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Dr. Parameswaran Hari, MD, MRCP, MS
Interview date: January 24, 2014
Who should consider an allogenic (donor) transplant? You may be surprised. While it is not for everyone, Dr. Hari describes myeloma patients who are to benefit the most from allogeneic translpant: young, high-risk patients, patients that relapse quickly (in 1-2 years after treatment) or plasma cell leukemia patients. Allo transplants are the oldest immunotherapy in in the book - the donor's immune cells find and kill the myeloma cells. Dr. Hari shares how safety has jumped in recent years from prior dismal rates to a 5% mortality rate in young patients because of new transplant methods and new drugs. Dr. Hari describes the "mini" allo transplant, the "reduced intensity" allo transplant and why you may want to do an auto then an allo transplant in tandem. He previews a large, multi-center study that will open in a few months for high risk patients or those with a single relapse using the allo transplant with or without an oral proteasome inhibitor. For those who are struggling to find a matching donor in the Be The Match registry, Dr. Hari describes a very interesting early study that uses a family half-matched family donor (like a sibling) with natural killer cells - what looks like a very effective immunotherapy one-two punch to kill myeloma cells. He emphasizes (again!) that we should do deep diagnostic testing at a myeloma academic center so we will be positioned later to learn which treatments are better for which types of patients. If we start treatment without correct diagnostics, that information is lost.
The live mPatient Myeloma Radio podcast with Dr. Parameswaran Hari
Jenny: Welcome to today's episode of mPatient Myeloma Radio, a show that connects patients with myeloma researchers to help become better educated patients, so we can receive better care and so we can help support new discoveries by joining clinical trials. If you'd like to receive a weekly email about past and upcoming interviews, you can subscribe to our mPatient Minute newsletter on the home page or follow us there on Facebook or Twitter.
We also have new Facebook groups that we've created by myeloma subtype. Now, some of these include gene translocations or other gene deletions or additions. And if you don't know your disease biology, you should call your doctor today to find out. Then join one or many of the groups and post information about certain subtypes if you have it. Now at the end of the call we'll open it up for caller questions, and you can feel free to ask your questions by pressing 1 on your keypad if you are calling in by phone.
Now, today we are very fortunate to have with us Dr. Parameswaran Hari of the Medical College of Wisconsin who has some of the very highest survival statistics for myeloma treatment. We will find out what he is doing to achieve such stellar results and learn about his area of research, which includes transplantations specifically allogeneic transplants.
So welcome, Dr. Hari.
Dr. Hari: Thank you and thank you very much for having me on the show.
Jenny: Well, I would love to give an introduction for you if that's all right.
Dr. Hari: Sure.
Jenny: Dr. Hari is the Armand J. Quick/William F. Stapp Professor of Hematology at the Medical College of Wisconsin. He serves as the director of the Adult Blood and Bone Marrow Transplant Program at Froedtert Hospital. He is the Section Head of Hematologic Malignancies and Transplantation in the Division of Hematology and Oncology in the Department of Medicine. After medical school in India, he completed training in internal medicine and hematology at premier institutions in the United Kingdom and then in Medical Oncology and Transplantation at the Medical College of Wisconsin.
Dr. Hari is board certified by the Royal College of Physicians and Internal Medicine, the Royal College of Pathologists in Clinical Laboratory and Hematology and holds membership in the American Society of Hematology. His primary clinical interests are in allogeneic transplants, plasma cell disorders including multiple myeloma, amyloidosis and other monoclonal gammopathies. Dr. Hari is also the Scientific Director of the plasma cell disorders and lymphoma working committees of the Center for International Blood and Marrow Transplant Research.
So that's a lot to cover! Thank you very much for dedicating your work to supporting and helping myeloma patients. We're all benefiting because of what you're doing.
Dr. Hari: Thank you.
Jenny: So let's start out with your specialty. Let's start out with allogeneic transplants or donor transplants and kind of cover the who, what, why, where and how of those types of transplants and then we can continue to go on with other types. So I guess let's start with who. When you look at allogeneic transplants, what profile of person are you looking at for that type of therapy?
Dr. Hari: So let me start by saying that allogeneic transplant is not everyone with myeloma. It's actually a minority. It's more a minority of patients with myeloma who should even think about it. So it is potentially curative in myeloma and that's even without using any of the new drugs. We have data from old studies. We had a US intergroup study from the mid '90s which was a study that compared conventional chemotherapy in those days without even thalidomide or Revlimid or Velcade. So old-fashioned chemotherapy versus auto-transplantation versus allo-transplantation.
In those days, allo-transplantation or donor transplantation was quite unsafe. It was done with the heavy-duty chemotherapy so we call it the conventional allotransplant and it was quite unsafe. The study had to be stopped. So the allotransplant arm of that study had to be stopped. However, the people who did well with the allotransplant had survived the allotransplant itself, had essentially very minimal relapse after that. So it turned out that after many, many years of follow-up, we still see that people who had an all -transplant in the old-fashioned way have very low risk of relapse. So that study is kind of early sign that allo-transplantation works when it can be done safely. So that's why there's still some interest in allotransplant.
Now, subsequently, studies have gone either way and we have changed the way we do it. We have made allo-transplantation safer by reducing the amount of chemotherapy and changing the immunosuppression, many techniques. We will go into that in a bit. But in answer to your question, who needs it? It is generally the younger patient, generally the patients who have high risk myeloma, where the risk of relapse is very high, or people who have already relapsed one time.
So say, for example, you had conventional therapy with three modern drugs, auto-transplantation maintenance and you still relapse within first one or two years, there are still patients like that in that setting being sent after relapse. The chance of a subsequent relapse is very, very high and you should think about more aggressive options such as an allotransplant.
And finally, there are patients with primary plasma cell leukemia where the disease itself is of very high intensity and aggressiveness. You should be really considering allogeneic transplantation as an option in those patients too, and younger patients with this kind of profile.
Jenny: And so when you talk about younger patients, what high risk profile are you looking at for? And this before any other therapies, correct?
Dr. Hari: Right. So high risk profile, younger patient. I have patients who are in their 20s who get diagnosed with myeloma. So when you are 20 and you have high risk myeloma, you are looking at an average survival which shortens your life with a substantial amount of years. And being young, they have an advantage. In fact, allo-transplantation is relatively more safe in the younger patient.
