Digging deeper into high risk myeloma with Dr. Jesús San Miguel, MD, PhD, University of Navarra, Spain

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Originally posted on mPatient Myeloma Radio

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Dr. Jesús San Miguel, MD, PhD
University of Navarra, Spain
Interview Date: October 3

Summary

Dr. Jesús San Miguel describes his deep work for high risk myeloma patients. He starts by discussing the need for minimal residual disease testing – it avoids over or under-treating patients. When patients begin with myeloma treatment, they usually have high levels of tumorous plasma cells. After treatment, they usually have normal levels, but it is critical to know whether those remaining plasma cells are normal or residual malignant cells. The minimal residual disease (MRD) test can determine this. He shares that a standard international flow cytometry test is almost there, but that patients still need the test done at a myeloma academic center. He dives into the detail of high risk myeloma, naming the high risk features including  4;14 translocation, 1Q, hypodiploidy, 17p deletion, being Stage III and having high LDH levels. However, he stresses that having one of the high risk features is not as important as a patient having multiple features, which are called “ultra high risk.” He states that patients benefiting most from the standard use of transplant, proteasome inhibitors and IMiDs are the standard risk patients. He describes the new approach he is taking to further treat high risk patients more effectively – first, to create clinical trials for these patients specifically or to stratify patients before they begin the latest clinical trials before the study starts, so he can see which approach worked the best for each high risk feature. He notes that if patients are stratified before a study starts, then a variety of approaches can be taken by different multiple myeloma centers and then information can be compiled to give the myeloma community as a whole greater insight about specific groups of patients. He notes that in Europe, data exists that shows benefit for high risk patients using the double transplant. He is excited about the new anti-CD38 monoclonal antibodies for high risk patients but notes that time will tell if they are effective against high risk myeloma. He describes an upcoming clinical trial for high risk smoldering myeloma patients which will include carfilzomib, lenalidomide, dexamethasone, autologous stem cell transplant and lenalidomide maintenance with the objective for a cure for these patients. He does not recommend low or standard risk smoldering myeloma patients to receive treatment. He describes the goal to also address the bone marrow environment to see if the cells in the bone marrow can be treated to prevent the myeloma from growing. 

 

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Jenny: Welcome to today’s episode of mPatient Myeloma Radio, a show that connects patients with myeloma researchers. I am your host, Jenny Ahlstrom. If you’d like to receive a weekly email about past and upcoming shows, you can subscribe to our now called “Myeloma Crowd” Newsletter on the home page or follow us there on Facebook or Twitter. And please feel free to share these interviews with your myeloma friends.

Now, before we get started with our show today, we have a couple of things we’d like to tell you about. First, we’d like to have you take a look at the Myeloma Crowd. We’ve had several patients participate including Karen Crowley and Liz Smith. It is a growing and vibrant website that’s trying to provide the best information for myeloma patients from all sorts of resources around the world. So we’re very grateful for patients who are pitching in to help build this site and contribute to it. We would like to invite you to contribute as well. We have a doctor directory and on that site we are in full support of the Dana Holmes’ Mambo for Myeloma campaign.

We’d like to also tell you about a new music contest that we have going called Songs for Life. This is a new contest to support research for myeloma. So please take a look at the post about this, and we would love to have you socialize this with your musician friends to get a donation for myeloma research.

Now on today’s show, we are very, very fortunate to have with us today one of the foremost world leaders in multiple myeloma, Dr. Jesus San Miguel of the University of Navarra. Dr. San Miguel, it looks like you are live.

Dr. San Miguel: Yes, I’m here.

Jenny: I am so happy. It adds a little bit of complexity calling in internationally, but we’re just thrilled that you are here. Let me give a little introduction for you before we get started.

Dr. Jesus San Miguel is Professor of Medicine and Director of Clinical and Translational Medicine at the University of Navarra. He served as Director of the Hematology Department of the University Hospital of Salamanca for over 22 years. He studied medicine at the University of Navarra, Spain and completed his residency in internal medicine at the University Hospital of Salamanca

In 1980, after obtaining his PhD, he undertook a post-doctoral fellowship in the Leukemia unit at Hammersmith Hospital, the Royal Postgraduate Medical School in London. Professor San Miguel is president elect of the International Myeloma Society, member of the Academy of Pharmacy of Castille and Leon, an honorary member to the Royal Academy of Medicine of Salamanca, as well as a member of the Advisory Board at the International Myeloma Foundation, the MMRF, the Carreras Foundation, and a board member of the Spanish Hematology and Genome Foundations.

He is Associate Editor of Blood and was also Associate Editor of Haematologica. In addition, he is a member of the editorial board of several scientific journals. He served as Director of the Biomedical Research Institute of Salamanca, Vice Director of the Cancer Research Center in Salamanca, and as Chairman of the Spanish Myeloma Group. He was also the European Association Board Councilor and Chairman of the Scientific Committee for the 9th Congress and president for the 15th EHA Congress.

