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Engineered Toxin Bodies Targeting CD38 in Myeloma with Shaji Kumar, MD, Mayo Clinic
Engineered Toxin Bodies Targeting CD38 in Myeloma with Shaji Kumar, MD, Mayo Clinic image

Jan 06, 2022 / 11:00AM - 12:00PM MST
HealthTree Podcast for Multiple Myeloma

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Episode Summary

Shaji Kumar, MD
Mayo Clinic
Interview Date: January 6, 2022

We are familiar with monoclonal antibodies like daratumumab and isatuximab that link the immune system to a target like CD38 on the surface of myeloma cells. A new treatment called Engineered Toxin Bodies (ETBs) with a stronger mechanism of action is being developed by Molecular Templates. The ETBs move deeply within the plasma cell instead of just flagging the cell's surface. Unlike other CD38 targeted therapies, ETBs don't rely on the body's own immune system (the patient's T cells or natural killer cells) for effective myeloma-killing responses. ETBs deliver a modified bacterial toxin into the inner liquid material of cancerous plasma cells (the cytosol). When this toxin is internalized, it destroys the ribosomes (the location responsible for cell life or death). Learn more about this up-and-coming therapy that could even work in daratumumab or isatuximab-refractory patients by lead investigator, Shaji Kumar, MD of the Mayo Clinic.

Thanks to our episode sponsor

Full Transcript

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, Takeda Oncology, for their support of this Myeloma Crowd Radio show program.

Now, it's unusual for us to have back-to-back shows, but today, as well as yesterday, I want to wish everybody a Happy New Year. We have some wonderful plans for the new year, and we'll be introducing several new programs.

Now the theme at the HealthTree Foundation in 2022 is one of change. We think that if the COVID vaccine can be developed in 18 months, we can change and improve the way that cures are developed, especially for multiple myeloma. We already know that there's exciting change happening with the development of new myeloma treatment options, and we will be hearing about one of those new options today.

HealthTree’s goal is to help change the pace of myeloma research by providing myeloma researchers free access to HealthTree Cure Hub real world data that now has over 10,000 of you participating. Researchers can use HealthTree Cure Hub to run surveys or studies or just dig into the real-world experience of patients through the anonymized data. For example, that data could be used instead of using a control arm in a study making sure all patients get that trial arm treatment.

Now as far as we know, it's the world's largest and most comprehensive myeloma patient data set available. In addition to helping advance research by participating as a patient, you can also benefit by finding treatment options, seeing crowdsourced side effects solutions, participating in the forums and finding personalized clinical trials. You can join HealthTree Cure Hub at healthtree.org.

This year, we're also launching a Change for Change initiative where you can donate spare change and round up to the nearest dollar, for everyday debit card types of purchases. You can learn more about that on myelomacrowd.org. https://app.roundupapp.com/p/discover/details/9e597184-169d-11e9-8e15-0b66e02f4cf0

Now, onto today's show. Today's show is another new myeloma therapy called Engineered Toxin Bodies, and we are excited to learn about this from the primary investigator on this study, Dr. Shaji Kumar, at the Mayo Clinic. Dr. Kumar, welcome to the program.

Dr. Kumar: Hi, Jenny. Good afternoon, good morning, everyone. Thank you so much for having me on this call.

Jenny: Thank you so much for joining. Let me give an introduction for you before we get started. Dr. Kumar was named the Mark and Judy Mullins Professor of Hematologic Malignancies Endowment in 2020. He's on the editorial advisory boards for the Lancet, Clinical Oncology News, Advances in Therapy; and is currently associate editor for the American Journal of Hematology. He's a board member of the European Journal of Clinical and Medical Oncology, and the Leukemia Journal, and is a member of the institutional review board at the Mayo Clinic, which is the governing body for all Mayo Clinic clinical trials.

His clinical practice work includes stem cell transplant, the myeloma clinic work and the Mayo Clinic CAR T-cell therapy program. Dr. Kumar's research focuses on the development of new treatments in myeloma, primarily in phase one or phase two studies. He also performs research on combination myeloma therapies, bone marrow microenvironment, high risk myeloma, amyloidosis, and the progression of precursor conditions like MGUS and smoldering myeloma to active myeloma. Additionally, I just want to mention, he's simply the nicest person you will ever meet.

