Insights from the RedirecTT-1 Study: A Potential Game-Changer for R/R Myeloma with EMD

Podcast Transcript

Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals, exploring the latest innovative research and clinical advances in the field of oncology. Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale Shepard, a Medical Oncologist Co-Directing the Cleveland Clinic Sarcoma Program. Today I'm happy to be joined by Dr. Shahzad Raza, a Hematologist here at Cleveland Clinic with a focus on multiple myeloma. He was previously a guest on this podcast to discuss advancing multiple myeloma treatments, and that episode is still available for you to listen to. He's here today to talk about insights from the RedirecTT-1 study. And so, welcome back.

Shahzad Raza, MD: Thank you so much, Dale. Thank you for having me here.

Dale Shepard, MD, PhD: Absolutely. Maybe remind us again what you do here at Cleveland Clinic.

Shahzad Raza, MD: Sure. I am a plasma cell expert. My expertise are treating the multiple myeloma, which are complex relapse refractory. I perform CAR T-cell therapy, I do bispecific treatments, and I've been conducting many clinical trials as a principal investigator and coinvestigator.

Dale Shepard, MD, PhD: Excellent. Well, we are going to talk about many of those very things. So we're going to talk about data from a trial that was just presented, actually, with bispecific antibodies. But maybe, as a backdrop, this is for patients with refractory recurrent multiple myeloma, but specifically with extramedullary disease. Let's take a big step back, a lot of people might be listening, what exactly is that?

Shahzad Raza, MD: Yeah, that's a very good question. So, as we know, the multiple myeloma means a disease which can cause high calcium. It's sitting in the bone marrow with a lot of plasma cells and then they can cause kidney failure and anemia. Sometimes the multiple myeloma come out of these territories. They can go to the liver, they can go to the lungs, they can go to the lymph nodes. We call these diseases as extramedullary disease. Sometimes we don't even see the M-spike and they just have this extramedullary disease.

Now what we know that these patients have 87% of the time less likely to respond to the conventional treatments. They do very poorly even with single-agent bispecifics or even with the CAR T-cell therapy. What we have discovered recently that these patients have a good chance to live longer if we do something innovative like combining the bispecifics, and see what happens. That's what we saw earlier in the clinical trial. And this study is actually the confirmatory study that what we saw earlier in the clinical trial, does it really translate into the larger population? And what we are seeing, is it really a game changer? So this is all about this trial, that using the two bispecific therapy, one is called talquetamab, which multiple myeloma communities is already aware of this drug, and another one is teclistamab. But combining the two is an innovative idea, that what we have done in this study.

Dale Shepard, MD, PhD: Just about the biology of the disease. Again, quickly, when we think about this being more difficult to treat, I guess two things, how common is it to have extramedullary disease compared to traditional multiple myeloma? And, I guess, the biology question is, do we think that it's more difficult because of the inherent biology or because of the ability of the drugs to get to the tumor?

Shahzad Raza, MD: What we know that both approaches, both hypotheses, I would say, would be likely true here. First of all, they're very different disease. They're not like conventional multiple myelomas. They have heterogeneous genomic complex; environmental heterogeneity is quite common, and they're very difficult to treat as well, because the drugs may penetrate, may not penetrate, depends on the area and the location of the disease.

But one thing is that when the myeloma is out of the conventional definition, we think they behave very differently. Sometimes we see the plasma cells are circulating it in the blood. You can call it like a plasma cell leukemia if they are high enough, or if they are small number of size, they can still deposit to the tissue, can cause extramedullary disease. So I do agree that they have a different genomic complex, different biology. In some way they share the same thing as a multiple myeloma, but its response rates are very poor. And we are still investigating it, why this is happening, because our current treatments do not work at all in these type of diseases and many of these patients die within four months, six months maximum, because our response rates are poor. Or maybe we are not understanding how best we can treat these diseases.

Dale Shepard, MD, PhD: So we're going to be talking about data from follow-up data. There was a study that showed benefit of two bispecifics. Maybe as a backdrop, give us an idea why two bispecifics, what that initial trial showed.

