Dr. Frits van Rhee of UAMS discusses Total Therapy, his approach to address high-risk patient needs, and the importance genetic and imaging tests and how these pinpoint prognosis and best treatment path options

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Originally posted on mPatient Myeloma Radio

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Dr. Frits van Rhee, MD, PhD, University of Arkansas for Medical Sciences

Interview date: October 4, 2013

Summary

Dr. Frits van Rhee of the University of Arkansas for Medical Sciences shares how Total Therapy is modeled after the approach in childhood acute lymphoblastic leukemia that showed dramatic results (from 5% to 90% remission rates). He describes the importance, and pros and cons of each of the diagnostic tests including cytogenetics, FISH, gene expression profiling and imaging studies. He shares how new disease growth can show up on imaging studies even before they are presented in blood or bone marrow samples. He explains that with the use of the genetic profile test, all UAMS patients are separated into two subgroups – high risk and standard risk. He explains how he tailors treatment for each sub-type and how they are using different approaches for high-risk patients including shortened treatment-free intervals with more frequent, but lower doses of chemotherapy and other combination therapies. He also describes how high-risk patients are being treated in an open study with an immunotherapy, expanded natural killer (NK) cells. He shares his opinion that the highest unmet needs currently in myeloma are treatments for high-risk patients and describes a way to find the low-hanging fruit: finding and using existing therapies effective and available for other cancers with similar genetic profiles. He describes the advantage that UAMS has in the ability to follow their patients over the long-term and how that enables them to see large numbers of patient populations divided into subgroups and better tailor personalized treatment.

The live mPatient Radio podcast with Dr. van Rhee

 

Full Transcript

Jenny: Welcome to today’s episode of mPatient Myeloma Radio, a show that connects patients with myeloma researchers. The goal of this series is to help you understand that your participation in clinical trials matters. We now  have heard many times that yesterday’s trials are today’s therapies. I started this series because I had to ask myself “How long do I want to wait for a myeloma cure to be found?” and what can we do as patients to move that discovery forward faster? There was a lot we can do besides donate to a foundation although that is a great option, but we can join clinical trials.

So that, of course, is my cheerleading for today. I encourage you to sign up for our mPatient Minute newsletter where we post our upcoming show and our past interview and weekly email. You can do this on our homepage, www.mpatient.org, where you will find links to our Twitter and Facebook pages as well. So we encourage you to tell your myeloma friends and because it’s a great way to hear what is happening in myeloma all over the world.

So I’m very happy and delighted to be having a conversation today with Dr. van Rhee of the University of Arkansas for Medical Sciences. Welcome, Doctor.

Dr. van Rhee: Thank you for having me on the show.

Jenny: Thank you for joining us, we are so excited. The UAMS program is very well known. I’m very happy to be discussing your research as the largest US center with a single disease focus on myeloma. I’d like to share a short profile of you for our listeners, if that’s okay.

Dr. van Rhee: That is fine.

Jenny: Dr. van Rhee is a professor of Medicine and Director of Clinical Research with the Myeloma Institute for Research and Therapy at the University of Arkansas for Medical Sciences. He earned his MD at Erasmus University of Rotterdam in the Netherlands and his Ph.D. at the University of London. He was a Fellow in Hematology and a Research Fellow at the Hammersmith Hospital & Royal Postgraduate Medical School in London. He was also a Registrar Fellow in Hematology at John Radcliffe University Hospital at Oxford and at the University Hospital in Nottingham.

Dr. van Rhee’s research focus is on immunotherapy. He leads the Developmental Therapeutics Project in the Myeloma Institute’s PO1 grant called “Growth Control in Multiple Myeloma” from the National Cancer Institute. He’s a member of the International Society for Experimental Hematology, International Society for Cellular Therapy, and the European Group for Bone and Marrow Transplantation. He’s on the Editorial Board for Annals of Hematology, Bone Marrow Transplantation and Cytotherapy and he reviews for many journals including Blood, Clinical Cancer Research and the British Journal of Hematology and many others.

Dr. van Rhee, we are very privileged to speak to you today.

Dr. van Rhee: Yes. I’m very happy to be on the show.

