re running, but in your opinion, how does somebody best find the study that’s best for them personally?

Dr. Lendvai: Well, you mentioned clinicaltrials.gov. It is a great resource but can be very overwhelming, and it can be difficult to know what you’re eligible for. It’s probably a good tool to prompt your doctor to talk about or look into things for you that they may or may not have considered, especially if you are not at a myeloma center. But certainly, talking to your doctor, being informed by using websites like this one and talking to your doctor about the drugs that you’ve heard of is definitely helpful.

Jenny: I would just reemphasize the point you made earlier in the show in going to a myeloma center. So there was a Mayo study that just came out yesterday and we wrote an article on it, and it’s on our homepage, that talks about how patients who are seen at centers that have over ten new patients a year, more like 50 plus new patients a year. And you have hundreds of patients a year at Memorial Sloan Kettering, I’m sure. But you have a higher likelihood of living longer. Not only is there access to clinical trials at these academic centers, but you get better care because I think the doctors know how to treat this very complicated disease. Also, I would just add that about three years ago at ASH, I met Brian McMahon, who created a tool called SparkCures. We have that on our website as well. Brian’s mom died of myeloma. She had a very aggressive form of myeloma, and he thought about it and said, “They tried to get her into clinical trials. It’s a very difficult process.” And he created this simplified tool. It’s something that you can use. You can enter in your ZIP code, you can enter in some information about yourself, and it can narrow down the list of clinical trials you might be eligible for from hundreds down to a handful. So, I would encourage all our listeners to take a look at that. And you were saying, you took a look at that tool, right?

Dr. Lendvai: Yes. I was just going to say that after you mentioned it to me, I looked at it and I think that it is an amazing tool. It asks all the right questions, all the things that we usually look at to see whether you may or may not be eligible for a clinical trial. I think it’s an amazing new tool and I would recommend to everyone to take a look at it. I think it’s really going to make a huge big difference in people’s understanding of what their options may be. It’s a great thing to bring to your doctor the resource that come out of this and ask your doctor to look at it then help narrow it down further for you. But it certainly is a much, much more helpful and user friendly and personalized tool than clinicaltrials.gov.

Jenny: And we need the help as patients. We’re on medication and sometimes it’s hard to concentrate and it’s easy to get frustrated. Before we talk about selinexor, my last question just in general about clinical trials will be, are there any tips that you can suggest about getting into trials at Memorial Sloan Kettering?

Dr. Lendvai: I would say first off is that this is at least in my view not something that should be difficult because as I said, we have many, many clinical trials. They are addressing all the various stages that a myeloma patient may find themselves in or at. And we are always looking to give people this opportunity. I would certainly say that if you have newly diagnosed myeloma, it helps to contact us before you start treatment. But if you have started treatment already or if your myeloma has relapsed, that should not discourage you at all from contacting us and coming to see us because as I said, if you are in the middle of what we call induction therapy, the initial treatment for your myeloma, we may have clinical trials for you that are built around transplant. Or we may have clinical trials for you that look at various maintenance strategies. I think the important thing is to make that phone call and recognize that we can partner with your local oncologist often, and that we are there to help and to help translate the information that’s out there regarding clinical trials.

Jenny: Well, let’s talk about a specific clinical trial because I’ve heard about this drug, selinexor, and I don’t have a lot of specific questions about it just because I don’t know anything about it yet. So, you’re the first to give us the heads up about selinexor. Why don’t you explain what that is and how you’re studying it in your trial?

