Viktoria Bachanova, MD, PhD
University of Minnesota
Interview Date: March 12, 2018

Natural killer cells are the body's way of eliminating cancerous cells. When a myeloma patient's immune system is too weak, the natural killer cells can't effectively do their job to eliminate myeloma. A study is now being done to test donor natural killer cells in relapsed myeloma patients. The natural killer cells are collected and combined with IL-2 to help them grow and expand. Elotuzumab is used to help the NK cells migrate to the myeloma tumor and has anti-myeloma effect on its own. Dr. Bachanova shares why elotuzumab is used over daratumumab and how participation in this study would not preclude patients from joining other CAR T or T cell therapy studies.

Thanks to our episode sponsor, Celgene Corporation.

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

Now, we've heard a lot about immunotherapy in multiple myeloma, and we know there are a lot of different types of immunotherapies including monoclonal antibodies like elotuzumab and daratumumab and isatuximab, vaccines, CAR T-cell products, the checkpoint inhibitors, bispecific antibodies, and others. And today's show is about a combination of immunotherapies and something new that you may not have heard about called NAM-NK cells. We have Dr. Viktoria Bachanova of the University of Minnesota to help us understand more.

So Dr. Bachanova, welcome to the show.

Dr. Bachanova: Thank you. It's great to be here.

Jenny: Well, let me introduce you before we get started. Dr. Viktoria Bachanova is Associate Professor of Medicine in the Division of Hematology, Oncology and Transplantation at the University of Minnesota. She is an expert in the use of natural killer cells as cancer therapy in leukemia, lymphoma, and myeloma, and has expertise in both autologous and allogeneic transplantation. And some of her previous awards include the Young ASCO Investigator Award, the CALGB Clinical Investigator Award, and the KL2 Scholar Award, and I had the pleasure of meeting her in person at the recent BMT Tandem Conference in my hometown of Salt Lake City.
So it was such a pleasure to meet you. We have a video that we'll be sharing as part of this radio show with you as well. So welcome again.

Dr. Bachanova: Great, great. It's great to be here. And I am looking forward to share my research with your listeners.

Jenny: So maybe you want to give everyone an idea about natural killer cells to begin with because a lot of patients may not be familiar with what they are and how they work. Why don't we start there?

Dr. Bachanova: Sure. Natural killer cells are white cells which we all have in our blood. This is a counterpart to T-cells. They are lymphocytes, white cells, and they are there to protect us from viral infections, for bacterial infections, and in fact they are our natural protection against tumor development, cancer development. They are screening our body continuously through life and are getting rid of the cells which are becoming cancerous. That way, they are controlling our body to get rid of the cancer cells. So they are very powerful and very potent. But often as cancer develops or progresses, they find a way how to circumvent this system. The natural killer cells can become dysfunctional or eliminated so they no longer can do this work. But they are natural protectors against cancer in our body.

Jenny: Okay, wonderful. And your background is in transplantation. So can you share just a little bit about your background in transplant for all of the blood cancers and then maybe how you got interested in this line of research?

Dr. Bachanova: Sure. The patient with blood cancers, lymphoma, myeloma, or leukemia often can respond to chemotherapy. But for some patients, the chemotherapy would not lead to cure. It's not powerful enough to eliminate every single remaining cell. So over the many decades of research we learned that if we use immune system of the donor, or the patient's own stem cells, the immediate effect can be more powerful and, in fact, lead to cure for some patients.
So I have been in this field of bone marrow transplant mostly using the donor cells from the donor either related or unrelated. In fact, we are using the umbilical cord blood stem cell as a source of immune system which is infused with a patient's system. So they derive a new immune system. And this new immune system is, in fact, able to look for those hidden cells, cancer cells, and mediated the rejection by the immune-mediated process.
We learn about this over many years and our center has developed a new way how we can use these new immune cells but without going through the entire process of transplantation which, as many people know, is very complex and have some long-term or acute side effects and also often can be very dangerous. So that's what led us to using NK cells from the donor without stem cell transplantation, just the NK cells as a cellular product and use that as a tool to fight the cancer.

Jenny: So you have a lot of expertise in the allogeneic or the donor type of transplant. And in multiple myeloma, a lot of people get the autologous where they use their own cells. So you're talking about using natural killer cells from someone else, not your own natural killer cells because those are not working properly, right?

Dr. Bachanova: Exactly.

