Natalie Callander, MD
University of Wisconsin 
Interview Date: September 30, 2019

Cancer cells have a different thickness of cell membrane than normal cells. A new treatment is exploiting that difference by delivering a targeted therapy to just the cancer cells while avoiding the normal cells. Cellectar is developing a new treatment called CLR 131, which is a compound that allows the delivery of a radioactive iodine to enter specifically into tumor cells. Radioactive iodine has been used for many years to treat thyroid cancer and has a long history of safety and a short half-life. Dr. Callander describes how this is being used in multiple myeloma and other blood cancers to treat relapsed disease. 

Thanks to our episode sponsor

Jenny: Welcome to today's episode of Myeloma Crowd Radio, a show that connects patients with myeloma researchers. I'm your host, Jenny Ahlstrom. We'd like to thank our episode sponsor, GlaxoSmithKline, in their support of Myeloma Crowd Radio.

Before we get started, we'd like to share an update on a tool we created called HealthTree. As many of you know, HealthTree is an online tool you can use to track your myeloma in a single place, find personally relevant treatment options, find clinical trials you can join that you're personally eligible to join, capture your myeloma story and to help accelerate research. One way that you can do this is to join a study inside of HealthTree as we're using HealthTree as a study tool.

So recently, I shared an article on the Myeloma Crowd website about the microbiome which is kind of an expanding field in myeloma and a whole new area of research that's just opening up. The researcher mentioned a pathway called interleukin-17. When I posted the article, another patient commented on that article asking how IL-17 and psoriasis related to myeloma. So I thought that was a great question and did some more research learning that IL-17's pathway that drives bone damage as related to inflammation in myeloma and there are anti-IL-17 drugs for psoriasis.

So now we're going to run a formal data study in HealthTree or an observational study, working with patients who have both psoriasis and myeloma. So far, there are about 50 patients in HealthTree that have both diseases. So if you have both diseases, which are both autoimmune disorders, you can create a HealthTree account (www.healthtree.org ) and make sure you answer the psoriasis question in the full health profile. We'll reach out and see if you'd like to participate in a study. This is just one of the ways we believe HealthTree will help identify completely new hypotheses that we might not have put together before and accelerating getting cure, and it's very exciting.

Also exciting are new approaches to myeloma care. Today's show with Dr. Natalie Callander is one great example. There's great innovation happening in myeloma today. Today, we'll be talking about a completely new approach to those that currently exist in today's standard of care.

So Dr. Callander, welcome to the program.

Dr. Callander: Thank you very much.

Jenny: We're so happy to have you. Let me introduce you before we get started.

Dr. Natalie Callander is Professor of Medicine and Director of the Myeloma Clinical Program at the University of Wisconsin. She's also leader of the Myeloma/Lymphoma Disease Oriented Team. Dr. Callander graduated magna cum laude from Yale University and completed her medical degree at Tufts University and residency and fellowship at NYU and UCSD. She's named one of the Best Doctors in America over a decade long period and is listed as one of Madison magazine's top doctors in oncology and hematology. She's received the Patient Experience Physician Champion Award from the University of Wisconsin many times and serves on many committees, including the BMT Clinical Trial Network Steering Committee. She's part of the ECOG group that runs many national clinical trials and is also on the NCI Myeloma Steering Committee. That's just several of many things she's working on.

Dr. Callander leads many myeloma clinical trials as principal investigator and has been the lead investigator on many new studies and new approaches such as daratumumab, transplant studies, smoldering myeloma clinical trials, targeted inhibitors, and the study that we'll discuss today.

So Dr. Callander, thank you again for joining us to discuss this completely new and unique approach.

Dr. Callander: Thank you very much for the opportunity to talk about CLR 131. I'm very happy to.

Jenny: Yes, we're excited to hear more about it because it's just something new and really completely different than other things. So this is from a company called Cellectar, right? So can you explain how CLR 131 works? What is it?

Dr. Callander: Yes. So this compound actually came from an observation that was made a decade ago that was looking at the cell wall membranes for tumor cells. There are many differences between tumor cells and normal cells. One difference is that the lipid, the fat content, and arrangement of the fats in a cell membrane seemed to be different in a cancer cell rather than a normal cell. Something that we call lipid raft appeared to be different.

So originally, a group at University of Michigan and then later at our institution, University of Wisconsin, looked at this and said, we should figure out a way to exploit this. We should try to figure out a way to use this information to do several things. One was to originally think about ways that you could image tumor cells very specifically by using compounds that could get into these abnormal cells with these abnormal membranes, but along with that was to also develop a way to figure out if you could bring drugs into those cells directly and avoid normal cells in the vicinity. This is really how this project began.

