Cristina Gasparetto, MD
Interview Date: February 17, 2017
Allogeneic stem cell transplant can be selectively and successfully used for young and high-risk myeloma patients. Allo transplant is considered the “first” ever immunotherapy. It essentially transplants a new immune system from a donor to the myeloma patient, replacing their own. There are several types of allo transplant: 1) myeloablative or the use of high-dose chemotherapy and non-myeloablative which is considered a “mini” allo transplant. Dr. Gasparetto explains the different types of allo transplant, their pros and cons of each type. She notes that because allo transplant patients can experience graft vs. host disease, that the use of allo transplant should optimally be used in the clinical trial setting. She describes her allo clinical trial for newly diagnosed patients that uses an allo transplant with an oral proteasome inhibitor as maintenance therapy and explains the rationale. Allo transplant can be used in both the newly diagnosed setting and in the relapsed or “salvage” setting. She notes that it is most effective in this setting if the myeloma is well under control. For patients consider an allogeneic transplant, this is a very informative show. To find clinical trials mentioned in this show, click the links below:
Dr. Cristina Gasparetto on Myeloma Crowd Radio
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 this is our 96th show. We’d like to thank our episode sponsor, Takeda Oncology, and we’re very grateful for their support of the Myeloma Crowd Radio program.
Before we get started, I’d like to invite you to participate in this year’s Muscles for Myeloma program. As you know, March is Myeloma Awareness Month. In the honor of that program, we are running a program that can help you to get fit. We’ll run this from March until the end of April and we’re doing it because although fitness matters for everyone, it’s especially important for myeloma patients who are being segmented into fit, unfit and frail categories. There are some treatments like stem cell transplant that we’ll talk about today that they cannot receive if they are not fit.
This year, we are inviting patients from across the nation to join us in support of their local myeloma academic center. We have over 20 teams in place where myeloma specialists reside like Duke, MD Anderson, Mayo Clinic and Dana-Farber, to just name a few. All the proceeds raised by each team will be donated to that center’s myeloma research and not the Myeloma Crowd. This is the way we want to support a national effort for both myeloma awareness and myeloma research during Myeloma Awareness Month.
You can register online at http://give.crowdcare.org/muscles2017. You can set your own fitness goal, so it doesn’t matter what level of fitness you’re at today. You can be right out of transplant or be in an extended remission and feeling good. It just doesn’t matter. Just set a stretch goal that’s right for you for that 60 days. You can update your page with a photo, your goal and even your photos, then share your page for Myeloma Awareness Month and invite your friends and family to support you in getting fit. We even have a real cool Muscles for Myeloma phone app that will allow you to track your daily exercise, your weight, steps taken and other kinds of metrics like that. Each team for Muscles for Myeloma also has 10 local challenges. If you complete those team challenges and mark them off in the app, you can be entered into a raffle for prizes like Fitbits and gift cards. You can join today so you’re ready to go on March first as we get fit together and help accelerate a cure.
Now, I know a lot of times stem cell transplant is just not an easy process. We’ll be talking about stem cell transplant today and specifically allogeneic or donor transplant, which is not used very frequently in myeloma therapy, but it could be a very effective strategy for patients to consider especially if they’re young high-risk patients.
So with us today is Dr. Cristina Gasparetto of the Duke University Medical Center to tell us more. Welcome, Dr. Gasparetto.
Dr. Gasparetto: Well, thank you. Thank you, Jenny. Thank you for having me.
Jenny: Well, you get extra bonus points today because I know you’re recovering from an illness. Thank you so much for joining us even though you probably wish you were feeling totally up to speed. Let me give an introduction for you before we get started.
Dr. Gasparetto is Associate Professor of Medicine at the Duke University Medical Center. She is on a variety of committees including the NCCN Guidelines Multiple Myeloma panel. She is co-founder of the Duke UNC Wake North Carolina Multiple Myeloma Study Group. She is a core member of the International Myeloma Working Group, a core member of the Aptium Myeloma Consortium and a member of the Connect Multiple Myeloma Registry and the Alliance CALGB, which is a clinical trial group. She has received the Cancer Treatment Research Foundation Award for Myeloma, the Lisa Stafford Award, Multiple Myeloma Research Award and the AMyC Award. Dr. Gasparetto’s primary interests are in developing immunotherapy approaches in conjunction with stem cell transplant. These approaches include vaccines and antibody therapy. She is running clinical trials that include dendritic cell vaccines, antibody therapies, different types of allo transplants, peripheral blood stem cell transplants and partial HLA matching transplants using cord blood. As I was doing my homework for this show, I realized how much extensive expertise she has with transplant. I am just really thrilled to have you on the show.
Dr. Gasparetto: Thank you.
