Dr. Noa Biran shares a new therapy in clinical trials that targets CD38. The new treatment called modafakusp alpha is now in later stage clinical trials. Learn why it was invented and how it works. 

Jenny: Welcome to today's episode of HealthTree Podcast for Multiple Myeloma, a show that connects patients with myeloma researchers. I'm your host, Jenny Ahlstrom. Before we get started with today's show, I have a very big announcement about a new product called HealthTree Connect. HealthTree Connect is a brand-new social media platform that's part of the HealthTree suite of patient tools. If you participate in the HealthTree Community Chapter Events, the webinars, or even if you don't, you can now connect and chat with other myeloma patients in these HealthTree Connect groups.

You can find HealthTree Connect by going to healthtree.org/myeloma, and clicking on apps and programs in the menu bar. It's quite similar to Facebook and function without all the other distractions. If you've used our forums in the past, we're moving those forums over to this new platform. It helps you connect. You can post questions or comments, comment or react to someone else's post, add photos or videos to a post, you can subscribe to certain groups which will put those conversations into your personal feed, and you can also view the general feed. You'll notice that more groups are coming including those not linked to a particular chapter. For example, we'll be adding a younger patient group, additional geographic groups, and a group for patients without caregivers. You'll find more groups over time. In the future, we'll be adding HealthTree Connect as a phone app to make those conversations easier. I'd just like to invite you to join HealthTree Connect.

Now, onto our show. We continue to be excited to see many new products being developed for the future myeloma clinic. Today's show is about one of those products called -- and I'm going to mess this up, Dr. Biran, modakafusp alfa. With us today is Dr. Noa Biran of the John Theurer Cancer Center in Hackensack, New Jersey. Dr. Biran, welcome to the program.

Dr. Biran: Thank you so much, Jenny. It is a pleasure to have the opportunity to speak with all of you and to educate you, in some fashion, regarding exciting new treatments and immune directed therapies for myeloma.

Jenny: Well, we're excited that they're coming. It just seems like they're coming at a pretty rapid pace. But before we get started with the show, let me introduce you. Dr. Biran is an attending physician and Assistant Professor in in the Multiple Myeloma Division of the John Theurer Cancer Center at Hackensack University Medical Center. Dr. Biran received the New Jersey Top Doctor Award in the last four years and was recognized as Doctor of the Year in 2015. She is deeply involved in myeloma clinical trials and is currently serving as principal investigator on 11 myeloma trials testing different drugs like iberdomide, selinexor, daratumumab, PD-1 inhibitors, carfilzomib, and others, and is serving on additional clinical trials as sub-investigator.

She has peer reviewed over 50 publications, is a very prolific speaker, and is on the editorial board of Frontiers in Immunology and Frontiers in Oncology for plasma cell dyscrasias. She also serves with professional and academic activities at Hackensack that include being a member of the Protocol Review and Monitoring Committee, the medical school course faculty, and a member of the Institutional Review Board for Hackensack.

Dr. Biran, I think there are a lot of patients that don't know much about this new treatment. It's been in early Phase I clinical trials, and it targets CD38. Maybe we just want to -- I think a lot of patients might be familiar with CD38, because that's the same target as daratumumab and isatuximab. But maybe, you just want to start by talking about why CD38 is such an attractive target in multiple myeloma.

Dr. Biran: Those are really important questions. I think that CD38, we all know, is a surface protein receptor that is present on a number of immune cells, most commonly, and most prolific, most prevalent is on plasma cells, both malignant and healthy. Almost all myeloma cells express a protein on their surface called CD38. CD38 is also present on healthy B cells and on red cells. As much as we're happy that antibodies to CD38 target and kill myeloma cells, they also can cause side effects such as anemia, low white count, and that's the off-target effect. The other effect that we see from daratumumab, and isatuximab, and other targets of CD38, is that not only do they have anti-myeloma effects, but they also have effects on neighboring immune cells such as T cells and natural killer or NK cells. There's both a cell-directed killing effect to the cancer cell and also, an immune stimulatory effect. They can recruit other immune cells called cytokines, which are immune proteins to be secreted and awaken the immune system to find other myeloma cells in the vicinity.

We've seen a lot of success, as you all know, and have probably seen before with anti-CD38 monoclonal antibodies. The difference and what makes modakafusp alfa unique is that not only does it bind CD38, and it does bind a different epitope, so patients who may not respond to daratumumab or isatuximab anymore, this therapy can still work because it binds on a different area of the CD38 protein. That's number one that makes it unique. The other unique part is that it consists of two molecules, not just the antibody that binds to CD38, but also, it has an immune cytokine called interferon, which can be introduced into the myeloma cell and activate the signaling inside the myeloma cell to die. It can also indirectly and directly activate other immune cells.