Shahzad Raza, MD: Before we go to the study, I would like to tell you that around 20% of the patients who have multiple myeloma, at some point they can have extramedullary disease as well. It can happen as a newly diagnosed myeloma, or it's a long journey when they get lot of treatments, eventually they develop progression of the disease.

Now, in the earlier trial that was not done in the United States but outside the US, what we have seen that combining the two drugs together can get patients about objective response rate close to 80%. But it includes all types of relapse refractory multiple myeloma, including some extramedullary disease patients. Having seen these encouraging results, which has already been available in the New England Journal of Medicine, so this study was undertaken with the hope that if we combine the two bispecific together, because these extramedullary disease have expressions of BCMA, and we have a bispecific therapy which takes our own soldiers of the body which are T-cells and direct them into the plasma cells.

So other one is GPRC5D, which is called talquetamab. Combining the two together, it was such an innovative idea a couple of years ago, if you combine them, maybe we can actually overcome the genomic instability, can give these patients a life to live longer with this disease. So that's how with an early signal, what we saw, we translate them into the Phase 2 study. And interestingly they included patients who have absolutely no M-spike, which is rare to see. Because many of our trials, they have a requirement that patients should have some M-spike, maybe 0.5, and in some studies 1. Here, absolutely, if somebody has no M-spike, they're still eligible for this trial.

So we were very fortunate to include all these complex cases, who are refractory to our current treatment, like they are not responding to immunomodulatory treatments, anti-CD38, which is daratumumab or isatuximab, they're not responding to those agents, or they're not responding to proteasome inhibitors. Now, traditionally what we see that if you treat myeloma, if they're already relapsing to these diseases, our response rates are very poor. Even with the CAR T-cell therapy, the response rates are much inferior what we have been seeing that patients who have no extramedullary disease.

So the study really looked at it many ways. They looked at it combining the two together with a proper step-up dosing, and then after that, adjusting the dose based on the response that what we are seeing then. So we actually included those patients. And then we tried to calculate the tumor volume, how much extramedullary disease somebody has. Because in myeloma, some people can have lytic lesions, renal failure, but they can also have extramedullary disease, like disease in the lymph node, liver, kidney, and other places.

So we included these patients, and our strict criteria was EMD has to be a pure EMD, which is not attached to the bone. So if somebody has a lot of liver lesions or many areas that lymph nodes are involved. So we calculate each lesion, and we measure them through a specialized PET scan that we do for these patients, calculate them, and then capture this particular information. And then we assess the response rates, how these patients have been doing, what's the overall length of the time, how these patients have done. So this study is all about follow-up, response rates, and seeing how effective it is in our population.

Dale Shepard, MD, PhD: Excellent. So tumor volume is more of a factor here than in solid tumor, or we think about resist criteria, taking a couple of lesions and measuring how wide the tumor is.

Shahzad Raza, MD: I think this is a very interesting concept. I think it has to be validated, but what we have done it that we calculate the volume like a 25 cubic meter, and then we go with 25 to 50, and then 50 to 100. That's one matrix that we used. Smaller lesions, in simple words, the smaller lesions have a tendency to do better for the long-term disease control. However, the complete responses were also much, much better for patients who have a high tumor volume. So organ-related extramedullary disease behave a little differently. They have also excellent results, but then with non-organ diseases they have different response rates. So we calculate different metrics, but across all the metrics, patients have done really good. Obviously, the less disease burden means patients have a better chance to respond better.

Dale Shepard, MD, PhD: So when we think about responses, what kind of magnitude or response did we see in this follow-up?

Shahzad Raza, MD: So we saw earlier signal around close to 80% response rates, objective response rate, for extramedullary disease. This trial is essentially showing close to the 80% response rates. And it's quite interesting, because EMDs, when they fail, we don't see these type of responses; survival is poor, they may get some responses, but here, you're seeing 80% response rates. The disease is not coming back from majority of the patients and there is still patients are on this type of therapy, they're coming in here, getting the treatment once a month. So higher objective response rates, one-year progression-free survival, is going in 60% range, which is quite exciting. And that type of responses we are seeing across all the disease metrics. Even somebody has a less tumor volume, high tumor volumes, organs involved with extramedullary disease, or non-organ extramedullary diseases. So it's quite interesting to see that all cohorts have been responding it well.