Jenny: Would you like to start by giving us an overview of Total Therapy and where it’s headed?

Dr. van Rhee: Yes. We started Total Therapy back in 1989. The idea of Total Therapy is to apply all available drugs upfront in an attempt to cure the disease. The approach was actually modeled on the treatment of childhood leukemia. The childhood leukemia induction chemotherapy is used to bring the disease under control, then there is consolidation to further try to reduce the tumor burden and then there is maintenance to eliminate any remaining cancer cells.

Using that approach developed at St. Jude Children’s Hospital in Memphis, the cure rates in the 1970s and ’80s was only 5% of childhood acute lymphoblastic leukemia. Currently it has risen to over 90% with the Total Therapy approach, so enormous progress had been made. And our Total Therapy approach has really been modeled on that. So we use combination chemotherapy to reduce the disease burden and then the melphalan transplant is a way of getting the patient in remission. Typically, one melphalan transplant gives you a remission rate of 20% and the idea of doing two came also from the this and due observation that’s been to complete remission rate of 40% in their patients; that is, patients being cured. So we had early on the very simple idea, let’s do two transplants with complete remission rate of 40% and maybe we’d be curing some patients.

In the early days, we had maintenance with drugs like dexamethasone and interferon. We later discovered thalidomide here. We added a consolidation and then maintenance with thalidomide, and in Total Therapy 3 versions, we started introducing drugs like bortezomib and thalidomide and Revlimid during the treatment program. So we made enormous progress in patients which we call standard or good risk. We separate patients based on gene expression profiling.

So what we do is we harvest — we take a bone marrow sample, we select the myeloma cells, and we look at which genes are overexpressed and which genes are underexpressed. Using that method we can get a molecular picture of the disease, and we can separate the patients into two groups. In one group the diagnosis is 85% of patients who have standard or good risk disease and 15% have what we call high-risk disease and have an increased risk of relapse. Both groups of patients go with equal ease into remission but the high-risk group has a bigger risk of relapse. Recognizing that, we are now treating patients with high-risk disease on a different protocol so we’re presently the only group which assigns treatments to patients based on the genetic picture of the disease.

Jenny: And I think we’d love to hear what you do for the two different groups.

Dr. van Rhee: At the moment we’re getting very good results with the standard or good risk group. They get two cycles of induction chemotherapy, two transplants about three months apart, two dose-reduced (what we call consolidation), and three years of maintenance with the bortezomib, lenalidomide and Dexamethasone.

The high-risk patients we approach differently. We think that many of these patients have very rapidly growing disease and we try to shorten the treatment-free intervals. In non-Hodgkin’s Lymphoma, a German group has pioneered using chemotherapy given more closely together in aggressive lymphomas and found better outcome there. So what we do is we give these patients chemotherapy on a six-weekly basis. The chemotherapy and the transplants are given closely together and the transplants are of lower doses than for the good risk patients.

So we give the treatment actually more frequently but when you calculate the cumulative drug dose, they actually less total amount of chemotherapy. The idea is to continue to give chemotherapy and to prevent regrowth of tumor. If you do two transplants three months apart, you can already have regrowth of the cancer cells. So we’re relying on drugs working together which we refer to as synergism between drugs and applying the treatments frequently in order to continue killing the cancer and preventing regrowth of the myeloma cells.

Paradoxically although we say we give more intense chemotherapy, the regimen because we give less chemotherapy it’s not a  tough treatment program for the high-risk patients.

Jenny: Is there any age kind of restriction that you have or no, it’s tolerable for everybody?

Dr. van Rhee: Well tolerability is obviously determined by the fitness of the patient and to some extent also, the age, but our frontline protocols are designed for patients up to 75 and whether somebody can handle the more aggressive treatment program is determined to some extent by age and obviously also by the presence of other medical illnesses.

Jenny: Well let me ask a question that sort of backs up a little bit. When you’re talking about gene expression profiling, I know this test came out of UAMS and it’s not available to everybody. I was at a patient conference where I asked everybody to raise their hand to see if they had have this test done and only about 10% of the people had had this test done. So can you help us determine beyond the different translocations, does it determine that — is that the test that determines the translocations? Because I know some of that is coming out of the cytogenetics test and the FISH test. Can you explain that for us?