Jenny: Well, why don’t we start in with just a broad overview of allo transplant in the myeloma setting?
Dr. Gasparetto: Well, you know, this is a very difficult topic because allogeneic transplant is difficult. It’s a difficult transplant. We generally use donor cells to establish immune system in the recipient, the patient. These allogeneic transplants for myeloma were introduced many, many years ago, but unfortunately the mortality associated with this approach back, I’m talking back in ’80, the ’90s, was very high, 40%, 50%. It was a very difficult decision to recommend allogeneic transplants to patients with myeloma because there was 50-50 chance to be able to successfully complete the procedure. I’m talking about a 50% chance of death.
The allogeneic transplant was abandoned in the ’90s for this reason, because the mortality was too high. When we went back and looked at the data, we were all surprised to see that actually patients were able to survive indeed well after allogeneic transplant, maybe were cured. There were some patients, there are patients alive and well many, many years after allogeneic transplant. We decided to bring it back in different ways, in different forms improving the transplant. The mortality rate is now down to 10%, 15%. We have different types of transplant, but for many years and we know even now that it’s very difficult to tell a patient that we can cure myeloma, but maybe with allogeneic transplant we have done that.
Jenny: Well, do you want to describe the different types of allogeneic transplants? Because there are some that are myeloablative and non-myeoablative and some minis or haplos, and sometimes it’s a little bit confusing to understand all the different kinds of allo transplants.
Dr. Gasparetto: It’s very confusing. It’s very confusing. The old-fashioned, the old way was to do a myeloablative allogeneic transplant — that means, myeloablative, we’re using a very high-dose chemotherapy so we can ablate, control, kill all the myeloma and the same time suppress the immune system of the recipient. That is the big transplant. Patients have to remain in the hospital for about a month until they have recovered and then they have to stay at the center of the transplant for an additional couple of months. And that transplant is difficult with a lot of complications. The mortality was, as I was saying, in the ’80 and the ’90s, was up to 50%. But we are getting better with that too and that is a possibility, an option for some patients whether somebody can do that, particularly in patients where the myeloma is now well-controlled. We are using the high-dose chemotherapy not only to suppress their immune system but also to kill all the residual myeloma.
Then because the mortality associated with this approach was too high in the ’90s, late ’90s, the normal ablative or the mini-transplant was developed not only for myeloma but for other diseases, of course, for other myologic diseases. The idea behind it was in order to do a myeloablative transplant, you have to have a young patient fit, good performance status with a good donor, and that was not the case for a lot of patients. So why not do these mini-transplants in the outpatient setting where we use chemotherapy to suppress, to immunosuppress them so they can’t receive the immune system of the donor? Because the bottom line is the allogeneic approach, the allogeneic transplant is to replace the immune system of the patient. The immune system of the patient clearly is not working, and so we are giving the patient a new immune system to control the myeloma from coming back.
With a normal ablative, the idea was like let’s just suppress the immune system and then use the donor cells to repopulate the immune system. While the approach is safer, the risk of dying on the approach is much lower and is now an outpatient procedure, when we analyzed the data that we saw there was not enough to control the myeloma for a long period of time. In fact, patients continued to relapse over time because unfortunately the myeloma was still there and it was not enough. It was not powerful enough.
There are different, a lot of strategies that are under development to improve both of these approaches. Generally, the ideal scenario is when we have a donor, a sibling, a match, related donor, but that is also very difficult, right? You need to have a sibling. You need to have one that completely match. We also do an unrelated match so we go to the donor search looking for a donor, a match unrelated donor. We also do haplo transplant where we use relatives. It could be a father, mother. It can be a child or a sibling that is only half matching. But the haplo, you kind of embark in a lot of other issues. I actually don’t necessarily use the haplo approach for a myeloma yet because the risk of having graft vs. host disease is high which is the immune system of the donor attacking the immune system of the recipient. You really need to suppress these patients for a long period of time. And I’m very concerned with myeloma because during the period of time, the myeloma can, in fact, light up and cause trouble. The key is to have a myeloma well controlled until the new graft, the new immune system, is able to repopulate and control the disease from coming back.
Jenny: Interesting. It might give a too big of a window (that allows the myeloma to grow).
Dr. Gasparetto: Yes, you need to have a long disease-free window, exactly. I always try to explain to my patients, with the normal ablative, I need to bring patients with a phenomenal response so I have a few months to work until the new graft, the new immune system is established. With myeloablative, I also control the myeloma with the high-dose chemotherapy.
Jenny: When the sibling is a complete match like a twin, what is that called?
Dr. Gasparetto: It’s syngeneic and is actually — there was an old study that was published comparing the autologous when you use your own stem cells. Allogeneic is from a donor and then syngeneic if you have an identical twin. Believe it or not, the syngeneic results were pretty remarkable, but unfortunately it’s very difficult to have an identical twin.
