Dan Vogl, MD, University of Pennsylvania
Yulia Nefedova, MD, PhD, Wistar Institute
Interview Date: January 5, 2022
When good immune cells like neutrophils and monocytes (which are usually immune system defenders) go rogue and become "pathologically activated", they can become something called myeloid-derived suppressor cells, or MDSCs. Instead of protecting us, these MDSCs help multiple myeloma grow. In this show, Dr. Vogl and Dr. Nefedova teach us what MDSCs are and how they work and how a new therapy called tasquinimod could help slow down myeloma growth. Learn more about this clinical trial using tasquinimod with ixazomib, lenalidomide and dex in combination to improve myeloma outcomes and slow myeloma growth.
Thanks to our episode sponsor
Jenny: Welcome to today’s episode of Myeloma Crowd Radio, a show that connects patients with myeloma researchers. I’m your host, Jenny Ahlstrom. We’d like to thank our episode sponsor, Bristol Myers Squibb, for their support of this Myeloma Crowd Radio show program.
Now before we get started with today's show, I just like to wish you all Happy New Year, this is our first show of the year, and share one of our New Year's goals with you at the Myeloma Crowd by HealthTree. Our theme this year is one of change. We see so much change happening in myeloma treatment options, like the one we're going to hear about today and many others that we heard about, potentially of ASH, and such exciting change. We are so onboard with change.
As an organization, we are trying to change the way research is performed by myeloma investigators by providing them a free access to HealthTree Cure Hub real world data, where we now have over 10,000 myeloma patients participating, to help them perform faster and less expensive research for us. The tool allows them to develop new insights and hypotheses with validated and anonymized data, and to our knowledge, this is the largest and most comprehensive data set in the world for myeloma patients.
We'll be issuing a call for proposals, research proposals later this year, to invite greater use of our platform, now that we've performed some initial surveys and studies and have gained some experience with that. We invite you to participate in this amazing tool because it can help you navigate your myeloma care at the same time that you're contributing for change in myeloma research.
One more thing, because our theme is change, we're also launching a Change for Change initiative, where you can donate your spare change with daily purchases that you may make using an app, called RoundUp. You can learn more about that on myelomacrowd.org.
Now onto our show. There's so much going on in the development of multiple myeloma therapies, and we are so fortunate that that wheel keeps turning to identify new options for myeloma patients. We already know that there's so much happening in immunotherapies like CAR-T and bispecific antibodies.
This program has always shared up-and-coming treatments with you as early as possible, so today's show will discuss one new therapy called, and I'm not going to get the name right, tasquinimod, that's in early clinical trials. You'll have to correct me, Dr. Vogl and Dr. Nefedova. Welcome to the program to both of you.
Dr. Vogl: Thanks so much.
Dr. Nefedova: Thank you, Jenny.
Dr. Vogl: You pronounced it exactly right.
Jenny: Okay, good. Let me give an introduction for you both before we get started. Dan Vogl is director of Abramson Cancer Center Clinical Research Unit, and Associate Professor of Medicine and faculty fellow for the Center for Clinical Epidemiology and Biostatistics at the University of Pennsylvania.
Dr. Vogl leads multiple myeloma clinical research and studies, including study of protein degradation pathways, international studies of new myeloma therapies like proteasome inhibitors, XPO1 inhibitors, determinants of health and others. As the director of the Clinical Research Unit at UPenn, which has very deep and very early expertise in immunotherapy, Dr. Vogl is leading the way to get revolutionary treatments like CAR-T therapy and other immunotherapies into the myeloma clinic.
He helped to create national studies, including randomized trials that run through the NIH-sponsored bone marrow transplant clinic trials network, and does analysis of myeloma transplant data from the Center for International Blood and Marrow Transplant Research, which is called CIBMTR.
We recently interviewed Dr. Vogl at ASH on another treatment, clinical trial he's leading called TAK-573, in addition to the one we'll be discussing today. Look for that article on the Myeloma Crowd website because it's another exciting new option, and we were talking that we might need to do a second show on that one later this year because it's so interesting.
Dr. Vogl's awards include the Bradley Award in Patient-Oriented Research at the Department of Medicine at UPenn, ASCO Foundation Career Development Award, an LLS Fellow and Clinical Research Award, an ASH Scholar Award, and a Brian Durie Humanitarian Award in the Philadelphia Myeloma Networking Group.
Also with us today is Dr. Yulia Nefedova, who is associate professor of Immunology, Microenvironment and Metastasis Program at the Wistar Institute in Philadelphia. She is also an adjunct Associate Professor in the Department of Biochemistry and Molecular Biology at Drexel University College of Medicine.
Her awards include a Russian Academy of Science Fellowship Award, the Ruth Christian National Research Service Award, Miles for Moffitt Milestone Award, and an MMRF Senior Award. Dr. Nefedova is going to join us for the first part of this show to help us better understand the science behind this new therapy today.
Let's get started. Dr. Vogl, maybe you can give us a broad, overarching perspective. What's the rationale behind this therapy in the context of other myeloma treatments, other immunotherapies or even other regular myeloma therapies?
Dr. Vogl: First of all, thanks so much for having us on the show. It's really a lot of fun to talk about this clinical trial and the collaboration that I've had with Dr. Nefedova, over the past few years, taking a lot of the work that she's done in the laboratory and coming up with new ideas of how to treat myeloma, and then being able to move that into the clinic while also getting samples from our patients who are in the trial and sending them back over to her lab to figure out if this these kinds of treatments work in patients the same way that they do in her laboratory models.