Jenny: So you're using natural killer cells from someone else. You're talking about natural killer cells that are called NAM-NK cells. What does that mean?

Dr. Bachanova: So we have used natural killer cell infusions in patients with lymphoma and myeloma, but now have developed a new program where the natural killer cells can be cultured in vitro. So in laboratory with a nicotinamide. This is a chemical with the abbreviation of NAM, nicotinamide. And that exposure of NK cells to nicotinamide change them in a way that they are more likely to travel into the tumor sites, more likely to travel to the bone marrow. They also persist longer in patients, and they have other favorable characteristics which make them to perhaps be better treatment products in clinical trials.
So we launched this nicotinamide-expanded NK cell in combination with monoclonal antibodies in myeloma patients is elotuzumab, as many of your listeners may know. And elotuzumab also doesn't work in patients because their underlying NK cells are dysfunctional. However, the combination of the elotuzumab with the donor healthy NK cells, which are in effect even more activated or charged in vitro with the nicotinamide, make this combination more promising. And in fact, we hope that more likely to work for refractory or more difficult myeloma patients.

Jenny: So in this way, you're able to combine two different immunotherapies. I have some other follow-up questions about that, but let's go back to the collection process. I think patients, when they think about stem cell collection and they think about the transplant process, there's a process to have those donor cells collected. So when you think about an NK cell donor, what type of donor are you looking for? How are the cells collected? Just what does that process look like?

Dr. Bachanova: We typically use related donors - either siblings or children of adult patient who are at least the age of 15, I believe we have there. So the donors are screened. They do not have to have a tissue match to the patients. In fact, we prefer or select those donors which are at least partially mismatched to the patient. Those NK cells are more likely to be reactive and to be more potent against cancer cells.
The donors are undergoing apheresis, or lymphapheresis, a blood donation where we select those lymphocytes from the blood. This is usually what we call unstimulated, so there is no need for the growth factor, other preparation for the donor. It's just one day collection of the lymphocytes in a five-hour procedure called apheresis. And those cells are subsequently, that the product is manipulated, so the NK cells are selected and are in our laboratory manufactured or co-cultured with nicotinamide for about two weeks. Afterwards these cells, the product is harvested and then infuse for the patients in combination with elotuzumab.

Jenny: I think it's wonderful. Did you mention earlier the IL-2?

Dr. Bachanova: Yes.

Jenny: With the NAM. You were saying it's more likely to travel to the bone marrow and persist longer with the combination? What is IL-2? What does it do, and how is it involved?

Dr. Bachanova: Yes, great question. The NK cells would not survive in a body for a very long period of time. They survive for several days, maybe up to a couple of weeks. And in order to prolong this time, we use cytokine IL-2 (Interleukin-2) in a patient, in a subcutaneous form for three doses - a couple of days apart - with the goal to allow these NK cells to persist longer, to allow them to expand in patients and to also activate them also in vivo.
Jenny: Okay. Wonderful. So you explained the process. Now, why elotuzumab? Because I know I asked you this when we met. A lot of people say, well, daratumumab is used so often in myeloma. You hear about it a lot. And there were some very specific reasons that you chose elotuzumab over daratumumab in this particular combination.
Dr. Bachanova: Yes, we did. Elotuzumab is an interesting antibody. Its target is SLAM protein which is on myeloma cells. However, it needs the effector cell, which is NK cell, to be able to elicit its function. And those NK cells are often dysfunctional in a patient with myeloma. So by infusing healthy cells with elotuzumab has a chance to work better. It's also interesting that the SLAM protein is also expressed on NK cells. But on these cells, it’s agonistic. So in contrast, it actually makes the NK cells more powerful by binding to the SLAM protein. So there are two separate reasons why we hope and it's been also a pre-clinical work that the combination of the healthy nicotinamide-activated NK cells with elotuzumab will result into a more potent myeloma cancer cell killing.

Jenny: And the two primary reasons that you were mentioning?

Dr. Bachanova: Two reasons are that the NK cells are binding elotuzumab with the SLAM but also with the regular, I would call, antibody mediated diversity. The other reason I wanted to say why we don't use daratumumab because, in fact, there daratumumab target is protein which is also expressed on myeloma and also NK cells. But there are two treatments, in fact, eliminate NK cells. It actually makes it go way or kills NK cells. So it would not be a good combination for what is our purpose which is to make the NK cells healthier and to make them persist.

