Full Show: Liquid Biopsies in Multiple Myeloma with Dr. Irene Ghobrial, MD, Dana Farber Cancer Institute

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multiple myeloma

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Irene Ghobrial, MD
Dana Farber Cancer Institute
Interview Date: September 27, 2017

Summary
Myeloma patients hate the bone marrow biopsy, which can determine the level of tumor burden as well as the genetics of myeloma. These biopsies are a literal pain in the butt for patients who see them as a necessity to gain information about how their disease is trending before and after treatment. Dr. Ghobrial shares the exciting news of the in-progress development of liquid biopsies (or biopsies taken from blood samples) that could track the DNA that is left when cancer cells die, but are still circulating in the blood. This great development would ease the burden on myeloma patients and would add incredible value to track the disease from early precursor stages through advanced disease with all of its iterative genetic changes. It would be particularly helpful for patients who have no M-spike (or are non-secretory). Learn more about how this new technology could dramatically improve patient’s lives.

Dr. Irene Ghobrial on Myeloma Crowd Radio

Full Transcript

Jenny: Welcome to today’s episode of Myeloma Crowd Radio, a show that connects patients with myeloma researchers. I’m your host, Jenny Ahlstrom. This is 103rd show, and I’d like to thank our episode sponsor, Takeda Oncology, for their support of Myeloma Crowd Radio. This month, in honor of Blood Cancer Awareness Month, Takeda Oncology is also sponsoring the Myeloma Crowd in their Music2FightMyeloma program. You can take two quick actions to help fund myeloma research that is supported by a Myeloma Crowd.

First, you can take a selfie and post it on Instagram with the #Music2FightMyeloma. Second, you can follow the Takeda Oncology Music2FightMyeloma playlist on Spotify. For each of these actions, Takeda will make a small donation to the Myeloma Crowd. You can find an article on our website with more detailed information, but we only have three days left to take advantage of this generous offer and the actions are so simple.

Now, I’d like to make a happy announcement that we have reached our $500,000 goal for the Myeloma Crowd Research Initiative. This is fabulous news for an effort that spanned two years to raise funds for high-risk research. If you aren’t familiar with this program, we asked the myeloma experts on our scientific advisory board what the biggest need was in multiple myeloma. They said it was high-risk research. So we invited researchers around the world to submit their projects. We received 36 proposals and our board helped narrow that to a top ten. We then held radio shows like this one for each project so you could learn more.

And with the help of our patient advisory board, we voted on two specific projects. One is a CAR T-cell research project at the University of Wurzburg targeting CS1 and BCMA, and the second is called MILs, which is an immunotherapy used with stem cell transplant from Johns Hopkins. And hopefully, you know by now, CAR T-cell research is some of the most exciting work in the world, so I am just proud to say that our process worked.

Two years before it was making news, we were able to identify this type of game-changing work and helped fund it, which to me is completely remarkable. We know that patients can make a difference and help accelerate the pace of research. This is one specific way where we’ve actually done it, and we have you to thank for this great success.

We also have researchers like in today’s Today Show to thank for doing the important work to bring new solutions to the clinic. This collaboration between patients and researchers really is a model for how more cancers and diseases could find cures. Dr. Irene Ghobrial of the Dana-Farber Cancer Institute is on a Research Initiative Scientific Advisory Board and her expertise helped select these projects early.

Now today, we may have both she and Dr. Solomon Manier – also of Dana-Farber – online, and maybe just Dr. Ghobrial. Dr. Manier is calling in from France, so that may be a bit of a challenge. But we know the topic today is a very exciting one, and so we would like to welcome you, Dr. Ghobrial, to the program.

Dr. Ghobrial: Thank you. Thanks, Jenny. And again, congratulations on reaching the half a million dollars, and hopefully we can get to one million if possible.

Jenny: Yes, I think we’ll just keep going.

Dr. Ghobrial: Yes, absolutely.

Jenny: Well, let me introduce you before we get started. And I don’t know if he is able to call into your cell or your phone line and connect that way. But if not, we will just move forward.