 I'll just say one thing, unless you have a question, about interferon. I just want to explain interferon because I think in order to understand how this therapy works, and we'll call it moda just for -- it's certainly, I don't know if that's what Takeda wants, but for the purpose of this discussion, and for ease, we'll call it moda. In order to understand how it works, we need to understand what interferon alpha is or interferon in general. Interferon is naturally secreted by the body's immune cells in response to a virus. When you think of what happens to our body when we get the flu or when we get any other virus, even Hepatitis C, is our body goes on fight mode. It starts to secrete all of these cytokines. One of the most important one is interferon alfa-2b. That cytokine makes you fight, and kill the virus, and go into a mode where your immune system is activated. That's why people may feel achy or exhausted with the virus. It's not because of the virus, it's because of your immune reaction to the virus. Initially, it was thought, well, if this molecule turns on the immune system to fight off viruses, why can't we use it to our advantage to fight cancer? Back in the '80s, interferon was actually used as a treatment for myeloma. It was one of the few treatments that we had.

Jenny: Interesting. What happened? I read that there were certain kinds of side effect profiles that were not that great. I'm just wondering about the efficacy too, how well did it work?

Dr. Biran: Yes, exactly. There were a lot of trials that looked at it both as single agent and also in combination with melphalan and other treatments. Remember, this was before we had IMiDs, before we even had bortezomib, or other proteasome inhibitors, so we didn't have too many options, and it worked. It worked in the lab, when it was tried on myeloma cells in the lab, you could see that it activated the immune system and fought and killed cancer cells. It also worked when we used it in early clinical trials. But as you said, the side effects were very difficult to tolerate because a) it caused a lot of anemia, very debilitating anemia, and also, it caused those flu-like symptoms that we see with a virus. Patients always felt exhausted, like headaches, fever, myalgias, or muscle aches, even dizziness and confusion. Even at worst, it could cause arrhythmias or heart palpitations.

They tried to reduce those side effects with a different formulation of interferon called pegylated interferon which is when it stayed in the body longer but in lower doses and much more not highs and lows, just a much more constant dosing. But even though it showed a slight benefit in response, the side effects remained. As we started to develop newer agents for myeloma specifically IMiDs like thalidomide, lenalidomide pomalidomide, the interferon-based therapy started to die down and be used less and less, and the study started to become futile.

Jenny: Well, it makes sense that they would move on to proteasome inhibitors and immunomodulators and things like that, if that was the case, because that's not very easy to live with as a myeloma patient. I've read too that moda is considered an immunocytokine. Can you explain just a little background about what that is?

Dr. Biran: Yes, I mean, it's a new term. There's all new terms that are coined. BiTEs, bispecific T cell engagers. ADCs, antibody-drug conjugates. We're really using the same basic principle, which is a monoclonal antibody. The reason that it's called an immunocytokine is because it's the first immunotherapy-based antibody to introduce an actual cytokine into the CD38 positive cell. Cytokines are not generally stable. If you infuse them into a person, they don't stick around long. It's difficult to utilize that form of treatment. This is a very unique and interesting way of introducing a cytokine directly into a myeloma cell. That's where you get that term immuno. That means monoclonal antibody-directed therapy, and then the cytokine part refers to the interferon alfa-2b molecule itself.

Jenny: Okay, that makes sense.

Dr. Biran: Mainly what it's doing is very specific to the myeloma cell. You're not going to get all those off target effects that you see with regular interferon or pegylated interferon. You're not going to see that it affects the whole entire body. You're going to see it specifically affect those myeloma cells, those CD38 cells. It's really unique and exciting in that fashion.

Jenny: Can you cover a little bit more about how it is completely different from isatuximab or daratumumab in terms of -- this is what's confusing, I think, for patients. It is considered, this moda, a monoclonal antibody, but then you're incorporating the interferon piece. I think I just need a little more explanation or maybe I just need to hear it multiple times for it to sink in about how it's different. I think that's always helpful.

Dr. Biran: It targets a different part of the CD38 molecule, so we can get into the cells in a much different way. Actually, we see that when somebody had a long time of daratumumab or isatuximab. They start to down regulate, meaning the CD38 receptor. Those surface proteins on the myeloma cell start to hide once you've used the dara or the isa for a long period of time. It's hard. That's why patients become resistant to those drugs, because now, the drugs can't get into the cell or the cell can hide from the daratumumab or isatuximab.