The rationale behind this particular trial, I think, comes from understanding that up until now, most of our myeloma therapies have really been aimed directly at the myeloma cells so that we give treatments that we think, go into the myeloma cell and interfere with some basic process that they need to stay alive and to grow. We've just recently started doing treatments that really are immunotherapy that convince immune cells to directly attack the myeloma cells.
At the same time, both of those types of treatments can run into problems when the myeloma cells are protected by signals and support that they get from other cells that live in what we call the bone marrow microenvironment, that there are lots of other cells that live in the bone marrow normally and that somehow, in the setting of multiple myeloma, some of those cells provide direct support to the myeloma cells to stay alive, and others can provide signals to immune cells that tell them to stay away.
That can really interfere with the effectiveness of all of these types of myeloma treatments that we use now by protecting the myeloma cells themselves or by tamping down the anti-myeloma immune responses that we're trying to enlist in our immunotherapies. The idea that targeting the bone marrow microenvironment is a good thing to do, is something that's come up over the past recent years, and there's a lot of exciting work done on figuring out which cells are the problem there and which signals we could attack or block to make our other myeloma therapies more efficacious.
Jenny: Yes, so interesting, and a totally different type of therapy. This is not like anything else that's in the myeloma arsenal right now.
Dr. Vogl: Correct. Or at least, right now, the treatments that we have, it isn't clear that the main way that they work is by targeting the bone marrow microenvironment. There are some treatments that we use, for instance, the bisphosphonate therapies like zoledronic acid, also known as Zometa, or denosumab, also known as Xgeva, which we give to help protect the bones in multiple myeloma, may also have some effect on other cells in the bones near the bone marrow that can participate in a feedback loop.
Some of the treatments that we use already may have some effects on the bone marrow microenvironment and that might be part of how they work and how they help people, but they weren't necessarily developed that way. There aren't many treatments, even in clinical trials right now, that are truly aimed at modifying the bone marrow microenvironment as the primary mechanism of action and the main way that we think they're going to work.
Jenny: I've heard a lot of myeloma researchers talk about how critical the bone marrow microenvironment is to the development of myeloma and how one person's bone marrow microenvironment might be different from somebody else's, and that's maybe why people get different responses or a different clone grows out or things like that.
Dr. Vogl: Yes, there's still a lot to learn. Some of what I've been working on with Dr. Nefedova is taking samples from patients, both blood samples to understand the immune system and bone marrow samples so that we can look at the cells that are in the bone marrow and that she can start to tease out. It's a complicated process to figure this out, and there are a lot of different tests that one could do to understand different aspects of all of those cells there. There's really a big mix of them.
It's a complicated problem to tease out. Any individual treatment is going to chip away at one aspect of that, but if we can really show that we're starting to make a difference and then combine the attack on the bone marrow microenvironment supportive signals or immunosuppressive signals with other effective myeloma therapies, there's the chance to really improve treatment overall.
Jenny: Well, Dr. Nefedova, I know you have just a few minutes to be with us this morning, so we're going to let you go first. This target, you're talking about is called myeloid-derived suppressor cells or MDSCs. Maybe you can give us a broad overview in language that we're capable of understanding, because I know you're very smart about this. What are they and how do they work?
Dr. Nefedova: Of course. Our body has a large number of cells called neutrophils and monocytes, and these cells are actually defenders. They developed to protect us from infections, act with bacteria and viruses. In cancer, tumor cells start producing many factors that can absorb some of these protective neutrophils and monocytes into cells that actually inhibit the immune system. Now we know many mechanisms by which this change, this convergence is happening in cancer.
As a result of this convergence, neutrophils and monocytes that are defenders, join into pathologically activated neutrophils and monocytes. Pathologically activated means that the cells do not defend us anymore, but instead, they help cancer to grow. These pathologically activated neutrophils and monocytes are actually called myeloid-derived suppressor cells or MDSCs.
There are many ways by which these MDSCs help cancer to grow. First of all, they have multiple ways to deactivate cells of immune systems that are called T-cells, and natural killer cells that actually kill tumor cells. At the same time, they promote growth of new blood vessels. Also, they change the architecture of tumor surroundings that help tumors to grow and spread. One of the mechanisms by which MDSCs help cancer to grow is actually production of S100A9 proteins.
Also, I want to say that at any given moment, in cancer patients, neutrophils and monocytes that are protective, and MDSCs which are pathologically activated neutrophils and monocytes, coexist. The balance between these cells is one of the factors that helped to define the outcome and strength of immune responses. Therefore, we try to develop therapies, the target blood cells which are MDSCs and protect neutrophils and monocytes.
Jenny: Okay, so those two categories together are called MDSCs, the neutrophils and monocytes together. Patients may be familiar with neutrophils, because I know doctors are watching. I just finished immunotherapy trial, and they're watching my neutrophil count all the time just to see what's happening. Patients may be familiar with these two categories, I guess, of white blood cells. Right?
Dr. Nefedova: Yes. Yes, they are.
Dr. Vogl: In fact, your doctors were probably keeping an eye on your monocytes as well. They're just a lot less frequently seen in the blood, more often seen in the bone marrow, and so you don't usually notice the counts. Also, we don't follow their levels as much in terms of keeping track of whether patients are really at risk for an infection like we do with the neutrophil count, which is often something that we keep close track of in clinical medicine.
