Learn about all myeloma happenings on the new Myeloma Crowd site: the first comprehensive site for myeloma patients and caregivers. Dr. Pieter Sonneveld, MD, PhD Erasmus Medical Center, European Myeloma Network, HOVON Foundation Rotterdam, The Netherlands Interview Date: May 9, 2014

 With smaller individual myeloma patient populations, the Europeans had to develop a different strategy in order to make progress in myeloma treatment. Dr. Pieter Sonneveld, MD, PhD of Erasmus University shares how the foundation of the very effective European Myeloma Network, HOVON Foundation and International Myeloma Working Group were developed to build efficient and powerful ways to test new therapies in large numbers of patients. Collaborative trials recruit patients in big numbers and can test several hypotheses simultaneously. As an example, a 1500 patient trial has just finished recruitment that will determine whether high-dose or low-dose melphalan is needed now that newer drugs like proteasome inhibitors and lenalidomide are available. It will also study whether consolidation and maintenance should be used or if maintenance therapy is enough. It will also answer the lingering question about the best transplant approach - single or tandem. Recruiting patients into trials is easier in Europe, because local hospitals commonly refer patients to myeloma specialists, while they do not in the United States. Patients are also highly motivated to join clinical trials there to receive access to newer myeloma drugs which they cannot otherwise obtain. Dr. Sonneveld's work to help create an order and process for standardized myeloma care has helped patients around the globe. Dr. Sonneveld describes the necessity to create international myeloma treatment and diagnostic guidelines that take into account the availability and accessibility of drugs and diagnostic testing - countries vary when it comes to approval and insurance reimbursements. He discusses a trial with a drug called melflufen, a variant of melphalan, to keep the effectiveness of melphalan but minimize its long-term downside. He also describes an upcoming study in Europe that will test daratumumab, an exciting monoclonal antibody (immunotherapy).   The live mPatient Myeloma Radio podcast with Dr. Sonneveld

Jenny: Welcome to today's episode of mPatient Myeloma Radio, a show that connects patients with myeloma researchers. This series is in place to help you understand the need to join clinical trials. Today less than 5% of myeloma patients participate in clinical trials. But if we participated, we could step up the pace at which researchers can find new therapies and a cure. It's in our best interest to join these trials. If you'd like to receive a weekly email about past and upcoming interviews on the show, you can subscribe to our mPatient Minute newsletter on the homepage or you can follow us there on Facebook or Twitter, and please feel free to share these interviews with your myeloma friends. We have a new site called myelomacrowd.org that's the first comprehensive site for myeloma. Please take time to explore some of these links. There are references to everything in the world of myeloma, a list of who to follow on social media, new sources for myeloma, a growing online myeloma specialist directory and current articles on myeloma topics. You could also contribute what you're learning by clicking on the “Become a Contributor” link. Now, we are exceptionally honored today to have with us Dr. Pieter Sonneveld of Erasmus Medical Center. Dr. Sonneveld is the Head of the Hematology Department and is Professor of Hematology at the Erasmus University in Rotterdam in The Netherlands. At the Erasmus Medical Center, he is also Head of the Multiple Myeloma Research Group, Chairman of the Commission of Translocational Medicine, member of the Oncology board, member of the Internal Hematology-Oncology Integral Center, board member of Molecular Imaging, board member of the Committee on Laboratory Information Systems, member of the Biobank Committee and coordinator of the Pearl Program for leukemia. Outside of the region, he is very well-known as the chairman of the myeloma working party of HOVON which is a foundation, member of the HOVON executive board and treasurer, coordinator of the CTMM program for myeloma, coordinator for a population-based registry for hematologic malignancies. He's on the scientific advisory boards for the IMF, the MMRF and Myeloma UK Foundation, and the UK Leukemia Research Fund. He is the chairman and founder of the European Myeloma Network and consensus group for therapeutic guidelines in myeloma. He's a member of the scientific and executive board of International Myeloma Working Group, Chairman of the scientific working group for myeloma's European Hematology Association. He's on the editorial board of over eight major publications, including Leukemia Research and European Journal of Cancer and Clinical Oncology, and is Associate Editor of Haematologica. Unbelievably, I didn't mention everything he is doing or has done. Maybe you can first explain the HOVON foundation and your founding of the European Myeloma Network because I think that's just fascinating.

