Dr. Rodger Tiedemann discusses why myeloma persistently returns and his work to strike at the root of the disease by targeting earlier stage progenitor cells


Originally posted on mPatient Myeloma Radio

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Dr. Rodger Tiedemann, PhD, ChB, MB, Ontario Cancer Institute, Princess Margaret Hospital, University of Toronto

Interview date: October 18, 2013


Dr. Rodger Tiedemann describes why proteasome inhibitors are useful to treat myeloma but will never be a cure for myeloma. He shares how they are more like a persnickety goat, eating the weeds and flowers of the myeloma, but never touching the root. He explains his findings that genes IRE1 and XBP1 cause stress in the plasma cells, which create the M-spike. Interestingly, the earlier progenitor cells don’t have this XBP1 gene and are less sensitive to this class of drugs. He shares how proteasome inhibitor resistance can be either resistance from the get-go before any treatment is given or resistance that is acquired over the life of treatment. 

He takes us back to 10th grade biology and explains the hierarchy of cell production: stem cells regenerate both new stem cells and also multiple layers of progenitor cells, which eventually become plasma cells. He describes his next step to screen drugs to see which ones affect the earlier progenitor cells before they turn into plasma cells to hit both early and later stage myeloma cells. He describes the 8 sub-types of myeloma and describes his search for genes that affect myeloma growth – how he has used RNA screening of 8,000 possible genes to find a short-list of messenger genes that are signaling myeloma cell growth. He shares an open clinical trial that targets the signaling shutdown of one of these genes (XPO1), a drug that essentially “kills the messenger.” He also describes an additional study of his trying to accomplish two things at once: using busulphan and melphalan together before transplant to improve impact on remission and at the same time looking at the impact on progenitor cells. He explains how he is able to overcome past toxicity issues by adjusting the dose of busulphan for patients individually.

The live mPatient Radio podcast with Dr. Rodger Tiedemann

Full Transcript

Jenny: Welcome to today’s episode of mPatient Myeloma Radio, a show that connects patients with myeloma researchers. This is fast becoming a way to get up to speed very quickly on the very latest research and new discoveries in myeloma from experts all over the world. If we understand the research, we can make better choices about our care and about joining a clinical trial.

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I am very happy to be talking today with one of those experts who recently had a new discovery about why myeloma keeps coming back even after aggressive treatment. We have with us today Dr. Roger Tiedemann of the Ontario Cancer Institute and Princess Margaret Hospital in Toronto. Welcome, Dr. Tiedemann.

Dr. Tiedemann: Thank you, Jenny. It’s very nice to be here.

Jenny: Before we start, I would like to give everyone a little introduction for you if that’s o.k.?

Dr. Tiedemann: Sure.

Jenny: Dr. Roger Tiedemann is a scientist at the Ontario Cancer Institute and a hematologist specializing in multiple myeloma and lymphoma within the division of Medical Oncology and Hematology at the Princess Margaret Cancer Center and is an Assistant Professor of Medicine at the University of Toronto with appointments from the Department of Medical Biophysics and in the Department of Medicine.

Dr. Tiedemann is a New Zealand-trained hematologist and fellow of both the Royal Australasian College of Physicians and the Royal College of Pathologists of Australasia. Before pursuing medical studies, he was a national representative to the 29th International Mathematics Olympiad (which is very cool). In 1997, Dr. Tiedemann completed medicine and surgery degrees at the University of Auckland and separately completed a PhD in Molecular Medicine examining lymphocytes activation by superantigens. In 2005, Dr. Tiedemann moved to the Mayo Clinic in Scottsdale as a post-doctoral fellow in multiple myeloma.

In 2006, he won a National Haematology Society of Australia & New Zealand Young Investigator Award. In 2007, he was awarded a North American Multiple Myeloma Research Foundation Fellowship. In 2008, he was appointed as Staff Hematologist position of the Mayo Clinic and from 2009 to 2010 he was an Assistant Professor of Medicine at the Mayo Clinic’s College of Medicine. In 2009, he received an ASH Scholar Award in Clinical Translational Research. Dr. Tiedemann’s peer-reviewed publications include articles in Cancer Cell, Blood, JCI, Journal of Experimental Medicine, Journal of Immunology and the Proceedings of the National Academy of Science.

He’s an author of a US patent application for a new cell cycle therapeutic. His research focus includes multiple myeloma stems, progenitor cells, genomics and the development of new therapeutic strategies for myeloma based on an understanding of the tumor biology.

We are very, very happy to have you on the show.

Dr. Tiedemann: Thank you, Jenny. I very much appreciate the invitation.

Jenny: Would you like to start by kind of giving us an overview of your research or would you like to jump in to this most recent discovery about progenitor cells?

Dr. Tiedemann: Sure. Why don’t we start at the most recent discovery and we can go from there?