Dr. Kumar: Thank you, Jenny. I think that's probably the best part of that introduction. Thank you.

Jenny: You are the nicest. Okay, let's get started. It's so fun to hear about these new therapies in myeloma. We already know about the bispecifics, and they're on their way. CAR T is on its way. Hearing about these brand-new things that we don't have any experience with is really fun. Maybe you can give a little background on this new therapy by Molecular Templates.

Dr. Kumar: Absolutely. Thanks, Jenny. We have a lot of advances being made in myeloma, as Jenny mentioned. We have, obviously the bispecifics. Hopefully, one of them will be in the clinic fairly soon. We'll have a second CAR T in the clinic, hopefully in the next few months. Obviously very excited about those highly effective treatments. Knowing what we know about myeloma, I think we always need to have different ways to try and get rid of these myeloma cells, especially the ones that become resistant to the treatments that we have currently, so we're always looking for new mechanisms of actions or new types of therapies to deal with this.

We all know about the antibodies that are conjugated to, or attached to various kinds of toxins. We all started off with just the antibodies themselves, which all of you are familiar with, like daratumumab or isatuximab, Darzalex or Sarclisa, the trade names. Those are just the antibodies. They recognize the myeloma cell because of the protein on the surface and utilize the existing immune mechanisms to try and get rid of the myeloma cells.

Now, we take that one step further by adding a toxin or a poison to the antibody, which is what we have in the clinic, like belantamab mafodotin or BLENREP, which has been approved. In that particular situation, we are taking an antibody that recognizes a protein on the surface of the myeloma cells, and then the antibody is linked to a poison which then gets into the cell and kills the cell.

Now, the Engineered Toxin Bodies are different in that it doesn't really use an antibody that's linked to the poison. Instead, we’re just using the the part of the antibody that is responsible for recognizing the protein on the cell surface. It's basically a piece of that antibody which is artificially generated, linked to this poison.

The particular one that had some early results at the ASH meeting, again, this is called MT-O169; that one actually uses a protein that recognizes the CD38 which we know is present on all the myeloma cells, and that is the target for Darzalex and Sarclisa, molecules that recognize CD38; and then another half of that which is basically a toxin, which is produced by the same bacteria that cause the Shigella.

Basically, that toxin is linked to this, so you basically have a single protein that both recognizes and also have a toxin activity. That is what we studied. Again, this is very early study, phase one, just started treating a few patients to see what would be a right dose for this particular molecule.

Jenny: Okay, I think I might need a little more explanation about how it works. Because I understand the antibody drug conjugates like Blenrep and stuff, you talked about that, that it’s delivering this toxic payload and then dumping it into the cell. You're linking it more? I'm not sure I understand how that works.

Dr. Kumar: Right. Basically, instead of having that NDR antibody molecule or immunoglobulin molecule, like what we have in Belantamab, it's basically, if you look at the BLENREP, it is like you take a poison, which in this case, in Blenrep, is MMAF; and also basically link that to, let's say, the antibody like Darzalex, except that with BLENREP, it is recognizing a different protein, DCMA, instead of the CD38, like Darzalex.

Here, what we're doing is you're just taking that antigen or protein recognition piece of the antibody, and it is synthetically created. It's basically what we call a single chain fragment of the antibody that recognizes that, in which case, here, it is CD38. Then it is linked to an Engineered Toxin which is similar to what is seen in the Shigella bacteria. Basically, what it does is poke holes in these cells, so that single chain piece which recognizes CD38 brings the toxin into the cell. Basically, that toxin then does what it usually does in the cell, which is killing them.

Jenny: So it's more of you're linking to that recognition piece.

Dr. Kumar: Basically, it's a small protein compared to using an NDR antibody.

Jenny: Oh, interesting. Has ETB work or Engineered Toxin Body work been done in other cancers or other blood cancers, solid tumor cancers, anything like that?