Dr. Sonneveld: Okay. So the whole foundation is in The Netherlands, Belgium and Luxembourg, the so-called Benelux. It was founded approximately 30 years ago in order to setup clinical trials in Hem-Onc in the early years only, in acute myeloid leukemia, and then later on also in all the leukemias, myeloma and malignant lymphomas. Currently, it's the major cooperative network for performing clinical trials in the Benelux. A total of more than 135 trials have been initiated and many of them are already completed and published. Also in multiple myeloma, we have been active in setting up prospective, randomized Phase III trials, I think somewhere around 1995 when we started with myeloma trials. Because it is important with all the new agents coming to clinical trials that we can perform trials so they can relatively show us the time period, and this why we concluded that we needed a larger yearly accrual of patients for the trials. The only way to accomplish that was by initiating a more European type of approach. This is why, with all the people from Italy, Spain, Germany and so on, we have initiated the European Myeloma Network. This is a network of the cooperative groups from the different countries. So GIMENA from Italy, the GMMG from Germany, and HOVON from Benelux, the Nordic Myeloma Study Group from the Scandinavian countries and several other smaller countries like Austria, Switzerland, Greece, etc. that participate in one common myeloma network, the European network, and this is fairly successful I would say. In this setting, we were able to set a large prospective trial, the EMN-02, with 1500 patients and that this trial just was completed in less than three years. So this is how we work now in Europe in order to accelerate patient accrual to clinical trials and to be able to do several trials at the same time in the same patient group.

Jenny: That's the goal of this whole series, is to help patients understand the importance of participating in clinical trials. So as this group is constructed and more researchers come together, how does clinical trial participation work in Europe? And how is that different from how it works in the United States? Because several researchers in the US have noted how they're sort of envious of how you are able to construct the trials more quickly and recruit more quickly.

Dr. Sonneveld: I think that in Europe there's probably a little bit more awareness of the developments of clinical trials, also among patients, and this is because we are used to working in smaller networks already. For example, my hospital is University Hospital in Rotterdam, in The Netherlands, and our patients are approximately four million people with 20 hospitals, and from those 20 hospitals patients are sent to the Erasmus University Hospital for referrals, especially if they are young and have, for example, hem-onc disease like leukemia or multiple myeloma. There's a constant interexchange of information between the local, the community hospitals, and the university center in order to discuss whether patients are eligible for trials, whether they should be included or whether they are better off just staying in their community hospital and get standard treatment. This has increased the awareness of trials and also the list of patients to participate in trials because they also know that they don't have the newer drugs if they don’t participate in the trial. And so, for myeloma for example, the transplant-eligible patient group, more than 80% of those are included in clinical trials. So that's how it works.

Jenny: That's stunning because less than 5% of patients participate in myeloma clinical trials in the US.

Dr. Sonneveld: Yes. But maybe that's also because in the US, the patients -- I mean they are diagnosed in private practice offices and they are not referred or discussed with the center. There's also maybe a financial aspect to that, and this is not present in Europe, at least not in The Netherlands, in the Scandinavian countries, in Germany and so on.

Jenny: Right. Well, can you explain also -- well, you explained a little bit about the HOVON foundation. When did that begin?

Dr. Sonneveld: It stared approximately 30 years ago, in the early '80s, when hematologists of university hospitals came together in order to explore whether they could do something to improve the outcome of patients with acute myeloid leukemia, which was at that time very dismal, and in some respect it still is. So they started their foundation, HOVON, in order to create a platform for performing clinical trials, this also initiating a data center trial monitoring local and central data management, and all the things that you need to perform clinical trials - financial offices and fundraising to pay for the clinical trials. This has grown to, as I've said, also myeloma and non-Hodgkin's lymphoma, NCOL, and the most common hemo diseases.