Jenny: Okay.

Dr. Tiedemann: Basically, what we did was we were very interested in understanding why we’re failing to cure multiple myeloma with the current therapies and we were particularly interested in why the drugs known as proteasome inhibitors, bortezomib or carfilzomib fail to cure multiple myeloma. Previous studies by others had suggested that these drugs inhibit the proteasome and induce stress in myeloma cells in a number of different ways and that perhaps mutations in the binding site of the proteasome where the drug binds with the proteasome might mediate resistance to these drugs, i.e., the tumor cells escape the drug by mutating the site where the drug is bound and so the drug no longer had an effect.

But that work was all done in multiple myeloma cell lines and it turns out that when you look at the multiple myeloma patients and their tumors, that those mutations weren’t there. And so it seemed that there was another mechanism causing proteasome inhibitor resistance in patients. We tried to investigate for what that mechanism might be and we had previously done a high throughput screen of more than 7,000 genes in multiple myeloma cells, looking for genes that modulated the response of the tumor cells to bortezomib also known as Velcade. We reanalyzed that data and looked for genes whose loss rescued the cells from Velcade treatment and we identified the gene called IRE1. Subsequent work with IRE1 and its downstream signaling gene XBP1 demonstrated that both of these genes could modulate the sensitivity of multiple myeloma tumor cells to proteasome inhibitors.

From that point onwards, we were able to demonstrate that XBP1 expression in multiple myeloma tumors that are resistant to proteasome inhibitors is reduced, at least the expression of genes that are driven by the expression of XBP1 is reduced.

We explored the mechanism by which IRE1 and XBP1 were modulating Velcade resistance in multiple myeloma. After a series of experiments, we showed that the mechanism was in fact not directly through the role of these genes in controlling stress within a certain part of the cell called the endoplasmic reticulum but in fact the role of these genes in modulating the response of myeloma cells to Velcade was in determining the secretory maturation of the tumor cells.

If I can try and put that simply, these genes, IRE1 and XBP1, drive the maturation, the development of the multiple myeloma plasma cells and promote the secretion of the immunoglobulin which we measure in clinical test as an M spike and that by taking away these genes from the tumor cells, the tumor cells started to look different. They didn’t make this immunoglobulin or M spike any longer. As a result, these cells were less stressed and when we threw in drug like bortezomib, the cells didn’t response with the same level of stress any longer. And so it appeared that by unstressing the cells, by taking away this IRE1 and XBP1 genes, that we could make the cells relatively resistant to proteasome inhibition by drugs like Velcade and carfilzomib.

Jenny: Now, I have a question. Are these two genes expressed from everybody with myeloma or certain types or at just across the board?

Dr. Tiedemann: Right. That’s a great question. It turns out that these genes are just expressed in the plasma cells in the plasmablasts of multiple myeloma tumors. So what our work also showed is that multiple myeloma tumors consist not only of plasma cells and plasmablasts but also of earlier progenitor cells that don’t express activated XBP1. I think this was an important finding from our work.

So what our work shows is that in addition to the plasma cells in plasmablasts that we commonly see under the microscope in patients with multiple myeloma tumors in their bone marrow, there also exists rare progenitor cells, earlier versions of those cells which hadn’t yet matured into plasma cells which are less sensitive to drugs like proteasome inhibitors. And the reason that they’re less sensitive is that they are not making immunoglobulin. Their endoplasmic reticulum, the part of the cell that makes the immunoglobulin, the M spike is not really ramped up or geared up into production in this earlier stage cells and so these cells are just least sensitive to the drug.

In fact, we believe that all patients with multiple myeloma, all myeloma tumors have these progenitor cells and that when we target multiple myeloma with drugs like the proteasome inhibitors, Velcade, we just fail to hit this early populations of cells and so we ultimately end up killing the more common differentiated cells that we see under the microscope but not the earlier progenitor cells.

Jenny: Can you describe what the differences are between a progenitor cell and a regular stem cell?

Dr. Tiedemann: Right. A stem cell has certain implications. A stem cell is something that can self-renew almost endlessly and as a result of that, as a result of asymetric renewal when the cell divides, one daughter cell becomes another stem cell but another daughter cell becomes a progenitor cell. It could go on to ultimately mature into some form of a mature tissue cell. Stem cells, if you imagine a hierarchy where at the bottom of the hierarchy there’s a lot of mature tissue cells like plasma cells and multiple myeloma plasma cells, at the very top of the hierarchy is one or only a couple of stem cells that drive the proliferation of multiple levels of progenitor cells and ultimately plasma cells at the bottom of that hierarchy.

Stem cells have a lot of connotations. We avoided the term in our paper because we hadn’t done the work to demonstrate that what we were looking at were in fact stem cells. And I think a lot more of what needs to be done on this in multiple myeloma and in other cancers as well to define what is a stem cell and how many of these progenitor levels have properties of self-renewal and to what extent.