This molecule is unique. It binds a different portion of the surface CD38. It finds a new way to get in, even using the same receptor, and then, it's a little bit sneaky. It injects that cytokine directly into the cells. The isa and the dara don't have the interferon component. This has the potential of restoring response or working in patients who have already failed daratumumab or isatuximab. The studies will show that as well. I mean, the studies that have so far been presented, the early studies that are Phase I and II of moda are actually showing that. Even patients who have failed dara or isa can respond to this treatment. This treatment can still work. That really proves the point that it is different than just what we call naked CD38 monoclonal antibodies.

Jenny: That's remarkable for patients because there are a lot of patients. By the time they failed the proteasome inhibitor and immunomodulatory drug, and then there's the monoclonal antibodies to CD38, then they're starting to look at other options like CAR T, or bispecifics, or things like that. This gives them a whole new option, which is fantastic. Can you talk about NK cell function? I know you mentioned at the beginning of the show that daratumumab and isatuximab might affect NK cell function and reduce the number of NK cells or the efficacy of the NK cells. But do you want to speak to that? Maybe just a little explanation. What are natural killer cells? How do they work? How are they affected by the CD38 monoclonal antibodies, and then by this?

Dr. Biran: Natural killer cells are very, very important cells of the immune system. They're lymphocytes, which is the same family as your B cells and your T cells. They come from the same precursor or baby stem cell. They're part of what we call the innate immune system. They really have the potential of increasing your immune response against, anything foreign – a virus, a bacteria, a cancer. What they do is they push out little granules or enzymes that can kill tumor cells or even kill viral cells. They're extremely important in terms of myeloma response to therapy. They've been shown even to correlate with improved survival. Patients who have healthy natural killer cells do much better in the long term.

We know that every time you get treatment for myeloma, we're depleting those NK cells. Part of it is the treatment we're using. But also, it's the disease itself, the myeloma itself, like to reduce the natural killer cells, both their function and their quantity in your body. We don't exactly know why or all the specific mechanisms, but we know that we do deplete the NK cells with time. We know that certain treatments rely -- go ahead.

Jenny: Do the NK cells ever come back? You can drop it down, and it's similar to the idea of this T cell exhaustion idea, but can you recover them over time [0:17:22] [Indiscernible] therapy?

Dr. Biran: Yes, absolutely. We see that with deepening of response, with long time remission durations, those NK cells can return to normal, or at least close to normal functioning. In some people, they don't recover, but in many people, they do. There are a lot of different treatments that rely on those NK cells. That's why now, a lot of the trials are looking at using those specific treatments earlier in relapse, not waiting until fourth or fifth line relapse when those NK cells are depleted.

Jenny: I think that's the complexity of immunotherapies, because it seems like all of these different CAR T's, bispecifics, vaccines, this, monoclonal antibodies. They're all more effective potentially upfront when you have a better shot at having a functional immune system. Also, the blessing and the challenge, what do you use when?

Dr. Biran: Exactly. That is the question. If you ask ten different myeloma doctors that question, you will get 12 different answers, because nobody really knows. The problem is there's no comparison of what to use when. For example, there's studies showing that daratumumab in the upfront setting in combination with bortezomib, lenalidomide, and dex, have remarkable responses. But it's never been compared to a triplet, head-to-head, it's never been compared to VRd or KRd. Even though it looks like it's really, really effective, we really don't have the long-term data to tell us if using a CD38 antibody in the upfront setting is really going to help you in the long run. These therapies do have other side effects like depleting your healthy lymphocytes, and affecting, in a negative way, your immune system early on. I think those questions really are yet to be answered. We need to do more studies that are looking at regimens and comparing them head-to-head.

Jenny: Well, I agree. We attended the International Myeloma Society meeting in Los Angeles last summer. That was one of the big presentations. It was the GRIFFIN study read out and talking about dara and VRd, I think, versus CRd. We went back and pulled some data because there was a debate during that meeting about do we need to run a Phase III trial and really see what's happening? We came back and ran some of our HealthTree data against it. We'll be publishing on that. I think you're right. With all these different combinations, you have this exponential number of treatment combinations that you're trying to compare, and there's just not enough time to run all the trials to compare all the things and all the combinations. That's the challenge now.

Dr. Biran: Exactly. These drug companies don't want to do it, because what are they going to gain out of it? They're expensive trials, and they're not in it to prove inferiority or reduce their patient population.

Jenny: Can you also talk about how this new drug is administered? Is it an IV? Is it an oral medication? How often is it given? For how long do you take it? Things like that.