Jenny: Does that contain a tissue bank also?

Dr. Sonneveld: Yes, also tissue banking and population-based registry. Both are parts of the HOVON trial organization. So there's central tissue banking, also central LAPs for correlative studies like gene expression profiling or SNP analysis, flow cytometry, and all these is centralized in one or two laboratories.

Jenny: And your data registry -- that's just for the three countries or does that expand throughout the European Myeloma Network as well?

Dr. Sonneveld: Well, the population registry is only for The Netherlands at this time, but we know there are similar activities in Germany and in Italy, Czech Republic and the Scandinavian countries. At this time, we are busy in merging those clinical databases in order to be able to perform analysis. This is, I think, almost realized now for multiple myeloma; and for leukemia there are also activities in this field.

Jenny: It just seems that that would be very key to making decisions and I know you're part of the -- you're leading this effort internationally to ensure consistency. Maybe we do want to talk about that because I know that you are very key in leading the effort to establish this consistency for myeloma management guidelines, for consistent diagnostic testing and risk assessment. Can you talk a little bit about the progress that you've made in those areas?

Dr. Sonneveld: Yes, of course. So in HOVON, we started to develop guidelines especially for myeloma and lymphomas, CLL, for both diagnostic approaches and treatment guidelines. And because we are living in Europe, where often there are differences between countries, differences in reimbursement for the novel agents, and also different treatment customs and approaches. We decided to develop guidelines from European guidelines within the European Myeloma Network as well. These guidelines, they have to be useful and they have to serve the different interests in the European countries, and also take it to account the availability and accessibility. For example, diagnostic procedures that are not so common yet in eastern part of Europe. So the guidelines of European Myeloma Network address also the differences in availability of the diagnostic procedures and also availability of drugs. So we are not only focusing on the best treatment, we are also focusing on the available treatments and how to assist the treatment between those.

Jenny: And have this expanded to other countries outside of Europe with these guidelines? Because I know everyone is looking at these guidelines.

Dr. Sonneveld: Well, we are restricting our activities to Europe at the current time, although sometimes, also the Australian group is participating. But it's internal, it's only Europe at this time, which we know that also from the EHA, the European Hematology Association, there comes a lot of interest from people in the Middle East to participate in these kinds of activities and they are really looking at our guidelines as well.

Jenny: And what have you determined so far in guidelines and risk assessment and myeloma management? Do you want to go into a little more detail about what you've determined?

Dr. Sonneveld: Well, one of the issues that we have paid attention to is whether bortezomib should be used in first-line treatment because it was only approved in elderly, in normal transplant-eligible patients for first-line. It was not approved for transplant-eligible patients for induction treatment. And so this is something that we explored and we highly recommend it, to use bortezomib also in the younger transplant-eligible patients. This was in the end, I think, taken off by the EMA and now it's standard treatment across Europe and all the different countries for younger patients. But this took about three or four years to get this accomplished and it started with the guidelines. So by taking such a specific issue and really address it in a guideline, from the European guideline, we can also have some influence on the authorities and the agencies that are responsible for the reimbursement process.

Jenny: And also for a standard testing, I know there have been several researchers on the show in the US that have talked about the need to standardize the FISH test, and I know a lot of work is being done in flow cytometry in Spain, and that I guess you would get what you test for in FISH from what I've learned, and not all the tests are standardized. So can you talk about diagnostics for a minute about how that has been standardized or what you're finding?