Dr. van Rhee: Sure. We’re talking really a little bit about three different tests here.

Jenny: Okay.

Dr. van Rhee: The first test is called metaphase cytogenetics. What you do is you put the myeloma cells in culture and when they’re dividing, you can actually see the individual chromosomes under the microscope and you can see whether there are abnormalities there. In our hands, about 30% of patients have abnormal chromosomes visible. In 70% of patients, the test is not informative and the reason for that is that the myeloma cells cannot grow outside the bone marrow so they need the support of the bone marrow to grow. It means that these patients have less aggressive disease. So the advantage is that of the metaphase cytogenetics is that we identify the patients with more proliferative, more aggressive disease and you can look at all the chromosomes under the microscope. The disadvantage is that it’s not informative in 70% of patients.

The FISH Test, which is especially been promoted by the Mayo Clinic is you look at certain “hot spots” on the chromosomes and you look for specific probes. So you can find and see whether chromosomes 4 and 14 are linked together which is not uncommon abnormality in myeloma. So the FISH Test you can do on the resting myeloma cells, they don’t need to be dividing in test tubes and it’s informative in all patients. The limitation is that you can only see what you look for. In other words, there are a limited set of probes and a limited set of abnormalities which can be looked for. So again, the advantage is informative in everyone; limitation is that you can only see what you look for.

Gene Expression Profiling is actually commercially available. Again, you purify the myeloma cells and you extract the genetic material applied to chip and you can see which genes are on or off and you get the molecular picture of the multiple myeloma. Based on that we’ve recognized at least six subgroups of multiple myeloma and then again, based on the expression of 70 genes, which are either highly over expressed or under expressed, we can assign patients to high-risk or inversely lower standard risk.

Jenny: Can you identify those six groups? Or what those are?

Dr. van Rhee: Yes. The groups are identified on the expression of 100 genes, 50 are over and 50 are under expressed. We have a disease group which we call Low Bone Disease and which patients truly low bone disease and we’ve got a CD1 subgroup , a CD2 subgroup and an MMSET subgroup where it’s very often translocation 4:14, we’ve got a proliferation subgroup where the patients typically have more aggressive disease with activation of genes in the growth of cells. We’ve got a subgroup identified by the activation of certain oncogenes which are called MAF and MAFB.

So those are some of the molecular subgroups that we identified. To make things more complicated, if we look at our 70-gene model, we find that most of the patients with Low Bone Disease have standard risk and there’s enrichment for high risk disease in the proliferation subgroup until a lesser extent in the 4:14 subgroup and the MAF subgroup. So it’s very complicated.

In myeloma, there are a number of molecular subgroups and then we’ve got high and low-risk disease so myeloma is really multiple diseases. There’s also an important subgroup which we refer to as the hyperdiploid subgroup where patients have more than one chromosome, typically uneven chromosome numbers — chromosomes 3, 5, 7, 9, et cetera.

Jenny: Well, it is complicated and so it’s nice to have someone help us explain it in terms that we can understand.

Dr. van Rhee:  It’s important that you understand that myeloma is really multiple diseases and to some extent we even say that every patient has a unique disease.

Jenny: And so because UAMS probably has a very enviable position, having very long-term data and a lot of it, can you explain how you approach this at UAMS — I guess how you look at that data and some of it has to do with databases. I know there are some facilities that it’s just a technical challenge putting all the data together and subdividing it based on the database that you have, not just the research that you have but the database that you have.

Dr. van Rhee: I think one of the uniqueness of our program is that we try to follow all our patients life-long. Total Therapy also means long-term follow-up on our patients. The program here was initiated by Dr. Barlogie in 1989 and we have still patients coming from that era. So we make an effort to really follow everybody long-term in order to get ideas what the long-term outcome is and also the impact and side-effects of certain treatments. We have a randomized trial initiated in 1998 called Total Therapy 2 where patients were randomized with thalidomide or no thalidomide during their treatment program and the long term follow-up felt that differences in overall survival to eight years to emerge, which is really a very interesting observation and also points to the need for long-term follow-up of patients to discern late appearing outcome differences.