Dr. Lendvai: So selinexor is a really fascinating drug. It’s the first drug in its class that targets what’s called the nuclear export protein. Just to take a step back. I think most of you may remember from your biology classes, the cell has a nucleus, which, if you will, is the business center of the cell. So, that’s where the DNA is and that’s where a lot of proteins are, and some of those proteins are called tumor suppressor proteins and they are supposed to fix things when they go wrong in terms of mutations that occur in the DNA. It turns out that it’s very important for these proteins to be in the right place at the right time to be in the nucleus and not, let’s say, in the cytoplasm where they cannot perform their function. So, there is normally trafficking of these proteins between the nucleus and the cytoplasm. The cytoplasm being the rest of the cell that’s outside of the nucleus. And there are certain proteins, what’s called exportin, XPO1, is the prime protein here. The job of this protein is to export hundreds of proteins out of the nucleus into the cytoplasm. And what’s been found is that in tumors, in a number of cancers, Exportin 1 is up regulated. Meaning, there are increased numbers of these proteins shuttling proteins out of the nucleus into the cytoplasm. The end result of this is that proteins like the tumor suppressor proteins are not where they should be when they are needed. What selinexor does, and the reason it’s called selective inhibitor of nuclear export, is it basically shuts down this channel, this exporting protein, and keeps the proteins, the tumor suppressor proteins among others where they should be in the nucleus. This is at least one of the major mechanisms that starts to work. The reason that the myeloma community is so excited about these drugs, well, first of all, is oral. So you take it at home. Second, when researchers looked at it in a study called the STORM study, almost 80 patients, they found that even if patients were previously exposed to all the standard myeloma drugs, Revlimid, pomalidomide, Velcade, carfilzomib, and even in those who were refractory to at least one of what we call the IMiDs and one of the other class of drugs, the proteasome inhibitors, still 20% of them responded to this drug. That may not sound like a lot but the reality is that in people who have gone through all these other options, and in fact, a number of the patients on this study, also were refractory to daratumumab, the anti-CD38 antibody. So, 20% in patients who have had five, six, seven lines of prior therapies, which is actually are pretty significant number. Other studies have gone on to build on this result and to combine selinexor with the known myeloma drug. So, a study called the STORM study, combined selinexor with Velcade. When this was last reported, it was still a very small study with only 16 patients. But among the ten patients in this study who did not respond to Velcade or carfilzomib previously, or became refractory to this drug, 70% of them responded to the combination. So it seems as though this drug, selinexor, may be able to perhaps resensitize patients’ myelomas to these other drugs that the myeloma had previously become refractory to. Along the same line, I was thinking selinexor was also combined with carfilzomib. Again, when this was last reported, it was extremely early on in the study with just eight patients. Six of whom were previously refractory to carfilzomib, and there was a 75% response rate (six out of eight patients responded). I believe both of these studies will be updated at the ASH annual hematology meeting in December of this year. I think we’re going to hear a lot more exciting information about these studies.

Jenny: So, patients who become refractory to things don’t necessarily need to be discouraged because you’re saying you can add it back and then 70% to 75% of them are responding again. That’s amazing.

Dr. Lendvai: Yes, I agree that there’s certainly hope to recapture some of those. The sensitivity to some of those drugs, I do think that these numbers are so small that we should probably not put too much emphasis on what percentage of patients will be able to see the sensitivity of their myeloma recaptured, but I think that this is very, very hopeful information.

Jenny: In your selinexor trial, what combination are you using?

Dr. Lendvai: I am combining selinexor with a drug called ixazomib. The trade name is Ninlaro. And this drug was FDA approved in November of last year. Ixazomib is the first, and so far only, FDA-approved oral proteasome inhibitor. So it’s in the same class of drugs as Velcade and carfilzomib, but it’s oral. So I’m combining ixazomib and low dose dexamethasone with selinexor in this study. The advantage of this is that it’s an oral regimen.

Jenny: Yes, that’s great.

Dr. Lendvai: We’ve been working on this for a long time. So we’re very excited to be able to offer it to patients.

Jenny: Who is eligible for that study? It’s for patients who have relapsed or are refractory, and then, do they have to have had both those IMiDs or immunomodulatory drugs and proteasome inhibitors or one or the other?

Dr. Lendvai: Patients will have had to have at least one immunomodulatory drug and at least one proteasome inhibitor. But remember, that means that you basically had to have had Velcade and Revlimid, which most patients will have had once they were treated initially. Eligibility requirements for this particular combination for this particular study are not really restrictive.

Jenny: And it is for people who have relapsed. So not newly diagnosed or anything like that.

Dr. Lendvai: This is for patients with relapsed and refractory myeloma.

Jenny: Well, we’re excited to hear more about selinexor. I’m grateful that you explained it because I didn’t understand how it worked. So, that’s teriffic. Now, you have so many different clinical trials open. Do you want to help us understand different options? Because you really have something for people at every stage of their disease.