Dr. Sonneveld: Yes. So our idea is that if we standardize tests in clinical trials, usually they will also be adapted and then those standards will be used for patients not included in clinical trials. So with the large European trial that I've just mentioned, with 1500 patients, we find the number of FISH probes that we thought will be necessary to determine the risk group of a patient. And so, we defined five probes and this was used universally throughout the different European countries using the same probes for the same abnormalities. And what I understand, at least this is true for The Netherlands, Benelux and also for the Scandinavian countries, is that in general practice the same probes were adopted for use in patients not included in clinical trials. This is true for diagnostics but also for supportive care, and all the topics that are important. If you define those quite well in the context of clinical trials, practitioners will start to take those for use in the context of their general practice, also for patients not included in clinical trials.

Jenny: And do you find that the guidelines that you're developing that -- like you're saying, the local oncologist will follow those protocols. Because there's a really wide variety in the United States about how myeloma is treated so maybe we want to talk about that next. How you're able to increase consistency, I suppose, on the treatment or what is the standard treatment for a European network?

Dr. Sonneveld: So as you know we have developed international guidelines in the International Myeloma Working Group over the past years for a lot of different situations. But they do not always address a typical European situation. So we have in the European Myeloma Network, we also addressed other questions so that we're able to develop the guidelines. For example, how should we determine the presence or absence of lytic lesions? In most European countries it's not possible to use MRI in the diagnostic situation for any suspicion of lytic lesions. Many countries are still using conventional radiography. What we have tried is to introduce in the guidelines the kinds of order in which you can use different diagnostic procedures. So if you have only X-ray available, what can you conclude from it and what can you not conclude? And then when do we need to change to bone CT? Or go to the specific situation then you really have to go for an MRI. I mean just to be practical in the different countries and get people some kinds of reference when they should use the different techniques and how they should integrate the data.

Jenny: Well, I read a little bit about the UK and their MRI new technique that they were using the whole-body imaging. I wonder how that would become available both in Europe and in United States. We've lived in a foreign country before so I completely understand availability in some countries and not in others. How long do you think that will take to become more prevalent?

Dr. Sonneveld: Well, that depends also on the financial reimbursement. In Europe, this is different from the US probably. You cannot always use the preferred technique because it will not be reimbursed. So as for the whole-body MRI, many insurance companies do not reimburse this for multiple myeloma since they think that with bone CT you can have results that are sufficient for clinical handling. So I'm not sure whether we should use whole-body MRI in all patients. We have been more practical and so we recommend bone CT. If the patient has pain, complaints of pain in a part of the body where the CT does now show an abnormality, then you should make an MRI. If you cannot detect something on the MRI, then you should move to PET-CT. So it's more like an algorithm for using more complicated and more expensive techniques only when you really need them rather than putting everyone in an MRI.

Jenny: As a standard routine. That makes a lot of sense. And do you do the GEP standardly, the gene expression profiling?

Dr. Sonneveld: Well, this was partly developed in our laboratory here. So we have performed a lot of work in that area. We are trying to introduce the gene expression profile now in some clinical trials. It will also be used maybe in Mayo Clinic to determine the gene expression-based risk group of patients, and a lot of our next trials in the European Myeloma Network will be based on gene expression profiling as a way to identify high-risk versus standard-risk patients across different treatments. But this is a new technique of course and people need time to get used to it because they think with FISH you can do the same, but this is not really true because FISH only looks at predetermined abnormalities, a total of five or six in most trials. Well, with gene expression profiling, of course, it determines the risk group of a patient based on biology, across all DNA data available.

Jenny: I have a question about the gene expression profile because you have expertise there. I think I had the 70 performed and now I heard about an 80, are those just testing for more genes or how does that work?

Dr. Sonneveld: Now, there are a number of signatures in the literature. There's a 70 gene-based and an 80 gene-based, both from Arkansas, from Little Rock published by the group of Dr. Barlogie and we developed a 92 gene-based gene expression profile, and really the numbers don't matter. It's about what genes come out as being most effective for outcome in the group of patients that was uniformly treated. This may be 17 or 70, or 80, or 92, or maybe 150, or maybe only 5 and this is not -- I mean the number doesn't really matter. It's about how these genes come out of a statistical analysis performed on the whole 30,000 genes that can be detected from the gene expression platform. And maybe in ours, it was 92 genes and it could be, and if we analyze another set that maybe 50 genes is also enough.