Essentially, the transplant related to mortality or the fatalities we induce by our treatment are exceptionally low in young patients. Nowadays, most experienced centers would quote a transplant-related mortality rate of 5% or less for a young patient in their 20s or 30s when they have either a matched sibling donor or a matched unrelated donor. In those patients with young age and with high risk features such as 17p deletion, chromosome 1 amplification, (14;16) translocation, in addition to other features such as high beta2-microglobulin.
So if you have a Stage III disease with high risk chromosomes, that generally predicts for a high risk disease, and some of these patients are even called ultra high risk disease; people who have highly proliferative disease with abnormal chromosomes which mark for high risk genes and also high stage. So those patients have been sometimes termed ultra high risk disease, and ultra high risk disease is an indication in the young patient to consider this option.
Jenny: Did you say (14;16) translocation or did you say (4;14)?
Dr. Hari: Yes.
Jenny: Oh! I didn't know that that was -- I didn't know that that was high risk, (14;16). Oh, because we have a group, a Facebook group, and someone on that group was just asking that question. Is this high risk or not? So now we know the answer to that.
Dr. Hari: Right.
Jenny: Well, let's go on to talk about how to go about the transplant, and I guess you could cover the entire process. How does somebody go about finding a donor? At what point in time do they find a donor and then how do they go through that process?
Dr. Hari: So first of all, if you have one of these abnormalities, so the first thing I would advocate to all patients is to actually know your risk profile. So if you know your risk profile and if you're a young age person, you should think about this as an option. And also, I forgot to mention the more modern tests like the genomic profiling test. So there is the personal risk score with genomic profiling that's modeled after the Arkansas data, and another European way of doing it. So these are genomic profiling tests.
And that sometimes your doctor may have done it, then they also sometimes indicate resistance to agents such as bortezomib. So if you have a higher genomic risk score, sometimes it can indicate that proteasome inhibitors such as Velcade or Kyprolis are not going to work for you very well which essentially takes you to high risk group because this is probably one of the platforms on which most of our therapies are built. So the primary stone of that platform is not working. So that means that you're not going to benefit as much from our modern therapy.
So in that case, you would try to think about an allotransplant. Allotransplantation works by being an immunotherapy. So basically, the disparity between the immune cells of the donor and your own myeloma cells makes the donor's immune system able to detect the plasma cells that are growing in the patient's body and fight them off or kill them off.
Now, how do you go about doing it? Once you are identified as a candidate by yourself or your doctor, you have to have a consultation with a transplant specialist and they do what is known as tissue typing or HLA typing. HLA stands for Human Leukocyte Antigen. Basically, these are some proteins on the surface of the white blood cells of the body and these proteins, they're essentially present on almost all cells of the body. And the protein profile on the HLA of your body should match with that of the donor, and then only that person can donate for you. Otherwise, there's immune complications which would involve later rejecting your transplant or the transplant cells attacking your body which is a condition called graft-versus-host disease. So in order to avoid both of those situations, you need to have an HLA-matched donor. We call it tissue-matched donor.
So this HLA typing is a very simple test. Almost all hospitals do it. You basically have to have a sample of blood drawn or a cheek swab, something which has your DNA; and you can do the HLA test off of that. And then if you have siblings, each sibling has a one in four chance of being matched to another sibling. So if you have, say, several siblings, it’s quite likely that you might find a match within your family. If you don't have a sibling, the option is to go and look for an unrelated donor.
So there is something called the National Marrow Donor Program nowadays known as Be the Match Registry. So Be the Match had typed about 12 million individuals of who are in their database with known HLA typing, and you can search your HLA type against those people in the registry. And if you find a close enough match, the person will be contacted and the person's blood comes to the transplant center and they test for your blood versus their blood. And most Caucasian individuals have a 90% chance of finding someone close enough in the registry. So those are the two primary ways of doing this.
Now, I get this question always, can a parent be the match? Can a child be a match? Can a cousin be a match? Can a neighbor be a match? All those things. So a parent is only a half match to their child typically and same thing for your child versus you. So a child or a parent can only be 50% matched. Now we do 50% match transplants in some situations, but that's not the first line of a donor search. To find someone from your neighborhood or from your friend's group that's matched to you, that's actually very, very long odds. I would not bet on that. You are much more likely to find it in an NMDP Be the Match Registry.
So this is all happening in the background when you're getting your treatment for the myeloma. And once you get into a good remission, that's the time to consider an allogeneic transplant or a donor transplant.
Jenny: Well, if you don't mind, let's go back to testing for a minute because I want to help educate patients about the types of testing. Normally, I know when someone goes in, most facilities will do the FISH test which might give you some of the translocations and some of the genetic profiles. But you were talking about a more detailed genetic expression profile test, correct?
Dr. Hari: Yes.
Jenny: Yes because I would say 90% of the patients that I talk to have no idea what their disease biology is. So I think that point your making is really, really critical. And in lots of instances I've said, call your doctor, just call them today. Talk to the research nurse or your coordinator or whoever you need to help you look through your chart and find out if that type of testing has been done. And I have a curious question. When you say a high risk score may identify you being Velcade resistant, tell me more about that. What are you looking for in that profile to see if you're Velcade resistant or not?
Dr. Hari: So this is basically gene expression testing. So the most common gene expression test in the US is called MyPRS. So it stands for my personal risk score. It is a test done by this company called Signal Genetics. And Signal Genetics is -- their test is based on the data that came from Dr. Barlogie's group at Arkansas. So what happens is they need plasma cells from the individual at diagnosis or even at relapse. So whenever you have a bone marrow biopsy and if you have about 30% plasma cells in the bone marrow, you can have that test.
So the exact type of test is called a microarray-based gene expression profiling. So there are genes in every cell in our body. Some genes have turned on or they are working. It's just like the lights in your house. If you have hundred lights, the light bulbs in your house, not all of them are working at any one time. If they're all off, you can say that everybody in the house is probably sleeping or away. If they are on in the living room, you can say that they are probably living room either chatting or watching TV or whatever.
So similarly, by looking at which genes are turned on in a myeloma cell and which genes are turned off, you can say how this myeloma cell is going to behave. And the micro arrays detect which genes are turned on and which genes are turned off, and it gives basically dynamic information regardless of the proliferation rate and other things that other cytogenetics do, conventional cytogenetics the cell needs to divide. If they don't divide, you won't get conventional karyotyping.