One question that we have in the cancer biology field is if you took out the stem cell with the drug that just got rid of the stem cell, how long would it take for the rest of the tumor to involute and die on itself because it didn’t have that basic root to the system and it might be that it could be quite a long time because the other progenitor levels might have quite the potential self-renewing properties or it might be that you got rid of the stem cell and within a couple of months the tumor was all gone as well. So I think that kind of question has not yet been answered in multiple myeloma and in fact in most other cancers either.

Jenny: And that’s a question to answer in the lab, right?

Dr. Tiedemann: Right. That’s going to be something that’s really going to have to be worked out in the lab with very carefully done experiments. Because I think it’s a very important question because ultimately that’s going to lead us to where we should be designing drugs to cure multiple myeloma or should we be targeting the stem cell or the progenitors or just the plasma cells. I think the answer is that targeting just the plasma cells is not enough to achieve a cure. We do need to go to earlier stages.

Jenny: Are there any drugs out there that target stem cells or progenitor cells right now?

Dr. Tiedemann: There are a number of drugs out there that have attempted to target stem cells through identifying characteristics of the stem cells and then targeting the pathways that appear to be important in them, none of which as yet I’m aware of has shown benefit in the clinical setting certainly in multiple myeloma. So I think more work needs to be done to identify exactly what we need to target in a stem cell and in a progenitor cell to properly eradicate these populations.

Jenny: These cells are resisting proteasome inhibitors and you likened this to the weed analogy. Can you explain that for people who have not read the paper?

Dr. Tiedemann: Sure. If you think of multiple myeloma as a weed and certainly that’s the way I do think of it, then plasma cells or what we see under the microscope which is predominantly plasma cells are like the flowers on the weed and the leaves. These are the things that we see most frequently. But there are progenitor cells, which are like the roots and we don’t get to see them quite as easily and if you like, you can think of the stem cell as a seed at least to the original growth of the plant in the first place.

And then if you think of proteasome inhibitors like a goat, a persnickety goat that comes along and eats the weed but it really only just likes the flowers and the leaves and it leaves the roots behind. So the proteasome inhibitor or the goat then moves on to the next weed and the roots are left behind allowing the tumor to regrow. I think we need drugs that target the roots or the progenitor cells so that we manage to eradicate the weed altogether.

Jenny: Well, I agree. With proteasome inhibitors, why can they be effective for a period of time and then at some point they’re not anymore? Is there any indication about why, for timing purposes, why they might work for a while and then not?

Dr. Tiedemann: Great question. So we think that when we talk about proteasome inhibitor resistance, there are actually at least two major forms of resistance. The first is intrinsic resistance. This is a resistance that we believe is present in tumors from the get-go and when we treat a patient initially with a proteasome inhibitor, we don’t cure that patient from the get-go and that is because of intrinsic resistance which we believe reflects the presence of progenitor cells that are just intrinsically resistant to proteasome inhibition. And then there’s a second class of resistance that I’d like to call secondary resistance or acquired resistance where after a certain amount of time of treatment on a proteasome inhibitor or after a certain number of courses of re-treatment with a proteasome inhibitor, a patient might find the tumor becomes resistant to proteasome inhibitors.

It seems there that that mechanism may in some cases be different to the resistance mechanism that we’re describing. But in some cases, it maybe that the myeloma tumor has developed a maturation arrest, meaning that the tumor cells no longer mature all the way through to being plasma cells but now they stopped maturing at an earlier stage like a pre-plasma blast or even an activated B cell stage. And now, those progenitor cells as we demonstrated are the least resistant proteasome inhibition. And if tumor’s maturation are risked like that, then they are able to escape proteasome inhibitors and grow on treatment. So that’s acquired maturational risk might enable the phenomenon that you’re describing which is progression on treatment. But I believe there may be other mechanism as well that also promote the secondary proteasome inhibitor resistance.

Jenny: I know there’s sort of a debate when it comes to transplantation. Some doctors will say, “Well, gosh. You don’t want to treat really heavily before a transplant because if you do, then you have resistance to those therapies,” and some take a wait and see and they start with the combination therapies including the proteasome inhibitors and then do transplant later. Do you have an opinion on that based on your experience now with these progenitor cells?

Dr. Tiedemann: Right. I think it’s a really complicated question and it’s one that’s very difficult to answer from a theoretical basis. That’s one that’s better answered by clinical trials because there are so many factors that go into whether by keeping the population down with additional treatment that might diminish the emergence of a resistant clone or alternatively that might open up the niche for the emergence of a resistant clone and you’re providing a selective pressure for the development of resistance. Theoretically, you could argue it either way. I think the only answer will come from clinical studies.