I think the key point that Dr. Nefedova was making is that these MDSCs are very similar to the helpful protective neutrophils and monocytes. It can be tricky to figure out how to kill off, for instance, the MDSCs that are helping the cancer to grow, while leaving in place the protective neutrophils and monocytes that keep us safe from infection. There's a lot of complicated work going into figuring out, well, what makes the MDSCs different, and how can we deal with them specifically?
Jenny: I guess you're saying that when they're “biologically activated”, then they become MDSCs. That's how you differentiate the bad from the good. Is that what you're saying? Sorry, this is a good biology lesson for me.
Dr. Nefedova: Right. They became pathologically activated by factors produced by tumors, and because they became activated, they acquire new functions. It is tricky to distinguish them from normal monocytes and neutrophils, but now we know specific markers that allow us to do that. While normal monocytes and neutrophils, they defend us, the function of MDSCs is different. Actually, they do not defend us. They help cancer to grow. This is the big difference between these cells in their functional activity.
Jenny: Like you're saying, there are a lot of tests that you can do to try to differentiate. How is that tested? When you look at normal levels versus a myeloma patient, is that something we should always be testing in myeloma?
Dr. Nefedova: It's a good question. Usually, MDSC levels are measured in blood, but they also can be detected in the bone marrow. How do we detect MDSCs? They have a specific phenotype, which means they have a specific set of markers that express on the cell surface. Now we know markers that distinguish them actually from normal neutrophils and monocytes, and these markers could be detected in the lab using flow cytometry.
Usually, in healthy people, only a very small population of cells with similar phenotype exist, could be detected in the blood. Usually, it's between 0.5 to 1%, but could be even less. In myeloma patients, the number of MDSCs significantly increases several fold and can reach 10%. It could be even higher. There are not that many studies actually done in myeloma on MDSCs. This is something which is upcoming, I believe. There was a study that demonstrated actually the presence of MDSCs in myeloma patients, significantly correlated with the stage of the disease.
Jenny: It’s so interesting. Yeah, go ahead Dr. Vogl.
Dr. Vogl: I was just going to say, from a clinical perspective, I think it's really important. A lot of people listening are patients and they're then going to start wondering, should I go out and get my level of MDSCs measured? I think it's important to emphasize that we're really very early in the evaluation of this whole branch of cancer therapy so that the tests that Dr. Nefedova does in her laboratory to count up the number of MDSCs in a blood sample or in a bone marrow sample, these are tests that are not available in a regular laboratory. Even if they were, right now, we wouldn't really know what to do with the information.
What you just heard is that patients who have higher numbers of MDSCs, or we see higher numbers of MDSCs in patients with more advanced multiple myeloma, and that's not necessarily surprising that these higher numbers are associated with more aggressive or higher stage disease. What to do about that or whether that's going to influence a success of any particular therapy is still something to be worked out.
I could imagine that in the future, if there were a treatment that worked really well for patients with high levels of MDSCs, but not very well for people who had low levels of MDSCs, we might have a test then that we could do in the laboratory, but we're still a ways away from even knowing that that would be a good thing to test for. Right now, we're really at the point of trying to understand how the levels of MDSCs or the function of MDSCs impact the response to various therapies or, specifically, therapies aimed at the MDSCs, like the ones we're talking about in the trial that we're discussing today.
Jenny: Right. Well, the reason I asked too, is because with all these immunotherapies, sometimes you'll hear, oh, the immune system has been exhausted or whatever. There's a lot going on in the immune system, obviously, that's very complicated. Looking at just understanding every aspect of it, could that be a potential marker to say, oh, this could influence the way you react to a bispecific antibody or a CAR-T therapy or something like that. Do you have high or low levels? I don't know. It just seems like the more that we can put our arms around and capture into that immune system status, I guess, would be helpful for researchers and patients.
Dr. Nefedova: Absolutely. Actually, I just want to mention that MDSCs have been much more extensively studied in the solid tumors. In the solid tumors, there's a growing body of data, showing positive correlation of presence of MDSCs with the stage of the disease, and response to therapy, especially with checkpoint inhibitors. In fact, there are about 90 ongoing, currently ongoing clinical trials that actually look at the level of MDSCs as a factor that can either predict response to checkpoint inhibitors or allow to monitor the effect of the therapy.
Jenny: In solid tumors, which solid tumors are being studied most with MDSCs?
Dr. Nefedova: I would say lung cancer and neck cancer, pancreatic cancer, melanoma and many others.
Jenny: Oh, that's a lot.
Dr. Nefedova: Breast cancer.
Jenny: It's newer in blood cancers. When these MDSCs are targeted, they're just targeting the supportive immune cell environment. Obviously, they're not necessarily, like you said earlier, Dr. Vogl, killing the myeloma cells directly, but they're affecting this supportive environment. Any MDSC-type therapies, are they always used in combination with other more toxic or cytotoxic cancer therapies?
Dr. Nefedova: Right. Yes, MDSCs attack the immune system and inactivate normal immune cells, which allows tumors to grow uncontrolled. Also, actually, MDSCs could interact directly with tumor cells and protect them from the effect of cancer-killing therapies, which helps tumors to survive and eventually relapse.