Jenny: We don’t have a lot of them.
Dr. Gasparetto: Yes. I have done three at Duke and very successful and particularly I have one that now it’s many, many years after. It would be great but it doesn’t happen very often unfortunately. At the same time, sometimes we don’t want so much — we don’t want the same type of immune system. We want a little bit of disparity because we want it be able to suppress the myeloma with the new immuno system, with immunotherapy. And so to have the same type of immune system might not work but the data with syngeneic were very interesting.
Jenny: Like you just mentioned, I’ve had other doctors say this too that the allo transplant is really the first “immunotherapy” that has been used in myeloma because you are basically replacing the immune system.
Dr. Gasparetto: You are replacing the immuno system. That is the concept. You are giving a patient a new immune system. We have data showing, even a whole data showing that even after allogeneic transplant using boosts of donor lymphocytes was helping to re-control the disease. And we have a lot of data showing that the immune system plays an important role in myeloma and all the different type of immunotherapy of course that is growing tremendously, but allogeneic transplant is a form of immunotherapy. We’re giving a patient a new immune system. We replace the immune system. We transplant the immune system. And that’s the reason why it’s so risky, it’s so tough, but over the last 20 years was improved tremendously.
We have data showing that the mortality, the chance of dying during the procedure went all the way down. We have a phenomenal team with great supportive care. We are carried through this transplant. We have new drugs that we did not have available, anti-fungal, because during the period of time when the patient is immunosuppressed because he has to accept a new immune system, there is a high risk of infections. Now, we have phenomenal drugs. We track viruses every week. We have anti-fungal. We are very proactive while in the past, we didn’t know. We didn’t know what was going on.
Jenny: It just wasn’t available yet. Well, let me ask you about matching before we kind of talk about what I really want to get into. But how closely do you — you said you may not want an exact match for the immune system. So how closely do you want a match? I know sometimes there is a score, like a 10 out 10 and you would think that’s a great score. And then I hear some doctors say, well, maybe we can do an 8 or 9 out of 10 and that might be even better. Maybe you want to just talk about that HLA matching process.
Dr. Gasparetto: The human leukocyte antigens are pretty much a code of our immune system and they help our immune system to make sure that it does and they reject everything that is foreign. We are trying to match it but, for example, if you have the best match will be a 12 out of 12, but we know that there are some things that we are not checking. We know that if we have a donor from the donor registry even if it’s 12 out 12, it is not an identical twin, so there are going to be some disparities there.
And then when you have a mismatch of one, it’s very difficult to explain because you can do a 9 out of 10 and still very successful but depends on where the mismatch is. We go through all this testing, we test the sibling. We compare it. We do additional testing and the donor registry will do the same. It’s all computerized where they gave us an idea of many potential donors a patient could have, and then we go more in depth to find out if the coding can match. It’s very difficult to explain. Ideally, it will be a 12 out of 12.
Jenny: Well, it’s a process.
Dr. Gasparetto: It’s a process. You inherit half of the codes from your mom and from your dad. If you have siblings, they have 25% chance of being the same as you. In a haplo situation, we use a sibling. They may have already half the coding that you have.
Jenny: Interesting. Okay, well, I know in doing some research just on what to talk about today, you have such extensive experience with transplant in general and outcomes. Maybe you want to give us just an overarching view of what you have learned in general. For example, you did work on auto-transplant and outcomes for older versus younger patients, and then you did post-transplant outcomes in high-risk versus not high-risk patients. What have you learned in looking at the transplant setting and why are you considering the allo transplant as a potential great strategy?
Dr. Gasparetto: You know, I am not pro-chemotherapy. I wish we could come out of the chemotherapy. But unfortunately, from all the data that we have and also from my experience, high-dose chemotherapy given at once to kill all the residual myeloma remains a very important part of the treatment for patients with myeloma. And the autologous transplant should not even be called a transplant. We collect the stem cells of the patient to rescue them after the high-dose chemotherapy. But you know, we have data – four new studies in there of all this with new agents still showing the superiority of transplant because the bottom line, we are able to achieve a deeper response with the high-dose chemotherapy. The strategy works and then we use the maintenance to improve the durability of response. Unfortunately, it works for the majority of patients, but you still have a population of patients and the transplant is not as durable. You have some patients progressing within a year. That is a very difficult situation because the moment that the patient progresses after transplant, you know that you are dealing with a very aggressive myeloma.