For FISH, the problem is you put a limited number of probes on the myeloma cells. So if your doctor doesn't order the correct FISH test, you may only get effect for, say, 17p. So you wouldn't know if you had for, say, (14;20) or (14;60) or chromosome 1 amplification or some of the other things that are high risk. For a FISH, it's limited by the amount of number of probes you have and the number of probes that are ordered. So gene expression is a more comprehensive test. However, gene expression has been validated in a big fashion only with the Arkansas data. It has not really gotten out in the community and been tested in a multi-center setting. Those studies are actually underway right now.
It is an expensive test. Some insurances don't cover it. You can only test for it when you have active myeloma and active plasma cells because you need the plasma cells do the test. And it basically gives you -- they look at about 70 myeloma-related genes and they give you a risk score, and the risk score predicts how aggressive your myeloma is. That's how it works.
Jenny: And which part of that is telling you if you're Velcade resistant, just by ultimate score that you get or is there something specific on that?
Dr. Hari: No, they actually can predict Velcade resistance from the MyPRS score. The test result will tell you if this patient is likely to be Velcade resistant or not.
Jenny: Oh, wow. I had no idea. Now, I was talking to my doctor about that and asking -- because in some of the interviews we've been doing, I know some researchers are holding maybe BRAF mutation studies or MEK studies. So I asked him, does the gene expression profile show those mutations? He said no, you have to do the deep gene sequencing; but I didn't learn more about that. Are you doing the deep gene sequencing now too?
Dr. Hari: Deep sequencing at this time is essentially only done as a research test. We don't have a commercial test. So for most patients, it really cannot be done. You can’t do it as a commercial test. Even gene expression profiling, there are issues where insurance companies don't pay for it, et cetera. But many, many insurances do pay for it and this company is actually very good with waiving cost when insurance doesn't pay. So I have really not had any patient actually had to pay for it out of pocket so far.
Jenny: And how much is the test?
Dr. Hari: How much does it cost? I think it cost around $2,000.
Dr. Hari: It is covered my Medicare, that's for sure.
Jenny: Oh, that's good to know.
Dr. Hari: And most myeloma patients are actually on Medicare.
Jenny: Well, maybe you want to talk about now what the process is of the allotransplant, if you could kind of walk us through the steps of how it works.
Dr. Hari: So once you find an appropriate donor, you would go ahead and decide with your doctor whether allotransplant is right for you. So there are two ways of doing it. One is in a planned fashion after an autotransplant. So if a person has not established a complete remission or a deep commission after the initial induction therapy, there are some thought to doing it as a double transplant technology.
So basically, you have an autologous transplant with your own cells first time, which takes you to a deeper level of remission. And then you follow it up with a reduced intensity allogeneic transplant. It's not the old-fashioned, heavy-duty chemotherapy but reduced intensity chemotherapy. Some people call those mini-transplants which are not quite the same but is basically a tandem approach, double transplant approach; one with your own cells, one with the donor cells and the two transplants are usually separated by about three to six months.
So first of all, you would collect your own cells and go through your autotransplant the normal way which is you get high dose of melphalan as your chemotherapy then you get your stem cells infused a day or two later and then you wait for those stem cells to grow. And you recover in about two and a half, three weeks. You get out of the hospital or if you're not even admitted, sometimes in some centers like ours, we don't admit patients all the time. Sometimes we do it entirely as an outpatient. And then about the next two or three months you recover and you get back to your usual state of health, and then you decide whether you want to go ahead and do the second part of the planned procedure which is the allogeneic transplant.
So for that, you get chemotherapy and for us the common form of chemotherapy that we use before transplant is a combination of two drugs. One is called fludarabine, which is an immune suppressive drug; and the other is melphalan, which is the same drug that you use for an autotransplant. So you get a combination of both, fludarabine and melphalan, -- so the melphalan is one day; fludarabine is four to five days. And after that, you get your donor cells infused. The donor collect cells the same way you collected them for yourself, basically get G-CSF injections and then get put on the plasmapheresis, leukapheresis machine and then get your cells collected.
So the donor cells come in typically fresh. They get collected in the morning or afternoon and you get it later in the day. And you have to take immunosuppression medications to prevent rejection and also to prevent graft-versus-host disease. So basically, if your body doesn't like the donor cells, that's rejection. You just reject the donor cells. That's very rare in bone marrow transplantation or stem cell transplantation but can happen.
The other form of immune incompatibility is called graft-versus-host disease. So that’s where the donor cells just don't like the fact that they're in your body. So they detect that they're in a foreign person's body and they attack the person. So this attack leads to what is called graft-versus-host disease. So basically, it can attack your skin, attack your gut, liver, essentially any organ in your body. And the acute form of it, the more serious form of it is called acute graft-versus-host disease. It happens within the first hundred days after transplant typically, and it can sometimes lead to death. That is really the most fearful complication of a donor transplant.
This later complication is a more indolent form, more slow growing form of a graft-versus-host disease. It's called chronic GVHD. And chronic GVHD is, the majority of time, more of a nuisance than a life-threatening illness but it can also be life-threatening at some point sometimes. It turns out that this disparity between the donor and the recipient is also what helps myeloma get controlled. So if you have a little bit of disparity between the donor and the recipient, that makes the donor cells fight the myeloma cells and that is what prevents relapse in this setting.
Jenny: So that might be like a double-edged sword a little bit?
Dr. Hari: It is a double-edged sword. GVHD is a double-edged sword. As we've looked at our own data from hundreds of transplants and turns out that acute graft-versus-host disease with the more life-threatening form of it which happens in the first hundred days after transplant, that is more damaging than helpful and it is more risky to life. However, a little bit of chronic graft-versus-host disease does prevent relapse and both our group from the CIBMTR and the European Bone Marrow Transplant Group (EBMT) have both shown that with chronic graft-versus-host disease, you do get an anti-myeloma effect. So it’s not like we wish GVHD to happen but a little bit of GVHD is not necessarily bad.
Jenny: Oh, that's really interesting to know. I have a friend who's preparing for one and is going through the whole matching process. He found a donor that was nine out of ten and they said, "No, you really need a ten out of ten." I don't really know what those numbers mean, but maybe you can explain now.