Dr. Kumar: Yes, there are others studies that are ongoing. There is none that is approved right now for any of the cancers which uses this particular platform. It's very early on. I know there are studies that are ongoing in, I think, treating prostate cancer and others, as well as a lymphoma. Here, this particular one, targeting CD38 is specifically focused on the myeloma population.

Jenny: CD38 because -- maybe you want to give a little bit of background.

Dr. Kumar: Definitely.

Jenny: I think that will be nice.

Dr. Kumar: CD38 is present on all the myeloma cells, and this usually present in pretty high density, and that is the same, and also less with Sarclisa. CD38, we don't really know what the true function of that particular protein is, but it is present in a variety of cells, particularly in the myeloma cells, expressing at very high density, so the antibodies can very effectively bind to the CD38 on the end. That's an excellent way to target the myeloma cells.

Jenny: It's not necessarily on a lot of normal cells which is why it's a good target or -- because I hear investigators talk about that all the time. You have to find good targets that are not a lot of normal cells, so you're not damaging things.

Dr. Kumar: Correct. CD38 is present on some normal cells too, but the most intensity of that is on the myeloma cells. Unlike something like, for example, what we use a lot in Empliciti (elotuzumab), which targets SLAMF7, which tends to be primarily on the myeloma cells and maybe some, what we call, natural killer cells. The CD38 can be found on some other tissue as well, but the intensity is what matters. The myeloma cells have some of the highest intensity of the CD38, so they are likely to be much more targeted compared to normal cells. It's unlikely to cause unintended harm to the normal cells.

Jenny: I know patients who are on isatuximab or daratumumab. Some of them can relapse after that. Do we know what's the cause of relapse? Is it a loss of CD38? Because I wonder how that will affect this treatment at the same time.

Dr. Kumar: Yes, that's a very good question. There are multiple mechanisms through which myeloma cells escape treatment. One of them, especially with the antibodies, is to get rid of the protein that the antibody is targeting. Now that does not seem to be the major mechanism why patients stop responding to Darzalex or Sarclisa because most of these myeloma cells at the time of relapse still have CD38 on them. It seems there are other mechanisms in play. Maybe some of the immune mechanisms through which Darzalex works is what is getting shut down, rather than really the expression of CD38.

Now, having said that, we do see that CD38 just become a little bit dimmer on those cells, at the time of relapse, and when you check them later on, they seem to be brighter. Now, what we don't know for sure is how much of that is related to the Darzalex or the Sarclisa being bound to the CD38. Hence, the assays are not optimal. There are also some examples of patients, myeloma cells completely losing CD38, but it's very, very uncommon.

Jenny: Oh, okay. There are other ways which might mean you still have a target to go after, with a new therapy going after it in a completely different way. Yeah.

Dr. Kumar: Exactly.

Jenny: Okay. Well, maybe give us a little bit of background on this. I think this originally was a joint venture with Takeda Oncology, and now Molecular Templates is a different company moving it forward on their own. Right?

Dr. Kumar: That is correct. It really started off as a collaborative development, and for reasons which are unclear to me at this point in time, it seems like Molecular Templates has taken on the responsibility for moving this molecule forward, and the phase one trials are ongoing right now.

Jenny: That was my next question. What phase of trial is this? I think you might want to take a few minutes to explain just phase one, two and three trials, and how they work and what their objectives are, just in case people aren't familiar with that.

Dr. Kumar: Absolutely. It's a very interesting journey that these drugs take, from the time when they're first identified or discovered, to the point where they are used in the clinic. It also can be quite expensive and also can take a lot of time. Those time frames have shrunk in recent years, as we have more and more technology, different clinical trial designs, as well as ability to onboard patients faster.

The first time when you identify molecules, sometimes these molecules can be developed with a specific target in mind. A good example is you've probably heard about venetoclax in myeloma. That molecule was originally synthesized specifically to target BCL2 protein in the tumor cells, knowing that BCL2 is very important for cell survival.

Now, some of the drugs are identified because you screen a whole bunch of drugs, and you come up with one that seems to work better. There are plenty of examples of that in the clinic, including drugs like Revlimid and Velcade and so forth, which have come out of, again, screening experiments of multiple different subsets that have been developed to either target a particular mechanism, or they looked similar to something else that seemed to have worked in the past.