Dr. Ghobrial: Sure. I mean I’m happy to have him call me. I’m just not sure how will that work. But I think we should just go ahead and get started.

Jenny: Okay, sounds great. Dr. Irene Ghobrial is Associate Professor of Medicine at the Harvard Medical School and Director of the Clinical Investigative Research Program at the Dana-Farber Cancer Institute. She is Co-director of the Center for the Prevention of Progression of Blood Cancers, which has a focus on early precursor conditions like MGUS and smoldering myeloma, and is also the Co-Director of the Blood Cancer Research Partnership, is Chair of the Egypt/US/ EU Joint Collaboration Initiative Meeting and a Co-chair of the European Society of Hematology Multiple Myeloma Meeting.

Dr. Ghobrial serves on many national boards including the City of Hope Scientific Advisory Board, the Medical and Scientific Affairs Committee for the Leukemia and Lymphoma Society and is on the Scientific Advisory Board of the Myeloma Crowd Research Initiative as I mentioned earlier. She is a Chair of the ASCO Scientific Committee and Chair of the Scientific Committee on Plasma Cell Neoplasia for ASH. She is an ad hoc reviewer for over 32 major blood cancer publications and is a member of the editorial board of Blood Clinical Cancer Research and others.

Her most recent awards include the 2015 Women in Medicine Award from the Whitetulip Health Foundation and the 2017 Ken Anderson Young Investigator Award from the International Myeloma Society.

Just a little background, she’s had a collaborator on this project named Dr. Solomon Manier, Instructor in Medicine at the Dana-Farber Cancer Institute. He received his medical degree from the University of Paris in France and his PhD from the Université de Lille in France. He is focused on the creation of these liquid biopsy tests and a genomic and epigenomic dysregulation in multiple myeloma.

So Dr. Ghobrial, maybe we want to just start because I watched a little bit and tried to do a little bit of homework. And there was a lot of discussion about cell-free DNA or cfDNA and I had never heard that term before, but maybe you can start by explaining what is cfDNA.

Dr. Ghobrial: Absolutely. So cfDNA or circulating-free DNA is one of the two or three things that we look at in something called blood biopsies or liquid biopsies. And the whole idea is can we use the blood samples instead of doing bone marrow biopsies or doing tumor biopsies for other cancers. So this is not just unique for myeloma or Waldenstrom’s or smoldering disease, but it’s truly for every cancer. Can we find all the changes that happen in a cancer by looking at the blood?

And one of the things that’s very unique here is all the cancer cells, when they’re dying, they shed off or they let go of their DNA, and it has to go out in the blood before it goes to the urine, and that’s how we get rid of it. So while it’s in the blood, we can actually now, because we have all the new technologies, something called next-generation sequencing, we can take a blood sample, and I believe that DNA that’s in there, and actually try to understand what are the changes, meaning all the DNA changes that happen in a cancer cell, by just looking at the blood sample.

The beauty of it is that potentially this could change the way we think of doing bone marrow biopsies, but it can also help us understand what’s going on in a patient as a whole. Instead of taking one sample from one area, what if the patient has another cancer in another — or the same cancer, but in another area, and it has different mutations or different chromosomal changes? So as the technology improves more and more, hopefully this will actually come to the clinic where patients can get one blood sample and understand better what’s going on with their disease.

Jenny: I think patients are so excited for this opportunity, and it’s just incredible. So as you said, it’s just a simple blood draw, right? It’s nothing more special than what we always get when we go and get a lab draw or something.

Dr. Ghobrial: Absolutely, exactly.

Jenny: Is that correct?

Dr. Ghobrial: Correct, yes. It’s just one blood sample. It’s the same sample that we usually do but by taking a couple of tubes extra for a research for now and hopefully for clinical samples in the future.

Jenny: So when you hear about multiple myeloma, I know you’re talking about other cancers that you’re trying to use this across the board for every type of cancer potentially. But in multiple myeloma, we always hear about circulating tumor cells in the blood or circulating plasma cells and how that kind of indicates a more aggressive type of myeloma. But this is completely different from that approach, correct? It’s not really related?