Dr. Biran: Yes, it's given IV. The dose right now hasn't been exactly finalized. But I can tell you that in the Phase I trials, we look at what is the correct dose. The earlier Phase I studies, we're dosing it weekly, then they were seeing a lot of side effects. Specifically, low blood counts, low platelet counts, some skin rashes, but really, it was the blood counts that were really low, then they went to every two weeks. Finally, every four weeks. It looks like the efficacy was excellent. At four weeks, it was working. Also, it was much more tolerable. They didn't have to hold the dose or delay the dose. It looks like it's going to be on a weekly basis -- I mean, a monthly basis. Every four weeks. IV. The way they determine is they look for something called maximum tolerated dose, which is like when there's too many side effects to go on, they have to go down on the dose. It's probably going to be a fixed dose. It's not going to be a weight-based dosing. It's going to be IV. They're looking at two different doses, 120 and 240 milligrams, at least for single agents. Once you start combining it, l that could totally change. But at least once a month seems like a reasonable frequency.

Jenny: Yes, very reasonable. That's much better than once a week, that's for sure, from a patient standpoint. How long does the IV take to administer?

Dr. Biran: Certainly, you have to give the pre-meds. Based on the studies, it takes not more than an hour. But again, that's still being worked out, so we'll see. They didn't have a lot of infusion reactions. It was about two patients in the most recent study at the weekly dose had an infusion reaction, and it was not severe. I think that infusion time may even become shorter.

Jenny: That's what's different too than daratumumab or isatuximab. You have these longer initial doses, and then they space it out over time. I think that's what we saw, as patients too, for -- and we'll talk about the approval process and things that you've learned maybe with the data. But I think it's so interesting. They're trying to look at this as a single drug. But most of the time, myeloma, drugs are given in combination with other things. You saw that with blenrep too. They've tried it single, and then started combining it with other things, and then we're able to space out the frequency. That'll be interesting to see if they're able to do that as well. You talked about the difference between daratumumab and isatuximab and this drug. I think the ability for patients to use this drug after they relapse after those things, what you're seeing in the data right now, do you think that this drug will end up being a replacement choice for either one of those drugs? I mean, maybe you just don't know yet. You don't have enough data. But that would be an interesting idea too. Is it a next generation tool or it's just one more tool in the toolbox?

Dr. Biran: I think until this disease is curable, we're talking about increasing our tools and increasing our -- I always call it a box of chocolates or chocolates in the chocolate box. I think there may be a role for it, earlier lines of therapy, especially, the side effect profile, there's no real toxicities that, to me, would be limiting in terms of giving it to a patient. For example, there isn't any severe cardiac events that we're seeing. There isn't a signal that's really, wow, this is a dangerous therapy to give. It seems like at this most recently found dose, the therapy is well tolerated. We need to have many therapies. I think that the CD38 are convenient in terms of dosing and administration, and I don't think they're going away anytime soon. But I do think it's very exciting that the response rate for moda is the same in the people who did and did not have dara or isa. That tells you that it can really rescue patients who have failed anti-CD38, which is a big deal. Not all drugs can do that.

Jenny: It's huge. No, it's huge. It's fantastic. Wonderful. Well, do you want to talk a little bit about where it's at in the development process? I heard about it a very long time ago, but I heard more about it and last year's ASH. Maybe you just want to talk about some of the data that you've seen last year's ASH and this year's ASH.

Dr. Biran: I think this year's ASH is really the more recent data. More patients were enrolled compared to last year. There were two really important studies this year at ASH that were presented. One of them was about how it activates NK cells. I think that's interesting. That was more of a laboratory analysis, because they took the serum of patients who were exposed -- the blood of patients who were exposed to this, and they proved that NK cells were activated in the setting of this drug. That proves your concept or proof of concept how it works. I think the more clinically relevant study was the final results from the Phase I-II studies.

The study was presented by Dan Vogl at ASH. It presented data from about 30 patients who received moda at what we call the therapeutic dose or the monthly dose. Patients who were included in the study had at least three prior lines of therapy. They were fairly heavily pretreated. They have to be refractory, meaning they've already exhausted a proteasome inhibitor and an IMiD. The study basically treated patients until progression of disease. This was not a study that stopped, like a fixed duration study that other studies are now doing. This was a treatment until progression. The patients showed -- for the analysis, they focused on the patients that were actually treated at the therapeutic dose. More patients were enrolled. About 100 received drug, but most of them were in the dose escalation phase. They really received suboptimal dose or not enough drug to really make a statement about efficacy.

Among the 30 patients who received the therapeutic dose, the overall response rate was 43%. Just for historical purposes, so we understand the context, and this is now changing, the standard or what the expectation is, but in prior studies that looked at patients who failed three prior lines, including a proteasome inhibitor and an IMiD and the CD38 antibody, most of the patients who were on this trial did fail a CD38 antibody as well. In those patients, we expect a 30% response rate. That's how other therapies in this space have been approved. For example, selinexor was approved in a similar patient population with an overall response rate of around 30% of single agent.