So specifically this compound, CLR 131, is what's called a phospholipid ether. That's the compound or that's the element that allows the compound to enter the cell preferentially into tumor cells. We tested this compound in a number of different tumor types over 50 and found that it did, in fact, seem to enter these tumor cells in various cell lines preferentially over normal cells. But the idea here is that the basic part, this phospholipid ether can then be connected to various substances, either those that you could use to take pictures to do imaging, or you could actually do therapy.

So one of the ones that we were very interested in was attaching this to radioactive iodine, or what's called I-131. Specifically turning to myeloma, some of your listeners may know that radioactive iodine is the substance that's been used for many, many years to treat overactive thyroid or thyroid cancer. So it has a long history of safety. And as opposed to some types of radiation, we also know that the time that it sticks around what's called the half-life is relatively short. It's about eight days.

Furthermore, as many of your listeners may know, that radiation therapy is actually one of the oldest treatments out there for myeloma. This was something that was really started in the early 1920s. For many years, this was actually the only method of treating myeloma. It's used less and less today as we have better drugs. But as some of your listeners may know, it still seems to be a very good method to treat things like bone lesions that might be very painful, or if you have one isolated spot of myeloma, what we call a plasmacytoma, it can be very good at treating that. Actually, in some patients, that therapy in itself is just curative.

So what we decided to do was pair these two modalities. So we developed this drug, CLR 131, which is this phospholipid ether attached to radioactive iodine. We were very excited because of those different cell types we tested, myeloma cells, in particular seem to be quite sensitive to this approach. So we developed a clinical trial that is currently going on. We actually have two. And let me explain to you a little bit of what these are.

The first one is what's called a Phase 1 trial. As your listeners probably know, a Phase 1 trial is basically a trial where you're trying to figure out the optimal dose of a drug and also side effects. Of course, in this kind of compound, we had used it for imaging purposes in some patients with solid tumors. These are things like kidney cancers, lung cancers, things like that. So we knew that this compound could help us image, but we were wondering about how effective it might be.

So we have started the original study. It's what's called a Phase 1 study and have gradually increase the doses of radioactive iodine that we're delivering over time. This is also done in a very careful stepwise fashion to make sure that at each level, the drug has safety. And then as you get into higher doses, that's when we're looking to see whether there's really some efficacy, whether there's really some action.

So we are now at a dose level that we feel that we are seeing about 50% of the patients respond to this treatment. A response in myeloma, as I'm sure many of your listeners know, means that you see at least a 50% reduction in an M-protein, that's the IgG or IgA level, or you see a 90% drop in light chains if that's what your myeloma makes is light chains only. So we are now at a time where we're seeing about 50% of the patients respond.

One thing that we're very excited about with this compound is we're seeing one major type of side effect with it, and that is that we're seeing patients have lower platelets in a lower neutrophil count usually for a period between a week to 10 days. Oddly enough, one thing that seems to be helpful to actually minimize that is to do what we call splitting the dose. So we are also testing out giving a dose, sort of a half dose, essentially one week apart, and that seems to help us limit some of the side effects in terms of low platelets and low neutrophils.

On a very positive note, the things that we're not seeing is that we're not seeing nausea or vomiting. We do not see hair loss. We have not seen an increased risk of various types of infection so that many of our participants, at least at our institution, have actually been in their 80s. We felt very comfortable treating with this because the side effect profile, otherwise, has been very, very, very good.

Now, one thing that we're trying to figure out is then what kind of patient might be best for this type of treatment. We have had people who are very, what we call, refractory. That means that they're not responding to their current treatment or their last several treatments. We've also had patients on this trial who have no longer responded to daratumumab as, again I'm sure your listeners know, one of the most widely used drugs originally for relapsed myeloma, now this is being used as part of newly diagnosed myeloma.

What we're hoping to do, we have our second trial which is actually looking at a fixed dose of this drug, and we're using it in myeloma that may be a little bit less advanced or through some fewer treatments. But we're also examining this drug in other types of blood disorders, specifically various types of lymphoma. That includes things like diffuse large B-cell lymphoma, mantle cell lymphoma, chronic lymphocytic leukemia, and a couple of other varieties. We're also seeing responses in those patients as well.

Jenny: Can I ask you a question about that?

Dr. Callander: Sure.

Jenny: When you are targeting -- because I know this drug has been thought of in also head and neck cancer.

Dr. Callander: Correct. That's right.

Jenny: And other type cancers. So how do you get that to be targeted to those particular cancer cells if they're different targets?