Dr. Ghobrial: No, it’s not related, but in a way it is related. So circulating tumor cells, so in the blood, there is, of course, all the circulating regular cells — the red cells, white cells, and so on. There are the circulating tumor cells which we can isolate also, and then these are just pieces of DNA, fragmented pieces of DNA that are circulating free, and that’s why we call it circulating-free DNA. So it’s not inside a tumor cell like a circulating tumor cell.

In fact, we try to ask this question – exactly what you’re asking. Can we compare a circulating tumor cell content, the DNA inside the circulating tumor cells, compare to the circulating-free DNA which is just in the plasma, and try to see do we understand or do we get information from one better than the other, or when we combine them together, do we get much more information compared to a bone marrow biopsy?

So the bad thing about the circulating tumor cells is you need to get the sample fresh. You have to isolate the cells quickly before they break off basically. So sometimes it requires a little bit of more technical work. You need to sometimes have to do something called flow cytometry or bead selection. So it needs extra work on the blood sample once we get it, and that means that maybe shipping samples across states or things like this may be challenging, and we may lose some of the information.

The circulating-free DNA, the good thing about it is you don’t need any of that. You just spin the sample down and you take the plasma or the serum and it’s good to go. So it’s a much easier way to get the information. However, they are different. Circulating tumor cells may have much more information in some areas and the circulating free DNA may have other information. And we actually compare the two head to head in the same patient, and we find that interestingly when you do a bone marrow biopsy on a patient as well as the circulating-free DNA from their blood and the circulating tumor cells also from their blood, on the same day, you can get all the information and even much more from the blood samples when you’re combining both circulating tumors cells and circulating-free DNA together. But one of them is actually almost as good.

So 90% of the information is in each of those compartments, is in either the circulating-free DNA or the circulating tumor cells. And when you combine them together, it’s much better than even doing a bone marrow biopsy because you get information about other areas where the myeloma is present and is hiding other tumors with other mutations.

So it’s very exciting for us because potentially if we take this to the clinic, we could understand everything that’s happening for a patient from the MGUS stage all the way to myeloma and relapsed disease and post-treatments by just doing blood samples.

Jenny: Wow. That’s so incredible. Do all myeloma patients, like even in these precursor conditions, have some circulating tumor cells? So you can combine these two things, or only a few patients have the circulating tumor cells?

Dr. Ghobrial: Yes, great question. Some patients may have very, very small numbers of cells circulating, or circulating-free DNA. It’s a very, very low content again because they have a very small amount of tumor in their bone marrow. However, we are developing now something called deep sequencing, meaning can we go even deeper to try and find even if there is one or two molecules of DNA, can we capture those and get it?

So as we get much more sensitive in our detection level, we may actually find that all MGUS patients have something, and we were just not detecting it earlier because our technology was not good enough. And that would be beautiful because in the future, I can see someone who has MGUS, detect the information, and say if they would progress or not. In fact, with the technology we have right now, with something that we collaborated with the Broad Institute I’m doing, we took samples from about 150 patients including MGUS and smoldering and real myeloma, overt myeloma, and we did something called whole genome sequencing but a very lower level, at 0.1x. And the nice thing about this is that it can be used very fast as a screening method, and it only costs $20 to $30 per sample. So it’s a very cheap technology to get at an answer.

Jenny: Wow.

Dr. Ghobrial: And when we just look at the amount of DNA, the tumor’s DNA that’s in the blood, it actually correlates with progression. So patients with MGUS had a much lower level than smoldering higher, than myeloma higher. So we’re trying to see if that can be used to potentially predict who will progress and who will not. Can we use it as a prognostic marker for patients? If I see someone today with MGUS or smoldering, can I use some of this technology to not just reflect what’s in the bone marrow but also to tell me this patient will likely progress to real myeloma or this patient will likely relapse from their disease.

Jenny: And you’re looking at level of disease, amount of tumor burden basically. Is that right?