Some studies are ongoing looking at that type of question as to how many cycles of treatment are required prior to transplant or is transplant required at all but at the moment I think the answer is yes. Our approach is to try and give several cycles of treatment to get the patient to deal with the issues that have arisen at presentation and get the patient in a better state and get the tumor under control before we go to transplant. That’s probably a pragmatic approach as much as anything.

Jenny: It sounds like proteasome inhibitors even though they might not cure myeloma are still are really important drug class in myeloma.

Dr. Tiedemann: Right. We studied proteasome inhibitors and resistance maintenance primarily for the reason though that these are one of the most important class of drugs for the management of myeloma and I think they still are. I think they are excellent at suppressing the end-stage of the tumor growth, the plasma cells and the plasma blast and for preventing complications because essentially they keep cropping off the weed as soon as it emerges out of the ground. So by staying on proteasome inhibitors and keeping the weed at bay, patients can still do extremely well.

Jenny: And I know everybody is using them. In your article, you mentioned that this discovery had implications for new clinical trials that can be run sort of quickly and what do you hope that next stage of clinical trials does with this new information?

Dr. Tiedemann: Right. So I think because we can identify these progenitor cells and the method for doing that is in our paper, we can measure the amount of progenitor cells in any patient bone marrow and we can put patients on clinical trials where we test any existing drug or a new drug for their ability to attack these progenitor cells and to reduce their frequency in the patient’s bone marrow. And so we can quickly move to clinical studies and look for evidence that drugs do target these progenitor cells. We can start screening drugs in this process and when we identify drugs that do target progenitor cells, then we can combine them with drugs like Velcade that target more mature tumor cells and come up with a combination that really hits the tumor across the board.

Jenny: How do you go about screening drugs? It seems like it is kind of complicated.

Dr. Tiedemann: Right. I think the best way would be to do it in a laboratory setting first and then to take the most promising drugs to clinical trials. We could screen a number of drugs against patient bone marrows in vitro in the lab and then look at their effect on progenitor cells and then take the most promising drugs, put them into patients at known doses if they are known drugs and look and see whether this takes away the progenitor cell population. Also we’re working on developing some better in vitro models of progenitor cells. At the moment, when we work with progenitor cells, we really have to get those cells from patients because we don’t really have any good corresponding model systems in the lab to work with and we would like to develop some models in the lab of progenitor cells so we can do bigger and better high throughput screens to work out the vulnerabilities of these progenitor cells.

 Jenny: And is that done with a bone marrow biopsy?

Dr. Tiedemann: At the moment, we’re doing all our work on primary patient material which comes from a bone marrow biopsy. So all of the work that was included in our paper came from patients that agreed to go on one of my clinical studies where we collect bone marrow samples from patients and correlate that with drug response. I’m very grateful to all patients that participated. I think they really made a big difference.

Jenny: How many patient samples would be considered sufficient for you? I’m just curious.

Dr. Tiedemann: Well, we have a limited ability to process them. Each sample that we process we have to run through our flow sorter machine and then we do FISH analysis and immunofluorescence on multiple different subpopulations so that’s actually quite labor intensive. But we typically process a couple a week and I think that’s been very helpful to us trying to get a better understanding of myeloma biology.

Jenny: And as somebody who has been studying the early stages of myeloma for a long time, do we know what causes myeloma or certain subtypes of myeloma? Could myeloma ever been created by (sounds like treated) in vitro by anybody?

Dr. Tiedemann: To answer the last question first, has it been treated in vitro? There’s been a lot of work done looking at treating multiple myeloma cell lines or plasma cells from patients with various different drugs. A lot of that work often precedes the introduction of a drug into the clinic and the clinical study. A lot of new anticancer drugs that may not have been designed for myeloma go through that process of being screened, to see whether they are in fact active against myeloma cells in vitro.

Jenny: My question is has it ever been created in vitro?

Dr. Tiedemann: Has it ever been created in vitro?

Jenny: Yeah.

Dr. Tiedemann: There’s an animal model of multiple myeloma in mice developed by Leif Bergsagel and Marta Chesi at Mayo Clinic. I think that’s the best model of multiple myeloma that we have outside of patients. Beyond that we’ve got myeloma cell lines that have been immortalized and grown and cultured in the lab but those are derived from patients.

Jenny: Oh, okay. Can we go backwards to my other question? Do we know what causes myeloma?

Dr. Tiedemann: In one sense yes and in another sense, no. There’s been some very good work from Sandra Grass in Hamburg, Germany that has shown that in familial cases of myeloma, where multiple family members have myeloma, which is rare but does occur that it appears that chronic autoimmune stimulation or chronic activation of immunoresponse underlies the development of the myeloma clone. So they were able to show that in those patients, the multiple myeloma was always producing an antibody or an M spike so it targets against a self antigen.