Jenny: And a follow-up question and I know you work in all the blood cancers including myeloma, but if daratumumab is eliminating NK cells for other therapies that are using daratumumab or patients who are becoming refractory to daratumumab, I know it's a really powerful drug and one that people like to add to a lot of different combinations. Would that preclude patients from using anything else in the future? Is it a temporary elimination of the NK cells or I guess just what are other considerations, I suppose?

Dr. Bachanova: I guess prior treatment with daratumumab would not exclude patients from being involved in our clinical trial. The patients, although should not receive a prior elotuzumab, we would like them to be elotuzumab naïve. How the daratumumab affects the NK cells long term, many of these anti-myeloma therapies do not work through the NK cell mechanism, so it may not be relevant for them. It is, though, an area of active research. These are the good points. It is something which we don't understand fully.

Jenny: And for your study, this is a study for relapsed and refractory myeloma patients, correct?

Dr. Bachanova: Correct.
Jenny: And then who can join the study? Who are the types of patients that you were looking for for this study? And then who are the types of patients that cannot join this study?

Dr. Bachanova: Sure. The study is designed for patients who had either relapsed myeloma or are refractory to prior therapies. They have to have a progressive disease after the most recent therapy. The patients could fail prior autologous transplant, that is acceptable. The patients should not receive prior elotuzumab. They need to have a measurable disease either by the M spike or having light-chain detectable in blood. They also could have bone extrameduallary disease but they have to have somehow the measurable disease. And the product is quite open in its inclusion. The age limit is 18 to 70 years of age. And there's organ function, just reflecting the proactively good health. And the patients have to be off steroids. They should not be on any prednisone or dexamethasone and need to be free of active infections.

Jenny: Okay. And how does steroids impact this? I'm just curious about that.

Dr. Bachanova: What is it? Steroids?

Jenny: Yes. What's the relationship there?

Dr. Bachanova: The steroids are immunosuppressive for the immune system in a way. So they could decrease the function of natural killer cells. So it's one of those interactions you would like to avoid.

Jenny: Okay. That's great. And as a strategy, I know a lot of patients are looking at these different strategies. So let's say you are relapsed from your stem cell transplant, and you are looking for different treatment combinations to potentially use. I know some patients are looking for ways to bridge to other types of therapies. Is this more curative? Is this in the bridge category to something else that you would suggest? I guess my question is how powerful is this type of therapy?

Dr. Bachanova: Well, I must say that it is a Phase 1, Phase 2 clinical trial.

Jenny: So you don't know yet.

Dr. Bachanova: We are at the early stages of investigations, and it is not really yet clear how powerful it is. We hope that it's going to be more effective. In fact, I see this therapy more for patients who have failed prior treatments which are easier. But it is potentially a therapy which can be very useful for patients who become more refractory or more difficult to control disease and still are in a good health and could potentially consider allogeneic transplantation.
The therapy, if it's effective, it can be a bridge towards transplant. It could be also a definite therapy for some patients. For patients who achieved stable disease or have some response, our recommendation is to continue elotuzumab maintenance on this protocol until they have benefit from it. We also could consider the patients who failed prior CAR T-cell therapies, for example, or somehow not interested or not candidates or if the CAR T-cell therapies are not available, this is certainly a good alternative.

Jenny: I think it'd be a very good alternative because it's going after a completely different protein. So most of the CAR T studies that are in for myeloma are going after the BCMA target, and this one is the SLAMF7 or the CS1 target, so two completely different targets.

Dr. Bachanova: Exactly. And that's why even failure of the prior CAR T wouldn't exclude patients and, in fact, they still potentially could benefit from this type of treatment.

Jenny: Well, I think that's important for patients to understand because it's a challenge. Sometimes you feel like you don't want to join a trial if it would preclude you later from doing something else. So this sounds extremely flexible in that way.

Dr. Bachanova: Yes. I must also mention that just similar to CAR T therapies, we do use a short course of lymphodepleting chemotherapy prior to nicotinamide NK cell infusion which consist of fludarabine and cytoxan, just very similar three days of this low-dose chemotherapy, which is often outpatient, the treatment of the NK cell infusion is inpatient. We keep patients only for about three or four days following the infusion, and the rest would be with a follow-up in a clinic. So this therapy, we so far really haven't had any cytokine release syndrome or any very serious or severe toxicities. It's actually quite well tolerated, and it is considered more of an outpatient type of treatment also, although the patients have to come to our center and will have to stay with us for at least four to six weeks.