You screen them against a lot of different cell lines, and cell lines are basically cells which are derived from the tumor that can grow in a petri dish. They take those cell lines, apply these multiple different compounds to those cell lines, and find out which ones work the best. Then you take the best candidates forward and do more experiments, trying to understand how best do they work? Do they work better alone, or do they work better in combination with other drugs? You do all those work on cell lines, and then you take the promising ones to look at the tumor cell that come out of, again, the bone marrow biopsies that are done on patients.

So many of you on the call may have donated some of those tumor cells for clinical research. Those cells get used in assays where these potential future drugs are applied to. When you find that some of these ones work better in those tumor cells, we then take them into animal studies where we might use small animals to see, does it work outside the petri dish?

Once we feel like we have a molecule or a set of molecules that have significant efficacy against the tumor cells, then we have to do a whole series of what we call large animal studies that are often, again, sometimes in dogs, sometimes in chimpanzees. The different models are chosen depending upon the particular drug and the way that is metabolized by the body. The intent is to try and see what would be the type of side effects we should anticipate once we move into human studies.

Now, based on what the findings from those animal studies, then we do the phase one trials. These are the trials designed to understand what can be the side effects in humans, and what would be the ideal dose for a particular molecule to move forward. This is really the transition between just having a molecule in the lab, to actually having a drug in the clinic.

Those phase one studies often start with very, very low doses of these medications, and we have a variety of different designs that can be used where you might either treat three patients, if they look good, three more patients with that dose. If everything looks good, then we go up to next higher dose, and treat six patients and so forth.

There are also designs which can look at the data from one patient at a time, at each dose, what we call accelerated titration design where you can actually move ahead much faster, looking at a set of data, both in terms of side effects and also what the blood levels or the ability of the molecule to hit the target that we are going after.

Either way, the core goal of that phase one part of the study is to identify, one, what are the toxicities that we are seeing; and two, what is the best dose to move ahead to see if it is something that is effective. We will also get a good sense if whether this drug has efficacy. Let's say we treat 20 or 30 patients on a phase one study, and we start seeing some patients are starting to respond. The myeloma is actually slowing down with treatment. Then we know that we have something that's probably a promising thing before we move onto the phase two portion of the study.

The second phase of the study, the primary objective of that second phase of the study is to understand what kind of efficacy are we looking at? Is it at the dose that it's decided is safe to use? Is it 30% of the patients who are going to respond? Is it going to be 60% of the patients? Are there certain subgroups of patients who might respond better?

For example, with the Venetoclax, if you have a translocation 11;14 myeloma, we know that those patients would respond better. With that particular monoclonal antibody, maybe a subgroup of patients where the myeloma cells have high expression of that target, they may respond better. It tells us the overall efficacy, but also gives us some early ideas as to whether there are subtypes of myeloma that might benefit.

Now, once we get through that phase two portion, and we know that this particular drug X can respond in, let's say, 50% of the myeloma patients that were treated. Remember, these phase one and phase two studies are often done in patients where other treatments have stopped working. Once we get a sense of what is the efficacy and what groups of patients the drug works, then we look at phase three trials.

Now, primary objective of the phase three trial is to demonstrate that a particular drug either used by itself or in combination with ongoing or a current standard treatment, is better than the standard treatment. These are randomized trials where patients are assigned to one treatment, which is either the standard treatment or the experimental treatment, by the flip of the coin, that's why it’s called randomization, and to see if the new drug adds anything to the current approaches that we use in myeloma.

This will hopefully lead to the approval of a new drug, if that shows benefit compared to what we have. Now, for approval, the gold standard for all these clinical trials is to have a phase three trial that shows that a drug is better than what we already have. However, it can take quite a bit of time. If we already see that a drug can be quite effective in the phase two trial, we want to try and get those drugs to the patient sooner than the phase three trial results come out, and that is a pathway that has been used for a lot of myeloma therapies, what we call an accelerated drug approval that the FDA has put in place.