Dr. Ghobrial: Exactly. That’s it. And then within that, you can actually find copy number alterations which is basically if you have certain deletions of chromosomes for example if I have 1q amplification or a 1p deletion or I have a 17p deletion, we can detect this in that same very cheap method of technology.

Jenny: Wow. It’s so amazing. So a couple of questions, how long do these — you mentioned the CF cells, they die or the cells die and then they have this DNA marker basically. And they’re in a blood for a time and they go through the urinary tract and are extracted out of the body. How long do they stay in the body?

Dr. Ghobrial: Great question. We don’t have a very strong answer, but it may be just two hours or so. But more of it comes and more of it comes and so on. So there is constantly free DNA in the blood.

Jenny: Okay. That makes a lot of sense. Myeloma is so complicated and then sometimes you’re killing one clone, and then another clone is growing up. So if the test is $20, then run it all the time. I don’t know.

Dr. Ghobrial: Yes, I know.

Jenny: It may be great.

Dr. Ghobrial: Unlimited samples, right? So as we get samples from many of the patients once a month or once every three months, we have actually in that paper that we submitted, some of the samples serially and it can show that indeed that can help us a lot in finding out who will progress and who will not because you have multiple samples from the same patient. I agree with you, we would love to take that to the next step of making it into clinical practice, but it needs large samples, prospective cohorts, and a lot of, of course, funding for that idea.

Jenny: Well, I want to come back to that a little bit later because I wonder if they can use the same model that you have used for your MGUS and smoldering myeloma study because I think that’s really unique and wonderful. So can you share a little bit about how this was developed? Because this is really a huge game changer for patients.

Dr. Ghobrial: Yes, I mean the original idea of using circulating-free DNA was done for other cancers over the last few years. It’s a very hot topic because originally when we were talking about lung cancer or breast cancer and if you have to go in and take a biopsy especially when it’s a very invasive procedure, so for many years we have been trying to find a way that reflects what’s happening in the tumor.

And now we said, well, myeloma is also a disease that’s hiding in the bone marrow and many of those tumor areas, what we call multiple myeloma or multiple areas, could not be understood by just one single bone marrow biopsy. Remember, we just put a needle in one area of the bone marrow. We don’t know what’s going on in the other areas of the bone marrow. And we know very well, like you said, that a certain clone can develop, let’s say, in one of the areas in the back and we have no idea what’s going on in that vertebra of the back, let’s say T11 or T12 when we see just the sample from the hip, from the bone marrow.

So we’re missing a lot of information that could be very useful for that resistance. And hopefully, with this new technology and was getting even better as deeper sequencing happens, we can truly understand the whole myeloma in the body and not just one area and then reflect that for decisions of treatment for MRD, for progression, for so many questions to be answered.

Jenny: Well, this is an important point and I don’t think that a lot of myeloma patients know that, that when they get a bone marrow biopsy and the samples taken out, you’re just looking at that, like you said, that one area of your hip and you can have something, like you mentioned, in your spine that could have totally different myeloma genetic features. I think most patients don’t know that.

Dr. Ghobrial: Yes, absolutely. And that’s why we’re doing this together.

Jenny: It’s great. So when you were talking before about the whole exome sequencing or the whole genome sequencing, you were talking about counting the tumor burden. But are you counting the tumor burden or just the genetics using this new liquid biopsy type test?

Dr. Ghobrial: This counts both. So it counts for us the tumor fraction, the tumor DNA fraction inside the whole blood, so this is a percentage of how many tumor DNA fractions are there. So if I have 5% or 10% or 20%, a reflection of the tumor burden, it’s not an exact number but it’s a reflection of how much tumor burden you have. And then within that, the type of DNA you have, it can tell me if they have large chromosomal amplifications or deletions. We’re working on actually getting a method to count also translocations. That’s a harder one to do, but we’re trying to get it done. Then you can also get mutations if you do the whole exome sequencing in those same samples. So I can get to know if the patient has a KRAS or NRAS mutations which are the well-known mutations of myeloma and so many others.