He organized the 9th International Myeloma Workshop held in Salamanca and has received numerous awards including the Waldenstrom’s Award in 2007, the Robert Kyle Lifetime Achievement Award, the EHA, Jose Carreras Award, the Rey Jaime 1 Medical Research Award, and Spanish Awards for Oncology and Translational Research. He has published over 600 original papers in international journals and his areas of interest include myeloma, the biology of leukemic cells and their prognostic implications, and minimal residual disease.

Dr. San Miguel, we are so honored. I consider this a great privilege to have you on the show today.

Dr. San Miguel: It is my privilege to be with you today.

Jenny: Well, you are relatively new to the University of Navarra, so maybe we begin by having us understand what your goals for your new position are and then maybe we can discuss the most recent International Myeloma Working Group meeting, some of the findings there.

Dr. San Miguel: Okay. You are correct. After 30 years in Salamanca and 22 as head of the  Hematology Department in Salamanca, that is in the west part of Spain, I moved to the north, to the University of Navarra as Director of Clinical and Translational Medicine. The goal of this job, of this position is to try to integrate what I had been doing in Salamanca for myeloma and hematology but now for all the medicine. This is to integrate research with the clinic and  teaching all together. This is what I am trying to do here.

But in order to survive from such a bureaucratic job, I also continue to keep myeloma research and myeloma patients as part of the oxygen that I need to survive. When I moved to Pamplona, I brought with me Dr. Bruno Paiva, who is the leader in minimal residual disease. Also, I brought  from Boston Dr. Patricia Maiso and several other people that have joined me to try to maintain and really to continue improving the myeloma research. Apart from this we continue having a very, very tight collaboration with the Salamanca team, Dr. Ocio, Mateos, Gutierrez, et cetera, and the Spanish myeloma group. In fact, next week we have a meeting of the Spanish myeloma group and I continue as one of the co-chairmen of the board of directors.

Jenny: Well, it’s wonderful. We would expect nothing less. I know you have led the way in many areas and I know this will be no different.

There were many people who are very impressed with the International Myeloma Working Group Meeting that was held in Milan recently, I guess in the spring and specifically for high risk. But I guess before we talk about that, your specialty historically has been studying minimal residual disease and I am familiar with the Black Swan Research Project of the IMF. So maybe we begin by talking a little bit about that project and the importance of minimal residual disease testing.

Dr. San Miguel: This concept of minimal residual disease is considered rather old in leukemia. In fact, in 1990, I organized a meeting minimal residual disease in acute lymphoblastic and acute myeloblastic leukemia. The reason for that is in these two types of leukemia, the rate of complete remission was high, around 60% or 80%, but some of these patients that achieved a complete response then subsequently relapsed. If this occured, this meant that there were some residual cells responsible for that relapse.

In the myeloma arena, this was not of interest in the ’90s. To achieve a complete response then with the introduction of transplant, it became more frequent. And then in the late ’90s, the introduction of novel drugs, the number of complete responses significantly rose. Then I thought that at that time it was the right time just to start to think also about minimal residual disease because in other diseases, it is the evaluation of a good response under the level of detection of the conventional methods. For myeloma, the conventional methods for detection of disease are: the morphology, the bone marrow examination by morphology, and the tumor of the M component.

Let me explain to you the morphology in the bone marrow. You and me as healthy people, we have around 2% or 3% of plasma cells in our marrow and these normal plasma cells are responsible for the production of the immunoglobulin, the antibodies, and this is critical because this is part of the defense against infections, et cetera. Then to have 2% to 3% of normal plasma cell is extremely important.

What is the problem with multiple myeloma? The problem with multiple myeloma is that one of the cells transforms into a malignant plasma cell and grows and grows. Then if you treat appropriately in multiple myeloma patient, you will be able to eradicate most of the plasma cells. And if you evaluate a multiple myeloma patient that had received appropriate treatment, for instance, induction with bortezomib, lenalidomide, dex, followed by transplant or non-transplant, and you go and you examine the bone marrow, a diagnosis included, for instance, 50% plasma cell of the total plasma cell, 50% of the total bone marrow, 50% were plasma cell.

This was the tumor, this was the with the myeloma. You treat appropriately the patient, you go, you examine the bone marrow and there is only 3% plasma cell. The problem I have is: is this a malignant plasma cell, residual malignant plasma cell, or are these normal plasma cell that you and me have always in the marrow? Impossible to make a differentiation by morphology. Then we need more sensitive and specific tools in order to investigate if these residual cells are malignant and these can be done by two methods.

The two methods are immunophenotyping. In other words, by the antigen expression of the plasma cell we know that the malignant plasma cells have identified an antigenic signature that is different from that of normal plasma cells or molecular technique looking for the clonal arrangement of the residual plasma cell. And these techniques are the techniques of minimal residual disease that allow the detection of one malignant plasma cell within 105 or 106 one million normal cells. Then this is a high sensitivity for the detection of residual disease.