In preclinical settings and preclinical models of cancers, targeting MDSCs alone demonstrated anti-tumor effect, but this effect was much more stronger when this targeting MDSCs was combined with other therapies, including checkpoint inhibitors and therapies that killed tumor cells. Our studies in mouse models of myeloma demonstrated anti-tumor effect of targeting MDSCs with tasquinimod. When we combined tasquinimod with either lenalidomide, Velcade or Revlimid, the anti-tumor effect of the drug combination was significantly stronger.
Jenny: Dr. Vogl, go ahead.
Dr. Vogl: I was just going to say, what I think you're hearing is that there is the potential for a treatment that's targeted at MDSCs to work by itself, but it may not be the strongest effect as a single agent, and might work much better when combined with other treatments. There's a rationale to combine it with immune therapies. In other cancers, especially lung cancer, colon cancer, there are these treatments called checkpoint inhibitors.
The classic one is pembrolizumab or the brand name Keytruda. That can work really well to activate immune cells, especially T-cells which are the immune cells that usually have the job of killing cancer cells. By turning the T-cells on, nonspecifically, just turning them on, you can get some really amazing cancer responses. That medicine has not worked particularly well in multiple myeloma. Or at least the to the extent that it worked, it was balanced by some side effects, especially when combined with other myeloma treatments.
That kind of immune-stimulating therapy is still very investigational in myeloma, and figuring out how to make it work better would be a significant step. What Dr. Nefedova showed in her laboratory research in mice is that if you take other treatments for myeloma that are really aimed directly at the myeloma cells and trying to kill them, and combine them with a way of blocking the immune-suppressive and supportive signal that they can get from from MDSCs, then you can really make the treatments work a lot better.
The medicine that she used, that we're using here, tasquinimod, blocks this one particular protein produced by MDSCs that signals for blood vessel growth and signals for suppression of the immune system in the bone marrow microenvironment. This medicine, tasquinimod, can block that signal. Therefore, when we combine tasquinimod with other myeloma treatments, we can see in laboratory models, that that makes them work much better than they do on their own.
Jenny: Yes, wonderful. Dr. Nefedova, I know you have to go. Is there anything else that you would like to share about MDSCs before we have Dr. Vogl talk about the trial?
Dr. Nefedova: Well, MDSCs have been extensively studied in solid tumors, and targeting MDSCs was successful in the clinical models. Currently, there are several ongoing early stages clinical trials in solid tumors which target MDSCs, in combination with checkpoint inhibitors or chemotherapy. However, these cells are not studied that well in blood cancers. This is something that’s probably emerging and will be an upcoming area of research.
We believe that this could be potentially, very successful therapy, especially considering the fact that blood cancer, actually, specifically myeloma, grows in the bone marrow, a location with a high number of MDSCs and place where MDSCs actually originate. Of course, we don't know that because we don't have data, but it's possible that strategies targeting MDSCs could work even better in blood cancers, compared to solid tumors.
Jenny: Yes, that will be interesting to see. Thank you for all the lab work you're doing to understand, and I love what Dr. Vogl said in the beginning, how he's working with you that you're trying to take this bench-to-bedside kind of approach to see exactly what's happening both in your lab and then in patients in the clinic. I think that's fantastic.
Dr. Nefedova: Thank you.
Jenny: Yes, thank you so much. Dr. Vogl, is this the first study of MDSCs in multiple myeloma?
Dr. Vogl: It's the first study that I know of where we're specifically doing a treatment that we really think is primarily targeted at MDSC. Dr. Nefedova and I were talking recently about this, and we identified a couple of other medications that have lots of ways that they might work to help treat cancer and myeloma specifically, and that one of their effects might be that they affect MDSCs in some way. Even those studies are very much in the early phases in multiple myeloma.
This treatment, this tasquinimod medication is the only one that I know of that we think directly blocks a signal specifically that comes from these myeloid cells in the bone marrow to help provide the supportive bone marrow microenvironment to the myeloma cells.
Jenny: What protein is tasquinimod blocking? You said it blocks blood vessel growth, and it blocks the suppression that the immune system goes into when these MDSCs are present.
Dr. Vogl: The idea here is that when normal neutrophils and monocytes, these normal protective cells that are growing in the bone marrow, get into close proximity to cancer cells, and specifically myeloma cells, there are some signals that go out from the myeloma cells that signal to these otherwise helpful protective immune cells to become supportive and immunosuppressive and start sending out signals to other cells in the bone marrow that cause them to be more supportive, to allow more blood vessels to grow in and provide more nutrients to the cancer cells, and then specifically, to suppress T-cell function in the area right around the myeloma cells.
The main protein that we're focusing on that are produced by the MDSCs is a protein that's known as S100A9. Dr. Nefedova noticed that this protein was probably important, specifically looked in mouse models of multiple myeloma and found that that was true, that it seemed like S100A9 production by the myeloid cells, by these MDSCs, contributed to the growth of the myeloma and its ability to evade the immune system, and that if you actually got rid of S100A9, the myeloma didn't grow as well.
It turned out that there's a medicine that's been around for several years that's still investigational called tasquinimod that has the function of blocking S100A9, so the idea of using tasquinimod to treat cancer is not a new one. It was developed a few years ago, actually went through a very large clinical trial, over 1,000 patients were treated with tasquinimod. In prostate cancer patients, you could actually see that when patients got tasquinimod versus when they got a placebo pill, it took their prostate cancer longer to grow than if they just got the placebo. We actually had, even before starting our trial in myeloma, some evidence that tasquinimod could really have a biological effect on cancer and preventing cancer growth.