Dr. Hari: I can explain that in a second, yeah. So when we look -- remember I told you about the HLA typing, tissue typing? So we look at HLA proteins on the person's cells and we look at the HLA protein on the potential donor cells. So if we look at five sites in the cell and each site there is two proteins so basically ten. So it's like looking at five, A, B, C, D, E. And there is A1, A2, B1, B2, like that. So there are two places in each of those five sites.
So if all five sites, both places in each site are all matched, then you're a ten out of ten match. If one of the places, the protein is different between the recipient and the donor, then you're only nine out of ten matched. Some centers will insist on having a ten out of ten match. Some centers might go with a nine out of ten match. So it's a little bit variable. And some centers only look at eight places or like four places with two sites in each place. Like our center, we look at eight places and there's enough data to suggest that data you only need to look at eight antigens.
Jenny: Do those numbers correlate with what you're talking about with graft-versus-host?
Dr. Hari: Your risk goes up. The more disparity there is, the risk of graft-versus-host disease goes up. So if you have a mismatched donor in several sites, if you look at the seven out of ten donor, we don't use those donors because the risk of graft-versus-host disease is very high. So whereas ten out of ten and nine out of ten, the increase in graft-versus-host disease is only minimally high, so we might go with it.
Jenny: And a question I guess just about finding a donor, how long does it usually take to find a matching donor?
Dr. Hari: So if it's a sibling, usually the process is very quick because you can call your sibling and say, "Hey, go and get yourself tested." Whereas, if it's an unrelated donor, it could take anywhere from six weeks to 12 weeks or 16 weeks. Generally, if you're an ethnic minority, there are less people like yourself in the registry, so it takes a little longer. And sometimes you may not find a donor even after worldwide search because most of the donors that are in the registry are actually either US or Caucasian from Western Europe. So there is a little bit of a disparity there based on your minority stages: the African Americans, Hispanics, Asian Americans. We all find it very difficult to get donors through the NMDP.
Jenny: Now, I know that a lot has been done to improve the safety of the allotransplant. Can you talk about what you are using in the best and latest technology to reduce the risks?
Dr. Hari: Sure. So like I said to you, when we did the US intergroup study in the mid '90s, the allotransplant arm had to be closed down because the 30-day mortality, the mortality within the first month was as high as about 40%. Now, nobody would do a procedure like that anymore.
Essentially, for all types of allotransplants, things have become much safer within the last few years. The biggest change that has happened is change in the immunosuppression, changes in antibiotic use, changes in sterility practices, lowering the rates of infection, et cetera. So nowadays, we do allotransplant for even myeloma and other diseases, all the way up to age 70. In fact, there are a lot of people above the age of 70 having allotransplant for diseases like leukemia and myelodysplastic syndrome, et cetera. So the allotransplants, in general, have become dramatically safer.
Number two, myeloma patients are actually going to transplant in a much safer condition than they used to before. In the olden days, every treatment was predicated on giving chemotherapy and high, high doses of steroids, essentially dexamethasone at 40 milligrams four days on, four days off which would involve like 160 milligrams of dexamethasone every week. So that has gone away. Conventional chemotherapy has gone away. So myeloma patients are actually getting to transplants, whether auto or allo. They're getting to transplant in a much safer situation. So they're not more, you know, what do I say? Not as beat up as they used to be. So they're able to tolerate the transplant better.
Thirdly, the technology of doing transplant has changed. We used to give people heavy doses of radiation or chemotherapy. We call that myeloablative transplant. It stands for destroying the marrow type of transplant. So you essentially destroy the recipient's marrow and then you put the donor's cell marrow in.
Now, we don't necessarily have to do it. We figured out that just depleting the immune system is all that you need to do. In fact, the major allotransplant trial in myeloma that was done in the US was done with a single dose of radiation. So essentially, the patient had one dose of radiation in the morning of the transplant, such a small dose of radiation that you wouldn't even know you got it. Essentially, your hair doesn't fall out. You don't get any mouth sores. You don't get anything. You could get discharged the next day.
We call it two grades of radiation, just one dose of radiation in the morning to suppress their immune system and then you get the cells from the donor in the evening. And you stay on immunosuppression medications for the next two months. That’s how we did it. That’s called a non-myeloablative transplant or a mini-transplant. So many people like doing it that way.
But what turned out was that many groups looked at the mini-transplants with the older way of doing transplants with heavy-duty chemo. It turns out that if you do mini-transplants, you do get that immune effect against myeloma but you don’t get enough myeloma control from the chemo itself because you’re not getting any chemo. You’re not doing enough radiation. So then the pendulum started swinging the other way, but it has not gone all the way back. It’s just kind of right in the middle now. We call it reduced intensity transplant. So it is not as light as the mini but it is not as heavy as the fully ablative transplant. So it’s right in the middle. It’s called reduced intensity.
And the most common regimen right now that’s being used across this country is a combination of two drugs: fludarabine and melphalan. And here you would definitely lose your hair. You would feel some mouth sores and all that. And it’s about as intense as going through an autotransplant or a little bit less intense than that. We actually do this to as outpatient. If the patient lives within an hour of us, we do it the whole thing as an outpatient.
Jenny: Oh, well, I’ve done an outpatient transplant and I just loved doing it outpatient. And I think it's psychologically easier.
Dr. Hari: Oh, much better. I was just looking at our infection base for 2013. In the outpatient transplant, we had 5% infection rate during the first month of transplant. So that’s just amazing. And in hospitals, I think the number of people coming in and out of your room, the number of doctors seeing you, all of that is much higher in the hospital. And like I tell my patients, the bugs in your own house, they know you and they won’t attack you. But the bugs in the hospital, they don’t know you and you’re fodder for them.
Jenny: Well, I guess you were saying you’re trying to reduce enough of the tumor burden. That's the overall goal, right? Reduce enough of the tumor burden to be effective to kill the cells and then give the new cells. So when you’re talking about the -- sorry to interrupt you -- for the reduced intensity but maybe you could keep describing that.
Dr. Hari: I can explain on that a little bit. So the goal of a transplant is to really do -- and all transplants should do two things. One is to have as little tumor burden in the patient as possible after transplant. The second goal is to have a change in their immune system. So essentially, if you have myeloma, it means that your own immune system is not very good at sniffing out the myeloma. If you have a new immune system from a donor that is generally compatible with you but slightly incompatible, unless you are an identical twin, nobody else has the same exact immune system as you. Even when you’re sibling, fully matched sibling, there are minor incompatibilities that we don’t care about.