Jenny: And where does flow cytometry fit in there? Is it immunophenotyping or molecular testing?

Dr. San Miguel: Correct, in immunophenotyping. By flow cytometry, what is flow cytometry? Flow cytometry is a technique that allowed the analysis of millions of cells characterized by the antigenic profile. You can nowadays with eight colors simultaneously, stain one cell with eight color different antigens and with highest deficity to identify this residual plasma cell.

What is the current problem of this? The current problem is that the technique is working very well in the hands of a few but is not available generally. The flow cytometry is available in most centers but for detection of residual disease it’s only available or it’s only working well in the hands of experts that have research labs. For this reason, Black Swan Project under the umbrella of the International Myeloma Foundation has granted the Black Swan with the goal, a double goal.

The first goal is to standardize the technique. In other words, to make this technique available to all the centers that are treating myeloma patients and we have almost got it. The second step of the Black Swan and the IMF is just to try to have this technique automatized similar to what you do when you do a blood test. You take the sample, you put it through the computer, you get the result. You get the level of the leukocyte, hemoglobin. Our goal in the Black Swan Project is to have an automatized system that would allow people to get the sample, the bone marrow sample, to put in the machine, and the machine tells whether you have or not residual  malignant plasma cell in the bone marrow.

Jenny: And as part of this automated process, I know some people have said there is eight color staining and there is 12-color staining and there is 24-color staining. And so there’s quite a wide variety about the test that’s offered and then the results that you are getting back. So I’d like to hear a little bit more about the progress you made because you said you’ve almost got it which is very exciting.

Dr. San Miguel: We worked for a long time with just four colors. Particularly the Spanish and the UK group have demonstrated in our last series of patients that to have residual disease, malignant plasma cell after transplant or after non-transplant treatment with drugs is associated with an adverse prognosis. Moreover, to monitor minimal residual disease will be of great help to monitorize the tumor load during consolidation of maintenance phase and probably would allow us just to stop the treatment if the residual disease has gone or to continue the treatment if the residual disease persists.

In other words, would allow us to avoid both under or overtreatment. Then I think this is going to be a critical technique. And this was demonstrated with four colors. The standard that we want to standardize eight color. Twelve could be but with eight it will be enough. And what I told you is that we are very close to have this completely standardized.

Jenny: So what I hear you saying is the question you are trying to answer with the MRD testing is do you keep going with treatment? Have you had enough treatment to satisfy the tumor burden or do you need to keep going? Is that correct?

Dr. San Miguel: This is completely correct. This is one, one tool. The other tool is to use minimal residual disease as a diagnostic factor similar to complete response. You know that if you received treatment up front or at relapse, achieved a complete response, your prognosis is much better. Then I can tell you that if you achieved not only a complete response but immunophenotypic or a more normal response, the prognostic is ever better. Then this is another very important tool of evaluation of residual disease.

Jenny: Well, I would think it would help you choose which therapies you pick, how aggressively you are going to hit it. And when you say it is prognostic factor, you know more of what you are dealing with.

Dr. San Miguel: Yes, definitely. I mean this is similar to the cytogenetics. Nowadays, cytogenetics have become mandatory because it identifies high risk patients and you can differentiate from standard risk, and in the near future probably we will separate the treatment according to cytogenetics. Similarly, we can separate the treatment probably in the near future according to the level of residual disease after appropriate treatment.

But let me add, when I talk about minimal residual disease I like always to emphasize what minimal residual disease should include the evaluation of not only of the bone marrow but also outside the bone marrow. And for this purpose, in the near future, the PET scan, the CT-PET is going to be also a very important tool for evaluation of minimal residual disease outside the bone marrow. And these techniques are going to be complementary, not one or the other, both.

Jenny: And how frequently are you thinking with the PET scan?

Dr. San Miguel: This scan, again, should be done when you need to make a decision. Imagine that you had been treated with whatever induction it is. And I think after the transplant will be an ideal moment just to decide, okay, should I go with maintenance for how long? This could be help to have the residual disease evaluation inside and outside the bone marrow. Should I finish the treatment? Please, before I finish the treatment, if I am finished, be sure there is no residual disease, or imagine that I am receiving whatever treatment it is and my minimal residual disease persists and persists, please change the treatment because you are not doing the best.

Jenny: All right. And now when you say that it was only available in academic centers and you are trying to automate it so it can be available at, let’s say, any lab, is it to that point yet that it’s available at any lab, at any facility, or do you still feel that patients need to go to a myeloma academic center in order to get the right diagnostic testing?