Dr. Callander: Right. So what we're capitalizing on here is this mechanism in the cell wall which we think is shared by lots of tumor types. So these changes in the cell membrane, in the envelope, if you will, that contains the cell guts, that it is different than normal cells in a lot of different cancer types. We think that those types of differences allow various things like it helps it have the ability to pump out chemotherapy drugs fast. It might help in cell migration, in development of metastasis.

So these are features that are shared by lots of different tumor types which is why we are testing it in other tumors. As I mentioned, some of our initial what's called preclinical work, that's the name of experiments that you do before you start treating patients. It seemed like this compound had activity in over 50 different tumor types. So we think that it may be a good approach.

Part of the reason that we picked, as you mentioned, head and neck cancer in children, we are looking at rhabdomyosarcomas, but part of the reason we're looking at that is those are tumors traditionally that have had sensitivity to conventional radiation therapy. Therefore, we thought those were good types of tumors to pick for this type of approach.

Jenny: So it's not like with daratumumab, where you're looking for CD38 on the surface of cells and how it's having an impact. You're just looking at this type of cell membrane and regardless of the cancer type that might be inside the cell, you can tell that it's different. If you had a few different cancers, that might target both of them at the same time.

Dr. Callander: Right. This is an approach that I know you're very aware of in that more and more we're kind of doing this as a different approach, if you will, in cancer treatment is many of you may know that the traditional approach to cancer has been to say, okay, we're going to treat myeloma this way, we're going to treat colon cancer that way, breast cancer a third way, but we're going to think that they're all different. As more of the biology of tumors has been investigated, it's clear that there are mechanisms that tumor cells share so that not everything is the same between myeloma and a colon cancer, for example, but there can be some features that are similar, so some of these pathways.

You mentioned at the beginning of the show talking about IL-17 production, that is something that can also be seen in other tumor types so that we think maybe the future of cancer treatments are to capitalize on shared mechanisms between cancer types and not just on what the cell of origin, if you will, that it's coming from a blood cell like myeloma or it's coming from a colon cell like colon cancer

Jenny: Yes, that's really unique and a completely different way of thinking about it which is nice because then you can go more broadly.

Dr. Callander: Well, that's what we're hoping. We think biologically that makes sense, that for tumors to grow, they do share some mechanisms that seem to be similar, not universally and there are certainly some important differences, but we think that this more and more makes sense to look at these kind of shared mechanisms. What that means is that we hope that there's going to be a move in the future to sort of repurpose other drugs that might have been used for different interventions, maybe even not cancer indications that there may be a role down the road for this kind of investigation which I think is very, very exciting.

Jenny: That's so interesting. So you talked a little bit about the Phase 1 study and that you're testing for safety and dosing, and you think you have the dosing nailed down. Can you give us a little bit of perspective? Because you're seeing all this. You've run so many trials, and you're so experienced with it that you know the relevance, how exciting this is out of a Phase 1 study? Can you help patients understand that?

Dr. Callander: Right. So many, many times when you're doing a Phase 1 study, one of the things that, and again, if somebody has participated in one, you're not sure if the drug or the intervention is going to have activity. So we could tell early on that we were seeing some declines in monoclonal protein levels, but they were sort of transient. It's now that we are at a higher level, we're very happy about that, that they seem to be durable.

Now, one thing that I think patients, in particular, have liked about this approach, as I mentioned, we give patients either one or two injections and that's it. That's the therapy. We are asking for a few weeks that patients take some dexamethasone weekly. That was something that we built, and originally we weren't sure if we if that would be necessary or not. It's conceivable that in future, for the lymphoma patients, for example, it was not required. It is probably something we're going to phase out. But what my patients have liked particularly about this approach is that you're not taking drugs the rest of the time.

So instead of being maybe on a weekly infusion or taking several types of pills every day or maybe once a week, this is sort of a one or two and done approach which many patients appreciate. Like I mentioned, we actually had older patients. I've had several in their 80s who had been on this protocol. The nice thing is that that has been, I think, beneficial for their quality of life.

Now, the other thing is, as everyone I think on the call knows, right now we still don't believe that we have the cure for myeloma. We also know that if patients have gone on to progress on this particular treatment, that they can also take other therapies. So that hasn't seemed to interfere with that either which is also something you would like to know, that a person can go on and receive different therapy. So that's been true.

One thing that we're very interested in as cancer doctors is what could you do with this drug in combination? It's very difficult to start thinking about combining a drug realistically until you're sure that you know all the properties before you'd say like, well, could you give this with an IMiD drug like lenalidomide or pomalidomide, or could you give this with an antibody drug? Several of my co-investigators have been very interested about potentially using this as an additional ingredient in autologous stem cell transplant. We think that might be something to consider. But what we're still trying to do is make sure that we are able to identify the benefits and also make sure that we have fully characterized any potential side effects. That's why the studies are continuing just with the drug by itself at this point.