So those incompatibilities result in the donor’s immune cells having an antimyeloma effect. We call that graft-versus-tumor effect or graft-versus-myeloma effect. And there are several lines of evidence. We can actually test that in mice. We can give immune cells after transplant and that controls the myeloma in people who relapse after donor transplant. So there are many ways of figuring it out if such an effect exists. And it has been proven time and again that there is a graft-versus-myeloma effect and immune cells can attack myeloma cells. That has been proven.
The only barrier is to use it successfully so that we don’t result in harm to the patient doing the transplant, and we also have enough immune effect to prevent a future relapse. So you want to reduce a tumor burden to as minimal as possible so that the immune system has less work to do.
Jenny: When you think about doing either the autotransplant first and then the mini allotransplant or this reduced intensity allotransplant. How do you make the decision for your patients about which option is best for them?
Dr. Hari: So let me tell you what I do in practice myself. If a patient is in a really good stringent complete permission after that induction treatment and they’re in a really good place, I sometimes just go straight to the fludarabine/melphalan reduced intensity allogeneic transplant, but that’s the minority. For most of my patients, after induction they have either a complete remission with a few cells detectable by flow cytometry or they’re in a very good partial remission, et cetera. So for those patients I do an autotransplant to further reduce the tumor burden and then come in and do the allotransplant. So that I would say is 90% of what I do in practice.
There are other patients that I wouldn’t even consider doing just an allo up front. Those are patients with like primary plasma cell leukemia and things like that. The disease is very aggressive and I always worry about subclinical disease, the disease which we cannot detect by our tests but that may be present. So the goal is to do the auto first to actually kill as much disease as possible and then soon thereafter come in and do the allotransplant. So most of our patients up front, we are doing that.
At relapse, again, most people would actually do several cycles of induction, re-induction treatment at relapse and get them to a deep remission and then do the allo straight up.
Jenny: So for relapse patients, do you ever do an auto and then an allo with relapse patients or no, just trying to reduce it as much as possible?
Dr. Hari: Yes, try to reduce it as much as possible and then do the allo. So most of the time I have done in the relapse patients allo after a tumor bulk reduction. And there are some insurance issues around it too. It’s very difficult to get tandem transplants approved at the relapse setting. But I have to say that insurance companies have generally been okay with allotransplant once a patient had a relapse.
We get pushed back from insurance companies because the studies have gone either way. So if you think about the auto followed by allo studies, there was a study from Italy published by Dr. Bruno. That was a study of double auto versus one auto followed by allo with the mini allo. That was published around 2006 I think. And that showed that the people who got auto followed by allo survived longer than the people who got double auto. So that was a smaller study, although it was a high profile publication.
And then we had a US study which was a large US study of almost 700 patients. This was called a BMTCTN-01-02 study which stands for the Blood and Marrow Transplant Clinical Trials Network. This study was published in Lancet Oncology and that showed that there was no difference between double auto and auto followed by mini allo. So that was a negative study for mini allo. It wasn’t as if the patients who got mini allo did poorly; it is that they didn’t do any better than the people who got double auto.
The criticism for this study is that this follow-up has not been long enough. So we are actually seeking to update that study within the next few months, and there will be a follow-on publication to that looking at long-term effects for the allo because the benefits of allo most people think are in the long-term disease control, not in the short term.
The third study is a very, very long study with very long follow-up coming from the European group. It’s called the EBMT-NMAM 2000 study. And the follow-up is up to eight years now. And that has been published twice. One is in the Journal of Clinical Oncology, and one in Blood. And both times it was shown that the people who got an auto followed by allo lived longer than the people who got double auto. So there was a survival advantage.
In addition, it was shown that people who got the allo, when they relapsed they had a better survival after relapse. This is something that I seem to be seeing in my own practice too because I think people who get the allo, they generally are younger. So that may be just the effect of age, but it’s also that they have other options. They have the option of what we call donor lymphocyte infusion or immunotherapy strategies after relapse then you had an allo platform in your body.
Jenny: And I hope we’re going to talk about that later because I want to talk to you about your studies. In the Italy study, how long of data did they have?
Dr. Hari: So they have also published twice. Their second publication was by Dr. Giaconi as the first author, and I think in that they had almost seven years to follow up.
Jenny: And the US study had how long of follow-up, because you said it wasn’t long enough?
Dr. Hari: It wasn’t. It’s only about two and a half years, so three years to follow up when the US study was published.
Jenny: And a follow-up question about these studies, are they able to subset the patients by risk type or maybe translocation type or genetic mutation type and then determine who it is working for in a better way?
Dr. Hari: That’s a very, very good question. So the US study is the one where we had risk stratification. These studies were designed in the early 2000s. So you have to understand that our risk stratification methodologies were not as good as now.
So the US study used only two markers, beta2-microglobulin and the presence of chromosome 13 by karyotyping, which is chromosomal test. Now, most people would say that chromosome 13 by conventional karyotyping is not really a high risk marker anymore. Well, we actually do it by FISH or karyotyping. If you have it by conventional karyotype, it is a high risk marker. But if you have it by FISH, it’s not really a high risk marker. So this study out both categories in the high risk, so that’s one problem.
The other problem is just a straight up beta2-microglobulin plus chromosome 13, none of the other newer markers. So we did look at high risk versus low risk and there was no benefit, but what we did see was that people who got chronic GVHD had a benefit against relapse. So that was still shown in the US study. So there is some benefit if you got chronic GVHD but no overall benefit compared to double auto at three years. That’s all we can say.
Jenny: And can they go backwards? Can you go backwards and look at all these data now that you know little more or you just don’t have data about what patients had or didn’t have?
Dr. Hari: It’s almost impossible to get it. The problem is that the upfront typing -- so that's why this is again a great question in a practical sense is that your diagnosis of myeloma is usually made not of the transplant center. It’s not even possibly made at an academic center for the majority of patients. So the only way to do it, to establish the right risk stratification is to go a major myeloma center and have a repeat bone marrow biopsy because if you didn’t get it done and you started on treatment and your plasma cells started disappearing, we would never be even able to establish the diagnosis later on, establish the risk scores later on. So that happens to most of the patients.
In the US study, they got enrolled in the study three or four months after diagnosis, then they went to the transplant center. By that time, the window had passed and it would be impossible to retrieve the bone marrows from various centers and test them again.