If we treat a sizable number of patients with relapsed myeloma who really don't have very many options, with this new drug, and you see that a significant number of them have now responded to treatment and have lived beyond what you would have anticipated without the drug being there, then the FDA often allows accelerated approval of the drug. We can use it in the clinic, with the understanding that a phase three confirmatory trial is ongoing, that will give you that definitive proof that this is indeed a good new, effective drug.

Finally, the studies which are often referred to as phase four or post-marketing studies, those are to collect more experience with a drug once it's approved and it is in the clinic. It is good to have a lot of the pharmaceutical companies to do that, so that we can understand what happens when these drugs are used in patients who might not have been able to get on clinical trials.

As you all know very well, a lot of clinical trials are hard to get into because you don't check all the marks. It may be because your white blood count is a little lower, or your platelets are a little low. We also want to know how these new drugs work for those patients in the real-world setting, and these phase four trials allow us to define those.

The second is, even though these phase three trials are large, they’re still limited number of patients. If you have a side effect that occurs maybe one in 1000 times, if 600 patients, phase three trials, nobody might have it. You might start noticing it once you have 10,000 patients treated with that drug. That's the importance of having those phase four or post-marketing trials.

Jenny: You're seeing how things work in the real world. That process that you just described, I think I've heard it said that the average is 17 years. Maybe you have a different number.

Dr. Kumar: Yeah, the average is longer but, Jenny, I think the good thing is those numbers are getting shorter and shorter. I think with some of these new therapies, they have gone from, definitely, at least from the first patient on the phase one study to being in the clinic, at about four to five years now.

Jenny: Yes, it's amazing. I think what you mentioned about phase two, after phase two, some of these myeloma drugs being approved, is really a radical idea that the FDA has been using, I think, to go ahead and get it out there into the clinic. Because you're waiting years to get results sometimes from these trials. How long do we need to wait? It's great.

Dr. Kumar: A word of caution. It’s a double-edged sword as well. There is some element of risk. Best example is Pepaxto (melflufen) that was just withdrawn from the market, which was approved based on the phase two studies, but then you did the phase three trial. It seems like not all patients benefit. In fact, some patients might be harmed. Yes, there is an element of risk. I think FDA is continuing to optimize that process to decrease that element further.

Jenny: Yes, that was so interesting because it was approved and then they didn't have the right confirmatory data. Good that they're watching it and took action. Okay, let's talk a little bit more about this study. This is a phase one study. Was there data presented on this at ASH?

Dr. Kumar: Yes, it was more in terms of a trial in progress. We were just looking at what type of patients are going to be going on the clinical trials. Right now, there's only a handful, under ten patients who have been treated so far. We do early phases. We have to be very careful with every single side effect, to make sure it is not related to that. At this point, the trial is working through that process of looking at the side effects that have been seen so far, and then trying to go up to the next dose level with the drug so that we can we can continue to learn on it.

Jenny: Because you're looking at dosing and you're looking at side effects, like you mentioned, have you seen any certain side effects that you see with this therapy? I don't recall how this therapy is given, I guess. I guess that's one of my other questions.

Dr. Kumar: Yeah, we don't really have a lot, unfortunately, not a lot of data. As I said, we have a handful of patients, and these are patients who have had most of their myeloma treatments have low counts to start with. How much of that is related to myeloma versus how much of it is related to the drug, becomes really hard to tease out. Hopefully in the next year, year and a half, as we finish up the phase one study, I think we’ll have a good sense of what this drug can do for myeloma.

This particular Shiga toxin that is being used, has been studied, not as in ETD, but also as in other formats, in other cancers, and has, in the previous studies, been associated with some increased leakiness of blood vessels, what we call a capillary leak syndrome. Again, we haven't seen any of that yet in this setting, but that is something which we have to be carefully watching out for.

Jenny: Okay, great. How many patients are needed in this phase on trial? Because usually, it's just a small number of patients for phase one, right?

Dr. Kumar: That is right. The phase one study, it all depends on where we start seeing those side effects. We keep adding six patients at each level. We are hoping that we should be able to get this done with about, somewhere between 30 to 50 patients.