Jenny: Right. If it is a single-agent trial, maybe you can explain the difference between a single-agent trial and some of the trials where you're studying combination therapies.

Dr. Callander: Right. So as many people know, in myeloma, with the sort of the new paradigm or the recent paradigm of how to treat people, both a diagnosis and a relapse, is to use multiple drugs at once. In order to say that any drug in cancer research is helpful, you typically do have to have a period of time where you're testing it exclusively by itself, and that is primarily to look at a safety profile because if you started off saying maybe giving this drug with lenalidomide or maybe bortezomib, two very commonly used drugs in myeloma, and then you start seeing, for example, low platelets or low white cells, it would be confusing to say, okay, which of the drugs is causing it, or is it a property together?

That's one of the reasons we test things by themselves initially. We do already have data long ago from using lenalidomide as a single drug and bortezomib as a single drug. So we know what those kind of rates of low platelets and low white cell counts are. So by the time we get ready, potentially, down the road to combine this particular drug, CLR 131, with other drugs, we have a pretty good idea of what some of the combined side effects might be. But this is pretty standard in cancer.

The other thing I think to share with your audience is one of the best characterized mouse models in myeloma is a model that was developed originally through the Mayo group in Scottsdale, Arizona. It has a special name called the kappa mixed mouse. This is a mouse that has been engineered to essentially develop myeloma over time. This mouse model has been used a number of different ways, but one way is to sort of screen drugs, if you will, for use in myeloma. The investigators that have worked the most with this mouse model published a few years ago their analysis, and that showed that if you didn't have at least a 20% response in this mouse model, that you were probably not going to have a successful drug in myeloma, and they gave various examples of this.

So we've done some testing in a mouse model and have shown much better than 20%. As I mentioned, right now the dose we're at, we're showing about a 50% response rate. So that means, as I mentioned, those parameters are what a response rate is. So we're excited that this is really going to be able to go someplace in the future and help more patients.

Jenny: It sounds amazing. So when you said in a Phase 1 trial that, I mean, you're successfully treating older patients and it's maybe dropping the lower platelets, but the half-life is pretty short. So do they recover after that? You would think they would, right?

Dr. Callander: They do. This doesn't sound logical that this would somehow be better, but it does appear with this split dosing that the impact on platelets and neutrophils, those are the preformed white cells that come ready to fight infection, it seems to be less severe, less low and less long so that we have had a few patients that have required transfusion support for a period of time that patients recover. And then, as I mentioned, one test is, besides durability response is, can you go ahead if the patients need it somewhere down the line and treat them successfully with other drugs and not worry about their blood counts? We've been able to do that.

Jenny: Yes, it sounds like a great approach. Would you ever consider doing another dose later to add to the response? I mean, this is like a one and done which is awesome and patients love that, but what about in the future?

Dr. Callander: So in our Phase 2 trial, what we call the CLOVER trial, we are allowing patients, if they have tolerated, if they've had benefit, if their physicians who are treating them think this is appropriate, to go ahead and have a dose somewhere around nine months later to hopefully maintain a response. So that is an option in the Phase 2 trial. So this is again difference between Phase 1 and Phase 2.  Phase 2, we are studying a dose, and now we are looking more for the effectiveness rate in various types of blood cancers. As I mentioned, this Phase 2 study includes myeloma, but it also includes different types of lymphoma. So we are offering that option in that trial to receive a second dose of treatment.

Jenny: Well, let's talk a little bit more about this Phase 2 study, this CLOVER trial. So what type of patient -- I mean, you mentioned that you're combining it with lymphoma, so that's great. The lymphoma patients can join also. But specifically for myeloma patients, what type of myeloma patient would be joining your trial? How many lines of therapy have they had to have and that kind of thing?

Dr. Callander: Sure. So we have some criteria that patients have to meet, and they cannot be newly diagnosed. That is clear. They can have had any number of therapies, so there's no maximum number, which is nice. They have to have had at least two treatments, but there's no requirement that says, for example, that they have to have had a stem cell transplant. That's not required. They can have had previous radiation therapy. But as maybe some people know, if you are irradiate, say, a spot of bone for cure or to completely kill the myeloma in that area, there can be sort of the maximum amount of radiation a person can have. So if they had had extensive radiation previously, that can be a reason that they would not be eligible.

We do ask that patients have a reasonable platelet count. Currently, our cutoff is around 100,000. They can be on anticoagulant. For example, some people in your audience may know that if you've been on a drug like Revlimid and pomalidomide, those drugs can predispose patients to have blood clots. So if a person has had a blood clot but they're, otherwise, doing okay with it and they're on a stable dose of anticoagulation, that is fine.