Jenny: Okay. And I think as patients think about clinical trials, I think it's important for them to understand that travel is possible. In my opinion, it's worth the extra effort to go somewhere at such a place like this because this is the only center running this study, correct?

Dr. Bachanova: Correct. We are the only center. This is in collaboration with Gamida, which is a company which is providing nicotinamide to us, and we are working on collaboration with them to develop this product. This is the only study center. We have a Hope Lodge or other abilities for the patients to stay with us in a closed-door center. So I'm happy to work with the patients on an individual basis to really meet their needs.

Jenny: And for relapsed myeloma patients, they could have failed the transplant, you said. Are they required to have failed the other types of myeloma therapies like a Revlimid or a Velcade or something like that? Or if they have failed the transplant they could come to you?

Dr. Bachanova: Yes. They have to have exposure to either one of the IMiDs, so either Revlimid or pomalidomide and then also have to fail one of the proteasome inhibitors, either Velcade or the others. So they have to be exposed to both of them and show that they just responded to them or they have progressed on them. And then in terms of the prior autologous transplant, they have to be at least 60 days after prior autologous transplant.

Jenny: Okay. And that sounds very normal for other clinical studies. That's very common for them to have those, the same type of criteria. Can I ask you something also about the age of the donor of the NK cells? So if you're thinking about the study and you want to have your sibling or your children or something be your donor for the cells. In our last show with Dr. Matsui, he was talking a lot about the age of the donor for allo transplant is really impactful. So it's much better to get a younger donor. So if your elderly, your children or even your grandchildren over getting a tighter match. I know you have expertise in allo transplant, and this is a Phase 1 study so you don't have a lot of information about it, but do you think that would be the case? So when you pick a donor, you're kind of choosing somebody really young and who have a strong immune system?

Dr. Bachanova: Absolutely. This is absolutely true for this therapy too. We do prefer and we are looking for younger donors. And we know that the NK cells are actually better, more powerful. We have tested just random donors in a preparation for a trial, and that's been a case also with the nicotinamide expansion. Younger donors usually produce better products. So we try to select donors who are in their 20s, 30s, but we still don't exclude the donors if they are older of course but prefer the younger categories. There is something about the immune system aging which is not perfectly well known but I think we are learning about it as we are learning to use the immune cell product from the healthy volunteers.

Jenny: And just a question and this may be a very naïve question because I don't know that much about allogeneic transplant. I know a little but not a lot. When you are transplanting in an allo situation, you're really replacing the whole immune system. And so what you said at the very beginning of the show is that NK cells are just one type of white blood cells that are being generated. So you're not replacing the entire immune system, you're replacing one portion. Would that be an accurate way of saying it?

Dr. Bachanova: Yes, very much so. We are not replacing stem cells, not making completely new lineage of all blood elements. We are just really replacing immune cells which are, in fact, responsible for most of the antitumor activity or part of the antitumor activity in healthy people. The immune cells will not stay there forever. But if they stay there for a period of a few days to a couple of weeks up to several weeks, during that time, they can harness a very powerful antitumor effect.

Jenny: And another question about just development. So when you go to create a Phase 1 or a Phase 2 study and you're doing I know a lot of work in the lab to bring it to Phase 1 and 2 study, what types of things are you looking for? Do you assess genetic different markers of myeloma at that stage, or do you wait for the Phase 1, 2 study and kind of assess different types of myeloma patients that are participating in the study? I guess is there any indication of type of myeloma that this type of treatment might be the most effective for?

Dr. Bachanova: Yes. That's another interesting twist on the questions we have to ask clinically and both in laboratory. It is very difficult to do these things in laboratory just because the myeloma cell lines are very much not representing of what's happening in a patient. So these questions can, in my opinion, only be addressed in a clinic. From the experience with the allogeneic transplantation, we know that these things become less relevant for immunotherapies. The immune system is really using such different ways to kill cancers. There is a type of genetic aberrations or type of molecular abnormalities in cells may be less important if we are using immunotherapies.

Jenny:  I've heard that too, like with the CAR T stuff too.

Dr. Bachanova: Yeah. And they may work just as well for all kinds of different subsets. That I think is a reasonable biological reason to believe that that's the case, and we have to wait for the more experience to be able to show it in clinic.