This is a very good overall response right now. I think teclistamab is going to change, which is the BCMA bispecific T cell engager may change that bar, because we're seeing response rates around 60%. Again, you cannot compare trial to trial. In fact, these patients, a subset of them, already failed BCMA therapy. I would argue these are even more refractory patients. I think overall response rate of 43% is very, very good. That means that 43% of patients have a response of a PR or better, or a 50% reduction in their tumor burden or more. The median time to response is 1.2 months. It works pretty quickly. The median progression-free survival, which is a reflection of the duration of response was 5.7 months. The side effect profile was what we would expect with treatments in the setting. Most had low white count, including neutropenia. Most had a low platelet count. Infection was seen in about 10%. They were severe infections, which again, is fairly common in myeloma patients receiving therapy in the third line or greater.

I think, this is still a very small number of patients. It's not a long follow up, so the data is going to change, the number is going to change. I think what's more important is looking at the patients who already had an anti-BCMA therapy. That includes, at the time of the study, belantamab, CAR T cells, and possibly a bispecific T cell engager, because teclistamab and other ones, elranatamab and another one, Regeneron has one too, were already in clinical trials. I think in patients who already had anti-BCMA therapy, the overall response rate was 27%. Again, it's a small number of patients, we can't take this – these numbers will change with time. But certainly, this is very promising. For just a single agent, we're happy with these results. We think it has potential, especially when combined with other agents.

Jenny: Can we talk about that for a minute? This idea of resetting the bar, because I think the FDA is starting to do that a little bit, but I don't know from a patient standpoint, if they really should or not, because you mentioned Selinexor, I think carfilzomib was approved like that, I think even daratumumab. They were all in the 30-35% response rates, and then they were combined with other things. Even teclistamab just had data that came out showing like it was in the 60s, low 60s or something, and then it was combined with other things. It was almost 95% overall response rates. It concerns me as a patient to have this higher 60% bar, and then everything has to meet that bar that's being developed, because once you fail that, then you're out of options. It doesn't make sense to quash everything else and hold it to that higher standard. I don't know.

Dr. Biran: You're absolutely right.

Jenny: I think that hopefully the FDA is not going to only look at response rate, but it's also about toxicity. For example, teclistamab really depletes your immune cells. Patients can have significant infections, viral infections. They may have prolonged COVID, even parainfluenza, recurrent pneumonia. That was in a large subset of patients, 40% of patients had infections that were meaningful. I think the FDA is also looking at that. You don't necessarily want to expose somebody to this risk of infection early on in the disease course. You want to give them a chance to respond to other therapies, at least that's my opinion. Before you start introducing, even though it may have a higher response rate, the patient is likely to respond to almost anything in the early lines of therapy. You really want to optimize quality of life at that time. You want to give them something that's going to work but also that's not going to debilitate them or put them in the hospital every other week. I think the FDA is looking at the big picture. I think right now, I am not concerned that the FDA is going to not approved therapies based on a response, that are less than a 60% response rate. I think that's an unreasonable expectation.

You can also see with the CAR T cell data, even though that therapy was approved based on a very high response rate and relapsed refractory like 90% almost, the FDA still approved other therapies after that which had much lower response rates. That's an example that speaks to looking at the big picture.

Dr. Biran: Yes, I agree. Well, having everything on the table as a patient is so important, because you just never know what you're going to need and when you're going to need it, and in what line of therapy. You want to have options, of course. For sure. You just never know. People respond differently. I have patients, even when they're doing really well, and they're in remission, they're always saying to me, well, what's next? What are my options moving forward, if this stops working? You always want to have that knowledge that there's something next. For now, I can still say that to almost everybody.

Jenny: Well, absolutely. Well, let's talk for a minute about what it's in clinical trials with currently, because I think it's really fun to watch clinical trial design change a little bit, in my opinion. I'm seeing changes with multiple arms all at the same time, because the company is trying to figure out, how does this work best and in what combination? Do you want to go over how it's being tested now in clinical trials?

Dr. Biran: Yes, I think you're right. I think, the reason we use daratumumab in every single line of therapy and in every combination is because the company that makes it put trials out all at the same time, all different arms, in all different settings. Then, you see what sticks in what works. Then, doctors are more likely to use it, even if it doesn't have that indication in the NCCN guidelines. Once you have a study supporting that combination, that combination is going to be used. It's really to the benefit of the patients, the doctors, and the drug company to diversify their portfolio of trials.