Jenny: It's such a critical point and the same thing happened to me. I went to a general center and he didn’t even do a bone marrow biopsy and said, “Okay, I think you have myeloma. We’re going to start you on Velcade on Friday.” I don’t think that’s such a great option. So I ended up going to an academic center that did all the testing, and I’m very grateful I did because now I can go back to it and be a little more specific about what I’m looking for. So I want to encourage other patients to do that as well.
Dr. Hari: Yes. Myeloma is not a one disease; it’s many different diseases rolled into one. What we call myeloma now will be defined molecularly as different diseases in the future. There are people with myeloma with very different survival profiles. There are a lot of people who don’t even need any transplant perhaps, and there are people who need every aggressive step that we have right now. So how do you differentiate? The only way to differentiate is up front with whatever tools we have and these tools are getting better and better. And if you don’t do it up front, the chance may be lost.
Jenny: Well, that’s really important information so we’re going to pass that around.
Dr. Hari: Sure.
Jenny: Let’s talk about your studies because I know you have a study for allotransplant using natural killer cell therapy. And so I want you to explain -- the list of drugs in this therapy or different approach is just really extensive, so you kind of need to go through one by one I guess and explain your research.
Dr. Hari: Sure. So let me talk about the allotransplant studies that are in development right now, and I will talk a little bit about the NK cell study too. NK cells study is really not -- we haven’t done too many myeloma patients on that although we have a couple and they’re doing fine. But there is a national allo study that’s being proposed and it’s being worked on right now through the Blood and Marrow Transplant Clinical Trials Network, the BMTCTN, which is the group that did the previous large US study.
So this study is mainly for high risk patients, so we kind of learn from our mistakes. We’re not going to do it in low risk patients. So you have to have high-risk myeloma up front defined by what we talked about earlier, the high risk markers, high international staging system stage, high beta2-microglobulin, et cetera, or primary plasma cell leukemia. And if you are upfront myeloma with all this high risk markers, you have to get to a VGPR or better with induction treatment and then you can go on the study. The study will use standard allotransplant with the fludarabine/melphalan regiment.
So it’s not mini; it is not fully ablative. It’s kind of in the middle. And after transplant, patients are going to get randomized to either an agent called ixazomib, which you might have heard about. It’s an oral proteasome inhibitor or observation. So basically, these different things rolled into one for high risk patients, it is a question of transplant followed by a maintenance versus no maintenance because the proof of maintenance is not yet there in allotransplant.
Another way you could get on the study is if you relapse early after an autotransplant. We have not quite defined that. That study is still in the works. It’s not yet approved by the National Cancer Institute or anything yet and we hope it will get approved soon. But this is one of the national high risk studies that hopefully will be online soon.
Jenny: And when you say soon, is that sometime this year or --
Dr. Hari: This year, within the next four to six months hopefully. There’s a group of us who are actively trying to develop the study and get it online.
There are also centers that do their own studies. I know Memorial Sloan-Kettering, they have their study which is ongoing; but hopefully all these centers will collaborate and this is designed as a multicenter study. So essentially, all the big transplant centers in the United States will have the study open. So patients with early relapse after an autotransplant or patients with up front very high risk disease can go on to study. So that will be a good option for younger patients with ultra high risk disease and patients who have relapsed too soon after an autotransplant.
Nowadays, with modern induction, autotransplant followed by maintenance, people should be getting 4-5 years of disease control with that initial approach. And if you don’t get that, it is time to think about more aggressive strategies. So that’s the one study.
Jenny: And I want to stress that this might be really easy study to join for patient with those criteria instead of just -- because you’re doing the same things that you would in a normal standard of care. You’re just trying to see if something is even more effective
Dr. Hari: Correct. Absolutely. About the haplo in case, that’s a Phase 1, 2 study. Basically, we are trying to develop an approach by using 50% matched donors. So basically, if you have a family member, that’s 50% matched to you. That can be your parent, your child, or one of the brothers or sisters who are only half-matched to you. So those type of donors are called haploidentical donors. You are half-matched. That’s not the same as if you had a random donor unrelated to you who’s 50% matched to you by chance, that is not a haplo donor. The haplo donor has to be a family member because there is a difference between being 50% matched from within your family versus from outside because these proteins that we look for are inherited in the same fashion within the families.
So the haploidentical donors, they are always family donors related to you that are a 50% match to you. So your potential for getting it and almost everybody will have a haplo donor because you’ll have either a brother or sister that’s half-matched. The chance of having a haplo sibling is about 50%. And then the parents, children, many people can be donors. So in my practice, I do see a lot of ethnic minority patients including African Americans who have a very low chance of getting fully matched donors from the registry. So this expands the options for those patients too.
The second thing about haploidentical donors is that there is a system outside of the HLA system. We talked about the Human Leukocyte Antigen system which we look for tissue typing. There’s another system called the KIR system. That stands for killer immunoglobulin receptor system. So that’s another part of your immune system that can detect and attack -- it helps self-detect and attack foreign proteins and foreign cells.
So there is a particular immune cell in people’s body called NK cells, natural killer cells; and NK cells use this mechanism, the killer mechanism to detect and attack unwanted cells. So it turns out that if you have a disparity in KIR which is favorable for the NK cells to detect cancer, these haplo transplants become suddenly more effective.
So we have used an approach where we actually have the patients' donors donate bone marrow first and then we do a bone marrow transplant. After that, we have the donor come back and we collect NK cells from their blood and then we infuse the NK cells as a cellular treatment to kill off more myeloma. So these NK cells have a property of preventing graft-versus-host disease and also killing cancer. So it’s kind of like the Holy Grail of transplantation. It is by no means a proven technology, so that’s why it’s in a study and there are several centers doing it. We happen to be one of the centers that have pioneered this approach through one of my colleagues. So our program uses this and we have transplanted myeloma patients with this technology.
Jenny: And I know some people have talked about allotransplant as the oldest immunotherapy treatment because you’re really changing the immune system. But this sounds like it’s combining that with the newer immunotherapy type treatments.
Dr. Hari: That is very true, exactly. You are absolutely right. So the NK cell dose, by no means, we don’t know the exact dose of NK cells we need to give, but all that we are going up stepwise in the number of cells, NK cells we are infusing in patients. It has been very well tolerated so far. I'm very happy to report that we have had essentially no major complications in patients doing this kind of transplants and no unexpected complications. Patients are tolerating this procedure very well and the technology itself is going very well.