Jenny: And now that you're doing the gene expression profiling and you have such detailed level of it, what are you seeing with the risk stratification? When I first started this series in July of last year, it was very, very early and I would ask researchers, "How is that changing treatment?" And they said, "Well, pretty much not quite yet." But it seems like that's starting to change. What have you seen and what are you doing with this extra information?

Dr. Sonneveld: Well, what we observed in our analysis is that if you compare gene expression with FISH or ISS or combined analysis, gene expression always pops up as the most significant test for identifying the real high-risk patient. So this is the 10-15% worst prognosis patients. If you combine gene expression with ISS, so let's say biology with the clinic, this is especially statistically very powerful, and it's always better than FISH. We think that FISH is, in fact, a kind of a more simple analysis of the biology, just looking at some very common abnormalities but it does not take into account all the different genes that may be evolved in the biology of myeloma. Gene expression looks at those genes and picks out the most influential ones. But gene expression by itself is also not enough. We should also look at mutations as you probably know. So it's not yet finished. We are now looking, like all the rest, the combination of gene expression with SNP analysis, and also look at newer techniques like RNA sequencing technique as a next level of looking at the underlying biology of the individual patients.

Jenny: Is RNA Sequencing the same thing as whole-exome or the whole-genome sequencing? Is that the same or it's something completely different?

Dr. Sonneveld: No, it's different. With RNA sequencing you will look at RNA. So this is like with gene expression, it also looks at RNA but RNA sequencing is more detailed. It doesn't just look at the expression of the gene. It also looks at the composition of the RNA that is expressed by the gene, and this is older than whole-exome sequencing. With exome sequencing you'll look at the DNA, and DNA is of course - if the gene is translated into RNA then you can detect it with RNA-Seq, but if is it not translated then you will only find it with exome sequencing. Exome sequencing can be done by looking at predetermined areas of the DNA then we call it the captured exome sequencing. For example, if you want to look at known abnormalities in myeloma, you can use the technique or whole-exome sequencing, which means the whole DNA is sequenced, and that's more complex, time-consuming and expensive.

Jenny: And then what do you do with that information?

Dr. Sonneveld: Well, of course we want to -- well, a lot of things but the two most important ones are to be able to identify patients that may respond to different treatments because they have a specific biologic abnormality that may respond best to, for example bortezomib or may respond best to another drug. That's one thing and the other is that we want to get more insight, of course, in the biology of the myelomas. And one thing that is important, if the biology changes from diagnosis, to relapse, to second relapse and so on.

Jenny: And are you changing therapies based on that incarnation at the present or is that still in the future?

Dr. Sonneveld: Yes, that's in the future. It's too early now. This is clearly one thing that we want to go and with the techniques becoming more standard and less expensive, we can apply them to our large biobank from the clinical trial which means that we can analyze hundreds of different myelomas. Hopefully, this provides information that we need. And in our next step we probably -- but maybe that's in two years or so, we will be able to run these sequencing techniques for individual patients, then determine the risk class of those patients based on the biology, and then assign them to a certain treatment in a clinical trial.

Jenny: Well, let's talk about your clinical trials for a minute. You mentioned the one with 1500 patients; that's a stunning number of patients to aggregate for a trial. Can you describe what that trial was trying to determine and then what you found?

Dr. Sonneveld: Well, this trial was about two questions. The first question is do we need high-dose melphalan in stem cell transplantation at the time when we have all these novel agents available, so with proteasome inhibitors and lenalidomide. So we decided to randomize between high-dose melphalan in one arm and extended-dose melphalan given as PMP in the other arm, and so this is one question. And the next question in the trial is whether it's really required to get give consolidation and maintenance after the induction or whether we should only give maintenance. So the second randomization is consolidation plus maintenance versus maintenance only. These are the two questions that we want to address, and hopefully, in a few years from now we will know the answer.