Jenny: Now, question two, I know this is Phase 1 and I'm asking some questions that are probably not going to be answered until you finish this part of the study. But I know lenalidomide and elotuzumab have been combined a lot because -- you said earlier that the elotuzumab on its own isn't really doing a lot of myeloma killing. But when you combine it with lenalidomide, then it does. Would that get in the way of these NK cells, manufactured cells? Would it potentially be an additive strategy later or does that just kind of gum up the works with what's happening in the immune system because I know lenalidomide changes the immune system also?

Dr. Bachanova: That's a very reasonable question to ask. And in fact, it may be a good combination. Lenalidomide is, in fact, synergistic with NK cells. It does improve NK cells function, although the mechanism is not entirely well understood, but it may also increase the endogenous. One of those cytokines IL-2, patients on IL-2 can be increased with lenalidomide. So this can be a combination for the future. It's a reasonable suggestion and we are in the middle of doing some other preclinical work to see what combinations to develop as we move forward with the development of this product.

Jenny: The NK cells don't last that long. So how do you find out how long they last especially in a clinical trial? Are you looking for things in a clinical trial to see how long they're persisting and then how powerful they are? And I like what you said that they're kind of non-discriminant about the different types of clones. So we hope they go after all the clones.

Dr. Bachanova: Yes. We do look for them, and we have a special molecular flow cytometry-based method to detect NK cells or donor-derived NK cells in the blood and also in the bone marrow. So there are some biopsy seven days after NK cell infusion. And we know from other studies, for example, with the acute leukemia, we always find them in the marrow. They go there and they persist there, and then you see them actually doing their job quite nicely. And we are possibly going to do biopsies if there is a myeloma plasmacytoma tumor or other site of disease where we can biopsy. We will try that to detect the NK cells also in the tissues. But for right now, routinely, we are probing the blood and the bone marrow.

Jenny: Well, that's nice because I know sometimes you go to do bone marrow biopsy and the myeloma in the hip is different than the myeloma in your shoulder or some other part of your body. So maybe those two things together will give you the information that you're looking for.

Dr. Bachanova: Exactly. And then we look for them pretty frequently -- weekly first and then every couple of weeks. We are also collecting them and, in fact, doing some extensive characteristics and analysis in the laboratory in terms of how they are functioning and what they express, and that is very useful. Any study we do, we are really trying hard to learn as much as we can from the patient's samples because it just provides such a unique window into this fight between the immune system and the patient.

Jenny: And it's such a complex thing and I'm so thrilled to see these immunotherapies coming into this Phase 1 and 2 trials. It's just so exciting for myeloma patients. On the side effects side, you mentioned that there were not a lot of side effects. And even I know there are more minimal infusion-related reactions with elotuzumab and daratumumab. But what can patients expect in a study like this?

Dr. Bachanova: Yeah, the patients would develop some cytopenia. So a drop in their neutrophil count and platelet count, typically about ten days after the NK cell infusion. This is partially due to the chemotherapy but also partially due to NK cell infusion. Some patients may develop a need for transfusions. Perhaps slight risk of infection or neutropenic fevers. The other side effects are related to the IL-2, which is a cytokine which can result into development of the flu-like symptoms: fevers, occasionally chills or myalgias, muscle aches, that only would last for a few days. We did not see any high fevers or really severe drop in blood pressure or something that significant. We also so far did not observe any neurotoxicity or any CNS type of side effect. And we expect to recover their count in about two to three weeks.

Jenny: Well, that's significant.

Dr. Bachanova: Other immune early side effects could be related to the NK extension. But as I said, at the most, there would be fevers or rigors or chills or occasional mild increase in the liver function tests.

Jenny: Well, that'll be so interesting because you're giving this dose. You're giving an expanded form, right? You're growing up these donor cells to how many times of a normal person, so they can go do their job.

Dr. Bachanova: Right. They are expanded by several fold, but we are at a dose escalation study with a cell dose now being escalated. So far, it didn't look like the higher dose will have the more side effect, but there is so much more to learn.

Jenny: And this study includes other blood cancers, correct, with different monoclonal antibodies?

Dr. Bachanova: Correct. There is another cohort which is developed for patients with non-Hodgkin lymphoma. The antibody here is rituximab, anti-CD20 monoclonal antibody. And it is targeting the CD20 which is the most common marker on the non-Hodgkin lymphoma cancer cells.
Jenny: And so you just have a myeloma group and you have a lymphoma group, and the myeloma group will be using the elotuzumab.
Dr. Bachanova: Correct.