And the way we are assessing the response is the PET scans in majority of these patients, and the PET can give us the idea how the metabolic activities have been going. What I have seen is that the patients who are responding it well, they continue to do well. And that was something interesting that we have seen. So we get the early signal and get an early sense, like if the patients got a couple of cycles, in four cycles, if they are in VGPR means a very good partial response, or CR, like a complete response, we are seeing that these patients are continue to do well; provided we keep an eye on the toxicities, provided we can keep an eye about how the tolerance has been happening. So if we keep those metrics and checks in place, I think we can actually do pretty good job by managing these patients for the long term.

Dale Shepard, MD, PhD: So not only good responses, long time until there's a recurrence, but also durable response.

Shahzad Raza, MD: Absolutely. The durable response have not hit the median. That is very interesting. We have updated follow-up beyond close to, I would say, 18 months now, but we are not hitting the median on the duration of response. Now, each EMD is different. I mean, I would like to emphasize that. Someone has an extramedullary disease with a different disease biology compared to others, and sometimes these patients are very, very difficult to treat, and sometimes they don't have time to be enrolled in the studies. They are very aggressive. We are very fortunate that we participated in this international study and Cleveland Clinic was the forefront on this study in evaluating the response rates. But as a principal investigator, I can tell you it's a very challenging study. One of the challenging studies I've ever seen, because these patients are aggressive, and from the trials you need to follow the model and you need to make sure patients are eligible with a reasonable performance status. And these things are time-dependent. Patients can crash very quickly.

However, I do see that since the patients, who are some of these patients that we enroll, they're sick patients, and I was not hoping that they do good on the study. But this is mind-blowing to me how well these patients have done it, despite of bad relapses, not doing well on any of these therapies, and then suddenly you are seeing the magic, like magic in a way that all the disease is gone. And I do get the responses from the patients that they are so happy that their quality of life has improved, they're back to their life, and this is a hope for our patients to have a life. When they are struggling with a life with a lot of toxicities, not meaningful response, and suddenly we give it something great that helps them and back to their life, that's what makes me happy. And I think our patients will also appreciate that this new combo or combination can be a game-changer for them.

Dale Shepard, MD, PhD: Yeah. So you mentioned toxicity, so it's good to hear improvements in quality of life because people might be concerned about the toxicity with bispecifics. Okay, now you're using two bispecifics and sometimes one and one is not two. What have you found about toxicity with these combinations?

Shahzad Raza, MD: This is very common in an oncology world that when you combine one drug versus two drugs, toxicity increases. Two versus three drugs, our toxicity is a little more than usual. We did not see any increase or more new toxicity signal compared to two drugs versus the one bispecific drugs. And I think the patients should have a right information as well. Like okay, if the toxicities happen, how we manage them. So cytokine release syndromes and ICANS neurological toxicities, as whatever the data has been suggested before for individual drug, we've been seeing the same things.

However, I would like to point out that the one thing that we have seen is an infection risk. And infection risk is very well-known with the bispecific therapies, because we actually deplete the immune system, and when we deplete the immune system, these patients are at increased risk of opportunistic infections. But when the study was done, the bispecifics were new and people were learning the way how we can take care of these patients, how to prevent them from infection, and that was at the time when viral infections were quite prevalent.

So, keeping those things in mind, what we have learned that if we prophylax them or giving the immunoglobulins IVIG, we do drop infection risk quite significantly. And it's been seen in this study as well, it's been seen with other bispecific studies as well, and I think that is something I would say in the long term, this is what we have been keeping. We are not checking the IgG levels. That is a very common concept within our oncology colleagues that if the IgG is low, then you give IVIG. Not for bispecifics. We keep giving them bispecifics once a month to keep their immune system healthy, and the moment we do this thing, our infection rates did come down.

However, these are a sick population. As we know, they can crash because of the disease, they can crash because of an infection. So if we are very vigilant from an infection perspective, I can assure you that one of the main reason why the patients can get complicated, we can control them. So CRS, ICANS, which is we can take care in the hospital setup, we can watch them in the hospitals, make sure that they do well. So there are three step-up dosings. So after that the dosing will be every other week, which is different what we do with the bispecifics in each individual bispecific, and after four months we were doing this as once a month. So you can see that the quality of life has changed, and once a month they came in, they get two bites, and then they get IVIG.