One thing that we always wrestle with is how to enroll people who, for whatever reason, are not making very much protein. So those people around, those are non-secretors. We actually are allowing them on if they have something that we can measure. So by that, we might mean, okay, it's something that could be potentially evaluated by a PET scan. I think some people know, as patients live longer and longer with myeloma, we certainly are seeing patients who end up, for whatever reason, their myeloma cells stop making protein or very much protein, and that tends to disqualify them from many, many protocols.

So really, we think that for the Phase 2 study, the requirement that you have, to have at least two prior treatments, we do want you to have either bortezomib or some other proteasome inhibitor like carfilzomib or ixazomib and an IMiD. But as long as you had those two prior regimens, you could have had 20 prior regimens and if you meet the other requirements, that you will be eligible. Again, that's a fairly common thing. When you're testing a new compound, you'd like to make sure that you really do get a wide scope of patients because you're checking out how this is going to work. We think that the requirements for the blood counts means that we will still be able to treat people reasonably because they have to have some type of marrow function still around. As I mentioned, they have to have a platelet count, of at least 75,000, and a neutrophil count of at least 1,000.  

Jenny: Okay, well, great. Well, I like that inclusion criteria that you can try people that are non-secretors because very few trials are open for these people, and it's very frustrating.

Dr. Callander: It is extremely frustrating, yes. I have patients who are continually thwarted by that.

Jenny: We talked about this a little bit earlier in the show. You hear about precision medicine and all these targeted inhibitors going after a particular type of genetics. This is not the case, right? In your Phase 1 study, did you see any differences in patients who did or didn’t respond based on genetics or no?

Dr. Callander: As far as we can tell, still the number of patients that we had is still reasonably low. We've looked at things like high-risk cytogenetics, and that has not seemed to make an impact in terms of response. So I don't know that we have enough patients yet to say, okay, this is a person who is likely to respond versus one who is not likely to respond. In general, as you probably are well aware, when you're talking about myeloma trials, unfortunately, the people who've had more therapies tend to have the shorter time for response. Each time they get treated, it tends to be shorter and shorter. We've had some penta-refractory patients join the trial, that means people who have had both IMiDs in use here, that means both lenalidomide and pomalidomide, Revlimid and Pomalyst. They've had both Velcade and Kyprolis, and then they've also had daratumumab or Darzalex

So that kind of patient group we know from some retrospective data, unfortunately, tends to have often a very difficult time and might have a survival that's limited to just a few months. We have treated a couple of those patients and have been pleased with their responses. So I think though, to be very clear about who might be the best patient to benefit from this treatment, I think we need to treat more patients, and we're really hoping that some interest, say, from this radio program that we may be able to offer this to more patients

Jenny: And then it is happening at your location because you're leading this study. Are there other locations where it's going to be open?

Dr. Callander: Yes. So it is open currently at Loyola in the Chicago area. It is also open in Mayo Clinic in Jacksonville. There are sites in Seattle. Because there needed to be some experience from the radiation oncology or program, we do still have it limited just to a number of sites, but I can provide you all of them later. So there are places to find us. If you enter CLOVER-1, if you go into Google, you can find it, or Cellectar, they have a list of all those various sites

Jenny: When we put the transcripts together, we will include a link to the file, so people can find it too. How many total patients are you hoping for in the Phase 2 study?

Dr. Callander: We are hoping to have at least 20 of various tumor types. So that includes myeloma. We are a little bit still trying to figure out which patients are going to which trial. So we are looking at trying to accrue both of our Phase 1 and our Phase 2 trial. There are, as I mentioned, we're trying to do 20 of each type in the Phase 2. So that means it's like 20 patients from diffuse large cell lymphoma, 20 was mantle cell, et cetera, 20 was CLL. We feel by treating a number of patients, we'll have a good feel for how we're doing. Again, the difference between the Phase 1 and the Phase 2 is that we are allowing patients to consider a second round of treatment which we hope may keep patients off other types of chemotherapy for a long period of time.

Jenny: I love that idea because sometimes, you know, I know even when you talk about stem cell transplant, you're getting this large dose up front. In myeloma, in my opinion, you get your therapy over time, or you get it all at once, but you still get it.