Dr. San Miguel: At this time, I think it’s much better to go to an academic myeloma center just to have this test done. And it’s similar. It’s better if you go to an academic myeloma center just to decide what is the best option for you. You can go to a smaller hospital just to receive the treatment but always under the guidance and the supervision of an academic myeloma center.

Jenny: I think I want to stress this point because I think sometimes patients will get started with a center that may not have a specialty in myeloma. We are very big proponents of going to see a myeloma specialist. So what I hear you saying is that you should have the guidance and the counsel and the expertise from a myeloma specialist and then you can get treated anywhere. And I think people need to understand that and know that.

Dr. San Miguel: I think this is a very important message, a very important point you have raised. If I have multiple myeloma because there is an M component and there is an an M spike, I want just to have the best possible assessment of my disease. I would like just to know what is my cytogenetic profile, the genetic profile, identity profile of the tumor cells, and if possible, the presence or absence of extramedullary disease according to risk factor to know whether or not there is the option of a good clinical trial with some experimental agent that are probably going to demonstrate superiority.

All this information should come from an academic center that is really involved in myeloma. Then if the center makes the decision and they say, okay, this is the treatment, imagine that the center is 400 kilometers away from where you live. And in that particular area where you live, there is a good hospital with good hemato-oncologist that know about myeloma and prepared just to give you the chemotherapy perfectly well or the new drugs perfectly well and the consortium with that academic center will be ideal. You avoid the trouble of making frequent travels, but at the same time they are always under the supervision and under the guidance of an expert.

Jenny: Yes. And one of our previous interviews said that living well is not a matter of convenience or living, it’s not a matter of convenience. You have to get the care that you need when you need it.

Dr. San Miguel: Yes, definitely.

Jenny: Well, can we talk for a little bit about high-risk myeloma? Because I know part of this is to identify some of the cytogenetics of the disease and then to divide and conquer I guess, to separate out how an individual could be treated most effectively and then do this MRD testing and know what you are working with. So one of the questions that came about from that International Myeloma Working Group panel that I saw is how are levels determined to assess high risk?

Dr. San Miguel: Nowadays, we can identify high risk by using several tools. One of the most well accepted is FISH cytogenetics. FISH cytogenetics should be done, should be performed on isolated plasma cells in order to include the sensitivity of the method and again to be performed in a lab with really expertise on FISH cytognetics. There are several abnormalities that account for their prognosis: abnormalities in 1Q, translocation (4;14), 17p deletions, hypodiploidy. All these account for an adverse prognosis. But it’s not the same to have one instead of having two or three. And it is possible that one of these abnormalities is expressed in the sub-clone. All this information is relevant for prognostication.

On top these, we have the international stages system. Stage 3 is adverse prognosis. High LDH level is an adverse prognosis. The presence of circulating plasma cells that can be detected by flow, this is another major contribution of flow cytometry. The circulating plasma cell, it means more disseminated disease. It’s also in the prognosis. The presence of extramedullary disease detected by PET diagnosis is also an adverse prognosis and all these qualify for high risk.

Jenny: And that’s determining how far it spread basically, right?

Dr. San Miguel: Yes.

Jenny: When you are looking at circulating plasma cells?

Dr. San Miguel: Yes. Circulating plasma cell extramedullary disease reflects how spread it is. But not only how it’s spread; how resistant could be the cell. We are pretty much interested now in identifying intrinsic resistance and acquired resistance of the cells. And for this purpose, the circulating plasma cell is a very good tool for research.

Jenny: So from what I hear you saying, it sounds like we are at the point now where we cannot treat everybody as a nail with the same hammer. We can treat everybody differently based on their type of disease. So just a follow-up question on that high risk for the 1Q, how many copies of the 1Q are considered amplification? Is it three or more or five or more?

Dr. San Miguel: Yes, yes. But again, I mean what is very important is not to take into account one abnormality because sometimes the persistence of two or more are what determine to be not only high risk, but ultra high risk.

Jenny: And you are going to treat that differently.

Dr. San Miguel: Nowadays, we cannot identify an optimal treatment for the high risk or ultra high risk patients. The initial concept that intensive treatment with high dose therapy should be reserved for the high risk patient while the standard risk can do well without the transplant I think it was a mistake. The patient that really benefits from autologous transplant and the standard treatment with the proteasome inhibitor and an IMiD drug are the standard risk. For the high risk, we need to identify different approaches.

Unfortunately, we are not yet there. We know that some drugs apparently work and others, in high risk patients, for instance, bortezomib is working pretty well, not excellent but pretty well, in patients with translocation (4;14), carfilzomib as well. Pomalidomide probably is valuable in patients with 17p deletion but this is a learning process. We are not, as I mentioned, in the position just to make the best recommendation for high-risk patients. We are not there.

Jenny: And how do you get there faster? What would help you to get there faster? Because it seems like some of the studies are retrospective.

Dr. San Miguel: Clinical trials and to work together. I think clinical trials are extremely important.