Jenny: Okay, that seems like a big trial for a phase one study.

Dr. Kumar: Yeah, it could be lower too. If we start seeing some side effects at a lower dose level, it certainly could be. The variable that determines that it's going to be the best phase two dose, and I didn't talk about this before, is often based on the fact that you don't see side effects that would limit the use of the drug in in one or less patients, among six patients. If you see three side effects or three patients with that kind of side effects then, obviously, we have to go to a lower dose.

Jenny: Okay. Well, first, is this an IV medication? Or how is this administered and then how frequently, and how many cycles? Do you go on it forever? Do you stop after a certain time? How do you receive this type of treatment?

Dr. Kumar: You mean the schedule of the treatment?

Jenny: Yes.

Dr. Kumar: Basically, the patients are getting the treatments, IV. There are two different schedules that are being explored. There's one that is looking at weekly schedule, and there's also one that is looking at every other week schedule. In addition to the dose, right now, what is happening is we’re looking at the weekly scheduling, weekly schedule dose. Once we get to a point where we think we have reached the effective dose, we'll also start looking at the every other week and see if we can go with a higher dose given every other week, to see if the convenience of those things can be explored further.

Jenny: Yes, that would be nicer for patients if they don't have side effects that are going to impact them. Is this something you just stay on until relapse? Or is it something that's given for a certain period of time and you stop?

Dr. Kumar: Right now, the treatment is designed to be continued until the disease starts progressing, which is often the way we do these early phase trials.

Jenny: In myeloma, okay. Where is the trial open? Is it just open at the Mayo Clinic, or other locations?

Dr. Kumar: There are other locations too. We have it open at both the Mayo sites, Rochester and Jacksonville. It's also open at Vanderbilt. I believe they're also exploring some other institutions to open this up to.

Jenny: Let's talk about daratumumab for a minute. Because when I was trying to do some research for the show, it seemed like it could either be used in patients that were refractory to daratumumab, or even maybe combined with daratumumab, which I thought was super interesting.

Dr. Kumar: Yes, there are a variety of different trials now that are looking at combining with daratumumab. I think they are looking at daratumumab as a very good platform, again, because of the efficacy we have seen, and not a lot of hematological side effects, so that allows it to be combined with a variety of different drugs, including the other immunotherapies. For example, there was data presented on a different type of drug, the TAK-981, which is, again, it's more of trying to stimulate the immune system in a different way, and you're trying to combine that with targeting CD38.

There was data presented at ASH looking at the bispecific agents, like the teclistamab and the talquetamab, which are basically the new immunotherapies that are redirecting the T-cells to the myeloma cells, and they are being combined with daratumumab in the relapsed setting. Hopefully, these studies will allow us to move that even forward to the point where some of these new immunotherapies like bispecifics can be combined with daratumumab in newly diagnosed myeloma.

Jenny: I just think it's so interesting because it's going after the same target CD38 that you could use this in, or could you, let me just ask, could you use this in patients that are refractory or stopped using daratumumab because it stopped working for them?

Dr. Kumar: Sure. Sorry, maybe I misunderstood your question earlier. Yes, absolutely. Since this is a totally different mechanism of action, it's quite possible that this would work in somebody who's become refractory to daratumumab, once we figure out what is the right dose of the drug and make sure that the activity is good.  We don't have a lot of examples of CD38, one way of targeting CD38 followed by another way of targeting CD38.

We know for sure, if you do the same way, for example, if we use Sarclisa on somebody where the myeloma has stopped responding to daratumumab or vice versa, it's not really very effective. However, there are now CAR T-cells that are looking at CD38, and there are also other approaches like what we're employing here, going after the CD38 with a different mechanism. Again, not a lot of data, but at least we can extrapolate from the existing data that it's likely to work.

I would say the best data would be, again, there were some data presented at ASH from Mount Sinai where they looked at people who were having the myeloma come back after some of the BCMA-targeted immunotherapies. Then those patients were getting a different type of treatment that is still targeting BCMA, there were patients who were benefiting from that. I think there's a good chance, high probability that going after the same target but using different mechanisms would be beneficial.