I think the other uniqueness of the program is that right from the beginning, we’ve been doing the metaphase cytogenetics on all patients, MRI, we started doing PET scanning systematically starting in the late ’90s and gene expression profiling was added in 2000 to the work up of the patients. So we’ve got a very comprehensive data set on our patients.

Jenny: And what does the imaging add?

Dr. van Rhee: This really pertains to the issue of how you define complete remission. At the moment we say that complete remission is that the bone marrow needs to be clear and that there should not be any myeloma protein detectible in the peripheral blood or urine. Clearly, on the MRI we could see that 50% of patients will achieve an MRI remission over time. We also know that the number of focal lesions at diagnosis in the MRI influences outcome. The PET scan is based on a sugar dye which is taken up by the myeloma cells and you can see hot spots. The PET scan will image the whole body so you can also detect myeloma outside the bone marrow. We know that the number of focal lesions at diagnosis has prognostic significance. We also know that especially the high-risk group patients if you still have active disease after induction chemotherapy on the PET scan that you have worse outcome.

Changes on the PET scan are very dynamic and occur rapidly. On follow-up PET scanning after one cycle of chemotherapy you can see very significant changes. Changes on the MRI occurs much more slowly and achievement of MRI remission typically takes 18 to 24 months.

Jenny: Okay, well diagnostics is very important and it sounds like there are multiple approaches.

Dr. van Rhee: And the other thing I might add is since we systematically follow everybody with both imaging modalities, we do see patients where the first sign of relapse is not the reappearance of the myeloma protein or the reappearance of the myeloma cells in the bone marrow. But in fact we see a spot of myeloma growing or several spots on the PET scan or MRI. So we do see that the first sign of relapse can only be detected with imaging studies.

Jenny: Oh, so how frequently do you recommend that your patients do that?

Dr. van Rhee: We typically do MRI or PET scan after every cycle of chemotherapy or after every transplant. But during the maintenance phase, we follow them every four to six months and eventually once they’re off maintenance they go to six-monthly and eventually, yearly follow up.

Jenny: Okay. I just have a follow up question. This may be kind of a dumb question but if focal lesions are a very big indicator and then someone goes into complete remission, are those lesions able to heal completely? That you see on the imaging studies?

Dr. van Rhee: That’s a very good question. It depends to which extent the normal bone has been damaged. If there has been a lot of erosion and destruction of the bone then the MRI may never look normal again. Obviously the PET scan is a functional imaging study it looks at actively growing myeloma cells and the PET scan can be negative for patients who still have focal lesions on MRI. We’ve also systematically done biopsies of these focal lesions. On many patients we do not find myeloma. There are patients who still have dormant myeloma cells in the focal lesions so one of the areas of interest is whether these focal lesions in some cases can be dormant sites, sites that the myeloma can hide and eventually where the relapse may originate from.

Jenny: Well while we’re talking about diagnostics and complete remission, do you want to talk about Minimal Residual Disease and how you’re testing for that?

Dr. van Rhee: Yes. I think the minimal residual disease (MRD) has been especially promoted by a Spanish group in Salamanca. Professor San Miguel and his specialist there in this area is Dr. Bruno Paiva. He developed a method where he stains the cells with antibodies and he starts searching molecules at the cell surface and they run it through a machine called the flow cytometer and we can see the cells which stain where certain molecules that the cell surface light up and you can identify them and this way you can separate normal plasma cells from myeloma plasma cells and you can detect very small numbers of plasma cells in the bone marrow. Sensitivity can be as high as one in a million, which means that you can pick out one myeloma cell in the background of a million normal cells.

Studies done in England suggest that if you have no minimal residual disease detectible that your outcome is better. This type of minimal residual disease testing called by this test, flow cytometry, we conducted here and we’re doing this systematically on all our patients and we’re prospectively collecting data and we’re trying to figure out what it means.

Jenny: Now as I understand there’s different sensitivity that can be performed in this flow cytometry test and it has to do with the number of colors that are being run. Can you explain what the significance is of the colors?

Dr. van Rhee: We use 8-color cytometry and every color identifies a different molecule and more colors will give you greater sensitivity in detecting small number of cells and you can characterize cells better, you can detect them better in the background of normal cells.