So it was something that was reacting against the host body and in fact what they showed was that in family members who had multiple myeloma, they were all reacting against the same antigen. In fact, even in sporadic multiple myeloma where there may be no known family member who had multiple myeloma, some of those multiple myelomas, they’re also developing an M -pike that is reactive against this same autoantigen.

And so it appears that chronic immune stimulation, a chronic immunoresponse against an auto-antigen is the initiating event perhaps in myeloma. And Ola Landgren at the NIH has shown that MGUS always precedes multiple myeloma. So we can see this chronic immune stimulation in the development of a clone that produces this auto-reactive antibody and then Leif Bergsagel and Marta Chesi and Mike Kuehl and others have shown a number of recurrent genetic mutations that arise in MGUS which are carried through to multiple myeloma. So there were a number of recurrent chromosomal translocations that we see even at the early MGUS stage and then are carried through to multiple myeloma. Leif Bergsagel and others have demonstrated that in fact that it appears that dysregulation of the gene called MYC may be critical in the progression from MGUS to multiple myeloma.

So we have a bit of an understanding as to what’s going on at the genetic level and immunology level in terms of myeloma development. But if any patient came to me and said, “Can you tell me what caused my myeloma?” I couldn’t answer that and trying to answer that would be like trying to look at an avalanche where a billion cells were falling down the mountain and trying to work out what maybe the first — a billion rocks have all fallen down the mountain trying to work out what made the first rock start tumbling down the mountain. It’s very difficult.

Jenny: A follow up question. I guess when you’re talking about genetics, do we know if certain genes like the MYC, one that you just mentioned, create certain translocations? Has there been any work or study a particular gene and a particular translocation like a t(4;14) or an t(11;14)?

Dr. Tiedemann: Right. No, there’s been a lot of work done on that. So the recurrent translocations that you mentioned, 11:14, that regulates the gene called Cyclin D1 which is important making the cells stop proliferating. So those cells, those regulate the checkpoint in the cell biology that would normally stop the cell from growing and now the cell was able to grow and proliferate.

One of the other translocations, the t(4;14) translocation, that regulates the gene called the MMSET which is the gene that puts mark, that’s the gene that produces the protein and that protein puts marks on other genes to switch them on or off. And so by this regulating that one gene MMSET, you actually end up dysregulating the whole bunch of gene throughout the genome of the tumor cell and that may enable it to dysregulate its growth. MYC itself can be, that’s the MYC gene, can be dysregulated by translocation but often it’s dysregulated — that appears by other mechanisms as well.

Jenny: It’s complicated but it would be nice to get it subdivided eventually.

Dr. Tiedemann: Right. I think at this stage we can say there’s at least eight different types of myeloma based on different primary genetic events that are consistent in that patient. What I mean by that is that at this presentation and that later relapsed the genetic event is present in all of the tumor cells. There are at least eight different genetic events that we see in different patients, like that.

Jenny: Would it take too much time to go through the eight just quickly?

Dr. Tiedemann: Ah, sure. I mean they were, again, described mainly by Leif Bergsagel and Marta Chesi: so part of what we call the TC class of myeloma or translocation hyperdiploidy. So in essence, they are the recurrent chromosomes translocation. There’s t(11;14) which does regulate Cyclin D1. The t(4;14) which dysregulates the gene called EFGR3 and also the other gene MMSET. The t(14;16) which is a translocation between chromosomes 14 and 16 and which dysregulates the transcription factor called MAF. There’s another translocation that dysregulates another of the cycle in D genes, Cyclin D3 and then those translocations make up about half of all cases of multiple myeloma.

And then the other half of cases of myeloma tend to have something called hyperdiploidy, meaning that their tumor cells have extra copies of chromosomes, often three or four copies of odd numbered chromosomes when they should only have two copies of those chromosomes. And the hyperdiploid group of multiple myeloma can be further subdivided as to whether they dysregulate the Cyclin D1 gene or the Cyclin D2 gene or both. So it needs to separate down. That simple system breaks down myeloma into eight different, recurrent subtypes that we see recurrently occur in patients.

Jenny: That’s great. Thank you for going through that. I hope it’s not too technical for everybody.

Dr. Tiedemann: Sorry about that.

Jenny: No, no. I think it’s kind of important to understand what type do I have so I can start looking for things that are — and it goes to diagnostics and we’ve been talking a lot about diagnostics.

Dr. Tiedemann: Right. And I think it has a lot of prognostic information, some types do better, some types do worse. And some groups are looking at tailoring treatment based on these different subtypes, trying to give more intensive treatment to patients with myeloma or might be otherwise more aggressive.

Jenny: I’ve done some a little bit of homework and looked at part of your research where there was something called XPO1 and how it grows from MGUS to full blown myeloma. Can you kind of describe what that is and how that works?