Jenny: And this is an ongoing study. This is not a completed study yet, it sounds like.

Dr. Sonneveld: The study is completed - the recruitment has been completed. Recruitment was completed only a month ago but of course many patients are still ongoing in the trial so we -- it takes probably two more years before we know the answer and all the required number of  events have being achieved.

Jenny: And I noticed that in Europe a lot of times prednisone is used over dexamethasone. Is there a reason for that?

Dr. Sonneveld: Well, usually prednisone is used in combination with low-dose melphalan, like in the MP regimen but only there. In all other combinations, people prefer to use dexamethasone but in these times, primarily low-dose dexamethasone. So this is the 40 milligram per week, maximum.

Jenny: Because I had seen prednisone and I don't typically see it in the United States, so I was just curious about that.

Dr. Sonneveld: Yes, that's because in the United States the melphalan-prednisone regimen, which has been available since the '60s, is not used. People prefer len/dex or maybe thal/dex over the past few years or bortezomib/dex. This is the standard combination in the United States but not in Europe. In Europe we prefer to give melphalan, prednisone and novel agents like len or bortezomib or carfilzomib.

Jenny: And you have access to all the new therapies or is it something you get earlier or later than the US? How does that work typically when new therapies come out?

Dr. Sonneveld: Typically, we get them later than the US and that's not typical for myeloma or HemOnc, also for many other agents, that's the case. And so, for example in myeloma, we have now -- of the novel agents we have bortezomib, lenalidomide and pomalidomide, and other agents like carfilzomib or ixazomib or alemtuzumab or what you have are not yet available here, so they can only be used in the context of clinical trials. Maybe that's one of the positive arguments for patients to participate in clinical trials. They know that they get more easy access to novel agents.

Jenny: Well, I'm a huge proponent of that because I think there are a lot of advantages to participating in clinical trials, and access to drugs is one of them. But being able to collect your data first and know what you have, and then in the future as things become available, be able to take advantage of that because you have more understanding about your disease biology. That's another. And then I think sometimes you get better care because you're being watched very carefully.

Dr. Sonneveld: Absolutely. So as you know it has been shown that patients in clinical trials usually have better prognosis, better survival than patients outside clinical trials. But this may also be because there are selection criteria for clinical trials. So patients with significant comorbidities are usually excluded. So there are many reasons why the results in clinical trials are better.

Jenny: Yeah, because it's difficult to test if you have a lot of other issues, to see if the treatment is going to work or not. Well, do you want to talk about other trials that you're working on? I saw that you had a Phase I/II study using melphalan and something that I've never heard of before, flufenamide?

Dr. Sonneveld: Yes, that's called also melflufen. And melflufen is a prodrug of melphalan with less toxicity to the hematopoietic stem cells, and this has always been a major disadvantage of melphalan because if it harms stem cells, it might induce pancytopenia. It's also being associated with higher risk of secondary leukemias later on. So if you can develop, let's say, variants of melphalan, which is as effective as melphalan for multiple myeloma but less toxic to hematopoietic stem cells, that will be a major step forward and melflufen is one of those drugs that we are doing in clinical trial in the Phase I and Phase II study. By the way, together there are some studies in the US like Memorial Sloan and in Boston. The results are still in the early phase of development but the results seem promising. So we will continue our trials with this  drug.

Jenny: Well, it's fascinating too that you can not only make things better but determine completely new therapies through clinical trials. Do you have other studies that you'd like to share?