In general terms in cancer, we know that the presence of a few number of cancer cells doesn’t necessarily mean that the patient is going to relapse. Early in my career, I was involved in a disease chronic myeloid leukemia which is treated at that time with bone marrow transplantations from donors, and we had patients who were in remission for more than ten years and cured for all practical purposes. We still have a few chronic myeloid leukemia cells detectible in the marrow using very sensitive molecular techniques and in fact recently I saw in the clinic a patient who had been in uninterrupted remission for 13 years and still had a positive minimal residual disease test.

So we’d like to analyze our data in the context of molecular subgroup and risk that would mainly mean different things in different types of myeloma and that’s an ongoing area of research. Maybe in some types of myeloma, it’s not that important if you can detect a few remaining cells and it doesn’t influence an outcome. In other subgroups of myeloma, one can speculate that any remaining cells groups could be predictive of relapse.

Jenny: Okay and as I understand it — and this has happened to a friend of mine – after treatment sometimes that your profile changes.

Dr. van Rhee: Genetic profiles of the disease can change. Sometimes at relapse the disease is more aggressive. When we look at our program, when we look at relapsed patients, 50% of high-risk disease and 50% of standard or low-risk disease where at diagnosis 85% of standard risk disease and 15% have low-risk disease.

So one of the interesting questions arises, how this difference comes about and we’re involved as many other groups now doing what is called sequencing, actually sequencing the genes of the myeloma cells and one thing can postulate it. Sometimes it already has a small number of aggressive very neutered cells present a diagnosis and that the treatment clears out the easier disease and that’s then the aggressive disease rears its head and causes relapse. In other patients there might be perhaps still residual diseases present and over time additional mutations arise and then the patient transforms to high-risk disease. So there are different models on how high-risk disease can come about when the patient starts off initially with low-risk disease.

Jenny: Interesting. And how do you do the sequencing?

Dr. van Rhee: There are different methods. The sequencing can be done of the DNA or of the RNA. We’re having both platforms here. One of the things we’re trying to do is to identify what is called drugable targets so can identify mutations which may be amenable to drug therapy which is usually used in other cancers. For instance, we quite often see mutations in a certain pathway and we can use drugs to treat these patients which are used in different cancers.

Jenny: That would be the low-hanging fruit approach, right? See what’s already available and see if we can use it.

So if you are saying that there are 70 genes – that’s a lot of genes to try to target — and you’re trying to put your data together and I would think overlap it with each patient type to see if you can find similarities, have you found certain genes, like a targeted list of five or ten or have you been able to narrow down the list a bit?

Dr. van Rhee: We have been able to narrow down the list. There appeared to be five gene which are quite critical in determining the outcome so we can narrow down from 70 to 5 genes and make very similar predictions in terms of outcome.

Jenny: Okay. As I noted, the testing is getting cheaper and cheaper, should everybody be doing this gene sequencing test?

Dr. van Rhee: The gene test I refer to is done by gene expression profiling, but potentially we set up with the different molecular methods and could be done more cheaply and easier. I think the sequencing which is not only done here but also in other centers, is really in its initial phases and it will require considerable time to try and figure out what all the changes in the gene mean. So in other words, it needs to be seen in the context of treatment and long-term clinical outcome. So it’s very exciting new technology but it will take several years to try and figure out what exactly the important alterations are and what it means for treatment.

Jenny: And now I know that we’ve heard that maybe up to 10% of myeloma patients are potentially – I say this cautiously and we don’t know but we think — I’m just curious, who are these people? What are their profiles?

Dr. van Rhee: That’s a very good question. When we add other markers such as the Beta-2 microglobulin which mainly reflects tumor burden, presence or absence of abnormal metaphase cytogenetics, if we add that to the gene expression profile we can identify subgroups of patients with very good outcomes. When you look at the issue of curability, it is very interesting when you look at acute leukemia you can see that the survival curve becomes flat, in other words, high risk patients don’t come out of remission at around five years in acute childhood leukemia. We’ve done similar analysis on our myeloma patients and it looks like if you’re going to be in remission for 10 to 12 years or longer that we see very few relapses there. So we think that at least in some patients that the disease is curable and obviously that’s good news for the myeloma patients.