Dr. Tiedemann: Right, XPO1. So we came across XPO1 also known as CRM1 initially from a high throughput RNA interference screen. What that means is we did this screen using myeloma cells. We treated myeloma cells with a type of biological reagent called an siRNA which knocks down a single gene and we did that in seven or 8,000 different genes and we looked to see which genes were most important for sustaining the viability and growth of the myeloma or tumor cells. Ultimately, we came down to a short list of 30 or 40 genes that were critical for maintaining the growth of this particular myeloma cell line and XPO1 was one of those genes. It appeared that when you inhibited this XPO1 in the myeloma cells, the cells promptly died.

It appeared to be a potential target for inhibition to treat myeloma and in fact when we knocked down the gene in some normal cells, it appeared to have less effect. There appeared to be a therapeutic window for inhibiting the genes to get some dose of myeloma cells and without affecting the normal cells. I mean, some further work has been done by Keith Stewart and by the group of Dana Farber looking at an XPO1 inhibitor that is being developed. The version that is used in the lab is called KPT-276 and the version that’s used in the clinic is called KPT-330. These are drugs now that inhibit XPO1 or CRM1. What the drugs do is they inhibit this protein called XPO1 which exports protein out of the nucleus or the brain of the myeloma cells.

So if you think of the nucleus of the myeloma cell as the brain, then XPO1 is a little bit like the spinal column that transmits the signals out to the rest of the cell that exports some of the proteins out of the nucleus into the cytoplasm. And so when you inhibit XPO1, you inhibit that transport and you markedly interfere with the biology of the cell.

The KPT-330 is now in the Phase I clinical study for multiple myeloma and for lymphoma. We’ve already had one or two patients with a response to this drug although that is speaking from the lymphoma side. I don’t have much experience in multiple myeloma with it.

Jenny: Well, I think that’s really interesting how we can start targeting a particular gene and then find an inhibitor for that gene.

Dr. Tiedemann: Right. I think that’s the way that drug development has moved over the last decade or so. It’s a very rational design approach based on an understanding of the biology of the tumor cells.

Jenny: And you mentioned an RNA screen. So maybe we can go back to tenth grade biology and you can explain the difference between DNA and RNA and why are you screening RNA.

Dr. Tiedemann: Sure. DNA is how our genes are encoded. Our genetic information is all encoded on this double stranded helix called DNA, which is segmented out into 46 chromosomes in the nucleus. That’s where all our genetic information resides. But in itself, that DNA is relatively inert and it needs to get its message out to the cell to tell the cell what to do, what proteins to make, how to perform. And so it makes another molecule called messenger RNA and this RNA is a transcribed version of the DNA that’s transcribed in the nucleus and then it moves out into the cytoplasm or the endoplasmic reticulum where it’s translated and translated into a protein. The mRNA brings out the message from the DNA to another part of the cell where it directs the production of a protein and it’s really proteins that make the structure of the cell perform all the functions of the cell. Whereas the DNA is the brain, the protein is the muscle and the mRNA is just the messenger in between.

And so when we do an RNAi screen, what we do is we take complementary RNA that binds to the messenger RNA and take it out of action. They basically, they like the antisense of it, of the messenger RNA. They bind to it and cause degradation and so that messenger RNA no longer exists. It’s like the gene from that messenger RNA is not being expressed. It’s like switching off the gene and so we can see what happens to the cell when we switch off one gene at a time using these RNA interference techniques.

Jenny: So you’re basically killing the messenger.

Dr. Tiedemann: We’re killing the messenger but only one messenger at a time and there’s lots of them bouncing around in there.

Jenny: What do you think we need to do to get to more genetic-specific type treatment? What else do you think needs to happen.

Dr. Tiedemann: Well, what we would like to do, I think genetic-specific treatment is great and I think that’s certainly where the field is headed. But also I think we need to be able to address progenitor cells in a more broad sense and so what we would like to do is RNA interference screens in progenitor cells and identify the vulnerability of those cells as well as drug screens in those progenitor cells, just to get some sense of what the best therapeutic strategies might be to deal with these things. Equally we have done RNAi screens in the different genetic subtypes of myeloma so that we have some emerging sense of what the different subtypes are more vulnerable to, in order that we could develop drugs specific for one subtype or another.

Jenny: All right. That’s a great direction to head. Would you like to discuss your open clinical trials and I know that you have some and you can just select which one or ones you’d like to tell us about?

Dr. Tiedemann: Sure. Well, the two I could mention are the Karyopharm study of the KPT-330, so that’s the XPO1 CRM1 inhibitor that is just in the Phase I study at the moment so a dose finding study. But a therapeutic dose level appears to have been achieved now as an early part of that Phase I study. So patients with relapsed or refractory myeloma who are interested in a new drug, a new class of drugs, might be eligible for a Phase I study of this drug and that’s open at a number of different centers including our own.