Dr. Sonneveld: Yes, one of the upcoming trials that will start early next year - there will be a large prospective Phase III trial of HOVON together with the French IFM group, again in the context of the European Myeloma Network, investigating the role of daratumumab which is a monoclonal antibody against myeloma cells and combined with chemo, the VTD regimen in transplant-eligible patients. So in this trial we will create more, again, almost 1100 patients, randomize them between standard chemo high-dose melphalan, autologous transplant, standard consolidation or the same regimen plus daratumumab during induction and consolidation, and then followed by a second randomization for maintenance with daratumumab or placebo. We could say that this is a major step in the future because it's a new approach using a monoclonal antibody directed specifically against the myeloma cells. This is a drug or an antibody, I should say, that has shown single-agent activity which is significant in the relapse/refractory setting. So this will be the first trial in newly diagnosed patients, and again, this will start early next year.

Jenny: That's newly diagnosed patients, not relapsed/refractory. That's exciting.

Dr. Sonneveld: Newly diagnosed, indeed.

Jenny: And you said it's during induction and during consolidation, so in both areas.

Dr. Sonneveld: Correct, yes.

Jenny: Okay, well that's very exciting, the whole immunotherapy approach. I know patients are very excited about the whole immunotherapy use.

Dr. Sonneveld: Yes, we too, as treating physicians, because we have seen the success in lymphomas with rituximab and then also elotumumab in myeloma. But elotuzumab by itself is not very active. It needs to be combined. With daratumumab we know that it has also single-agent activity. So we are very interested in seeing if you combine this effective monoclonal antibody together with other effective agents like Velcade and thalidomide whether we can really further increase the CR rate and ultimately also cure rate in myeloma.

Jenny: In doing lots of these interviews, it has been interesting to figure out which one I would join upon relapse, and I think daratumumab study would be one of my top priorities to look at and see if it would be the best because it's a very exciting idea.

Dr. Sonneveld: Yes, I agree with you completely.

Jenny: In some recent findings, I saw that you had participated in -- it was something called cereblon expression that was important for thalidomide and lenalidomide. Can you explain what that is or what you found?

Dr. Sonneveld: Cereblon is a protein molecule in the myeloma cell. It is important for the activity of iMiDs, so thalidomide and lenalidomide. This has not been a major subject of research in our group, but since we have gene expression data available for a large number of patients from our previous trials, we decided to analyze if cereblon level indeed is predictive for the outcome in patients that receive an iMiD. And indeed it was for patients with a high cereblon level, the effect on progression-free survival was much more significant than a patients with low cereblon levels. So for effectivity of thalidomide and this has also been shown for lenalidomide by another group in the US, you need cereblon in order for it to be effective.

Jenny: And what is that? Is that a gene? I don't even know what that is I'm sorry.

Dr. Sonneveld: It's a protein in the cell. It is involved with NFkB metabolism. Well, this is biology but it's just one protein coded by a gene, and normally it doesn't play a big role in the cell. But in myeloma, it's upgraded in some patients and not in other patients. And it seems to be, cereblon by itself, with also related proteins, seem to be the major target of iMiDs,  thalidomide and lenalidomide, and probably also pomalidomide in the myeloma cell. If you don't have this protein in the myeloma cell, probably the iMiDs will be less effective.

Jenny: Well, that might be an important indicator. How do you test for that?

Dr. Sonneveld: Well, there's no routine test yet. So we got the data out of our gene expression database. But you can also develop a specific PCR technique to look at it. So it's one of the biological targets for the future to look at.

Jenny: And I think new ones are happening all the time, and the better the testing it seems that more things are being uncovered which is very exciting, even though its some biology it's important for patients to know that new indicators are being discovered.

Dr. Sonneveld: And I think one of the major conclusions over the past years has been that myeloma patients are not identical. So you need to know more about the biology of the underlying disease in order to make the right choices, but that will be more and more important in the future.

Jenny: I saw that you had also done some work on autologous transplant versus allogeneic transplant. Would you like to share what you found there?