Dr. Callander: Yes. I think one thing that you I'm sure know and know from your work in talking to lots of patients, I think, sometimes we are sitting back and saying, okay, well, why don't you take drug x now for three years or 10 years? We want you to continue on that every day. That's our plan. I think most of the patients that I see, for example, they really get tired of that, and they get tired of that there may not be intolerable side effects, but they are side effects nonetheless. I think people are also very cognizant of the fact that for some of these drugs we are worried maybe about some increased long-term risk, or we don't know what they are. But at least in my time working in myeloma, the treatment lengths are increasing, not decreasing. I think many patients would agree that this is something that if they had a way to either limit their treatments, they would really love to do that. We're hoping that this particular CLR 131, if it works out the way we hope it does, it's going to be an option that would essentially take people off therapy for some time which I think most patients really appreciate.

Jenny: Yes, they do appreciate it. I think sometimes too I've heard other doctors say that sometimes stopping treatment gives your immune system a break to kind of retool. So you can keep fighting other things, even infections or whatever. Maybe we want to talk about that just a little bit because you mentioned this a little bit earlier about how it might interact with other myeloma therapies. Do you have any indication at all? Because this is kind of an older technology, in a sense, not this one particularly but just the approach overall, how it might interact?

Dr. Callander: One area that we're actually hoping that we might see some ability to think about this, unfortunately, again some of your listeners know and I'm sure you're very aware, there's a lot of excitement right now in CAR T therapy for myeloma. But even people who enter what appears to be a complete remission and by that I also mean what's called minimal residual disease negativity, there are some people who unfortunately still relapse.

One exciting area that we think this drug might be able to move into is that there is some laboratory information that would suggest that sometimes a low amount of radiation might sort of reboot those CAR T-cells. So we're wondering about this kind of intervention. Say, for example, if a person's CAR T transplant failed, whether this might be a way to reset it, there's something that's been called an abscopal effect, if you will. This has been an observation made many, many years ago in other types of tumors that seemed to be more immunologically driven, one of the common ones is melanoma. I'm sure people get myeloma and melanoma mixed up. Melanoma is the skin cancer that metastasizes. The observation was made a number of years ago that you could irradiate one site of melanoma and potentially show that other sites regressed, went away on their own, stating that there's some sort of immunological effect from that radiation dose. So that is an area that we're interested in.

One thing that is very clear is many of our myeloma drugs like lenalidomide, like pomalidomide have probably numerous methods of action, not just the cereblon pathway that probably some people have heard about. So whether incorporating our drug, CLR 131, with those that we might be augmenting the immune system, you mentioned, we're talking about the microbiome, for example, I think we're only at really the tip of the iceberg here, trying to figure out the importance of a person's microbiome to, say, cancer responses. It's not only people are looking at change as, say, one person's microbiome to another, but that leads you to the next area. What if you change the microbiome, would that somehow do immune system boost? I suspect there's going to be a lot of research in that area in the future, trying to either augment certain bacteria types. But again, I think we're just at the very, very beginning of even having a glimmer of understanding of this.

So we do think that -- again, you may be very aware of this and some of your listeners -- there's always been this sort of ongoing tension in myeloma treatments with one sort of camp being you must wipe out every last myeloma cell in order to be victorious, and then there have been other people who have said, well, no, if you could just get a person's immune system to sort of tamp down their myeloma, yes, you might still have an M-protein and measure it. But if it turns into sort of like MGUS, that precursor state where really no organ damage is happening but your immune system is somehow controlling it, maybe that should be the goal. Maybe that's what we should be going for. There really are sort of different schools of thought about whether one should be the goal or the other. Again, I think there's going to be more back and forth about this kind of strategy, if you will.

Jenny: Yes, there's a lot of study being done on that. You mentioned minimal residual disease negativity and approach that you kill it all. What's your opinion on where MRD testing is headed? Because it seems to be a big topic nowadays.

Dr. Callander: Right. Well, I think there is still more to know. I think the jargon that people will use in this field will say is MRD actionable, and by actionable, it means if you do something about it, does it actually change things? Because there is the possibility that a person who becomes MRD negative, what that means is that their myeloma was somehow easier to treat or easier to control. It didn't mean that the therapy was so great. It just meant that their myeloma was easier to control.

So the studies that are looking at two things. One is if after whatever type of treatment, if you still are MRD positive, then you add more treatment to try to make a person MRD negative. I think it'll be very important to show if that kind of strategy makes a difference. Alternatively, if you're MRD negative, if you are able to take away treatment, that those designs, both increasing if you're positive and decreasing if you're negative, both of those studies are underway. The biggest one is a SWOG study called 1803 which is going to ask patients to have lenalidomide or lenalidomide plus daratumumab as a maintenance after a stem cell transplant, and after two years, if they're MRD negative, they're going to be randomized to continuing their treatment whatever it was they were assigned to or stopping it altogether. I think that's a very important study.