And then the other study that we have across Canada actually is the MCRN-001 study. This is a study for newly diagnosed patients and we’re comparing transplant conditioning using either the standard of care which is melphalan 200 mg meter squared or a combination conditioning regimen consisting of busulfan and melphalan together. The reason that we’re doing that is that a number of studies demonstrated the busulfan has activity against myeloma cells and in previous transplant studies in multiple myeloma, it appeared that when you combine busulfan with melphalan, you got more durable responses in patients. So their myeloma went away for longer after the transplant.

However, in the initial studies, there was more toxicity with combining the two drugs together and that tended to balance out any benefit from the treatment. But when busulfan was initially given, there was no monitoring of the dose levels. It was a very standardized dose that was given to everyone and that led to more toxicity and since that time we’ve developed a better understanding of how to give busulfan. We can measure the blood levels and we can dose suggest in individual patients and give the dose less toxic to patients. We believe that we can give the two drugs with least toxicity and still achieve that longer response duration and so that’s what the study is designed to do.

I think taking forward the work with the progenitor cells that we described earlier, as part of the study we’re receiving patient bone marrows both at diagnosis and then after a Velcade-based induction and then after this transplant with melphalan and busulfan. We hoped to be able to look for the progenitor cells after the transplant and see whether those progenitor cells are being hit by the busulfan-melphalan combination because I think one reason why this combination of drugs might give longer term responses is that perhaps the combination is eating more into the progenitor level of the myeloma rather than in just the plasma cells and therefore by knocking down the progenitor cells to a lower level that may give a more durable response.

So I think one early outcome measure that we can take from the study might be what’s happening to the minimal residual disease, the minimum residual myeloma that is left behind after transplant both in the plasma cell compartment and in the progenitor cell compartment.

Jenny: Is that how you tell if the progenitor cells are still lurking around, is the minimal residual disease test?

Dr. Tiedemann: Right. I think previous attempts to look at minimal residual disease in myeloma has focused largely on plasma cells although there’s a PCR-based test that probably doesn’t care whether it’s looking at plasma cells or progenitor cells. But I think our work let’s us look specifically at progenitor cells and as we want to take that forward and apply it to clinical studies. This is probably the first one that we are going to apply to, that we are applying it to by looking at progenitor cells before and after this form of transplantation.

Jenny: And was busulfan (am I saying that right?0 has that been used in myeloma by itself somewhere also because I’ve seen that name before but I’m not that familiar with it.

Dr. Tiedemann: It has been used in a number of different myeloma studies in the past and I think the focus of work with busulfan has ultimately led to its combination with melphalan for high-dose therapy prior to stem cell transplant that appears to be where it would be most effective. The studies that have been done to date have been promising and that patients did achieve longer responses but we needed to — I think we need to overcome the toxicity issue first before we can turn around and say this is a better therapy than the standard of care at present.

And so, this current trial is aimed at minimizing that toxicity by doing protocolized blood tests on patients, measuring their busulfan levels, adjusting the levels appropriately so that everyone is getting an appropriate dose. And by minimizing their toxicity and yet still hopefully achieving the longer term responses, I think we will make it a better treatment. I think it will take many years to know whether or not it is a better treatment and gives longer term responses but within several months, the patients coming out from transplant will be able to tell whether or not their progenitor cell numbers are down. Have we managed to diminish those numbers more than a standard transplant? So that will be an early outcome measure that we can look at from the study.

Jenny: Well, that’s a nice way that it seems like to do two things at once.

Dr. Tiedemann: Right. Yeah, we can do both. Why not? We would like an early answer and of course we’ll continue to follow the patients and over time we’ll get an idea of whether it was in fact the better treatment or not but we’ll get an early look I think at the progenitor cells from day one.

Jenny: All right. Well, I don’t want to take too much time with my own questions because I know there are other questions both via email and other callers. I have one last question, what does clinical trial participation mean to you and your research? What could that do for you if we were to increase that?

Dr. Tiedemann: Well, I think moving forward in multiple myeloma requires involvement in clinical studies from patients because we will make no progress unless patients go into clinical studies. For my own research, it’s all based on patient samples. Unfortunately, the best way to study myeloma is to have myeloma tumor cells in the lab that we can study and it’s only through the generosity of patients in providing that material that we’ve been able to understand Velcade resistance in myeloma in the way that we have. So I think it’s critical for understanding the biology of myeloma, for developing concepts that will allow us to develop new drugs for myeloma and then it’s critical for testing out those new drugs. And at the end of the day, it’s the patients themselves that benefit from the work that has gone on before and the work that will follow as a result of being involved in the clinical study.