So all of this can be done with the technologies that we have so far, and we’re developing even better technologies for deeper sequencing where I can get all the information with minimal amount of DNA.

Jenny: Wow. I think it’s stunning. So this is considered, this is called next-generation sequencing, right?

Dr. Ghobrial: Correct. All of these technologies are a part of next-generation sequencing, correct.

Jenny: And then I was reading just a little bit about it and I talked about how when you take these samples and you can extrapolate the numbers I guess. Is there a process to do that, or is it just part of the whole test?

Dr. Ghobrial: It’s part of the test. So we basically take the sample. We get the DNA, we purify it and do a few more procedures, and then we sequence it as deep as we want to. And based on that, we get all of that information. If there is a certain level of DNA, then we can go to the next step of whole exome sequencing. If it’s too low, this is where we’re thinking of the deep sequencing with the targeted panel.

Jenny: And how long has this been in development?

Dr. Ghobrial: So it’s still in development. Every few months, we come up with a new idea. The best thing is that we’re working with the Broad Institute, and I have to say they’re truly at the cutting edge of all the technologies. And every few months, we say, oh, we just got to a better level. Oh, we just got into much better ways of doing things, and we improve on what we’re doing. So it’s always a dynamic process of improving on the technologies that we’re using, and that’s the beauty of it. It’s so fast how much the technology is developing now, and we can really use it for our benefit for our patients.

Jenny: I think the collaboration that you have with the Broad Institute and the Harvard Medical School is really remarkable, because you have so many different facilities that are in partnership with each other and it really give you this advantage to be able to work with so many talented researchers. I think it’s truly amazing.

Dr. Ghobrial: It is, absolutely. I mean I can tell you it’s like a kid in a candy store. I’m always excited to see how much we can do, but also translating it to our patients is the best thing, right? Because the engineers can develop the best technology but if they don’t take it to the next level, if they don’t know what are the clinical questions and what are the needs of our patients, then it doesn’t help. So it’s truly that collaboration that we have that makes a huge benefit because we ask questions and they say, “Oh, yes, I have this technology. Why don’t we use it?”

Jenny: Amazing. So I was also doing a little reading that said that about the levels of cfDNA. So how do you know if you have enough cfDNA in a blood sample to be able to get relevant information from it?

 

Dr. Ghobrial: I mean this is easily measured. The one interesting thing is right now, we take only one or two tubes. The question will be, do we need more and will we get information more, or can we use the urine when we do the 24-hour urine protein electrophoresis? We collect all that urine. Could that give us even more sensitive results, or can we get serial samples? You know, several tubes in a row, would that help us get more information? So of course, the more blood we have, the more DNA we have, the more information we can get. But also, can we improve the technology that’s even with minimal DNA, I can go to the next steps?

Right now, what we do is I deliver DNA. If we have enough of it like 10 nanograms and we can go to the next step, which is going on the sequencer, if the sequencer gives us information that’s more than 3% of circulating-free DNA is there, then we can actually say, okay, this is good enough for us to trust the data. If it’s less than 3%, we don’t trust the data that much. And if it’s about 10%, we take it to whole exome sequencing. But again, the ones between 3% and 10%, we may be able to still get information from them with doing the deep sequencing. So we have certain levels and certain benchmarks to reach.

Jenny: So when you say you kind of move to these different levels of testing and maybe there are deeper tests, so I understood that the whole genome and the whole exome sequencing were much higher costs like $1,000 or $2,000 or something like that. You’re saying you can use this $20 test, then it will do a certain level. And then how much right now is the whole exome and whole genome sequencing? Has the price come down? I’m just curious.

Dr. Ghobrial: It’s starting to come down. Every year it gets lower and lower. But right now, average is about $1,000 for a whole exome sequencing. Average is about $2,000 to $3,000 for a whole genome at a certain depth. I mean once we’re doing with those samples, they still hold genome but at the 0.1x, and that’s why it’s $20 because you can put so many of them on the sequencer. Again, it’s not just $20 but on the sequencer, it’s about $20. But of course, there is cost to process the samples ahead of time. There are all those kits that you have to get ready. But it’s still cheaper than on the sequencer itself, $1,000 or $3,000. And that gives you sort of the first view and then those samples that have a lot of DNA, you can go to the next step that’s then more expensive.