ECOG will be opening a study shortly that after your transplant and assuming you've been on Revlimid, on lenalidomide, if you're still MRD positive at that point, then you are going to be randomized to continuing Revlimid or adding in the oral proteasome inhibitor ixazomib. I think both of those studies are very important. There are studies going on Europe which sort of are following the same kind of strategy, do you ramp it up or ramp it down, depending on what your MRD status is.

So I still think that there's a lot to know. My own practice is that we do check MRD status after a stem cell transplant, but I think even the timing of when that should be done isn't clear either. It should be done 90 days after the transplant where most people are doing it, or maybe it would be more informative if it was done a year or maybe two years after transplant, you might get more information at that point. So I think there's a lot we still need to know about this.

Jenny: I hear some doctors talk about MRD testing too that it's not maybe the single data point but maybe just how this person's myeloma is trending over time. We're also different as myeloma patients. So that's hard to know.

Dr. Callander: Right. We just had a myeloma meeting for patients and caregivers here in Wisconsin this past weekend. One thing that was brought up, and I'm sure you have listeners who also have lived this, we do have patients who have had monoclonal protein, so they're not in remission but it's been stable for years and not on any therapy. Like I said, we don't want to overtreat all of those people. If their own immune system was going to do it for them, just sort of control it. But I think it's very hard. Most of our studies, I think, maybe a combination of sort of a big clinical trial, like that SWOG 1803 study that I mentioned, is looking to enroll 1,100 people. It's huge. But I think people who are also looking at things like precision medicine to maybe sort of select out people that might be more likely to benefit. I think those kinds of studies should go in parallel really.

Jenny: Well, the work you're doing is so important. I just do want to call out this meeting that you just had because you had about 400 myeloma patients attend this meeting in Wisconsin, and it's just huge and fabulous. So watch for it next year if you're in the area.

Dr. Callander: We have it on the calendar for next year and it should be September 19, 2020. The person who really deserves a huge amount of credit, because we were in danger of not having this continue, is Dr. Hari from the Medical College of Wisconsin. It's really been his work that kept this effort going and has really helped us expand it. So he is really the mastermind. I know that all of us really appreciate his efforts. Certainly, all of our patients here in Wisconsin and their families appreciate that.

Jenny: Amazing. Well, thanks for doing that. So on this particular treatment, how far along is it in other blood cancers, or has it been run simultaneously as you're learning what you've been learning about myeloma?

Dr. Callander: I think you that in terms of all the different choices for people, say, with lymphoma and myeloma for that matter, I think radiation still sounds a little scary to people. So we are competing with other therapies. I think that's made our development slower than we would like. I personally have treated patients with lymphoma on this trial and have had some outstanding results. So I think it is success begets success. And my own feeling is that the more we have participation, then we'll be able to turn and show other people, look, this really was helpful. It really did work.

One of my patients in particular had a recurrence of a diffuse large B-cell lymphoma after a stem cell transplant and was treated with this. The patient had two doses as part of the Phase 2 study, and fortunately, that particular person has not had a recurrence in a year and a half, and we're very happy about that.

Jenny: That's great.

Dr. Callander: Another patient I know on this study with a disease called Waldenstrom's macroglobulinemia, which is kind of halfway between myeloma and lymphoma, has also had a very, very prolonged response after this. We think that there's activity in other tumor types.

Jenny: At the beginning of the show, you mentioned that this type of radioactive iodine type treatment was used in thyroid cancer and things. I mean, there probably are decades and decades worth of long-term impact studies.  What do you think about that?

Dr. Callander: We know that in terms of things like secondary malignancies with these compounds, we really think that that's very unlikely. One thing that's done because the reason this iodine 131 is used to treat thyroid cancer in an overactive thyroid, so it's used for benign conditions of thyroid, is because iodine is taken up preferentially by the thyroid. So as part of our study, we actually block the thyroid from taking this up because we don't want anybody's thyroid function to be diminished. So they take what's called potassium iodine drops to protect their thyroid, so that blocks the thyroid from receiving this drug and that seems to be quite effective.

To my knowledge, we have not had anybody on the trials at this point who's had any long-term issues in terms of either thyroid failure or, say, another malignancy showing up, something like that. So we feel pretty confident that this is a kind of radiation that is well tolerated.

Jenny: Well, I think thyroid is impacted by other myeloma standard treatments, stem cell transplant or other types of things. So mine was, I know.

Dr. Callander: Well, both lenalidomide and pomalidomide have a rate of interfering with thyroid function, either making the thyroid inactive or less active or actually making it overactive. So again, you're absolutely right that those side effects can be seen with other drugs.