Now, in prostate cancer, slowing down the growth wasn't quite a strong enough effect to get this medication approved for treatment, and so it still remains investigational, but based on Dr. Nefedova’s previous laboratory work and this previous clinical trial experience in other types of cancer, we were really excited to try this out in multiple myeloma, both by itself as a single agent, and more importantly, in combination with other myeloma therapies to truly explore whether it could augment the effectiveness of other treatments and really be an option for patients in the future.
Jenny: Yes, I love that you're connecting these dots between this target and then finding even a drug that's already been developed. That's so much more efficient than trying to create something from scratch, so I love the approach.
Dr. Vogl: We were also really lucky to join up with a small Swedish biotechnology company that had developed tasquinimod. Dr. Nefedova had been in touch with them and gotten a supply of tasquinimod that she could use in her laboratory work. When it came time to think about doing a clinical trial, it turned out that they were also really interested in looking at multiple myeloma as a potential area that this drug might have an effect, and we were able to set up a collaboration where they are providing the medication and some of the funding to run the clinical trial.
The Leukemia and Lymphoma Society provided a really important grant to us to run the clinical trial and also to fund some of the laboratory work that Dr. Nefedova is doing to try to figure out exactly how this medication works, what some of the resistance pathways might be, and then to also analyze the samples that we're getting from patients during the trial, to see if we can identify the same kinds of effects as we give this to people, as were seen in the mouse models that she uses to study myeloma in the laboratory.
Jenny: Wonderful. Will you share a little bit more information about this study? Is this a phase one study? Let's talk about all the study details.
Dr. Vogl: Sure. We're actually in the middle of the study right now. I think it's appropriate to call it a phase one study because we are still trying out a few different things with how the tasquinimod is dosed. Tasquinimod is an oral pill. It's taken once a day, every day. That was all worked out in patients with other types of cancer.
We weren't quite sure about the dosing schedule. It was typically given at a very low dose for a couple of weeks, then a medium dose for a couple of weeks, and then a full dose. That's a hard thing to think about when you're treating people with myeloma who might need treatment right now. We've been trying out faster increases in the dosing schedule, and we had thought about going to even higher doses.
The truth is, unlike other phase one studies where we're starting out with a brand new medicine and trying it out at very low doses and then slowly going up and maybe getting to doses that are way too high, we were already pretty sure when we started this study what the right dosing range was going to be. All of the people that we're treating as part of this study are getting doses that are right there in the range that should be effective.
The study was written to treat some people just with tasquinimod by itself, and then we also decided to try using tasquinimod in combination with a standard myeloma treatment regimen that's known as IRD. The I is ixazomib, also known as Ninlaro, which is a type of drug called the proteasome inhibitor; the R stands for Revlimid, also known as lenalidomide, which most people would call an IMiD; and then dexamethasone, the steroid medication.
IRd is a standard myeloma treatment regimen. It has the advantage of being all-oral pills, so when we combine it with the oral tasquinimod, it's an all-oral regimen, which is not such a common thing in myeloma therapy, and I thought would be pretty attractive to patients to be able to do everything with just pills. The reason we picked those specific medicines is because those are the medicines that Dr. Nefedova had looked at in the laboratory and found that tasquinimod could help those medicines, specifically ixazomib or bortezomib, which is a very closely related medication, also known as Velcade.
You could really see synergistic effects between tasquinimod and the proteasome inhibitors, and also additive effects with tasquinimod and Revlimid or lenalidomide, and so the idea of putting those together, which is a standard regimen that we know a lot about giving, and then adding in the tasquinimod and really augmenting the efficacy, we're very excited to see how well it works.
Jenny: Wonderful. Because this drug has been used in other cancers, I'm sure you have some kind of safety profile, like you do with the dosing. Have you seen any indication of specific side effects or things like that, in addition to the IRd combination or alone, I guess?
Dr. Vogl: We have not yet started the combination of tasquinimod with the IRD combination. That part of the study just opened up, and we're looking for patients to sign up for that study right now, here at the University of Pennsylvania. The part that we've done so far was we treated a total of ten patients with single agent tasquinimod, over the past year and a half, to try to understand what kind of effects that would have.
In terms of side effects, I think we've seen pretty similar side effects to what was seen with tasquinimod in other cancers. In general, it's a pretty well-tolerated drug. I would say most patients have minor side effects. It can cause some fatigue. It can cause some upset stomach. Probably the most prominent side effect that we saw that was seen before was some pain, either muscle pains or bone pains. For a couple of patients, that's been pretty intense; but for other people, not so bad; and some people, not at all. It's been very variable, person to person, whether the medication was causing any significant side effects.
We do think that the side effects are not as bad if you start off with a lower dose and then increase to the full dose. The study right now is planning to, at most, escalate or increase the dose to the full dose after one week of treatment. We're actually starting off with, right now, with one week at a very low dose, one week at a medium dose, and then getting to the full dose at two weeks, which might be exactly the way to do the dosing of the medication.
Overall, we're hopeful that when we add it into the IRd combination that we don't see too much in the way of additional side effects beyond what we would expect with IRd itself, which I think also overall is a pretty well-tolerated combination.