Jenny: That makes a lot of sense. So let’s talk about frequency. So you said serial samples. When you get a bone marrow biopsy right now, I know people want to limit the amount of biopsies that patients have to get. So can you compare the traditional timing and decisions about when to do this on a standard bone marrow biopsy versus this type of method?

Dr. Ghobrial: Yes, I mean this is whenever you are going for a blood sample, it can be used to measure how much you have as well as what’s going on with the genetics of myeloma. So let’s say you’re on a clinical trial or on treatment, you usually go to your doctor once a month to get your CBC, your chemistry, checking the liver function set, making sure your kidney function is working well. That’s a blood sample. Think about getting an extra one or two tubes for that study and you get to know if your disease is improving significantly or not. Are you getting a new clone of resistance or not? So it can be added to any of the blood tests we do routinely once a month for our patients. Just like we check the M-spike once a month, this could be the next step of checking the tumor information.

Jenny: And then you kind of hinted this a little bit in your last comment, but how would this impact the way that you treat multiple myeloma?

Dr. Ghobrial: So exactly that, as we get better and better in developing new methods of personalized medicine or precision medicine, let’s say that we have an (11;14) translocation and it’s a clone that’s growing now in a patient, then maybe we can use specific drugs for that, something like venetoclax. Or let’s say that the patient is not progressing but there is a p53 mutation clone, well, maybe that patient will not respond well to traditional therapy. Let’s think of immunotherapy or something more aggressive for that p53 clone. Or it can help us understand progression from MGUS and smoldering to someone who is now having multiple clones and significant progression and will go on to result in myeloma. So let’s watch them more carefully or put them on a clinical trial to prevent progression.

So in a way, it would affect how we make decisions, but again that’s the next step of trying to develop this into a clinical practice.

Jenny: And how about mutation resistance, could you watch for treatment resistance as well?

Dr. Ghobrial: Absolutely. Again, the same idea is as we understand better why there’s patient resistance, is it because of the clone growing that’s a resistant clone and which one it is? So give this a deeper level of not just saying, oh, the patient is resistant to Velcade and dex. But why? And how can we change therapy and would it respond now? This clone will respond to the next therapy or not. So it gives us more knowledge of what is going on, plus it’s more sensitive than just checking an M spike in a light chain, which are also a reflection of what’s going on in the cancer cells. But this is a true reflection. This is the genetic reflection of what’s happening in the cancer cells.

Jenny: So if a patient has a plasmacytoma also, this would probably work just as well, right? I mean if they don’t have, let’s say, active myeloma in that sense and they have a simple plasmacytoma or something. Could you still use this test for that?

Dr. Ghobrial: That’s a great question. We have not tested any patients with solitary plasmacytomas, and that could be a great question. We could potentially, if we have enough patients interested, ask that question, get blood samples from them, and see very well how was the detection level and do they respond to the radiation therapy or not? It’s a wonderful question.

Jenny: And I know some patients may have had the gene expression profile, but this seems to be — it might give you more information than that and be lower cost. Can you compare and contrast the two different tests just for people?

Dr. Ghobrial: Yes.

Jenny:  Yeah, I think it’ll be helpful.

Dr. Ghobrial: Sure. So the gene expression profiling is for the RNA level while this one is called the DNA level. We’re also developing it for the RNA, so there will be RNA expression studies also on the circulating-free RNA or from the circulating tumor cells. In fact, we are already doing that for the circulating tumor cells too. But they are very different. So remember the DNA gets translated to the RNA, not all of the information will show up in the RNA. So a lot of those mutations may not be defective in RNA. RNA is just an expression of a gene if it’s going up or down. So very different tests giving you very different results. And all the way of doing gene expression by something called Affymetrix is sort of an older technology. This is now the next generation technologies, two completely different and giving us a very deep level of understanding compared to the old way of thinking.