Jenny: And I know in high risk it might be more challenging to put together a high risk clinical trial because just of the number of patients available. I haven’t seen a lot of separated high-risk clinical trials but I think high-risk patients would love it.

Dr. San Miguel: Yes, you are right. But at least we should stratify the patient at the time of inclusion in the trial into a standard high risk in order to have the possibility right from the beginning to look into the high risk population — if they relapse, what type of relapse; what are the markers that predict risk of relapse. For instance, I can tell you, if you are high-risk cytogenetics and after achieving a complete response, you are minimal disease positive, you still have very poor prognosis. By contrast, if you have high risk cytogenetic but you achieve a minimal residual disease negative status, your prognosis clearly changes. Combining biology with treatment is the way and this can be done only in clinical trials.

Jenny: So how can you go about building clinical trials for high-risk patients? Because I think patients would be very excited about this.

Dr. San Miguel: As I mentioned, we have two ways to do that. One is specific trials for high-risk patients. This could be one possibility. And the second possibility is to try to think in what is the best treatment of this and to include both high-risk and standard risk and to discriminate, to stratify the patients into these two categories right from the beginning.

Jenny: Instead of retrospectively, which is kind of what happens now.

Dr. San Miguel: Retrospectively is what we have been doing so far and we need now to go far, to go into the prospective analysis.

Jenny: Oh, I love it. I love it. That’s great. Are there any high-risk therapies that you think are the best and most effective now? I know we’re not there yet but are there any that have given you clues or hints besides bortezomib and maybe pomalidomide?

Dr. San Miguel: I think bortezomib or carfilzomib, pomalidomide could be a very interesting combination to be tested. In high-risk patients, we have data, retrospective data from the European Consortium in Italy, Spain, France, Germany and Holland in which double autologous transplant was apparently of benefit in high risk patients. Then if you do a clinical trial with carfilzomib, pomalidomide, dexamethasone followed by double autologous transplant, this could be very interesting and then to have some consolidation or maintenance. This will be very important.

We are really excited just to see if the new monoclonal antibodies anti-CD38 or elotuzumab  work in high risk patients and all the interesting data with panobinostat that apparently was of benefit, similar benefit, high and standard risk. This is the time just to try to activate, as you mentioned, this type of clinical trials.

Jenny: Well, I think this is my personal dream come true. I have a high-risk feature and I would have loved to have a clinical trial that was designed or at least looking at me specifically as a certain type. And that was my next question: how do you see all these new immunotherapies working, particularly for high-risk?

Dr. San Miguel: Unfortunately, we have no data yet. But there is a lot of hope with the new therapies. Let me tell you. I may be too old, and when I just started to work in multiple myeloma, there was only melphalan and prednisone for more than 30 years. In fact, the high dose therapy is working on melphalan but in 2000 it started to change very rapidly. In one decade, four drugs. In the next decade, I hope again another four drugs.

When I was at the beginning of my medical career, acute lymphoblastic leukemia, I have a cousin that died from acute lymphoblastic leukemia. This girl nowadays would have been cured because acute lymphoblastic leukemia is a curable disease. Same to Hodgkin’s disease. Let’s  have the dream that we will evolve in the same direction in multiple myeloma.

Jenny: So you need more patients to participate and what else would be needed to create these very specific possibly high-risk clinical trials?

Dr. San Miguel: We need patients to participate and probably what we need is just to get together the different groups and to make complementary trials trying to ask questions that could be complemented in Germany, from France or United States or Spain. This I think will be very valuable for the patient. Imagine that I test one particular combination and at the same time in Italy or in Arkansas or whatever it is, another person is testing the same combination plus one immunomodulatory drug. And in this combination, the results are better, then we have the clue.

Jenny: Yes. And if you can do that simultaneously, it’s much faster.

Dr. San Miguel: Yes

Jenny: Well, let me ask you also because I’ve seen you’ve done some work about studying the bone marrow microenvironment, and I can’t even say this word but mesenchymal stromal cells. I am not saying that right but I want to know how you best shut down that myeloma cell support system or what you have found.

Dr. San Miguel: Currently, it’s well known that cancer is not only a problem of the tumor cell but also the difficult word that you mentioned, the microenvironment. It is mainly driven by the mesenchymal cells but also the T and NK, the accessory cells. If we talk to the mesenchymal cells, in trying to understand if mesenchymal cells for myeloma patients are similar or different from normal mesenchymal cells, and I can tell you that mesenchymal cells from the bone marrow of myeloma patients are genetically different from the normal mesenchymal cells. And if you put in culture myeloma cells with mesenchymal cells from patients versus the same culture of tumor cells but with mesenchymal cells from normal donors, the mesenchymal cells from the patients give a proliferative advantage to the tumor cells and give different genetic signals, then we know nowadays that by sure, this microenvironment of the myeloma also plays a role in tumor development.