That's not always feasible because it's expensive to run trials. I did a search of modakafusp in the clinicaltrials.gov. I came across a number of trials. They're all still in Phase I and II. We're not yet at the registration Phase III trial. I see a number of single agent. There's one in combination with daratumumab in patients with relapsed refractory myeloma. I think that's a great partner, because whenever you want to find a combination, you don't want overlapping toxicities. The side effect profile of dara doesn't seem to interact with the side effect profile of moda. Another trial is looking at moda in solid tumors with pembrolizumab. In fact, pembrolizumab is a checkpoint inhibitor. It blocks PD-1 PD-L1 interaction. That's another way to wake up the T cells, wake up the NK cells, stimulate immune response. I think that's a great partner. I actually wanted to do that in myeloma. I think that would be a great combination in patients with multiple myeloma.

Jenny: Can I ask about that before you go on? Because I know these checkpoint inhibitors -- well, when they were combined with immunomodulatory drugs, there were not good outcomes there. What is your experience been in bringing them back to the myeloma clinic because maybe in a new combination, that would be a wonderful treatment option for patients?

Dr. Biran: I think it's a shame that the checkpoint inhibitors were handled in the way that they were. I think there's a lot of evidence now showing that -- when those trials were shut down, there were a number of trials with pembrolizumab which is Merck's, PD-1 inhibitor, in combination with lenalidomide and in combination with pomalidomide, both in the upfront and the relapse setting. Initially, the Phase I and II look good. But later, when it started to become randomized, there were more deaths on the pembrol IMiD arm. Nobody could understand a pattern of deaths. It wasn't disease progression. It looks like there was a lot of toxicity that was not managed appropriately. Because when you have checkpoint inhibitors, they can cause immune mediated toxicity or reactions that are similar to autoimmune disease like colitis, endocrine disorders, fevers, cough that's not from pneumonia, that's from a pneumonitis or inflammation.

There's actually studies from those pembro trials where you're looking just at patient cohorts from experienced investigators, for example, the Japanese data. The Japanese published their own data from those studies. The checkpoint inhibitor arms look great. That speaks for putting these therapies in the hands of experienced investigators who have had experience with checkpoint inhibitors. A lot of the initial studies or the ones that were shut down by the FDA, were done not in the United States and not in countries where the doctors had experience managing these drugs. There are other studies published. One of them was here at Hackensack, before the FDA shut it down, using the combination of pembro, len, and dex after an auto transplant. The results were really good. It was a very small trial. But certainly, we didn't see any immune mediated toxicity. We saw a much longer progression-free survival in high-risk patients after an auto transplant.

I do not think that the checkpoint inhibitors story is over in myeloma. We've had at least here several discussions with FDA about looking at these drugs and being open to them. It sounds like there is going to be a future for them. Of course, the FDA wants you to do these trials in more advanced myeloma patients, because they don't want to risk toxicity to patients that have a lot of good standard of care options.

Jenny: That makes sense. Can you also explain when you say Phase I-II study, how do they break that out? Because Phase I is usually safety. Phase II is -- well, you can describe it better than me asking, but when they combine, I'm curious.

Dr. Biran: Yes. What a lot of studies are doing is a Phase IB/II. So that means that you're looking not only at safety, but also at efficacy. What they do is maybe a dose escalation. That's the Phase I. They started a really, really small dose. They calculate that dose based on mouse models. They test the drug in animals first, and then they see what's safe in an animal and they have a formula to calculate what would be safe in a human. Then, they reduce that dose even more. They look at how that those affects the organs. They do something called pharmacokinetic studies and pharmacodynamic studies, and looking at the drug and how it affects the body. If, for example, they'll dose three patients at a baby dose. If those patients don't have side effects, they go up on the dose, they go up to a second dose level, and then a third dose level, until they see toxicity. They monitor patients very, very carefully. They do EKGs, they do frequent visits, and blood tests to make sure you know the liver is okay, the kidneys are okay. That's the Phase I portion.

Once they reach a dose that is effective and that's safe, they start to do an expansion. They say, now, we're going to open it up to let's say, another 45, or 50, or 60 patients at what's called the RP2D or recommended phase two dose. That's where the Phase II portion comes in, and then you can expand it and see how effective it is in a much larger cohort of patients. Almost all trials now are combining.

Jenny: It seems like it's more efficient. It seems like it. It's cheaper probably and faster. I would think to do it like that. You talked about the FDA approving after the Phase III or the registrational type trials. I never understand that term until recently. But some drugs, it seems, have gotten earlier FDA approval. I think daratumumab was approved after Phase II, or things like that. Do you see this having to go through that whole process or do you see opportunities for this to have a faster approval?