Yes, we do have a lot of new drugs, but the nature of myeloma will eventually become resistant to all these drugs. That’s the reason we decided, because we know that patients relapsing very early after autologous transplant, we decided to explore the possibility of introducing allogeneic transplant for these patients. Transplant is safe, I’m trying to answer your question, for patients in good performance status. Older patients, we have data, retrospective data showing that if a patient is older than 70 but in good performance status, the transplant is safe and effective. The outcome is very similar to the younger patients. Transplants should be at least offered to consider it to all patients with myeloma. But, unfortunately, it’s not the answer for our patients with myeloma, and that’s the reason why we need to think about some other strategies. In addition to the allogeneic transplant, not all patients would be eligible for allogeneic transplant that we also modify the induction therapy, the maintenance.
We definitely need to develop these signature trials where patients are treated in a different way based on their genetics. But allogeneic transplant could be an option for patients with very high risk myeloma up front or were progressing very rapidly after autologous transplant because we know that we are dealing with a very difficult myeloma. I think we need to take the risks of the allo and try to overcome and maybe cure some of these patients.
Jenny: When I was first diagnosed, one of the ideas was that when you’re first coming into it as a newly diagnosed patient, when you haven’t had all the cumulative effects of a long-term treatment, and his opinion was you get the first opportunity of treatment is probably your best shot at cure. Let’s hit it as hard as possible to say could we achieve a cure at the beginning and is that possible? Is that some of the rationale behind the younger patients?
Dr. Gasparetto: Well, it’s becoming a new concept in the myeloma community. I remember when I started to three patients with myeloma, if a patient wasn’t able to achieve a complete response, just a very good partial response with more than 90% reduction of the markers of the program, we were okay with that. Now, we are trying to achieve a deeper response and we have data showing that if you achieve a deeper response that will translate in a longer durability, and so the idea is maybe we need to be — because you’re right. I think you need to play all your cards up front because the first response, the first time that you achieve a complete remission, the complete remission will last the longest. It’s the longest because when myeloma comes back, yes, we might be able to achieve a complete remission again or maybe not but the durability is going to become shorter and shorter, and that’s what we know.
We have to battle the myeloma up front and that’s the reason why we are developing trials where we are trying to achieve a stringent complete remission very quickly with the combination of therapy than the high-dose therapy, than the maintenance, with the idea maybe if we bring patients to a very big response, we are going to be able to cure some patients. At the same time, it’s very complicated because there are some patients who are evolving from smoldering, from an MGUS and they are there for many years before they transformed to a myeloma, then when you treat them, they go back to their MGUS state so they don’t need to achieve a complete remission because they are going to go there and they’re okay, but we are unable to identify these patients yet.
One of the crusades now in the myeloma community is trying to achieve a minimal residual disease, the best response, particularly younger patients with high-risk disease, so we can keep the myeloma in remission the longest. That is much what’s going on. Maybe if you treat some patients a little bit earlier we can cure some patients.
Jenny: And then how are you defining high-risk patients? Who would you consider to be high risk when you’re thinking about these younger high-risk patients?
Dr. Gasparetto: We would base our determination on the cytogenetics and so we know, for instance, the deletion 17 of chromosome 17 is a poor prognostic factor and then there are in translocation on chromosome 14 like the (4;14) translocation, the (14;16). We also have amplification or loss of chromosome one. If you want just generalized, I will divide the patients in two groups. So hypo meaning lacking, losing of chromosomes is bad, gaining chromosome so which you have the patient gaining different chromosomes is better. These two groups and then generally these are the cytogenetics. It’s not written in stone. It’s evolving. It’s changing a little bit even on the cytogenetics, and it’s very important to have such genetic done on the isolated myeloma cells.
But also, how we determine if the patient has high risk is how long the patient is able to remain in remission the first time? If a patient remains in remission more than 18 months, we think it’s a more treatable myeloma but if a patient progresses, relapses within 18 months from initiation of therapy, then we consider those patients having a more high-risk disease and then we become more aggressive. The durability of the response matters.
Jenny: So that’s just how you respond to treatment, not necessarily what your genetic features are.
Dr. Gasparetto: Yes. You can have a good genetic and then have the transplant and progress and three months later, you definitely have to attack, you have to treat the patient as a high risk.
Jenny: It’s about looking at both of those and being aware of that. I think it’s really important for patients to understand what kind of myeloma they have. And for those who are listening, if you have not had some of these cytogenetics or gene expression profiling tests done, then ask your doctor about it because if you have active disease, they can be found. If you have been on treatment, that’s in a remission type status, they’re not going to show up because you don’t have any of these cells. It’s really key for patients to be able to have these tests.
Dr. Gasparetto: Oh, it’s very important because absolutely, I agree with you, Jenny, because it also guides us, guides me how deep I want to go after a transplant. You have to be a little bit more aggressive to achieve the deeper response. It’s very important, absolutely.