Jenny: Where is the study being run, just at UPenn?
Dr. Vogl: Yes, so this study is just being run at the University of Pennsylvania. That's partly because it's a relatively small study. Also, because we really want to have the ability to take the samples, blood samples and a couple of bone marrow biopsy samples, from our patients and run them over to Dr. Nefedova’s Laboratory, which is located right across the street, so that we can really learn more about exactly how this works. Of course, if we start to see some really good effects, I imagine that Active Biotech and I will think about ways to expand this to a bigger research program at other institutions as well, but right now, it's just at the University of Pennsylvania.
Now, we do know that a lot of our patients travel some distance to be part of the study, so for this particular study, we worked very hard to try to write the study in a way that would not require too much in the way of visits at the study center. There are a couple of visits that you need to come to Penn in the first month. After that, it's a once a month visit to the University of Pennsylvania, and then everything else, if there's blood work that needs to be done in between, we can figure out ways to do that closer to the patient's home and work with their local oncologist to deal with anything that's going on, if they need it, and really minimize the number, the amount of travel that patients have to do, which can be a big burden associated with clinical trial participation.
Jenny: Right, and this is where the all-oral idea is a really good idea. That's a great trial design, in my opinion. Who are the ideal patients to join the study, relapsed or after how many lines of therapy, that kind of thing?
Dr. Vogl: Because this is all brand new and experimental, the FDA really wanted us to concentrate on people who had already been through the most effective standard treatments or had some specific reason why they couldn't get them. This is certainly for people with relapsed or refractory multiple myeloma, meaning that they've gotten prior treatments that have stopped working, and we're looking for people who have gotten all or at least most of the current most effective standard treatments. That's usually people who have been through three or four or more prior treatments for their myeloma, and there's some reason that they shouldn't use those treatments, either they weren't working or they were causing bad side effects.
Really, it's for people who have been through a lot of other things. Ideally, for this part of the study, people for whom using a combination of IRd, of ixazomib, lenalidomide and dexamethasone, would be a reasonable thing to do. If they've gotten those medicines before, we wouldn't want those medicines to cause really bad side effects in the past.
Jenny: Okay. Also, how many patients -- phase one studies are usually small -- how many patients are you looking to include? You said you're into the study already. Right?
Dr. Vogl: We are. We've treated ten patients so far. Part of the reason we're talking about this right now is we recently made public a small snapshot of those results, where we did see that as a single agent, we had two patients whose myeloma was clearly growing when they came into the study, and really seemed to stabilize for several months, four or five months on the treatment, so that we thought we saw a hint of an effect of tasquinimod by itself. At the same time, it didn't seem like a really strong effect, so we weren't wild about signing more people up to be treated with tasquinimod as a single agent, and really wanted to move onto the combination part of the study where we really think that this kind of treatment that bone marrow microenvironment will have its best effectiveness.
We're just starting the combination part of the study, and we're looking to treat a total of somewhere between, I would say, 18 and 30 patients. We start off small. Right now we're looking for three people to be the first ones to get this particular combination. If they do well, then we'll try a slightly faster increase in the dose of the tasquinimod, bumping up the dose at one week with the same combination. If that seems to be well-tolerated, we'll try to sign up at least 12 more patients and try to get a sense of, well, how well does it work? How well does it work specifically in people who have previously gotten combinations of imids and proteasome inhibitors that stopped working so that we wouldn't really expect the IRD to work on its own, and if we see some effectiveness against the myeloma, that we’ll really know that it's because we added in the tasquinimod to the regimen?
Jenny: Right, and combining something that's going to slow the growth with combining something that's known to treat, this triple combination, that's known to treat myeloma is a good approach because, yeah, I like it. I think it’s great.
Dr. Vogl: More importantly, in the laboratory, when we added tasquinimod to Velcade therapy, which is very similar to the Ninlaro that we're using, we saw that it helped kill myeloma cells better. To a slightly lesser extent, we saw the same thing with Revlimid. We're hoping that adding the tasquinimod really bumps up the effectiveness of these other medications and makes it a much more effective regimen.
Jenny: You could think that, once you get through this trial and you do this, I know everything starts in relapsed and refractory myeloma with clinical trials, but you might think that using it in smoldering myeloma or earlier forms of myeloma might really delay that progression. We have patients living 10, 15-plus years, so anything that would slow that process down would be truly amazing.
Dr. Vogl: I think that's really important. Of course, I could also imagine using a medication like this in combination with immune therapies where we're trying to get immune cells to kill myeloma cells and that, therefore, taking a medication that doesn't have too much in the way of side effects and combining it with other therapies all along the spectrum of patients with myeloma, could have a lot of effectiveness in lots of different places.
It's really important to pick some place to start. Because of how we think about things in drug development, we usually want to start our treatments in patients who are really in need of something new and don't have another good alternative. Therefore, if we jump in with a new medication, we really can figure out in the people who need it the most, whether it's going to have any effectiveness at all.
It's a lot more challenging to try out a brand-new drug, where you're not really sure that it's going to work in people, say, with smoldering myeloma, whose myeloma might not absolutely need treatment right now. That's always a little bit more challenging when you think both about the ethics and about the practical aspects of who's really going to want to sign up for the study. We are very excited about the possibility that if this works, it could be applicable in lots of different situations.