Dr. Biran: Sometimes, a drug company can apply for what's called fast track expedited approval. In order to get that approval -- and that approval is based on Phase II trials, not on randomized Phase III trials. You have to prove that, number one, there's not options for the patient. You have to have an unmet need. You have to have a rare disease. Even though we have a lot of myeloma patients, it is a rare disease. Also, it's not a curable disease. Many of these drugs are getting fast track approval. It doesn't mean that you're going to get it forever. Look at belantamab and look at other drugs, the melflufen, that were approved initially based on the fast-track conditional approval, and then when the Phase III studies came out, they said, nope, not good enough, or benefit does not outweigh risk. Toxicity is too high and benefit is too low. I think we're seeing a lot more of that withdrawal of approval.

Jenny: Yes, or more data is needed or something.

Dr. Biran: Exactly. More data is needed. I mean, I know in belantamab, they haven't given up on the drug. The company's getting their data and doing their studies hoping to get approval.

Jenny: Yes, makes sense. I interrupted you when you were going through the different trials in the combinations that are being done.

Dr. Biran: That's the only combination partner that's ongoing. Pembro in solid tumors and dara in myeloma. The rest are just -- actually, I think there's another one that has combination of lenalidomide and bortezomib. That's a Phase I trial with several arms. In one trial, they have many arms and different dose levels, because you still don't know what the right dose is when you combine it with lenalidomide. You may need much less of the drug, because that IMiD is going to maybe make the drug more effective, or it may increase the rate of low white count. It may increase the rate of infection. Whenever you do a combination, you have to start from scratch regarding dose.

Jenny: Absolutely. Well, all these different combinations, that's a lot to try to figure out and to try to get enough patients into each arm. It's statistically worthwhile, so you get an answer. I also saw one trial that was using it well. In one of the trials that looked like they had an open for doublets, and then they had it open for triplets, and then they were using it as maintenance therapy for newly diagnosed patients, which I thought was really interesting. How would you see this being used as maintenance therapy?

Dr. Biran: I think it's a great maintenance therapy, because I think the idea behind maintenance, and even maybe consolidation, maybe maintenance isn't going to be maintenance anymore. Maybe it's going to be just four months or six months of therapy, and then stop and give people an actual break. I think the field is headed toward that direction, especially with all these new treatments. What are we really doing by giving single agent low dose lenalidomide? What is it really doing in the long term? I think using this therapy in combination after transplant is a great idea, because what you're doing is you're taking the patient's myeloma, which is at the lowest probably it will be after a high dose of melphalan. Right when the immune system is recovering or resetting, and you're giving it a therapy that's going to reinvigorate your immune system, at the time of the least amount of myeloma, there's a very high likelihood you're going to get, durability, long-term remission, because you're training the immune system to keep the myeloma under check. I really believe strongly in immunotherapy after transplant. I think it would be reasonable to use it with an IMiD in that setting. Hopefully, the trials are going to pan out.

Jenny: That's so interesting. When you think about sometimes patients can go back to that MGUS-like state or even just from MGUS patients, I hear, and talking to different investigators, that it sounds like that escape outside of the immune system, keeping it in check, is what causes the progression. If there are these immune adjuvants, I guess, that spike that immune system or ramp it up to recognize and then control the myeloma, that would be ideal, and maybe you double your remission times between therapies or something.

Dr. Biran: I think that's really the way to go. I think that's the future of myeloma. I think we're going to be doing fixed duration therapy. The upfront setting is the most important and then after transplant for those patients who are eligible for transplant, rebooting the immune system, and teaching it how to control the myeloma, and putting it back into an MGUS state. I think you're absolutely right. We do see that with patients. I mean, we see patients quite often who are in remission with a small M-spike, .2, .3, no MRD negativity, just small burden of disease for a decade. It's certainly possible. Those are the patients we need to study and say, what's going on with your immune system? How are you doing this? These are patients who had real myeloma, who had lytic lesions, who had kidney problems, and now all of a sudden, they're MGUS.

Jenny: I have friends like that, that transplant didn't work, but maybe a single drug did, and they have this constant M protein, but it's just consistent over, like you said, a decade. Totally fascinating how these drugs, just the combinations, and how they work are so different. It's just so shocking to have another CD38 targeted drug, and then have it be so completely different from the two that are already in the space. It's exciting for patients to see that. Because you wonder how many more targets you can actually find. We have BCMA and we have CD38. Maybe there aren't 15 more targets to go after, I don't know.

Dr. Biran: I'm sure they are much more than that. We just have to find them, and be patient, and keep doing what we're doing. Patients help trigger and make the doctors move faster, and make the scientists move faster. We all have a role in this.

Jenny: There's a lot that patients can do. I want to open it up for caller questions. If you have a question for Dr. Biran, you can call 347-637-2631, and then press 1 on your keypad. We will start with caller ending in 9153. Go ahead with your question. Sorry. It's taking a second to bring them on. Go ahead with your question. Maybe they pushed the button and didn't mean to. Caller at 9569. Go ahead with your question.