Dr. Lendvai: We do, and we feel very strongly that if we want to increase clinical trial participation, we have to have choices so that people and the patients and the doctors can find the right study for them. So I thought that I would take a few minutes to highlight a couple of studies that we have for each of the phases of myeloma at Sloan Kettering. Starting with asymptomatic myeloma, my colleague, Dr. Mailankody, has a clinical trial with ixazomib, the oral proteasome inhibitor that I just mentioned in combination with dexamethasone. This is for patients with high-risk asymptomatic myeloma, and it’s aimed at looking at this approach as a potential way to decrease the chance of developing active myeloma. For newly diagnosed myeloma, my colleague, Dr. Korde, just opened a study last week with high-dose carfilzomib in combination with Revlimid and dexamethasone for initial treatment of myeloma. We know that the deeper patient’s initial response to myeloma treatment is better prognosis. So my colleagues, Dr. Korde and Dr. Landgren, have previously published their experience with using high-dose carfilzomib in this setting, in the newly diagnosed setting, and showed some very promising earlier results with deep responses. And Dr. Korde's study will expand on this now using carfilzomib at 45 and 56 milligrams per meter squared in combination with Revlimid and dexamethasone. Now, as I think most people listening are aware, autologous stem cell transplant remains a very important component of myeloma treatment for many of our patients. One area where I think really exciting things are happening in multiple centers, but certainly at Memorial, is the development of clinical trials, particularly, immunotherapies built on the platform of autologous stem cell transplantation. So we have a number of clinical trials at Memorial. Some of them are vaccine studies that are built around autologous stem cell transplant. So patients still get everything they would for the “garden variety” if you will, high-dose melphalan stem cell transplant. But they may get vaccines that are meant to help the immune system recognize and find leftover myeloma cells after the transplant, or in a study that was again just opened last week at Sloan Kettering. My colleagues, Dr. Chung and Dr. Lesokhin, are looking at using checkpoint blockade to increase the response - the depths and the duration of response to autologous stem cell transplant. Your listeners may be familiar with what checkpoint blockade means but it’s essentially antibodies against various molecules that have been in the news in the myeloma world, whether that’s an anti-CTLA4 or anti-PDL, anti-PD1 antibody. There are antibodies that are meant to take off the breaks off of the immune system and allow them to allow your own immune system to seek out myeloma cells and go after them. So, that’s what’s happening in the transplant part of the world at Sloan Kettering. And then of course, a topic that’s near and dear to my heart is relapsed myeloma. And I wanted to highlight two particular clinical trials that we have opened for our patients with relapsed myeloma that I think are very interesting and have the potential to really bring new treatments our way. And one of those is a study that Dr. Landgren is conducting. I have mentioned Velcade, carfilzomib and ixazomib as proteasome inhibitors that are FDA approved. So, the study that he’s conducting is a drug called VLX1570. And this is a drug that is also a proteasome inhibitor but it acts at a different part of the proteasome molecule. I think of proteasomes as the recycling bin of the cell. And myeloma cells are very dependent on proteasomes because they make a lot of protein, and all the protein needs to be properly recycled for the cells to function. So if you shut down the recycling bin, that causes a problem for the cell, and that’s what Velcade, carfilzomib, and ixazomib do. And it is thought this protein, VLX, may be able to do that even in cells that are no longer responding to the usual shutdown mechanism. That’s one study that I think is very interesting. And another one is a multicenter study that we are participating in, which is an antibody against a protein called BCMA. So BCMA is B-cell maturation antigen, and it’s a protein that’s found on the surface of most myeloma cells. And this particular antibody that’s made by GSK is linked up to a drug that’s toxic to the cells. This is a treatment that apears to have significant activity with myeloma and seems to be well-tolerated and it’s given once every three weeks over an hour. This is a new target. BCMA is a new target that has emerged in the last few years for myeloma, and it’s also of course the target of CAR T-cells, which is another exciting treatment modality that’s coming to Memorial sometime early next year. I will just mention that we also have a terrific clinical trials program for amyloidosis led by my colleague, Dr. Landau. That’s also something that people with this related disorder should take a close look at.

Jenny: Well, what I’m hearing you say as you review these clinical trials is that you’re trying to take what already exists and build on it, like the autologous transplant: “This is already effective. Let’s see what else we can add to make it even better.” And the same thing with the checkpoint inhibitors that you talked about. Those are not being used by themselves but they’re being used in addition to other myeloma standard therapies. And even what you said about the new proteasome inhibitor. I kind of wonder if you could end up using two proteasome inhibitors if they’re hitting different parts of the proteasome.

Dr. Lendvai: Absolutely. That thought has crossed our minds too.

Jenny: Well, it’s amazing what you’re working on and the variety of clinical trials that you have opened is really impressive. This is the benefit of going to an academic center. You have options like this. Well, I want to reserve a little bit of time for caller questions. So if you have a question for Dr. Lendvai, you can call 347-637-2631 and press the 1 key on your keypad. So, we will start with our first caller question. Please go ahead with your question.

Caller: Jenny and Dr. Lendvai, thank you for taking my call. First of all, I want to say how impressed I am with the Myeloma Crowd Radio. Week after week, you have this amazing breadth and depth of knowledge that you want to share with us directly. So, thank you for your service and for taking the time, both of you.

Jenny: Thank you.

Caller: Dr. Lendvai, it caught my attention when you mentioned the relapse is near and dear to your heart. If someone were to come out to Memorial Sloan Kettering that is relapsed and participated in a trial, how long does this study take? How long would I have to be there?