Jenny: Wonderful. Thank you very much for answering that question and for such a great explanation about your research. We want to open up for caller questions. So if you have any questions about Dr. Tiedemann’s research, you can call (347) 637-2631 and if you have a question, you can press 1 on your keypad.

Caller: Oh hi, Jenny. Hi, Dr. Tiedemann

Dr. Tiedemann: Hi.

Caller: This has been a great interview. First of all, Jenny, you’re living proof that chemo brain can be overcome.

Jenny: I still have it. 🙂

Caller: Pretty amazing questions and answers. Dr. Tiedemann, thank you for dumbing this down for us and taking very sophisticated concepts and making them understandable. Probably one of the most helpful interviews on the subject I’ve heard.

So Dr. Tiedemann, here’s my question. How would someone go about creating clinical trial across multiple kinds of cancers but specific to one gene mutation? I don’t know if this is a fair question for you but if you’re targeting a specific gene mutation but maybe it might be displayed in different types of cancers, is there such a clinical trial across cancers or you’re always just targeting a specific cancer?

Dr. Tiedemann: It’s a great question and those kinds of studies are coming about and I think this is something that the drug companies have been themselves interested in doing and a number of oncologists are pursuing actively. As we move forward with drugs that target specific gene mutations or specific pathways, those drugs maybe active in subgroups of many different types of cancers whether their particular pathway is disregulated in that subgroup of that cancer. And so I think rather than just targeting one cancer across the board in a sort of a random way with the drug, it makes a lot more sense to target patients with different cancers that all have activation of that particular pathway that the drug activates. I think regulatory authorities are open to the concept and I’ve seen one or two studies that have been done that way and there’s more coming.

I think it’s been done a lot already within, say, related cancers, so hematologic malignancies or closely related solid cancers but it could be done even more across the board where a gene maybe involved in breast cancer and maybe involved in myeloma. There may be such genes and I don’t think we need to limit ourselves at least initially based on looking at a single cancer. At the end of the day though, you’re going to have to compare that drug with the standard of care for that cancer and the standard of care differs across cancers. So as you get more and more towards determining whether the drugs are actually benefiting patients in that one cancer you’re going to have develop trials that become more and more specific.

Caller: I mean it’s just a different way of thinking about it as opposed to a location-based cancer. That mutation happened to be located in my kidney or my stomach or breast or brain but it’s the same mutation so why we’re calling — it doesn’t make sense. Rather than saying it’s a location-based cancer, it’s a mutation type cancer and our naming conventions maybe have blinded us from seeing these things more accurately.

Dr. Tiedemann: So what you have just described is personalized cancer medicine. It’s the basis of that and that’s the main thrust I think of where the field is moving.

Caller: All right. Well, thank you.

Dr. Tiedemann: Thank you.

Jenny: Okay. Thank you for your question and for the great answer. So we have another question but from email and this was a question from Carolyn and she asked, “If my doctor doesn’t talk about clinical trials, then does that mean they’re not right for me?” How would you answer the question?

Dr. Tiedemann: Well, that depends. Some doctors don’t get involved in clinical studies or don’t promote them so it could be just an issue with the doctor. On the other hand, often there aren’t clinical trials that are open in the neighborhood near you that might be appropriate to your stage of your cancer. So clinical studies in newly diagnosed myeloma are fewer — there are less of them than clinical studies in relapsed refractory myeloma which are generally open just about anywhere that has an academic center because there’s always a need for the clinical studies in that population group.

It could be either of those scenarios. Either your doctors are quite not necessarily interested in clinical studies or perhaps if you’re newly diagnosed or doing well with the standard care treatment, perhaps you don’t need to be on a clinical study just yet.

Jenny: I know that doctors and patients have great relationships with one another. Without, I guess, disrespecting your doctor in anyway, should you think about participating in a clinical trial somewhere else if that ever looked interesting enough?

Dr. Tiedemann: Yeah, I think so. I think if it was something that appears appropriate to you, then often that’s something that’s quite hard to determine just by looking at the headline for the clinical study. Often there’s a lot of fine print that goes into these clinical studies as to who can go on them and at what stage their myeloma has to be at. But I think if you’re interested in enrolling in a clinical study, you can of course always discuss it with your physician and if you’re not satisfied with the response you could always get a second opinion. But I know, Jenny, that you’re going to be working on putting together clinical trials website that maybe a little bit more accessible to myeloma patients. Otherwise, there’s always clinicaltrials.gov but it’s, as you know, it’s quite difficult to navigate through there.

Jenny: Oh, yes. Well, there are 540 open clinical trials on that.

Dr. Tiedemann, we are so grateful that you are participating today and we’re so thankful for your great work in the field of myeloma. We wish you the best in continuing your excellent research and your work.

Dr. Tiedemann: Well, I very much enjoyed it. Thank you for having me, Jenny.

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


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