Jenny: Yeah. Everybody wants to raise their hand to be in that group. I think if I could wave a magic wand right now I would really like to see myself categorized in context so I could see — for example, I have MAFB which is not a great thing but my cytogenetics might be good and the other indicators might look really good. So could I find all the patients that look like me and then see what they’ve done, who’s lived the longest and go backwards. What kind of approach worked for that subtype? I think that’s what I would love to see.

Dr. van Rhee: When we compare our successive regiments, we can recognize groups which seem to be particularly benefiting from certain drugs. For instance in Total Therapy 2 we did not have bortezomib in the program because it was not available yet at that time. In Total Therapy 3 we did have bortezomib and we could see that particularly the patients with — a translocation between chromosome 4 and 14, patients with deletion of chemosuppresive gene called P53, patients with abnormal metaphase cytogenetics – these are the patients who really benefited from the Bortezomib.

That brings us to the next question, how we can target our therapies better? In other words, we’re trying to figure out who needs what drugs.

Jenny: Absolutely.

Dr. van Rhee: So for the good risk patients, the goal has to be to make the treatment safer and to target the treatment better. The high-risk patients — I think we define high-risk those patients have a much higher relapse rate. We think that maybe in the order of 15 to 20% of patients in the long term of that group of patients might be curable but they often relapse early and that’s a group of patients which really requires new approaches and new insights and perhaps also new drugs.

Jenny: Would you like to talk about where Total Therapy is now and how you’re approaching these two different types in your clinical trials?

Dr. van Rhee: Yes. In the Total Therapy 5 we’re using combination treatments frequently applied at six week intervals and the patients get five of such treatments and then go to maintenance.

Jenny: Is this for standard or high-risk?

Dr. van Rhee: That’s for high risk and we are going through introducing the high-risk group in the next few weeks upfront also the new proteasome inhibitor carfilzomib in this particular group of patients.

Carfilzomib is a drug which binds irreversibly to the proteasome. The proteasome is like the garbage disposal system of the cell. It gets rid of unwanted proteins and if you interfere with that mechanism the cells will die. So we found that patients who were treated upfront with the proteasome inhibitor bortezomib., some of these patients responded to the carfilzomib drug. In our hands it looks like carfilzomib is more potent than bortezomib. We also think that there is possibly more toxicity associated with it. At least in the patient that we’ve been using it in the relapsed refractory setting where we see a higher toxicity signal in terms of cardiac side effects. However, that can be mitigated by very careful monitoring of the patient. Obviously cardiac side effects are much less when it’s used upfront in patients who haven’t been heavily treated.

Jenny: And in neuropathy — how is it different in neuropathy?

Dr. van Rhee: It is not give rise to neuropathy or rarely, so there’s a lot of difference in terms of neuropathy. In all fairness the administration of subcutaneous bortezomib has made a major impact on the side effect profile of bortezomib and there is significantly less neuropathy with subcutaneous administration of bortezomib.

Jenny: Okay. Are there other areas that you’d like to — other clinical trials you’d like to talk about for high-risk patients?

Dr. van Rhee: We are using at the moment Immunotherapy to try and treat patients with high-risk disease who have relapsed. We use natural killer cells which we cultivate with stimulator cells then we activate them and expand them then we infuse these highly activated cells after chemotherapy into the patient where they assist and we see large numbers of these immune cells activating and growing and expanding in the patient. Eventually they will lose their activity over time. This treatment is very early in its development and we have to go through a learning curve as how to best make the cells and we’ve made several modifications in the laboratory in how best to expand and activate them. So the results are early and we hope that to expand the nk cell therapy can contribute to the treatment of the high-risk patients.

The other area where we are exploring this type of therapy is in patients is smoldering myeloma. Smoldering are at increased risk of progression to frank myeloma compared to the benign monoclonal gammopathy also called MGUS. Based on the Gene Expression Profile we identified the group of patients who are at high risk of progression to frank myeloma and this group of patients were also going to explore the expanded NK cell therapy.