Jenny: So let’s talk about high-risk younger patients with allot ransplant. How do you approach that and what do you typically do up front and then during and then after as an approach for these patients?
Dr. Gasparetto: Because, as I mentioned, the allogeneic transplant is such a difficult procedure, a difficult treatment that we offer to a patient. I think I always recommend to consider a treatment as part of a clinical trial. We actually do have in a national clinical trial going on for this subset of patients where a patient with high-risk disease based on cytogenetic or gene expression profiling like you mentioned at time of diagnosis or patients who received their induction therapy and their transplants and then they rapidly progress. They have a clinical trial of an allogeneic clinical trial available and this is going on nationally.
This actually is a non-myeloablative transplant because we were concerned about the high-risk mortality and to improve the non-myeloablative transplant we incorporate a maintenance after allogeneic transplant. Maintenance is so important after autologous transplant, so we are exploring maintenance after allogeneic transplant.
Jenny: Okay. And you said it was non-myeloablative or it’s myeloablative.
Dr. Gasparetto: It’s non-myeloablative. It’s reduced intensity. There is chemotherapy but it’s an outpatient procedure and the patients need to go to this approach with a very well-controlled myeloma. And then we have a maintenance incorporated after the transplant.
Jenny: As I read about that trial, it looks like you’re using ixazomib to do your maintenance on that trial?
Dr. Gasparetto: Yes.
Jenny: So do you want to explain what that is for those who don’t know what that is?
Dr. Gasparetto: Well, the idea is we want to use a drug that can control the myeloma from coming back, but also potentially can help with graft-versus-host disease. What’s the graft-versus-host disease is one of the possible complications of allogeneic transplant where the new immune system is going to attack the patient and can be deadly. Deadly complications can manifest with the skin, GI, liver, tissue and can be really devastating. So the graft-versus-host disease we’re all concerned about because we treated the graft-versus-host disease, we treat the graft-versus-host disease with immunosuppressants, so that means that the patient is receiving more drugs to immunosuppress the immune system and that defeats the purpose of our transplant because we want the patient to develop a new immune system.
We have some data not with ixazomib but with Velcade, or bortezomib. The bortezomib might actually be helpful on controlling some graft-versus-host disease. In this particular clinical trial, we actually use both drugs. We use the Velcade after the chemotherapy as an anti-graft-versus-host disease drug and then we use the ixazomib maintenance. It’s a new oral proteasome inhibitor that was approved more recently. The idea is we don’t want to affect the quality of life of patients and this drug is by mouth is given only once a week. The idea is let’s control the myeloma and with the drug also maybe we can have reduced graft-versus-host disease.
Jenny: Now, a couple of things on that. I did hear — because I attended the ASH conference this last year and I heard also that sometimes the proteasome inhibitors were better for high-risk patients in some of the data that I saw as maintenance therapy versus like the IMIDs.
Dr. Gasparetto: Yes. We do have a lot of data on proteasome inhibitors for patients with high-risk disease. I will say that it’s very difficult in the maintenance because, for instance, all the maintenance trials with Revlimid, the CALGB, the US study was done without cytogenetics, so it’s very difficult to say if there was a difference between standard risk or high risk and the Revlimid was very successful, was very good for a lot of patients. In the Revlimid maintenance setting, in the French study it was also okay for the high risk, but nevertheless we think that the proteasome inhibitor, the additional proteasome inhibitor may be important for patients with high-risk disease.
The problem with the Revlimid, there were some study using Revlimid after allogeneic transplant but the Revlimid, the lenalidamide is an immunomodulator, so we add the trial that was done at the Moffitt Cancer Center showed an increased rate of acute graft-versus-host disease when the Revlimid was added earlier after transplant. And so that’s the reason why we decided not to use the Revlimid but go with the proteasome inhibitors.
Jenny: Just to clarify for patients, so sometimes you can have acute graft-versus-host which is the bad kind of graft-versus-host, and sometimes you can have a little bit of graft-versus-host disease and that’s actually kind of good from what I understood.
Dr. Gasparetto: The graft-versus-host disease is the new immune system reacting against the host, and so having the acute is not good but which if we are able to control very quickly, you can develop chronic GVHD. Sometimes we tell patients it’s not good to have graft-versus-host disease because it implies more therapy with the steroids and other immunosuppressanst, but sometimes we know that if we have a little bit of graft-versus-host disease, we might, in fact, have also some graft-versus-tumor effect. That means the new immune system is so strong that is probably reacting against the tumor as well. That’s the reason why you hear that having a little bit is not bad because it’s an indicator that (it might be killing the myeloma). What we are trying to do, what we are trying to develop with some studies where we actually selected the cells that we want to use after allogeneic transplant, the lymphocyte that we want to use. We want to use some lymphocyte that will not cause the graft-versus-host disease but only the graft-versus-tumor effect, and that is what the future what we are aiming to do with some of our studies. We can select the lymphocyte that we don’t want because they’re causing the graft-versus-host disease, but we want some lymphocytes that are very important as anti-tumor.