Jenny: This will progress through the Phase 2 clinical trial, and then the standard process is -- maybe you just want to walk us through how we take treatments like this and walk them through.

Dr. Callander: Yes. There's the scientific aspect, and then there's the practical aspect of this. The scientific aspect is we are hoping that we can define through both of these studies who are the patients that are most likely to benefit from these treatments, and that, of course, is the primary goal, and also to establish the best dose and also the safest dose. So those are our goals.

In terms of drug development, that is a very difficult field. I'm, by no means, an expert. This was a compound started in a research lab that then showed some promise. So a company, Cellectar, is developing it. They have their goals as well. So I'm sure one of the things that will happen is if, for example, the studies that are happening in pediatric oncology are more promising, at some point, the company has to make a decision about what they want to go for FDA approval for, whether it's in multiple myeloma or another type of cancer. I think we're not sure at this point what their strategy may be, and I think it's going to be based -- so I'm familiar with R2 blood studies. They are also running other studies, as I mentioned, in pediatric oncology and head and neck cancer. I think it would depend on which of these studies shows the most promise as to what they may do when they go ahead and try to seek out FDA approval.

One strategy that's being used right now in myeloma that I know you're aware of is, say, a drug like selinexor that was recently approved. What their strategy is they were going for what was felt to be an unmet need, and that is people who've had many treatments for myeloma and they're no longer working. So this is a group that we know is actually growing in number. That might be, for example, where Cellectar will go with this product and say, this is another option for people who have had very heavily pretreated myeloma who are looking for other types of treatments.

Jenny: Well, it's very exciting what's happening. So it'll be so fascinating to see how this progresses. We're just thrilled that you're working on it.

Dr. Callander: Yes, we're very excited.

Jenny: All these new approaches are just terrific, and the innovation happening in myeloma is really truly stunning.

Dr. Callander: I think one thing that's very gratifying to me as opposed to, say, 20 years ago, there are so many really smart people in the world trying to work on this, and the efforts that you and your group are doing, it's a terrific partnership because we obviously have our point of view when you're sort of developing to treatments. But as you mentioned, thinking about the IL-17, all of your efforts of trying to make sure that we are connected to patients, that we understand what's going on, that if there are patterns or specific ideas that come up, that we can try to work on them together. So I think this is a really great time. This is one of the really wonderful things about our interconnectedness is that projects like this can happen.

Jenny: Well, we are your cheerleaders. And if we can help do anything to share -- I mean, that was one of the big pushes of creating this radio program is patients need to know just what their options are. And if they know, you know, I'm thinking about two or three people that I know that are struggling with highly relapsed myeloma that might want to consider this treatment. So we have a lot to consider as a myeloma patient. We're just thrilled that people like you are pushing the field forward. So it's just really amazing.

I want to leave just enough time for questions, if you don't mind. So if you have a question for Dr. Callander, you can call 347-637-2631, and then press 1 on your keypad. We have a question at 310-5598. So go ahead with your question.

Caller: Hi, Dr. Callander. First, I just want to thank you so much. This has been very informative. And then my question is, you mentioned that you may want to use this treatment with stem cell transplant. Is that correct?

Dr. Callander: Yes.

Caller: So why do you think this would be a good combination?

Dr. Callander: Well, the reason I think that might be a good combination is that I think most people feel that one of the reasons that people can have an early relapse after a stem cell transplant, that's usually defined as earlier than 18 months after the transplant, is that we may have failed to eradicate myeloma cells. And so what we would hope is that combining this treatment, say, with melphalan, for example, that we would have a better effect at cleaning out the myeloma cells. And the other advantage would be, since we know that one of the side effects of this drug or the primary side effect is lower blood counts, that we could ameliorate that, we could help with that by having that stem cell infusion. So that's one of the ideas that we've had

Caller: Oh, okay. Thank you so much. I just wanted to know about that

Dr. Callander: You're welcome

Caller: Thank you.

Jenny: Okay, thank you so much. Well, Dr. Callander, thank you for joining us today to talk about this new approach.

Dr. Callander: Oh, my pleasure.

Jenny: Well, you explained it very clearly, and I was a little unclear on what it was before. So these types of shows so fantastic because you get to hear about it really in detail.

Dr. Callander: Good

Jenny: Well, keep going. We're cheering you on.

Dr. Callander: Okay, thank you. I appreciate that.

Jenny: And we hope you're very successful in everything you're doing. You're working on so many different things. So thank you for joining us today.

Dr. Callander: Okay, my pleasure.

Jenny: Thank you for listening to Myeloma Crowd Radio. We invite you to tune in next time to learn more about the latest in myeloma research and what it means for you.