Jenny: And what type of patient are you looking at for that study?
Dr. Hari: For this study, the way the study is written and because it’s experimental, right now I’m only looking at patients who don’t have matched donors. So if you have a matched sibling or a matched unrelated donor that can donate for you, then we’re not putting those patients on. Hopefully, in a few more years, if this is very safe, then it would become reasonable to offer it to patients who are, you know, even who have a matched donor. I’m feeling that we would be offering this in some situations to patients as a primary type of doing transplant, primary way of doing transplant even if they have a matched donor. There are centers that do that actually, like Hopkins where they prefer this approach.
Jenny: And do you ever do that type of approach with a compassionate use kind of approach just outside of a study?
Dr. Hari: Outside of the study, we cannot do the NK cells because that’s circulated by the FDA because it’s a cellular therapy and we have approval from the FDA to do it in a study only. But compassionate, let me talk about compassionate use in the setting of multiply relapse myeloma where a person’s disease has come back several times and you’re essentially resistant to many drugs that are active in myeloma, allotransplant is probably not a great option. We sometimes do it when the patient is young, but generally the long-term survival is in the 20% range. So the time to think about allotransplant is actually early on in your disease course. So if you keep waiting for too long to do an allotransplant, the disease itself becomes so resistant that the immune effect is just not able to kill it off.
Jenny: Well, that's good to know. What other studies would you like to share with us?
Dr. Hari: I have to emphasize that there are a lot of new drugs coming out and the other high risk study actually that’s already active now is the SWOG (Southwest Oncology Group) study with elotuzumab, which is an antibody using against a protein called the CS1 protein. So this is a study comparing the use of RVD (Revlimid, Velcade, Dex) regiments versus RVD with elotuzumab. And this study is also a very reasonable study for a high risk patient. In fact, if you did think about an allotransplant also, you could go on the study and then if that regiment does not control the disease, you could come back and have an allotransplant because our study will be written for patients. Even at first relapse, you could go on the allotransplant.
So I think since we have a lot of good options for myeloma, we left it open that patients who relapse also can go on but only first relapse. If you relapse more than one time, the allotransplant study will not take in patients.
Jenny: Well, that’s an interesting approach. So that study is using -- that’s a monoclonal antibody, right, elotuzumab?
Dr. Hari: Correct.
Jenny: And it’s using Revlimid, Velcade and dex together?
Dr. Hari: So the RVD induction is for high-risk patients, RVD plus elo, yeah.
Jenny: And that’s a non-transplant study. So what you’re saying is to do that study and then come and do a transplant later?
Dr. Hari: Exactly.
Jenny: It sounds like there are so many different options.
Dr. Hari: Absolutely. And I’m excited about the new classes of drugs that are being discovered. We have HDAC inhibitors that are seeming very promising. We have the kinase inhibitors like ARRY-520, which is very promising. We also have the antibodies, the CD38 antibodies that are extremely promising. So we have a whole variety of techniques that are coming, new classes of drugs.
What we need is new classes of drugs because myeloma, as we all know, is a disease that uses many pathways to bypass our drugs. So if we block every pathway, then it can no longer bypass. So that’s the thing. The treatment -- escape from treatment for the myeloma cell happens only because it has many different ways of getting out. So if you block every pathway, then you would basically keep the cells suppressed forever and that’s how it translates to a cure.
Jenny: Well, the discoveries are exciting. So it would be nice to see how they come out in your trials. And I think patients, the more we know about what kind of study might be right for us, the better off we’re going to be.
So I wanted to ask two final questions I guess. So what is the secret to your survival success? because you’re getting very, very -- just exceptional results.
Dr. Hari: So I have to thank my patients who are very compliant patients. I’m lucky to work with my wonderful patients. They usually understand what we want to do. I think my whole approach is that I’m not just here to do a transplant and make them better for the short term. I always think of an overall strategy for the patient if I see somebody who is 20 years with myeloma. The youngest patient I have is 21-year-old. She got diagnosed with myeloma and she is 21 years old.
Whatever I do now, the disease is going to respond. But how do I make this person go for a long, long, long time hopefully? How am I going to get the most out of life for this person? So the approach is not just, how do I fix it now versus what strategies should I use to keep all the options available. They need to have all the options available when they relapse or try not to have a relapse at all.
So my approach is generally to have enough stem cells in the freezer, use transplant judiciously, use the best non-transplant regiments available and have a lot of trial options for patients and preserve their general health. If you preserve your bone health, preserve your renal health, all that, you can go on trials. If your creatinine goes up, many trials will exclude you. So you have to make sure that the rest of the person is also taken care of during times of remission, and you are to basically have as many options as possible for every patient I think.
So I try to think ahead so that I can have many, many options for my patients. I think that’s the only key I can say.
Preserving general health is very important. I think doing things like making sure of the anti-venous thromboembolism prophylaxis, make sure the patients don’t have all these unexpected blood cloths, make sure that their kidney health is preserved, educate them about contrast agents, avoiding non-steroidal anti-inflammatory drugs, improving their bone health using bisphosphonates, et cetera.
So we will do that but it’s compliance which is an issue in some centers. If you don’t educate your patients well enough, they just don’t understand why they have to do all these things. When you’re in remission, it’s very easy to think. I'm in remission I can just take it easy now.
Jenny: Yeah, and you like to get out of the clinic as much as possible even though we love you and what you’re doing for us. You’re saving our lives, so we are so grateful.
My last question before I open it up to caller questions is clinical trial participation, this series, the goal is to encourage patients to join clinical trials and if more patients join clinical trials, what would be the outcome for you and your research?
Dr. Hari: I think one of the most depressing aspects of medicine in the United States right now is that the clinical trial participation for cancer patients is depressingly low compared to Europe. And as you all know, in myeloma, most of the big studies are coming from Italy or France or other countries. We have the best drugs being developed in this country but the studies have to be done abroad.
So I think that situation has to change. And I think the best thing a person can do before they start on treatment is to ask their doctor, what sort of clinical trials are available for me? And if you don’t have it, what is the closest place I can go and have a clinical trial? There's some tedium involved in some clinical trials that there is more blood draws that is regulated with it. But remember, there are a lot more people looking at your results. It is usually done by a group of people. Like today I have two trial investigator phone calls, conference calls where we all discuss everybody’s patients so that we are all sure that the next step in the trial can happen.