Jenny: That would be amazing if you could do that.
Dr. Gasparetto: Yes. Well, that’s one of the studies. That’s one of the studies that we do have with NK cells after transplant for that reason. There are a lot of strategies. What I’m trying to say it’s very difficult to explain all the strategies. But there are lots of strategies to improve the transplant, doing maintenance after a normal ablative to reduce the risk of relapse, doing boosts of lymphocytes for the same purpose, to use different types of chemotherapy to decrease the mortality, the complication of chemotherapy. There are a lot of strategies that we can do and that we have done over the last several years to improve the outcome and decrease the risks of allogeneic transplant.
Jenny: Let me ask this too because I see a lot of new immunotherapy type strategies being added to autologous stem cell transplant. Are there other strategies that doctors are thinking about or researchers are thinking about within the allo setting? Because your open study is great. You are using proteasome inhibitor maintenance with this reduced intensity allo transplant. Are there other strategies that are also being considered like using a drug like daratumumab or I mean then you are mixing your immunotherapy? Is that a good thing or are there some risks to doing that?
Dr. Gasparetto: Well, we don’t know that but that’s the reason why we need to design —
Jenny: You run the studies.
Dr. Gasparetto: Yes, do the clinical study because of course these drugs are phenomenal. We need to find the right niche for all these drugs, but we also be very cautious. We can use them outside of the clinical trial wherever we want because we can actually cause more harm than good. And so, yes, you are absolutely right. I think that there is so much that we can do to improve both approaches. That means they allo is not a treatment approach that can be offered to all locations because it’s too risky. The patients may not be fit enough or the age is the limit, the limitation. We can make the autologous transplant better there if we believe the immune system is very important using these immunotherapy strategies or antibodies after the autologous transplant. That is going to be the future. The next few years, you will see trials designed in that way.
Jenny: When you talk about performance status, I just want to stress to people that this is your fitness level, right? This is both your fitness and maybe other disease complications that you might have like, let’s say, you have diabetes or a heart condition or something like that. It’s kind of all wrapped up into that, but I think that’s why we are stressing fitness so much in patients.
Dr. Gasparetto: Yes. When you emailed me, I was so interested but because we have done studies looking for any type of other comorbodities, any other diseases that could interfere with the positive outcome, and actually we didn’t find anything with exception of the performance status. If the patient is young but has a terrible performance status, is not in good shape, it’s difficult for us to treat that patient. While the patient who is 70 playing golf, very active is a different story. You can treat that patent more aggressively. The performance status is important. I completely agree with you and I will be one of your advocates for your program, absolutely.
Jenny: Well, thank you and we’re excited to run that program. A question about this study that’s open right now. How many centers — it’s open at Duke, right? And it’s open at many of the centers and what’s the age limit for that? You say young patients, but what does that mean?
Dr. Gasparetto: I think the age limit is less than 66 years old, and I do not remember many centers in the country but there are several. But it’s open in all the big centers in the country.
Jenny: Well, we’ll include a link to that study in the final transcript that we do for this show so people can find it. We typically use this Spark Cures tool because it’s so much easier to find than on clinicaltrials.gov. Another question is when you think about the reduced intensity plus maintenance, I know sometimes other strategies like, let’s say, how does an upfront allo transplant for a young patient compare with a tandem transplant or an auto-allo, mini-allo or even an allo-allo which I think that would be crazy hard, but how do they all compare? And is there data that shows different approaches especially for high-risk patients?
Dr. Gasparetto: We do have a lot of data but it’s a little bit controversial. There was a huge study that was conducted several years ago in the United States where patients with newly diagnosed myeloma were randomized. They have a donor or not to receive a tandem autologous transplant versus autologous transplant followed by a mini-transplant. That trial so far is not showing difference between the two approaches while there are other trials. You can talk a lot about it – so you don’t want to do an allogeneic transplant for a patient who doesn’t need it because you increase the risk for the mortality, and you can really control the myeloma with other strategies, so you don’t want to do that. That’s the reason why we started to focus on the high risk.
There are some data that maybe they’re high risk, but there are some positive data from Europe showing the auto-allo was better than a tandem transplant. It’s very controversial. There are so many data but the allogeneic transplant, there are a lot of small studies that you compare and they have different designs. It’s very difficult to put all the data together, but the bottom line is that, yes, we see a plateau phase. That means the curve stops to keep going down, meaning that maybe we have reached a cure for some patients. That’s the reason why again I’m going back that we have to revisit this approach but it’s difficult.