Jenny: So I have a question about that. If you say they are genetically different, are you saying — I know a myeloma patient versus a normal person, is that the same as, let’s say, a myeloma patient who is in remission versus a normal person’s mesenchymal cells?

Dr. San Miguel: We have not looked to the analysis in remission patient and this is a good idea. You can give me one idea for the weekend.

Jenny: Good, good. 🙂

Dr. San Miguel: I will take it in the analysis. But what I can tell you is the genetic abnormalities that we have observed in the patient mesenchymal cells are not related at all to the genetic abnormalities that we identify in the plasma cells. In other words, in the mesenchymal cells you have no translocation (4;14). You can have 17p deletion, you have no 1Q gains. They are different. They are more subtle genetic abnormalities.

Jenny: Okay, yeah, they’re support cells, right? So they’re not going to have the myeloma indicators necessarily but maybe other indicators. Yes, I would love to know what you find out about that because you wonder if patients who are in remission and have these very pesky cells that are still remaining, even if you are MRD negative, that you have a support system that’s in place that’s still going to be conducive to growing that myeloma at a later time.

Dr. San Miguel: Yes.

Jenny: Kind of related to that, here’s another question for you. The resistant myeloma stem cells, is there any new information about the stage at which they become resistant? I saw that you had worked on a paper that showed that you were studying CD138 and like a heightened or they call it CD138++ and then a 138 low and showing that there was no difference. And I have to go back and read that again after I wrote that question —

Dr. San Miguel: I would try to explain to you but as soon as we finish this conversation, Jenny, let me talk to you just to offer a position in our team. Because you know about multiple myeloma so much that I will offer you a position for research.

Jenny: Okay. (laughing)

Dr. San Miguel: Okay. This story is trying to identify which were the stem cell for multiple myeloma, and some people claim that myeloma stem cell was CD20+ cell. By definition, most of the myeloma cells are CD20-. CD20 is a B cell antigen, okay. And most myeloma, the myeloma cell, the malignant myeloma cell lose 20 antigen usually. By contrast, the B cell, our CD20, the normal B cell is 20, and some people claim that probably the precursor of the myeloma cell is a B lymphocyte CD20 that evolved into a CD20- negative mature plasma cell. This was the theory.

And also some people claim that CD138, that there’s a marker for plasma cell, if it’s weak expression, this identify in mature plasma cell while the strong expression identify the mature plasma cell. Then we concentrate in these two populations, the CD20 positive and the CD138 negative or low positive. That would correspond in other words to theoretically the precursors of the myeloma. And we have performed a lot of experiments in animal models, et cetera, just to try to identify the clonogenic capacity of these two populations. And what I can tell you is that from a point of view, the stem cell, the precursor cell are not inside of this population because it’s a clonogenic capacity, the same tumor dissemination capacity as the mature clone.

Jenny: I know a lot of people are trying to go backwards and see the progenitor cell or earlier stage where is the myeloma happening. And that’s the goal. So do you have any other insight about why myeloma keeps coming back?

Dr. San Miguel: Our research now is focusing on two tools in order to get the standard biology of myeloma. One is to get the cells in minimal residual disease because by definition, this minimal residual disease are resistant and are responsible for the relapse and have clonogenic capacity. And the other group of cells that we are currently investigating are the circulating plasma cells. Our research is focusing strongly in these two cell populations, the MRD and the circulating cell.

Jenny: Because they are more aggressive?

Dr. San Miguel: Yes.

Jenny: Well, I want to leave some time for caller questions but are there some clinical trials? I see you have several open clinical trials. Are there some you’d like to discuss or share before we go to caller questions?

Dr. San Miguel: The clinical trial that we are going to activate, as you know, we conducted a clinical trial in multiple myeloma with lenalidomide, dexamethasone that has shown that early treatment in high-risk smoldering, only in high risk smoldering, is associated with a benefit in time to progression and a benefit in overall survival. Basically, we are yes in the process of activated. In other clinical trial for high risk smoldering, the aim, the goal is persistent MRD negativity. In other words, want to cure these patients.

Jenny: And what will that trial include?

Dr. San Miguel: This trial will include induction with CRD, carfilzomib, lenalidomide, dexamethasone followed by autologous transplant, followed by consolidation with CRD, followed with maintenance with lenalidomide. A heavy treatment for a high risk smoldering but we hope that we will be able to cure a substantial number of patients. This is the goal.

Jenny: And when you say high risk smoldering, are you looking at a specific like a deletion 17 or everything that you talked about earlier in the high-risk category?

Dr. San Miguel: Yes, everything I talked about.

Jenny: Okay. Well, I am so happy that you are working on the high-risk group. There’s so much detail behind it and that you are looking to segment people. I think that’s been a long time in coming. I am thrilled that it’s here. And whatever we can do in terms of helping to accrue patients in those groups, we’ve created these Facebook groups that are subdivided by translocation. So with those people can join and then be really aware of what’s happening for their particular kind of myeloma.