Obviously, the Spanish have done a trial with Revlimid and Dexamethasone. The Spanish collaborative group has shown that in some patients with high risk smoldering disease treated with Revlimid and dexamethasone that it delays progression of the disease and improves  outcome. So there is the debate in the myeloma community towards whether we should treat high risk smoldering disease earlier. The standard of care thus far has been and still is to observe these patients carefully and there are a number of clinical trials ongoing now where these patients are actually being treated early and to see whether the outcome is better with early intervention in high-risk smoldering multiple myeloma.

Jenny: And so what is your opinion so far about that? You’re not running trials currently for smoldering myeloma for that or no?

Dr. van Rhee: Except for the expanded NK cell therapy, that’s the only trial that we currently have opened. We’re planning another one, the monoclonal antibody. As such there is an increased interest in the myeloma community in treating high-risk smoldering disease earlier.

Jenny: And could you take a minute and just give us a quick explanation again of NK cells and then what’s the difference between a regular NK cell and an expanded NK cell?

Dr. van Rhee: Okay. Expanded NK cell is highly active so it kills tumor cells much better than a resting NK cell. The other aspect of the activation is that induces the NK cells to multiply. So once we grow them in the lot, the expanding numbers of NK cells you have more NK cells to attack myeloma cells and after infusion into the patients, they continue to expand for another seven to ten days. So we get cells which one have more activity and can kill the myeloma better and secondly they continue to expand in the patient.

Jenny: And how do you get them to expand?

Dr. van Rhee: We incubate them with a special stimulator cell which expresses it to the cell’s surface, a molecule called Interleukin-15 which is a growth factor for natural killer cells and it’s also expression molecule 4-1BB ligand which further stimulates the activation of the natural killer cells. This particular stimulator cell was developed by Dr. Dario Fontana at St. Jude Children’s Hospital and he has an interest in treating obviously childhood Acute Lymphoblastic Leukemia with this and he was so kind to share these cells with us and we’ve adopted this technology to try and treat the multiple myeloma.

Jenny: Well, I think the whole area of immunotherapy is so exciting and this is where your background is so…

Dr. van Rhee: Correct. I think there are a lot of interesting studies in the solid tumor area where one can show that monoclonal antibodies which take the break off the immune system can actually induce the responses and sometimes even remissions in patients with solid tumors which were otherwise not salvageable. Obviously solid tumors are much more frequent than the blood cancers so the pharmaceutical companies understandably are focused initially on the development of these antibodies in the solid tumor arena. The trials are now starting to emerge also in multiple myeloma and it will be very interesting conceptually to combine these antibodies with drugs which stimulate the immune system. These are the immunomodulatory drugs which we refer to drugs like Revlimid or lenalidomide and the newer version pomalidomide. So I think there will be a lot of exciting studies forthcoming in the future with immunotherapy.

Jenny: What phase is your NK cell study?

Dr. van Rhee: this is what we call a Phase 2 study. So there is an efficacy endpoint. So far the cells certainly been safe, we’ve not seen any side effects.

Jenny: I think that’s the beauty of immunotherapy is you’re using your own system to try to fight these cancer cells.

Dr. van Rhee: That’s correct, yes.

Jenny: Are there other trials that you’d like to share with us that you have open?

Dr. van Rhee: We’re obviously also using the oral proteasome inhibitor which is a newer version of bortezomib which is more convenient for the patient. And we also have an interest in using placenta-derived stem cells to treat patients. One of the side effects of some of the therapies that we give is a disease called myelodysplastic syndrome and this arises after treatment and it’s a disease in which the normal bone marrow does not grow well and there is a risk of transformation to acute leukemia. You see the clinical myeodysplastic syndrome in about 2% of our patients, myeodysplastic syndrome requiring therapy and we’re starting to give placental derived stem cells which we think may support the normal hematocrisis so that’s early in its development as well.

Jenny: That’s great. I just have a quick backwards question and I want to ask you before I forget it. When you say you’ve narrowed down the 70 genes into 5, can you tell me what those 5 are?

Dr. van Rhee: At the moment it’s going to be published so it will be out there soon. It’s actually under submission at the moment.

Jenny: Okay. When you say that immunotherapy –  how long do you think it will take for us to come to conclusions or for these studies to show us if those are really effective with myeloma?