Honestly speaking, our patients who are in this study, once we identify this particular effect, that infection needs to be monitored and mitigated, I do feel that we have done amazingly well. So total of 90 patients, 11 were the adverse, major adverse events, and close to five, I believe, is the five patients that what we have seen that they have bad infections and that lead to the death. So we learned from that, which it's one of the last lesson that we learned that we need to prophylax them, give them antibiotic three times a week, or maybe we can use is Bactrim, pentamidine, or any of these drugs which are available to us commercially. We use them too, against the PJP prophylaxis, sometime infection prophylaxis. So if we keep an eye on infections, I do feel that we can get them better and use these drugs much better way.

Dale Shepard, MD, PhD: So we think about toxicities of therapies, sometimes we think about early toxicity in a drug, and sometimes you think about cumulative toxicity. Is it really in this case more early toxicities, and then once you get started, everything seems to be going well, particularly with the infection control?

Shahzad Raza, MD: Bites are very tricky. Bites are one of those drugs that it's not our traditional chemotherapy and it's a debate whether we call it chemo or you call it with a different name, the immunotherapies. I think that cumulative toxicity can happen, which I do agree. Sometimes people can have dysgeusia, a lack of taste, a lack of smell. These things are very unique for the bispecifics. Yes, in those cases we have decreased the frequency of the drug, duration of the drug can be enhanced because the drug has a long half-life. This is how we manage these toxicities. However, if we talk about infection risk, yes, when you combine the two together, yes you can deplete the immune system significantly. But once the study, if you look at in the study we were doing this bispecifics once a month, I think we are easing it out that immune system in a way that can naturally fight against infections.

Earlier toxicities are quite unpredictable. It depends on how much tumor volume disease patients have, what is their disease markers are, and they're at risk of CRS and eye cancer. That's why we typically tell the patients even they're getting single-bite or CAR T-cell therapy that be careful things can happen, but we can do this antidote or this treatment to control their disease, and which we are quite effective controlling those side effects. But that depends on patient's disease biology, how bad the disease is. But in the long term, this cumulative toxicities do happen and we give them IVIG to make sure that their immune system remains healthy and they can fight against infection.

Dale Shepard, MD, PhD: What's the duration of therapy? So if you have a patient who has a great response, has a complete response, how does that impact duration of therapy?

Shahzad Raza, MD: We think that multiple myeloma is not a curable disease, still, and especially for this population where they are difficult-to-treat diseases. I think this is evolving concept, like how long we should treat them. For example, in lymphoma we see that we treat them for six months, or six cycles, and watch them. But if the disease recurred, then you have a different opinion and we can treat them as long as the disease remains under control.

I think same concept apply for multiple myeloma. Now the bispecifics, we are investigating it, can we do fixed duration of treatment? We have a clinical study here where we are using two bites together, one bite pomalidomide, talquetamab and pomalidomide, or we are using standard of care. And we are trying to understand that the fixed duration of treatment like a two-year is enough for these patients. However, in this particular study we keep it going, we continue to treat them, and you will be surprised to know that more than 50% of the patients who have responded, they're still on the treatment and they're doing well. So early response, continue to do well, and I will question myself why we stopped that. Hardly we heard from them any question because that's how much stability we are getting it from these patients.

Dale Shepard, MD, PhD: And I suspect that these are patients that came in with a bad disease that hadn't responded to things previously. So there's probably a little apprehension to come off of something that's working.

Shahzad Raza, MD: Absolutely. Now think about that the patient has tumor, myeloma in the stomach. I mean, which we not heard, myeloma in the stomach, bad myeloma in the liver, bad myeloma in the lungs, they couldn't breathe, and then within few doses you are seeing they are totally different person. I have seen this and I have witnessed this, our Cleveland Clinic population that we enrolled in that study they did amazingly. I would say that the data from us and all over the world data that when we compile them, it's an amazing results, and you will be hearing that very soon, that once the data will be out for the general public, how much effective these results are. And I've been very proud of the study that Cleveland Clinic was a part of that.