Jenny: And how many patients are you looking to do in the Phase 1 study? This Phase I/II study?

Dr. Bachanova: I think it's for about 30 to 40 patients. That's what it is designed for. And if we have success, then we are going to expand the Phase 2 study.

Jenny: I know some patients are familiar with the different phases like Phase 1 is to test for safety and Phase 2 and Phase 3. Can you explain why Phase 1 and 2 studies go together sometimes and your objectives in running the study?

Dr. Bachanova: Sure. So for Phase 1, it's really a dose-finding study where we have objectives set for 20 patients to show that the dose of the NK cells which we think is effective is also safe, so to identify the dose which is associated with the acceptable safety profile. While we have this dose, we also want to learn whether the treatment is providing the responses which we set as successful. And then we need a slightly higher number of patients just to assess a preliminary response rate for the disease of the interest. So we have two arms for the Phase 2, I mean in myeloma arms, and both of them are analyzed separately to find out the preliminary response rate.

Jenny: Okay, that makes a lot of sense. I know they're using elotuzumab in smoldering myeloma. It sounds like it would be a really nice study to include in smoldering myeloma with these donor NK cells. To me, it sounds like that could be amazing. Have you considered doing this in a smoldering myeloma type environment?

Dr. Bachanova: Yes. Maybe I should hire you to my team J. The Phase 1 is to establish the safety. And as we have the safety and the primary efficacy, then we have to think about whether this therapy could be brought to earlier disease stages or the smoldering myeloma. Certainly, it's too early right now, but it would be an interesting group to consider.

Jenny: Well, I think it'd be wonderful because with smoldering myeloma, you don't want to really treat because you don't want a lot of fallout for many treatment or things like that because you never know who is going to progress in smoldering myeloma or who is not. But if you have something with minimal side effects and that can kill everything really early without a lot of toxicity, that'd be really incredible.

Dr. Bachanova: Yes. Although I must say that there is no guarantee, of course, at this stage of the study. But if it is an effective therapy with the minimal adverse events, that's your huge tool which can be used in earlier stages. Also, this is not really a genotoxic. You are not causing a genetic hit to your stem cell which can result in secondary cancers or other potentially long-term side effects.

Jenny: And another question on future ability to use different therapies. So if a patient joins this type of study and it's targeting the SLAMF7, I know in the CAR T cell world, people are looking at all sorts of different targets and potentially even combining different CAR T cell protein targets. So if you have a therapy like this, could you still qualify in the future if there were some -- I know this is probably out several years -- but if there were some CAR T cell studies that used multiple targets on them including one that was that SLAMF7?

Dr. Bachanova: Yes. It's hard to tell but most of the CAR T studies exclude patients with a prior genetically modified cell therapies, but this one is not genetically modified. It is just co-cultured with nicotinamide, so there is nothing genetically modified in these cells. You don't need 15 years of followup. That's why I think being on this study should not exclude you from the future CAR T clinical trials. In terms of the target, that just depends. It depends on how the studies are designed.  SLAMF7 is certainly a good target, but I don't know whether it's going to be target for the CAR T cell therapy.

Jenny: I know. We funded actually one investigator who is doing it with the SLAMF7 in Germany, so it will be interesting. That's why I ask that question. It'll be interesting. And they're in the Phase 1 study in the EU right now.

Dr. Bachanova: Absolutely. It remains to be seen. It depends on whether they are going to exclude prior elotuzumab from their eligibility. But in other CAR T products, I don't think that this trial should exclude patients from being a good candidate for CAR T in general.

Jenny: Interesting. Well, that's so fascinating. And your study is open now, correct? Or is it open in the future?

Dr. Bachanova: The study is open. We opened it about a couple of months ago. So I think we will have it actively enrolling through this coming year. We are offering it to patients had actually slots which we assigned. So have launched the Phase 1. I have treated several patients and are fully open to enrollment. We are on clinicaltrials.gov and there is also an email and contact information for my research staff. I'll be happy to connect with any of your listeners or patients who are interested to learn more.