Dr. van Rhee: I think the highest unmet need in multiple myeloma are the high-risk patients who have a significantly worse outcome particularly when they go into the relapse refractory setting, patients who have seen prior therapies and relapsed with high-risk disease. I think we can get very quickly an idea whether immunotherapy or other drugs are effective or not. Because in a relapsed refractory setting when patients have high risk disease in general terms the outcome is not good so it’s easy to see whether the drug or immunotherapy or any therapy makes a difference in that setting.

Jenny: And I think when you were talking about the use of potential therapies that you took from childhood leukemias or other drugs, so this happened with Thalidomide at UAMS, taking something that was being treated for other diseases and taking that. Can you share what you think is the ideal process for trying to find these other therapies that might be used right now in lung cancer, or prostate cancer or something else and apply them to myeloma?

Dr. van Rhee: Well the idea is to look for particular mutations for which there are drugs available. So sequencing the genes of the myeloma cells is the way to do that and that’s something that we and the other centers are currently adopting so that’s an evolving field.

So I think the first step is to identify that whether a patient has a mutation for which there is a drug available and obviously the next step is then to determine whether that drug has actually clinical efficacy so this whole area is very early in its development.

Jenny: How much does it cost to sequence the genome for myeloma right now?

Dr. van Rhee: If you do a limited sequencing on it’s probably in the order of $1,000. More extensive sequencing is obviously more expensive.

Jenny: Does insurance pay for the sequencing?

Dr. van Rhee: Some insurances do pay for sequencing. Other sequencing obviously is done on a research basis so limited sequencing is available from a number of companies in the country.

Jenny: Okay. Well this might be an area where patients could start to request this.

Dr. van Rhee: Yes. The question is obviously first to identify the mutations, secondly then get the drug approved because the drug is used off-label so to speak, and thirdly we don’t have a good clue yet which of these drugs are really beneficial for the myeloma patients so there’s a lot of question marks and unknowns here.

Jenny: I guess that leads to a follow up question and then we’re almost out of time and I’ve hogged all the questions, but what can patients help do to help you further your research?

Dr. van Rhee: We are always very grateful to patients who are willing to donate samples for research, both blood samples and marrow cells. We are also grateful that we can treat the patients and that we can have the long-term follow up which is so very important in multiple myeloma.

Jenny: How do you do that follow-up? Because I know people move and insurance changes and all sorts of things, so how do you approach that at UAMS?

Dr. van Rhee: We try to get everybody back and many years out and then we try to do at least a yearly visit. There are actually patients in which the insurance changes or they’re financially not able to come to UAMS and those patients we try to follow up by phone and contact them once or twice a year and see how they’re doing and get their information for our database.

The other thing that we have obviously is we have a system in which they mail in monthly or two or three-monthly multiple myeloma markers and then the myeloma protein is looked for in blood and urine and we try to follow them that way to see whether there is any reemergence of the myeloma.

Jenny: Okay. Well, one final question. What is the significance to you for patients participating in a clinical trial?

Dr. van Rhee: I think clinical trials are very important. I think that’s the way we find out whether drugs have activity and contribute to improving progression-free and overall survival and what we call or are referred to as correlative studies like gene expression profiling and sequencing studies and other studies allow us hopefully to identify subgroups of patients which really benefit from a specific drug.

Jenny: Dr. van Rhee, we are so grateful that you joined us today. Is there anything else you’d like to share before we close because I know we’re out of time?

Dr. van Rhee: No. I’d just like to thank you for the opportunity to participate in the interview. I think patient advocacy is extremely important and powerful in the myeloma field and it has been very helpful both in getting drugs approved and in supporting and informing other patients.

Jenny: Well we are very, very fortunate to have you working on the target for myeloma and we wish you a great deal of success in your care for your patients and in your research so please let  us know patients if there is anything else we can help you do.

Dr. van Rhee: Okay. I will do so. Thank you very much.

Jenny: Well thank you so much for joining us.

Thank you for listening to another episode of Innovation in Myeloma. Join us next week for our next mPatient Radio interview as we learn more about how we as patients can help accelerate a cure for multiple myeloma.

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