Dale Shepard, MD, PhD: Was there much difference in responses or tolerance based on prior therapies? So, if patients had had CAR T therapy before, or kind of lines of therapy, did it matter?

Shahzad Raza, MD: Not for this study. I think the antigens are, one antigen is common, which is the CAR T is available for BCMA antigens, and we use the BCMA-targeted therapy. But we also use another antigen, like GPRC5Ds, to overcome the resistance. In other studies, what we have learned that BCMA target when you burn them, they may not do better for the other BCMA target. However, this is too preliminary to assess them. And even in this study we have 90 total patients, and within the 90 patients it's very difficult to have a subgroup, each therapy related, understanding how these patients are doing. But when we call it as a refractory disease, it's refractory, even if it's refractory to IMiDs, refractory to CAR, refractory to POM, and VRd/VRSM inhibitors. So the responses have been seen across all the subgroups that we have seen it for this particular study. So that's quite interesting to see that all these patients have been responding it really well.

Dale Shepard, MD, PhD: What do you think the world's going to look like with the success of two bispecific therapies? So patients come in, how are you going to decide between a CAR T therapy, a single bispecific, two bispecifics, what's the world going to look like?

Shahzad Raza, MD: Yeah, so we are already studying that. We have a clinical trial, and we have enrolled a lot of patients on that study, and if, whoever is listening to this podcast, it's something that we are exploring, this option, that when we combine the two bispecifics, how these patients do. I think things have been changing quite fast in this area. So we have now trispecific antibody, where Cleveland Clinic is going to be participating in that, that hopefully we will start enrolling it in early next year. So I think we are learning, and then applying the concept, and seeing if that helps the patients.

So higher response rates, deep remissions, MRD negativity are the goals, and we want to reach there. That was not the way we used to treat myeloma. We were just trying to control the myeloma. Now we are looking at it very differently. We are not only seeing the controlling the myeloma, but we're trying to eradicate. Like you are going to the beach, and you are seeing the surface of the ocean, you see the ships, but you don't know the whales. Whales are underneath the ocean. This is what we are trying to find out that myeloma respond well, yes. Are there in deep remissions or can we do something different for these patients? I think this will be the focus.

And how you achieve the MRD negativity, that's the whole goal. You can achieve with the two bispecifics, you can achieve with the one bispecific, or you can achieve with your conventional treatment that the patients are being on. I think this will be reserved for patients who have difficult-to-treat myeloma. Myeloma that is not responding. At least for the next couple of years we will be using, hopefully if it's approved, the combination is approved, we will be using two bites together, especially for extramedullary disease or patients who have circulating plasma cells, they have a disease which is difficult to treat. That's what I'm hoping that two bites might be better option than just using the sequential therapy.

The problem with the sequential therapy is many times they don't have a chance to get the second-line treatments. Their disease is so fast based. So we always think, as myeloma doctors, that we should use our best of the best therapy early so that patients can live longer. I do not know what would be the second line look like it if the patient is healthy enough to get the second line or third line. And we seen the real world the same thing. Even if you look at the CAR T data as before, there was a sharp drop in the curve in the first two months because they couldn't get the CAR T. The disease was so bad.

So I'm very optimistic. With this study, early introduction of these drugs together, bispecifics, especially patients who have bad disease biology, bad outcome, like an extramedullary disease, which we already know they do very poorly, I think that could be the practice changing, and hopefully this will help our patients and improve their life. We are happy if patients who've been come here and would like to get treated, I would love to see them and treat them based on this combination.

Dale Shepard, MD, PhD: Well, tremendous insights about this new data. Congratulations on the participation of Cleveland Clinic with this trial, and offering great therapies to our patients.

Shahzad Raza, MD: Absolutely, and I would like to tell you that very likely that this study will be published in New England Journal of Medicine. That will be available for all our colleagues, our patients, so they can look at more insight into the data.

Dale Shepard, MD, PhD: Fantastic. Thank you.

Shahzad Raza, MD: Thank you. Thanks a lot.

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