Dr. Lendvai: That’s an excellent question. That really depends. Most studies in myeloma will allow patients to stay on as long as they are benefitting, not all but most, and certainly in the relapsed myeloma setting. So if you’re tolerating the drug and you’re continuing to respond, you would be able to stay on study. Now, some studies like the selinexor-ixazomib study, certainly  for the first couple of months, people come in monthly. Some studies that are more intensive are difficult to do if you live far away. Many of these studies, or at least some of these studies, are not Memorial Sloan specific. So if you contact us, if we find a site that’s closer to you, we may be able to direct you there. And then there are also scenarios where you may be looking at another transplant, let’s say, but you need something to get your numbers down. So if you have the ability to stay close to New York for a few months, you may want to see if there’s something that we can give you to try to get you to where you want to be. Does that answer your question?

Caller: It does. So, there may be a possibility to do a study closer to me if I come out where, depending on the study, it could be once a month or it could be more intensive and I don’t have to be there for an extended period of time.

Dr. Lendvai: Right. Like I mentioned, the BCMA antibody study is an infusion once every three weeks. Depending on where you live, that may or may not be doable, depending on your circumstances. Yes. Certainly, some of these studies will have other centers that are closer to you.

Caller: It sounds like it would be very expensive to participate in this study because spending multiple months in New York with my wife, I’d go broke with all the shopping.

Dr. Lendvai: Yes. If we may have a budget for some of your travel expenses but probably not for Bloomingdale's? But please by all means, call us offline or off the air to discuss your particular circumstance and see if we can help.

Caller: No. All right. Well, I have a follow-up question.  One, is it too late to join a clinical trial if I’ve run out of other options? At what point?

Dr. Lendvai: I’m so glad you asked that question because this is truly, really important, and it’s something I wanted to mention earlier. My first reaction was it’s never too late, but actually, that’s not correct at all. A lot of people are saying that clinical trials are for those who run out of other options. The reality is that when people are out of other options, then usually they don’t qualify for clinical trials. And the reason for that is that all clinical trials will have some sort of a minimum requirement for how well your kidneys have to work, for what your blood counts have to be. And very often when patient’s myeloma has this coming back for the tenth time, they just are not able to meet these requirements anymore.

Caller: I have kind of a controversial follow-up question then. You probably guess what it’s going to be. But if you have to meet a certain requirement, are doctors trying to just improve the outcome of the clinical trial and they don’t want to mess it up with the patient that will hurt the numbers even though it could possibly work on that patient?

Dr. Lendvai: Well, the reason -- and now we’re really talking more about relapsed clinical trials, right? So, the reason that we have these guidelines, -- and again, it’s different for every trial. But the reason we have them is that when we’re working with a new drug that we have relatively little information on, we may not know all the toxicities that we will see. We want to make sure that you’re safe to the best of our ability. Let’s say that someone’s kidney function is really marginal. They may actually have more side effects from a drug if that drug is cleared through the kidneys or impart cleared through the kidneys than the next person. When we first are learning about a drug and how to use it safely, we want you to have a little bit of reserve so that if things that were not completely anticipated happened to you, you’re still safe. The other part of the issue is that if, let’s say, your platelet count going into the study is very low, and the drug reduces the platelet count further, well, you’re still safe but we may not be able to give you the studied drug for a week’s wait because we’re concerned about decreasing your platelet count even further, then you’re not getting the studied drug, you’re not getting any other treatment, you’re just sort of waiting around. So there is actually a reason that I think is to protect patients that we have these requirements, and these requirements tend to be more relaxed as the studies get to later phases. For example, a phase 1 study may have more strict requirements than a phase 2 study where we have more experience. Then we’ll know better how to keep you safe.

Caller: That makes sense. And also, maybe the possibility of an off-label or a compassionate use if you don’t meet the trial requirements as it’s later on.

Dr. Lendvai: Yeah, that’s a possibility in certain circumstances, yes.

Caller: All right. Well, thank you. I took more than my time, so I feel guilty. But thank you so much for answering the questions and also taking the tough questions.

Dr. Lendvai: Thanks for calling.

Jenny: Well, Dr. Lendvai, thank you so much for participating. We are so grateful to have had you join us. It really helps us understand not only selinexor but all you have to offer in clinical trials. So, thank you so much.

Dr. Lendvai: Thank you, Jenny. Thank you for having me. Thank you for having this forum for myeloma patients. I think it’s amazing, and really, thank you for all your efforts.

Jenny: Well, thank you again and we wish you well and we hope that we can help accelerate your research.

Dr. Lendvai: Thank you. Good luck. Good luck to all of your listeners, and let us know if we can help.

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