Dr. San Miguel: Definitely.

Jenny: Well, I would like to open it up for caller questions. So if you have a question for Dr. San Miguel, please call 347-637-2631 and press 1 on your keypad and we have many questions for you.

Caller: Yes, hi, good afternoon, Dr. San Miguel and Jenny. It’s a pleasure to speak to you.

Dr. San Miguel, I have a question for you. I am a smoldering patient. So I am thrilled to hear that you are continuing your work with the smoldering population and looking at additional trials. The trial that you just mentioned sounded similar to me — I think the University of Chicago is actually using that for newly diagnosed myeloma patients. I have a smoldering group on Facebook, and one of the gals who actually thought she was smoldering actually is newly diagnosed but she is in that trial, the CRD followed by the stem cell tranplant and followed by CRD consolidation with Rev. So that’s exciting to know that you are moving that into the smoldering group as well. It sounds like a curative approach. How would you best evaluate someone with smoldering myeloma? Obviously, you would use the flow cytometry that you are speaking about, right?

Dr. San Miguel: Yeah. I think it’s critical to smoldering. Most smoldering myeloma patients are low or standard risk and I never will treat such a patient. The only patients that are candidates for my point of view for embarking in clinical trials, no treatment outside the clinical trials for the smoldering patient. But for a smoldering with high risk, these are what I am going to talk about high risk in a smoldering. I would consider to include them in clinical trial. Again, no outside clinical trials.

Then if we focus on high risk, what is I consider high risk, I consider high risk smoldering, those patients that are more than three g/deciliter of M component plus more than 10% plasma cells. And ideally, if these plasma cell, if the total by flow are phenotypically aberrant, in other words, all the plasma cells are clonal. This is what that when more than 95% of the total are clonal, this is associated with high risk of progression. On top of that, new data shows that the presence of a high number of circulating plasma cell, we are working on this, the presence of high risk cytogenetics, we’re finding that translocation (4;14) can qualify for high risk smoldering.

Caller: Thank you so much for clarifying that. That’s important for the smoldering community because we have that gray area. We’re not quite sure who’s who and where we fit in.

Dr. San Miguel: Please, if I would be a smoldering patient with low risk, I never would accept nowadays a treatment on those. The chances of progression are very low. If I am an intermediate risk, I will not go for treatment. And if I have a high-risk, I will discuss with my doctor the possibility of being included in a clinical trial but in the context of high risk only, okay?

Caller: Thank you. And Dr. San Miguel, how useful is a plasma cell labeling index compared to the flow cytometry test that you use?

Dr. San Miguel: Okay. I think the labeling index, the old-fashioned of the labeling index is troublesome and we prefer just to use the flow.

Caller: Okay. And what are your thoughts about the multipeptide vaccine to induce cytoxic T cells? This is the vaccine that’s being run out of Dana-Farber and Mass General and it’s going to be coupled with a short-term dosing of Revlimid, about three months worth of Rev. Do you think that that holds promise for the smoldering community?

Dr. San Miguel: Yes, yes. I think I’m completely convinced that the immune system plays a very important role, not only in myeloma, in all cancer, in all this type of disease. It was almost abundant in the last five years now it’s reemerging. It’s not only because we have new drugs that work in the immunotherapy area but also because we have tools that can exploit the T and in K cells. And in fact, some of the immunomodulatory drugs work through this mechanism by enhancing the T and K cell activity.

Caller: Okay. And that’s what I understand that that peptide has actually done.

Dr. San Miguel: Vaccination looks into this direction.

Caller: And lastly, I don’t want to take up all of your time, but what imaging diagnostics are important for those with smoldering myeloma? Do we need PET-CT scans? Do we need MRI?

Dr. San Miguel: For the smoldering myeloma, my current recommendation is to perform an MRI of spine plus a low dose CT. This is my recommendation.

Caller: Very good. Dr. San Miguel, thank you so much. I’d like to apply for one of those junior research jobs in your lab someday too. I’d love to come over and work and learn more from you. It’s a fascinating interview today. Thank you so much for your time and your knowledge and for what you do.

Dr. San Miguel: Pleasure.

Jenny: All right. Thank you for your question. Our next caller, go ahead with your question.

Caller: Yes, hi, Dr. San Miguel. And my husband is a high risk with (4;14) and deletion 13 but that was not discovered until after transplant. He did have the cytogenetic testing done but it showed up as normal. So he was on a clinical trial. He did three cycles of RVD. He was in a partial remission when he had the stem cells collected. Then he did the cyclophosphamide and the high dose melphalan and the transplant. His M spike was the exact same after the transplant, two more cycles of RVD, and then went to the Revlimid maintenance. Two weeks on maintenance, his numbers went crazy up again. So he’s now on Kyprolis/Pomalyst and dex starting his sixth cycle of that.