Jenny: Even in high-risk smoldering where you know they're going to progress within a certain time frame or something, so that'd be really interesting. Another question, you say with immunotherapies, I know you're talking about that very broadly. I know you mentioned checkpoint inhibitors earlier in. When they did the checkpoint inhibitor studies in myeloma, and they combined it with lenalidomide, it did not go well for those trials. If they're using this with checkpoint inhibitors alone, I know checkpoint inhibitors might still be able to be wonderful in multiple myeloma, just combined with the right things. Do you think that type of immunotherapy would be selected for one of these approaches, if you start seeing impact in your study
Dr. Vogl: Well, on the one hand, I don't want to get too far ahead of where we are right now. Right now, I'm very focused on the trial that we're doing and really making sure we understand what effects we see of tasquinimod in combination with agents that we know we've shown in the laboratory should work better when we add tasquinimod in with them. We're really excited about that.
I am part of a bigger myeloma research program. My colleagues here at Penn and I are working on a wide variety of clinical trials that have all sorts of different effects on the immune system. We are continuing to do research on both existing checkpoint inhibitors and new, what we call, checkpoint inhibitors. They're called checkpoint inhibitors because these are ways of blocking signals to immune cells that keep them in check, that keep them under control and not functioning to the point that they could be, and so when you put these inhibitors into patients, you can really turn on the immune system.
Both, similar medications to ones that have been tried in myeloma but just in different combinations, and then new ones as well; and then other immune therapies where we're specifically guiding T-cells to the myeloma cells to kill them, either by targeting them with chimeric antigen receptors or CARs, or by using bispecific T-cell-engaging antibodies to draw the T-cells into the myeloma cells to attack them. All of these are either new ways of treating myeloma that are approved or are investigational but incredibly promising and likely to move into the clinic as approved treatments in the near future.
I could imagine trying a medicine like tasquinimod in combination with any of these because for any of them, the bone marrow microenvironment is a constant that we have to deal with. Myeloma cells don't exist just by themselves. When we study them in the laboratory, they behave very differently as just myeloma cells in a petri dish than they do if you mix them with other bone marrow cells or, more importantly, if you treat them in the context of an entire living organism, with an immune system and a bone marrow microenvironment.
We know that when we're treating myeloma in patients, we're going to have to take all of that into account for any of our treatments, and using a therapy like tasquinimod has the potential to make a real impact on any and all of these treatments.
Jenny: Yes, definitely. You think about CAR-T and maybe prolonging relapse after CAR-T, making it last longer. I don't know. There are a lot of different ways that this potentially could be used in myeloma treatments, so it's very exciting that you're investigating it, especially because I know UPenn has such deep expertise in immunotherapies. Will you consider this an immunotherapy? To me, it is because it's affecting the bone marrow microenvironment, which is part of the immune system, right?
Dr. Vogl: Sure. I think if you made a broader category of treatments that have some effect on the immune system, I think this could fit into that. I want to make sure I don't go too far because most of us, when we're really talking about immunotherapy, we’d concentrate much more on treatments that have a much more measurable direct effect on the immune system or directly harness the immune system. This is a little bit more indirect way of trying to help that system along.
Jenny: Okay, wonderful. Well, I want to leave a few minutes for caller questions. If you have a question for Dr. Vogl, you can call 347-637-2631 and press “1” on your keypad. We have an early question. We have a couple of questions. Caller, go ahead with your question.
Caller: Hi. It's a pleasure to be a part of this and to ask a question. I have some experience in doing research in the microenvironment. I know it's often a two-way street. There’s targeting the pathway to the tumor cell and then targeting the pathway that leaves the tumor cell. Has there been any look into tasquinimod and targeting tumor cell signal that is being released, recruiting or calling in this microenvironment?
Dr. Vogl: Well, now I'm a little sad that Dr. Nefedova isn’t here with us to field this kind of question. I will say that in this particular trial, we really do think that tasquinimod is blocking a protein that is primarily made by the tumor microenvironment, and specifically these MDSCs in the tumor microenvironment.
There is, I know, ongoing work that is looking at what signals come from the myeloma cells to the myeloid cells, the normal neutrophils and monocytes, that then turns them into MDSCs. I'm not aware of any clinical trials that are trying to block that at this moment, and that might be in part because we're just not sure that we've identified one factor that really could be effectively blocked.
This trial is really looking then at the next step, that once those cells become MDSCs, what signals do they send out that could be effectively blocked? We do think that this S100A9 protein is a really good target. It's clear that blocking S100A9 doesn't seem to lead to bad things happening in people. The question is, does it provide a strong enough anti-tumor effect that this is going to really be a good treatment for multiple myeloma in particular? We'll only figure that out by actually trying it.
Caller: Very interesting. Thank you.
Jenny: Okay. Thanks for the question. Okay, next caller, go ahead with your question.
Caller: Hi, Dr. Vogl. This is Cindy Chmielewski. How you doing? Yeah, this is really exciting. I am trying to learn all I can about this. First, with these MDSCs, the things that you were saying look like neutrophils and monocytes, but they act differently because in the presence of cancer, they get activated. If you don't have cancer, do you have MDSCs?
Dr. Vogl: Cindy, that's a great question. For those of you who don't know Cindy, Cindy is a fantastic patient advocate who I've known for many years, and always has good questions to ask. It turns out, it's almost a little bit silly, but in fact, the definition of MDSCs is that they're part of what happens in the presence of cancer. By definition, if you don't have cancer, you can't really have MDSCs specifically.