Jenny: We suggest that patients use SparkCures because they're a really amazing clinical trial finder tool. So I'll double check and make sure that this study is in there. We will add the link when we post the full show so that patients can find it really easily. In your opinion, when you think about clinical trial participation, when you're trying out a new drug like this, to me it just seems like if patients would want to consider different and new options that might even exceed the standard of care, that it would be a good thing to consider joining a clinical trial because it's how investigators like you really come to conclusions faster and help cure this disease better. Do you have any thoughts on just patient clinical trial participation in myeloma as a whole?

Dr. Bachanova: Well, we have done a tremendous progress over the last few decades as a result of clinical trials and basic research. But this is not a homerun. We are doing better, but many patients are facing a relapsed disease at some point. So in my opinion, we only can do better by doing more clinical studies. And I think every time I am going to use a standard of care therapy, I'm questioning myself whether I can do better, whether I should actually offer a new therapy to a patient on a clinical trial which is a potential to improve what we already are doing.
So I, of course, am very much encouraging people to think of clinical trials as the only progress, and the only avenue how we can progress and move medicine forward. Everything what we know and what we learn so far is a result of the prior clinical trials. So I think that if the patients have an option to participate in a clinical trial, I would always encourage it as this is how the medicine is moving forward maybe for us and maybe for the future, then maybe for our next generation.

Jenny: Well, I love what you're doing, and I love how you're combining different immunotherapies because it's just such a nice approach. It would be wonderful if we could get away from the steroids and the chemotherapy type approaches. I know that's not today, but in the future that would be wonderful.

Dr. Bachanova: Yes. That's what we are hoping for too. And I really appreciate this opportunity to share my thoughts with your listeners. You give me some very good questions, food for thought. So I appreciate the beautiful discussion we had.

Jenny: Well, I would like to see if there are any listeners with questions for Dr. Bachanova. And if you have a question, you can call 347-637-2631 and push 1 on your keypad. And we have a caller at 310-5598. Go ahead with your question.

Caller: Thank you so much. First, thank you for everything you have shared. This has been so great, very informative. So my question, you may have touched base on this a little bit, but I'm just wondering if you could administer this treatment during the course of the disease, when would you think would be the best time for treatment for a patient?

Dr. Bachanova: Well, the patients have to fulfill the eligibility. So it will have to be after prior Revlimid and prior Velcade therapy. If you, for example, had both of them injection and had an autologous transplant, it depends. If the transplant is not working very well and the patient has this high-risk myeloma, so the transplant works only for a couple of months, I think that patient would be a good candidate because it's a high-risk myeloma, high-risk disease which other therapies also don't have the durability that we hope for and that would be a reasonable timing. For other patients who have more responsive disease, I would say if you are already on your third or fourth agent and have relapsed afterwards, I certainly would not use it as a last resort. I will use it while you have still a couple of more drugs to go and to fall too in case this is transiently working.

Caller: Okay. Great. Thank you so much.

Dr. Bachanova: You're most welcome.

Jenny: Okay. Thanks for your question. Okay. Another question, go ahead with your question.

Caller: Thank you. I'm on dara, and I've had an excellent response. It's also, as you pointed out, destroyed my natural killer T cells. So I'm wondering what my experience and other patients on dara as well as your research says about the role of different T cells in fighting myeloma.

Dr. Bachanova: Well, we know that NK cells are useful in fighting myeloma. I am mostly doing the research on natural killer cell in that fight. The T cells in myeloma are a different field. It's less studied, but clearly they have a role just because we know that allogeneic transplantation works for myeloma and that usually results into a new fresh T cell which are donor derived  as well as NK cells. But T cells really mediate a major anti-myeloma response. But that field is still I think at early stages of understanding and development.

Caller: Okay. Well, is it possible that CD4 and CD8 T cells also play, at least in the -- would dara play a significant role in fighting the myeloma?

Dr. Bachanova: No, not to my knowledge. Daratumumab I don't think works on the T cells. T cells, typically, do not mediate the antibody, you know, antibody-mediated cell killing. So I don't think that daratumumab works through T cells.

Caller: Okay. Well, thank you.

Dr. Bachanova: You're welcome.

Jenny: Okay. Thank you so much. Excellent questions. Well, Dr. Bachanova, we're so thrilled that you joined us today. We love hearing more about your clinical trial. We will share it soon on the Myeloma Crowd website with a link to the study. So if people are interested, they can connect with you and join your trial. So thank you so much for joining us.

Dr. Bachanova: Thank you for having me. It was a lot of fun.

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