So it’s a lot more input that goes in. There is a research coordinator that’s following you. There's all sorts of benefits for being in clinical trials. So I wish more people would understand the benefits of being in a clinical trial. There is a lot of misconception around it as you very well know about being -- and no treatment trial in cancer will just have a placebo. That's just not going to happen.
Jenny: We are trying to help demystify some of the myths because even -- all the trials are excellent, and we've had nine new drugs in myeloma in the last ten years. I think -- what can we do if we even double the number of patients in clinical trials? We’d have so many options.
Dr. Hari: Absolutely.
Jenny: All right. Well, our time is running out, but I want to open it up for caller questions. So if you have any questions about Dr. Hari’s research, you can call 347-637-2631. And once you are on the call, you can press 1 on your keypad. So our first caller.
Caller: Hi. Thanks for taking my call. There’s a part of the interview that just kind of rocked me, but it felt like you just kind of glossed over it when you said, “Yes, we’re doing NK studies at our hospital. We’re having great results," and then just kind of moved on. That is like, as you said in the interview, the Holy Grail. Could you give us a little more detail on the natural killer cells studies?
Dr. Hari: Right. So the reason I glossed over a little bit was because it is not applicable to most of the patients, right? So the NK cells immunotherapy is being done by us as part of a clinical trial, and it's only applicable is the patient got a haploidentical transplant, so which means a half-matched transplant from either one of the family members that’s half-matched to them because it is very strictly regulate by the FDA what we can do and what we cannot do.
NK cells are really the Holy Grail of transplantation if they work the way we think they will work because they lower the rates of graft-versus-host disease and they give disease control. So the problem with allogeneic transplant or donor transplant is that whatever increases disease control also increases graft-versus-host disease. So graft-versus-host is a bad effect and disease control is a good effect. So they kind of go hand in hand. So that’s our problem. If there is immune disparity, there is more graft-versus-host disease. If there is immune disparity, there is actually better protection against relapse.
So NK cells hopefully could address both of those at one stroke. The problem is that you can only get a haplo transplant the way our trials are written if you don’t have a matched donor from either the family or just outside the family. So if you don’t have an unrelated matched donor or a related match donor, then you could get a haplo transplant. So right now it is limited access to most people.
I am hoping that it will become mainstream technology in the next couple of years but at this time it’s just experimental. It’s Phase 1, 2 trials right now.
Caller: So it’s not a pill you can take. It’s not an injection. It’s part of a transplant process.
Dr. Hari: It is for the transplant process.
Caller: Is that a medical trial or is that just part of the program that you run?
Dr. Hari: No, it is a trial. It’s a clinical trial. It’s a national clinical trial number. If you look at NK cell trials, you’ll find that.
Caller: Awesome. Thank you.
Dr. Hari: Thank you.
Jenny: We have one other caller at 636-1782. Let me get her or him on. Okay, go ahead, caller.
Caller: Thank you. Doctor, once you develop graft-versus-host disease? Are your options pretty limited for further treatment after that?
Dr. Hari: So let me explain that. So it depends on how bad the graft-versus-host disease is. So a little bit of graft-versus-host disease is not necessarily bad, as I told you. Chronic graft-versus-host disease or the type of graft-versus-host disease that happens after about a hundred days is most of the time very easily fixable. Sometimes it is more of a nuisance rather than a life-threatening illness although exceptions do happen.
The acute graft-versus-host disease which is the form that happens right after transplant within the first hundred days after transplant is more serious and could be life-threatening if not controlled well. That’s why most transplant centers will make you live near the transplant center for at least three months after transplant. But having said all that, the majority of people with graft-versus-host disease still get control of GVHD and get better and their options are fine afterwards.
So irrespective of the type of transplant, even if you have a transplant for myeloma with a donor, the biggest risk to the patient is still myeloma relapsing, not graft-versus-host disease or infection or a transplant-related complication. Over time, we’ve whittled away the transplant-related complications to less than 10% as a cause of death. So the majority of patients who do poorly after allotransplant for myeloma do so because the myeloma relapsed, not because of graft-versus-host disease.
Caller: Excellent. Thank you very much.
Dr. Hari: Thank you.
Jenny: And we have a final write-in question and it is from Irene and she says, “I’m not a patient, but I have always wanted to donate bone marrow for a transplant. How do I go about doing that?”
Dr. Hari: Oh, thank you, Irene, for having that thought. Actually, the best way to donate is -- so let’s hope that nobody in your family needs it then that’s -- we don’t want anyone getting cancer and you have to donate. Actually, to help other people, the best way to join is to join the Be the Match Registry, and there are a lot of donor drives happening all over the country that usually is held in churches or temples or educational institutions where you can just go. They will register, take your details and then they will give you a cheek swab. You swab the inside of your cheek, put it in an envelope, give it to them and that’s it; you are in the database. They will retain you by sending you emails and keeping you live on the donor network.
However, there is an age restriction. I think most recently the upper age limit is 45 years. So there’s an age limit to being a donor. And if you are thinking about how to become a donor for an affected family member with an illness or something, obviously you should volunteer and they would contact you. But let’s hope that’s not the case.
Jenny: Well, that’s great. I had no idea that there are age restrictions on donations.
Dr. Hari: Yes. Like everything else in life, the younger you are, the better you are. The younger donors are better donors. So NMDP -- it used to be up to 60 years, but more recently they are cutting back on the age. I think it’s down to 45 now especially for Caucasian individuals, because there’s a lot of Caucasian donors, so they don’t need any more. So they just have to replace the attrition rate.
Jenny: Well, excellent. Well, thank you. I know we have taken more time than we told you. So we are so grateful that you joined us today.
Dr. Hari: Thank you, Jenny.
Jenny: We hope you keep going! Strongly! And we would love to support in any way that we can. So thank you for achieving such great success and all your dedication and hard work for myeloma patients.
Dr. Hari: Thank you, Jennifer. Bye.
Jenny: Thank you for listening to another episode of Innovation in Myeloma. Join us next week for our next mPatient radio interview as we learn about how we can help drive to a cure for myeloma.
about the author
Myeloma survivor, patient advocate, wife, mom of 6. Believer that patients can help accelerate a cure by weighing in and participating in clinical research. Founder of Myeloma Crowd by HealthTree and the HealthTree Foundation.
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