So I guess couple of things. I think the horse is out of the barn I think but I’ve since learned that in my reading with the (4;14), probably it would have been better to do a bortezomib type maintenance. And I guess my other question is should his numbers have been a little bit lower before collecting those stem cells and going into the transplant? I listened to a talk by Dr. Lonial out of Emory, and he said the high dose melphalan for high-risk patients can be like putting gas on a fire.

So I guess I have a lot of questions. One is right now his numbers are coming down though the drugs seemed to be working. So can he overcome the situation that happened prior to that? And would you recommend another transplant? I guess those are a couple of my questions anyway.

Dr. San Miguel: First of all, let me tell you. For (4;14), I think both bortezomib and Kyprolis, carfilzomib, are very attractive drugs, and probably the Kyprolis is better than bortezomib in this patient with (4;14). We don’t have yet the data and this I would say that will be equivalent. I would expect that. Then I think it’s a very good choice.

The second, the point of putting that to risk, I don’t think this is a correct statement. And the reason is the European study that included the largest number of patients so far reported in the world based on the meta-analysis of the French, Italian, Spanish, German, and Dutch trials altogether has demonstrated that the best for patients with high risk for (4;14) and 17p, is  tandem autologous transplant. Then I am not sure that the statement that is put in — I don’t think it’s the correct statement. But in the case of your husband, I would not repeat now a transplant because the first one had not value. I would not repeat the transplant.

And finally, regarding your point about collection of a stem cell at that point in time, the problem in myeloma is not the number of plasma cells that you infuse, the number of tumor cells that you may infuse with a transplant. The problem is the cells that are residual inside of the patient and has not been able to be eradicated with a high dose melphalan. This is a problem. It’s not the infusion. The problem is what is inside. And I think your husband should be a patient also of a myeloma center because nowadays we have several alternative drugs also such as the immunotherapies et cetera, that could be of interest for him.

Caller: So I guess that was obvious, you know, eventually these drugs will stop working. So I guess then the next question is at that point, what is the next? What would you recommend after that? So what would be the recommendation after these three drugs run their course? And what kind of testing should we be making sure is done other than just looking at the M spike?

Dr. San Miguel: If I understand correctly, is your husband now receiving Kyprolis plus lenalidomide, dexamethasone? Is this correct?

Caller: Kyprolis, Pomalyst and dexamethasone, yes.

Dr. San Miguel: Then one alternative is to move into the monoclonal antibody, anti-CD38. This is probably the first choice that I would think about particularly if it’s in combination with lenalidomide or bortezomib. It’s a monoclonal antibody and there are several ongoing clinical trials in that direction. And in the case of your husband, I think it’s important just to evaluate the residual disease outside the bone marrow – the extramedullary disease.

Caller: So he has never had a PET-CT. You would recommend that?

Dr. San Miguel: Yes..

Caller: Okay. And I am sorry. I heard the monoclonal antibodies, did you say CDC38?

Dr. San Miguel: Yes, CD38.

Caller: CD38, okay. Okay, thank you so much for your time.

Dr. San Miguel: My pleasure.

Jenny: Okay, thank you so much. Now I have one question that was emailed in by Suzie Rose who says, “Can flow cytometry indicate if a progenitor cell population was killed off? And then if so, who does the test? Is it biopsy or serum? When would it be done? After consolidation, induction, or should it be used as a monitoring tool for maintenance? ”

Dr. San Miguel: Okay. Flow cytometry is always performed in bone marrow specimen. It’s a technic for bone marrow or a peripheral blood in the case of the circulating plasma cells. And the flow is done, can be done  at diagnosis, also after induction or after consolidation therapy.

Jenny: We have one more caller. Go ahead with your question.

Caller (in Spanish):  My question is for patients who don’t live in the United States, where can they get the best treatment?

Dr. San Miguel: At the Unviersity of Navarra, we have many clinical trials.

Caller: For example in Mexico or in Latin America.

Dr. San Miguel: The best treatments are in clinical trials.

Jenny: I think those are key, aren’t they? Clinical trials are the keys to get the very best in care. We will just thank you, Dr. San Miguel, for joining us today. We absolutely love what you are doing for high-risk patients. We love the approach. We love what you are testing for us so we can separate everything out. We are just so very grateful for your leadership and your research to move the field forward as quickly as possible. We are so appreciative of your time today.

Dr. San Miguel: It’s been a pleasure really. Always the patients are the driving force for a doctor. And in this case, the myeloma patients are my driver.

Jenny: Well, thank you so much for everything you do.

Dr. San Miguel: Thank you. Bye-bye.

Jenny: Thank you for listening to another episode of Innovation in Myeloma. Join us for our next mPatient Radio interview as we learn more about how we as patients can help drive to a cure for myeloma by joining clinical trials.

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