Jenny: Can you explain the different arms of the trial?

Dr. Kumar: Right. This one, there's obviously the dose escalation portion, which is basically looking at the increasing or trying to identify the maximum tolerated dose. That's part one. Then it is the part two which is what we call the dose expansion phase. That's where we would take the phase one dose that we deemed to be effective, and start treating more patients with that particular dose, but then we’re also including several subgroups of patients.

We are going to be looking at patients who are refractory to daratumumab. We're also going to look at a subgroup of 18 patients who have previously not received a daratumumab-like drug, and there's also going to be a group of patients with non-Hodgkin’s lymphoma. This expansion will happen both at the once-a-week dosing and also at the once-every-other week dosing. It's not like patients are being assigned to a particular arm. It’s just almost unintentional in nature.

Jenny: Right, so if you have relapsed after daratumumab, you can join that study arm. That's going to be interesting because then you'll have an early indication of whether that's true or not.

Dr. Kumar: Correct. Exactly.

Jenny: What type of patients are the best candidates for this type of therapy? How many prior lines of therapy that they have to have? Who can join and who cannot join?

Dr. Kumar: Right now, the phase one portion of the trial is basically for patients who have relapsed refractory multiple myeloma, who at least have received one proteasome inhibitor, one immunomodulatory drug like Revlimid, and has had at least three previous lines of therapy. In that way, it's fairly open. Again, the goal here is to look at patients where the available therapies that we know can provide benefit have stopped doing that.

Jenny: Okay, and this trial, I also was reading, is also for non-Hodgkin’s lymphoma. Why lymphoma?

Dr. Kumar: The expression of the CD38 can also be seen in some non-Hodgkin’s lymphoma cells. In fact, there are trials ongoing that are looking at daratumumab in that patient population as well.

Jenny: Okay. I know that everything starts as a single agent in a clinical trial. You're testing safety, and you're testing the dose. You talked a little bit about combining it with other things. Is there any indication that other standard of care myeloma therapies, like you talked a little bit about the immunotherapies, that it might be particularly effective with anything else, like the IMiDs? You probably don't know that yet, but I was just wondering what other type of clinical trials.

Dr. Kumar: Not for this trial. I think for this particular molecule, the future design is going to depend a lot on what we find, especially the aspect of, of course, knowing that there's a dose that can be safely given that is effective, is probably going to be the most important. What efficacy are we seeing in patients who have become refracted to daratumumab, that's going to be a key differentiator that will help us design the future trials.

Other ongoing trials out there, looking at immunotherapy, specifically looking at the immunomodulatory drugs because they seem like a natural partner for many of these drugs, like Revlimid and pomalidomide, because they, overall, tend to improve the immune system. Those tend to be the earliest candidates to be evaluated in combination with monoclonal antibodies, just like what was done with daratumumab and Revlimid or daratumumab and pomalidomide.

Jenny: Okay. Yeah. Well, since it's so new and hasn't been used in a lot of other types of cancers before, you don't have a lot of experience with this, but it seems like this is a type of technology that you could use with other types of targets. What other types of targets in myeloma could this technology be used for?

Dr. Kumar: Now, that's a good question. I'm not sure if I know the correct answer to that because, again, as I said, probably something more proprietary to the development pipeline. I am not aware of any other myeloma target that they are exploring at this point. I think they are looking at other multiple different cancers. Certainly, the platform seems to be fairly open or capable of employing different targets.

We know what are the good targets in myeloma. We know that DCMA is good. CD38 is good. There are trials looking at the SLAMF7. There are other molecules like what we call CD229, hDR5, GPRC5D. The whole slew of them are out there, which we know are good targets for myeloma. If any of them are specifically being explored by the company, I really don't know, Jenny.

Jenny: Well, sometimes this is so new that I don't know even what questions to ask. Is there anything else about ETBs, in general, that you think would be helpful for patients to understand?