I think that the study that was mentioned was for all patients without knowing their cytogenetics, and I don’t think it’s necessary. I don’t think that we need to do that and the data on the tandem transplant is also controversial too. We don’t even know now that we have maintenance if we need to do a tandem transplant. There were a couple of controversial studies at ASH. One from the US that didn’t show any difference but the European studies do. We still have a lot of research, a lot of questions to answer.
Jenny: Right. And this can be confusing.
Dr. Gasparetto: Yes, very confusing. I don’t want to come out of this and say the allogeneic transplant is going to be the key. It is only for selected patients and as part of a clinical trial. It’s still a very difficult approach and even for me, sometimes it’s difficult to offer to a patient because I know that there are possible complications involved with it. So sometimes I have to think about, and sometimes I have to change my strategies. Sometimes I change as they go because I think that the patient is doing well with the chemotherapy, and I do a tandem transplant, a consolidation based on the response that — I keep the allogeneic only for a small group of patients.
Jenny: Well, I think that just stresses the fact that myeloma patients really need to have a myeloma specialist in their corner because you’re dealing with a very complicated cancer. And it’s really, in my opinion, beyond the scope of what a general oncologist who treats 20 different cancers is capable of staying up to speed on. Even though they can be really important part of your care, you can get local care, you can travel to see a specialist and get their advice and go through some of these different scenarios with your myeloma specialist who’s seeing hundreds or thousands of patients versus seeing maybe five a year or something like that. I really want to stress that to patients that no matter how much you love your local oncologist, it’s in your self-interest to go find a myeloma specialist who has this kind of depth like you do.
Dr. Gasparetto: We work as a team. I always tell the patient, we work together so you come or we can make a recommendation and then work together so that they don’t have to transfer their care to the big institution necessarily.
Jenny: Right, and I do that with my doctor and I know lots of patients that do that. Another question about allo transplant. How effective have you seen it be as a salvage strategy for relapse patients?
Dr. Gasparetto: We have some good data actually that is effective in this setting but you have to be able to control the myeloma first. I actually do have a clinical trial at Duke showing the relapsed setting, but we use myeloablative. We use high-dose chemotherapy to prepare a patient because we know that we are dealing with a more aggressive myeloma. We have to use the chemotherapy to control the myeloma while we establish the new graft. So yes, I have done it but generally in the relapsed setting, until we improve the non-myloablative, until we found the strategy after the best maintenance, the boost with the lymphocyte, I think sometimes I favor the myeloablative.
Jenny: Right. Okay, well, I know you have other clinical trials open and before I send it to caller questions, I’m just wondering if there are other clinical trials at Duke that you would like to share because I know one of your patients helped me get connected with you and he said you have some interesting things going on.
Dr. Gasparetto: Well, like all big institutions, we are a part of the different groups, and we collaborate with each other. I think in the past in the United States, you could see every single institution having their own individual trials, and we were not able to accrue a lot of patients but now we work as a team. We have a lot of trials in collaboration with other institutions. Of course, we have new drugs. I’m sure at ASH we heard a lot about the Venetoclax. We work a lot with these drugs. We have another couple of trials opening with the Venetoclax in combinations. And then we use with PD-1 inhibitor, we have the combination with some different types of PD-1 inhibitors just so we are talking about immunotherapy again in combination with pomalidomide and other drugs. And then we have another drug that was also presented, the selinexor. We also have that available in different combinations. What else?
Jenny: Probably a lot.
Dr. Gasparetto: We have a lot, yes. We have some very interesting, in newly diagnosed, opening with the daratumumab that is just going to be incorporated up front. That is going to be very interacting to see if the daratumumab can improve the response rate up front, so that will be a key. We try to add new drugs, new combinations. And we do actually have a very important trial from a colleague of mine at Duke, Dr. Kang is with drug first in myeloma. It’s a world drug. We just recently opened this clinical trial which is going to be very important to see if we have another drug that we can add to the myeloma drugs. We’re trying to have and we’re always seeing the collaboration with different pharmaceutical companies, other institutions to try and to make sure that we have clinical trials available for the patients at different stages of their disease.
Jenny: Right. You need help. A lot of different options open.
Dr. Gasparetto: Right. Because when they come and they have progressed through lenalidomide, bortezomib, pomalidomide, bortezomib, carfilzomib, but then you are going to start to run thin. We like to have a combination so that can be available also in the setting or we can improve other combinations.
Jenny: Right. It’s just so clear that the academic centers and places where myeloma specialists who are practicing like you have a lot going on, and there is a lot to offer. And some of these, it seems like, well, for me it kind of was part of just the personality fit too. Some patients kind of want to hit it really hard out of the chute and other patients might be a little concerned about doing that or may not have to do that. So having a variety of options open to be able to tailor treatment is really nice.