Now, what you did here, Dr. Nefedova say, is that we do have some ways of differentiating MDSCs from normal neutrophils and monocytes, based on the types of proteins that they have on the surface of the cell. If you look in the blood of people without cancer, you can sometimes find a very low level of cells that have those same surface proteins on the outside of the cell that we would expect to see on MDSCs. If you look in people with cancer, there are a lot more of them.
We're not sure that in people without cancer, that those cells have any harmful role. In fact, because they can happen as part of the body's response to something, like many things in cancer, it may be that they actually have a useful, helpful role when you don't have cancer. It's only in the setting of cancer that the body's normal natural processes get somehow turned around and start protecting these cells that we really want to get rid of. So, it's possible that only in people with cancer do these types of cells have a truly pathologic role or a harmful one.
Caller: Okay, thanks. I'm trying to get this in my head. Can I just ask one quick question about the eligibility criteria? If someone is refractory to len or ixa, could they still be part of the trial, or is it people who are non-refractory to those two drugs?
Dr. Vogl: In order to get on the study, you have to be at a point in your treatment where just doing Revlimid or lenalidomide or just doing ixazomib or Ninlaro wouldn't be a normal thing that you would do. Because if those are good options, then maybe you don't need this study, specifically.
More importantly, both in this initial part that we're signing people up to right now and a little bit later on, we're also going to really be looking for people specifically for whom a medicine like Revlimid has stopped working and a medicine like Ninlaro has stopped working, more importantly even, that the combination of those two, which is a particularly powerful combination, or at least of those two classes has stopped working. Because those are specifically the people were, when we add in the tasquinimod, we're going to know that if they have a good response, that's really because of the tasquinimod.
We are looking for people who have previously gotten these medicines and had them stop working, and we're hopeful that when we add in this new medicine, that they'll work much better than the last time that people got them.
Caller: Good. Do you know about how long to the response you would see, how long would you know if they're responding to the tasquinimod, or we don't know that yet?
Dr. Vogl: I don't think we know that yet. My usual approach when I'm treating people as part of a clinical trial is to just take it step by step. Usually, we think we at least need to give something for about a month to start assessing a response. Usually, we want to try to give it around two months, and then really assess what direction things are moving. If it’s responding by two months, you know you're good. If it's clearly growing at two months, you're pretty sure you're not going to see any benefit from it. If it's staying stable and people are doing well, often we’ll say, you know what, maybe there will be a later response.
As long as people are feeling okay, we'll often decide to keep going and see whether we'll see a better response, or at least a very long period of stable disease, which for some people, if they're feeling well while they're disease is stable, can be a very good outcome that we're really happy with.
Caller: Okay, great. I have so many more questions, but I’ll let someone else ask them. Thank you so much.
Dr. Vogl: It was absolutely a pleasure to hear from you, Cindy, and from everyone else. Do you know if we have any other questions, Jenny. I think we may be running into some technical difficulties. If there's someone on the line who wants to ask a question, go ahead.
Dr. Vogl: I can hear you saying hello.
Caller: Okay. My relative has been doing RVd and after a stem cell transplant the labs are normal. How can we know if she is cured? She had a plasmacytoma.
Dr. Vogl: Of course, what you're asking is some very specific questions, and without having seen a patient, it's hard to know exactly all of the details. I do think that all of us in myeloma research and treatment are hoping that we're working towards the day when we can look at people and really say that we've cured them of multiple myeloma.
At least, right now, I think the assumption that we tend to have is that we don't have any treatments right now that truly lead to a cure so that for anybody with multiple myeloma, even when we've treated to a really deep response, we're still watching for the rest of their lives to make sure that whenever the myeloma starts to come back, we notice it early.
We do see some people for whom the myeloma never manages to come back during the time that they're alive, and that's great. Still, we assume that if we follow people for long enough, that eventually we'll see the myeloma again, and it's always a good idea to keep looking for it. In the meantime, we're going to keep doing other types of clinical trials and trying out new medicines and new approaches, until we can say that maybe we really are curing people.
Jenny: I just want to thank you for all the work that you're doing and in bringing these new therapies to the myeloma clinic. It's really stunning to me as a patient what's happening in myeloma, and it's because of work like this and like yours, so, just thank you so much. I know we went over a little bit. I appreciate your time and Dr. Nefedova’s time and expertise today. Just thank you so much for all you do for myeloma patients everywhere.
Dr. Vogl: Jen, you're welcome. I'll turn that right around and say thank you to you. I think that the opportunity to talk about this kind of research to patients is extraordinarily valuable, and I've really enjoyed it. I think the work that you're doing with Myeloma Crowd and with HealthTree is incredibly important, giving people a source of reliable information and a voice and an opportunity to contribute to our knowledge about multiple myeloma and how we treat it, and what outcomes are. It's such a pleasure to be able to work with you on that.
Jenny: Well, thank you. It's because I love this format because it allows patients to truly understand what this trial is all about, and this is how patients, how we as patients can contribute to our own care, is by participating in trials like these. What you're doing is very important, and we just appreciate you so much.
Thank you so much for joining us today, Dr. Vogl, and thank you, everyone, for listening to Myeloma Crowd Radio. We'd like to 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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Feb. 01, 2023
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