Dr. Kumar: I think the key thing is, just like any other phase one study, going back to the whole concept of how we develop studies. One thing I always tell patients, one of the differences between a lot of the solid tumor phase one studies and what we do in myeloma is, of course, we want to try and use these new new drugs in clinical trials as early as possible. Sometimes it's reasonable to consider trying one of these trials as an exciting new platform, knowing that there might be other options that you could always go back to, or even reuse some of the treatments in the past for treating myeloma. Just going on one of these phase one studies doesn't mean there's nothing else that we can do afterwards.

Jenny: Well, this is such a busy space, it seems like. It's so fun to listen to a brand-new therapy, especially because we know sometimes the CD38 target is a great target. Some of these drugs, daratumumab and isatuximab, are very effective and helping a lot of patients extend life and things, and we want to keep that going.

Well, I want to open it up for caller questions, to give it a few minutes for that. If you have a question for Dr. Kumar, you can call 347-637-2631, and press “1” on your keypad. Caller, go ahead with your question.

Caller: Doctor, I have multiple myeloma cancer. I have done a treatment with dexamethasone and Revlimid, and I discontinued that about nine months ago. Would I be eligible for this type of a trial at this point?

Dr. Kumar: It depends on what old treatments you have had, as I said before. This particular one, you would have had to have three different types of treatments in the past that have stopped working.

Caller: Okay, then can you answer me, are there other types of immunotherapy out there that have been approved for multiple myeloma that I would be eligible for, and how would I find that out?

Dr. Kumar: Right. There are multiple different immunotherapies that are out there, both approved and in-clinical trials. There are, obviously the CAR T that's approved. You have a second CAR T that probably will be approved in the next few months. We talked about the bispecific antibodies that are all going through clinical trials.

Now, it's hard for me to tell you exactly which one you would be eligible for, without knowing all the details about your clinical history, but if you need to find out which trial you could potentially be eligible for, I'm sure Jenny can guide you, provide you with some resources that HealthTree has. There’s also the clinicaltrials.gov and a variety of other resources out there.

Jenny: Yes, if you want to email me at info@healthtree.org, I can walk you through the process to find different clinical trials that you would personally be eligible for because we have that functionality in the HealthTree Cure Hub software.

Caller: healthtree.org. Do I specifically address that to you?

Jenny: You can just address it to me, Jenny.

Caller: Jenny?

Jenny: And I'll get back to you.

Caller: All right. Thank you.

Jenny: Yes, sure thing. Okay, we have one more caller question, go ahead with your question.

Caller: Hi. Can you hear me?

Dr. Kumar: Yes.

Jenny: Yes, we can.

Caller: Okay.

Jenny: So sorry you have a cold.

Caller: Oh, it’s okay. What is the best way to go about joining a clinical trial like this, especially if the trial is not held in my regular treatment center?

Dr. Kumar: Yes, you would have to be seen at the center where the clinical trial is being done. Unfortunately, with most of the clinical trials, that means you would have to, at least for the duration of the trial, transfer your care to that institution where you're joining the clinical trial because most of these, especially these early phase trials, the medication cannot be sent out. They have to be administered at the center.

Jenny: Somebody would basically find out where this trial is being held, and then call that center and say, can I become a patient? Or can you see if I'm eligible? What's the process of that, of just calling the center and getting that set up?

Dr. Kumar: Yes, you should be able to, again, every center works differently, but most of them, you should be able to go online and reach out to the appointment area and provide some very basic information. They will get back to you to find out what details would be needed to set up an appointment or at least determine if you’d be eligible for a particular trial.

Jenny: Okay, thank you. We hope you get better soon.

Caller: Thank you.

Jenny: I think so much is going around (colds and COVID). It's so crazy. Yes. Well, Dr. Kumar, thank you so much for taking the time to explain these Engineered Toxin Bodies with us. ETBs, I guess we can just say that. I think the work you're doing to create new therapies in multiple myeloma is truly wonderful and very much appreciated by the whole patient community. I just want to say thank you for participating and thank you for everything you're doing in terms of getting these therapies out to multiple myeloma patients. We're just so appreciative for you.

Dr. Kumar: Thank you.

Jenny: Thank you for listening to today's Myeloma Crowd Radio show. We invite you to join us next time to learn more about what's happening in myeloma research, and what it means for you.

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