Caller: Hi. My question is, are they doing anything with the high risk or non-secretory in the clinical trials? Then, this moda, do they still give you dexamethasone? You continue with Velcade, and daratumumab, and Revlimid?

Dr. Biran: Those are great questions. The first part of your question speaks to the patients who are high risk and non-secretory. I think there is, right now, a big focus on high risk. Most studies are actually requiring a certain subset of patients who are enrolled to have high risk cytogenetics. The definition of high risk is changing. We're learning about different mutations, next generation sequencing, and different ways to characterize high risk. I think in terms of non-secretory myeloma, it's a different story. We have had trouble in our practice getting patients with non-secretory myeloma on trials. Usually, early phase trials will allow it, but later phase trials who are trying to get their drugs FDA approved, do not. That's because it's much more difficult to know if the drug is working. It's not impossible. We can determine based on scans, based on biopsies. Some patients unfortunately have to get frequent bone marrow biopsies, but there are ways to determine response in non-secretory myeloma. It's just that in late-stage trials, their goal is to get a drug approved. They don't want to often include these patients. I think, in earlier trials, they are included. That's the first part.

The second part of your question was regarding dosing of the moda, and whether or not it's given with dexamethasone. This drug was not. I believe it was not but I'm going to check just to make sure I'm correct. Yes, activation, additional cohorts. Yes. Some cohorts were with dex and some were not. It was looked at both with dexamethasone and without. It looks like there still was efficacy in the cohorts that did not use dexamethasone. That's good to know.

Caller: Thank you.

Jenny: Okay, great. Thanks for your question. Okay. Caller go ahead with your question. Hello?

Caller: I'm a recently, I guess, you would say recently diagnosed. Actually, I was diagnosed in April of last year. I was on immunotherapy. I had three rounds of immunotherapy. I was in the KID study, and then I had an autologous stem cell transplant. I was told then in four months. I'm back to being able to go to work, but I was told that within four months, there'll be a second one, a second transplant. As I was listening to the program, I heard Dr. Biran say that she likes to do immunotherapy after the transplant. I'm currently in remission. After the second transplant, I'm where you were saying. What next? What would I do next?

Dr. Biran: I mean, I think certainly, there is an opportunity for what we would call consolidation therapy. I think it's going to depend on where your disease falls after the transplant, how your immune system recovers, and where your disease markers lie. I think that's certainly a conversation to have when you're all done with transplant. The clinical trial may, in some way, dictate what you're getting, but we'll see. It's a great question and a great discussion.

Caller: Well, I'm actually at the John Theurer Cancer Center.

Dr. Biran: Yes, I figured because you said you're on KID. That is an investigator-initiated study. I don't think anyone else has that except us, or Georgetown, so I figured.

Caller: Is it that there are different -- because there seems like there's just so many different treatments. Is it based on who your patient is?

Dr. Biran: It's patient by patient. It really depends on how deep the remission goes, how you tolerate the treatment, and what your initial FISH and cytogenetics are and what your risk of progression is. I think it's an individualized discussion, but it's important to know that there's many, many options. What you don't get at consolidation, you can always get a relapse. It's also about the timing.

Caller: Okay. I was just wondering, because there were just so many. I was just hoping KID is right one. Thank you.

Dr. Biran: Yeah, of course.

Jenny: Thanks so much. Okay, we have two more questions. Caller, go ahead with your question.

Caller: Thank you so much for a really wonderful talk today. I really enjoyed it. I had a question about this as an immunotherapy that activates the immune system and natural killer cell function. But there's also other drugs that do this too. How do you feel about any anticipated side effects and issues when you combine multiple immuno therapies for a patient?

Dr. Biran: I think they all are unique and I think they all have their own side effect profiles. As long as there's no overlapping toxicities, I think it's a good approach. There's data, for example, on dara in combination with IMiD. Dara and IMiDs. There's combination on other immune -- elo, for example, is a NK cell stimulator with IMiDs. As long as it's safe, and there's no overlapping toxicities, I think it's a very effective approach.

Jenny: Okay, wonderful. Thanks for the question. It is confusing to see all these different immunotherapy approaches and with CAR T, and bispecifics, and everything, everything works in a different way. Our last question, I can't tell what your phone number is. Go ahead with your question.

  Jenny: Dr. Biran, we’re thankful that you participated. We're so thankful that you're doing all the work that you are doing in myeloma. We're just so grateful for you, as patients, that you're working on things like this to move them forward.

Dr. Biran: Thank you for having me. I wish everyone the best. Thank you.

Jenny: Thank you so much. Thanks to our listeners for listening to the HealthTree Podcast. Join us next time to learn more about what's happening in myeloma research and what it means for you.