Dr. Sonneveld: Well, that's correct. Over the past ten years we put a lot of effort in trying to identify the role of allogeneic transplants or donor transplant in patients with myeloma because we thought that -- let's say a graft-versus-myeloma effect would be important if you really wanted to cure patients. So over the years we have treated quite a number of patients, at least 100 to 150 and compared the outcome of those patients with those in the trials that received only the autologous transplant. Unfortunately, allogeneic has not been shown to be superior. So there are some patients that do very well and probably they may be cured, but toxicity of the regimen is too much for too many patients between 25-30% and they do not survive the procedure. So this is why we, at present, put allotransplant on hold temporarily and to see how we can improve the safety of this procedure while maintaining the effectivity in myeloma patients. This is a different from the situation in acute myeloid leukemia where we give allotransplant all the time, the toxicity is less and the efficacy is very high.

Jenny: That's very interesting.

Dr. Sonneveld: Yes. So for this time allotransplant, with more sophisticated approaches to manipulate the graft-versus-myeloma, hopefully, we could re-introduce it in the next few years.

Jenny: And I saw that the Phase III study you were running had something to do with single versus tandem transplant also. Was that part of that study?

Dr. Sonneveld: Yes, I forgot to mention that. In that 1500-patient study we also addressed the question where a single or a tandem autologous transplant would be superior. So this is a sub-question in the trial. Half of the patients received it. Half of the patients who were randomized for high-dose melphalan received one single high-dose melphalan and the other half received a double autologous transplant. And this was treated by analysis of our previous trial that has indicated that a double autologous transplant might be superior to a single one.

Jenny: Are those done more frequently in Europe? I know they are done at UAMS and at University of Iowa and are they -- did that originate in Europe or is that a standard treatment in Europe or how does that work?

Dr. Sonneveld: You mean the double autologous transplant?

Jenny: Yes.

Dr. Sonneveld: Okay. Well, this was not standard both in the US and in Europe. But in some clinics in the Netherlands, also Italy and especially Germany, patients were routinely treated with the double autologous transplant. I don't know how and where this started but it has been in the clinical practice for the past 15 years or so in some of these countries, and people never addressed the question whether a single or a double tandem transplant would be better and there has been retrospective analysis. They never showed a difference. But now when high-dose melphalan is used in the context also of the novel agents like bortezomib and thalidomide, it may be that the tandem autologous transplant has superior activity. We have to check that  and this is why it was one of the sub-questions in our EMN trial because we don't know the results yet.

Jenny: Right. And that will still be the two years that you think?

Dr. Sonneveld: Yes, at least two years.

Jenny: Well, can I ask you a little bit about smoldering myeloma and how you treat smoldering myeloma or what you see on the horizon for smoldering myeloma?

Dr. Sonneveld: You are aware of course, of the Spanish trial, it was published in the New England Journal of Medicine, they have lots of materials in smoldering myeloma. So up to now we have not treated smoldering myeloma, at least not standard, but like in other trial groups, this time we are developing a randomized trial to see a treatment of smoldering myeloma, is useful anyway so not only high-risk smoldering myeloma but also standard-risk smoldering myeloma. Because if you look at the results of Dr. Mateos' trial you will see that in the high-risk smoldering myeloma, even there are patients relapsing within relatively small follow-up, short follow-up, so we think that possibly in standard-risk smoldering myeloma there may also would be a place for treatment. But this is a difficult question to address because many of these patients do not have complaints. They may have years where they will not have complaints. So if you want to treat those patients it's difficult to explain. And so, we are working on a protocol but we are not yet there.

Jenny: Yeah, I think that's the question worldwide, is how does that get treated?

Dr. Sonneveld: Yes, absolutely. It was really nice talking with you on these different issues.

Jenny: Thank you so much Dr. Sonneveld for joining us today. I think your work creating these amazing groups and compiling the number of patients that you are in these clinical trials is going to make a huge difference in patient care. So thank you for being so involved. Again, you resume is completely stunning. As patients, we're just so grateful that people like you are moving the bar forward.

Dr. Sonneveld: We have to get somewhere, don’t we? Thank you for your interest.

Jenny: Well, thank you so much for participating.