Dr. Gasparetto: I agree, yeah.
Jenny: Well, let me open it up for caller questions. If you have a question for Dr. Gasparetto, please call 347-637-2631 and press 1 on your keypad. We’ll start with our first question. Go ahead.
Caller: Hi, Dr. Gasparetto. First of all, I want to say I love your accent. That’s a pretty neat accent.
Dr. Gasparetto: It is a little bit strong at times. I’m sorry.
Caller: No, it’s a pretty accent. I wanted to ask how long this normally takes to find a match donor for minority group patients.
Dr. Gasparetto: Oh, that’s amazing. It’s a very good question. Sometimes we can’t because we don’t have enough donors. That’s the reason why we have advocates. I actually have a patient of mine that does that, goes around to teach younger people. He goes to schools, to colleges to educate and increase the number of donors for the disparities, for the minorities because you are absolutely right that it is easier to find unfortunately a donor for a Caucasian than is for an African American or Hispanic. Absolutely, that is a problem. We have to raise the community. We have the awareness. We have to make sure that the potential donors understand that it is very safe. It’s a very safe procedure for them.
Caller: How effective are some of those websites that recruit donors for myeloma?
Dr. Gasparetto: Well, that’s the reason why, they’re good but I think having people, the ambassadors, advocate going around and talking directly with potential donors is much more helpful because I think there is a preconception people don’t understand that the donation is actually relatively very safe. We generally at the beginning, they just do a buccal swab to store the initial material so we can have an initial idea of the HLA code. But I think we need to do more because we need more donors.
Caller: Well, thank you, thank you so much for doing this and answering my question.
Dr. Gasparetto: Sure, of course.
Jenny: Go ahead with your question.
Caller: I have a question, for younger patients age 52 of medium risk but who found the BRAF(V) (600E) gene alterations with the FoundationOne hem report and have been on chemo for the better part of three years. Do you advocate an allo at this point or only an allo after an auto? Also, I don’t have any siblings, so it has to be an unrelated donor. What do you see the balance of risks between age, the fact being on treatment, on chemo for about three years and —
Dr. Gasparetto: The fact that you are on treatment and doing okay, I imagine, for a few years, I think at this point, I will not even think about an allogeneic transplant because you are doing okay. I think as I say the selection, even when we do cytogenetics and gene profiling, the durability of response, I mean the selection is a little bit go behind that. So not all patients need an allo. I’m not an advocating allo for everybody. We wanted to talk about allo today because it’s an interesting, a different approach but no, there are a lots strategies particularly if you’re on therapy for the last two years and doing okay, I don’t think you need to worry about that.
Caller: I’m in a VGPR.
Dr. Gasparetto: Oh, no, I didn’t say that. It’s very difficult to answer your question because we’ll need to know the details of your myeloma, what’s going on and then, yes, can you be eligible for an allo or maybe you can remain on continuation of therapy. That is very difficult. Generally, when I talk about allo, I spend a long time with a patient and we go through all the pros and the cons and the alternative options. It’s a very difficult question that you’re asking me.
Caller: Sure. No, I understand. But in general, if a donor were found, would it be a straight up allo or an allo after an auto or it depends?
Dr. Gasparetto: Did you have an autologous transplant already?
Caller: No, not yet. No.
Dr. Gasparetto: Never, no, so you still have that option. The clinical trials that we have open nationally, we generally go directly to the allogeneic transplant but a little bit earlier on. In your situation, I don’t know. I will need again to see the type of myeloma that you have and what’s going on. If you’re coming to the point where an allo might be one of the treatment options, it will be based on a lot of things.
Caller: Sure, I understand. Thank you very much.
Dr. Gasparetto: You’re welcome.
Jenny: Okay. Thanks for your question. My earlier question was just is there any role for allo transplant in the smoldering setting?
Dr. Gasparetto: No, absolutely not. No, no, no, no. Actually, there are some interesting clinical trials for high-risk smoldering with intent of curing them, treating them early. No, I will not. I will never offer an allo in the smoldering setting.
Jenny: You would have to have progressed disease. Well, Dr. Gasparetto, it’s been very enlightening to have you on the show today. We’re just so thankful that you have joined us and just are so grateful for the work that you’re doing to help myeloma patients in all these different types of immunotherapies which includes allo transplant. It’s amazing.
Dr. Gasparetto: Well, thank you so much. It was a pleasure. I really enjoyed talking to you. It was good.
Jenny: Well, thank you so much for joining us. And to our listeners, thank you for listening to Myeloma Crowd Radio. Join us next time to learn more about what’s happening in myeloma research and what it means for you.