Jenny: I think it sounds wonderful. So I know patients are excited about this type of thing and would love to see it as soon as possible, so let’s talk about timing maybe. When do you anticipate this coming into potentially a clinical trial?

Dr. Ghobrial: We’re already taking samples to all of my clinical trials in smoldering myeloma. We’re already doing that routinely as a research sample as part of it, and many of the ongoing trials here at Dana-Farber up front for myeloma, we’re adding it already in the mixture to make sure that we take it prospectively on all our patients. But I think it will be wonderful to ask the question, what are the requirements to get this into clinical practice? How many patients? And really taking it to the next level or really having it available for everyone. You can order the test and your insurance covers it and you’re done. This will require a little bit more work, but I think it absolutely can be done.  

Jenny: If you say you need it to run as a large-scale clinical trial to gather the data and see how it’s all being tested, would it start as like an observational trial where you just send in samples or how would that work? Or would it be part of the treatment trial?

Dr. Ghobrial: So two ways. Right now, we’re doing it on all our PCrowd samples to anyone who is part of our MGUS and smoldering prospective collection of patients who are following us. This will be part of it. Already we sequence many of those samples. But also on large prospective clinical trials, this could be added as one of the courses and then can be used to understand better the disease. So we’re trying to negotiate with some of the people either in the US or in France.

So Solomon, for example, and he couldn’t join us today because of the call-in number, but he is indeed trying to add it already in the large prospective French studies so that as we get the clinical information, we also get the cfDNA information and maybe use that for approval to get the test done clinically. So hopefully, we can follow up with him on this, but this is where potentially we can get the huge benefits from large trials accruing 600, 800 patients. And we can truly say that this is prognostic for them.

 

Jenny: And I think people in the United States don’t really understand how the trials work in Europe, but I think it’s kind of helpful to know that a lot of patients are kind of — I don’t want to say corralled, but encouraged to join the clinical trials that run in their large, really large-scale trials and they have a lot of patients in them. So that sounds like it would be really great to have that run in the French group because they typically get hundreds of patients in these larger clinical trials.

Dr. Ghobrial: Yes , we do have also here clinical trials that are very large, but the accrual rate is much faster in Europe partly because of the way they practice and partly because they may have not had access to certain drugs. So lots of questions partly because they all go to academic centers where they all agree on the same trial. So it’s very different, but yes, definitely accrual is different in Europe and they can run a thousand patient trial much faster and get the information.

Jenny: Right. Well, you mentioned the PCrowd study, but I think it would be interesting for you to elaborate for a few minutes on this study because people may not be familiar with it. And what I think is important that maybe patients could do is the way that you have samples shipped to you. So maybe first you should just talk about the PCrowd study and what you’re trying to accomplish with that study, and then we’ll talk about the samples and how they’re gathered and collected because I think patients would be so willing to do that.

Dr. Ghobrial: Absolutely. So PCrowd stands for precursor crowd and just like yours, Myeloma Crowd, we were trying to crowdsource for patients and really to have this initiative that’s empowering patients to be part of a commitment to say let’s all together work on understanding what happens with progression from MGUS and smoldering to overt or symptomatic myeloma. And to do that, we need large numbers of patients with their sample so that we can understand better the disease.

Originally, we said instead of using the old ways of thinking of when you come to the hospital and you get seen, one of the physicians will consent you on this sample way and then we collect the sample. Let’s actually remove the physician as the middle man, because we don’t do a very good job, and let’s have the patients truly empowered to be part of that research. So we put it all online. Patients can go on that website for PCrowd. They can consent online. They give us access to their clinical information we collected and track their health, but we’ll also give them a new tool soon as we collaborate with the Broad Institute to track their health with it. We send them a kit by FedEx that they can get their blood or bone marrow samples drawn whenever they go to their local doctors, so they don’t have to go to a specific place. And then when we get that shipment back, as we go on and we collect those samples, we’re starting to sequence many of those samples and get large cohorts of information.

We’re hoping actually, we just got the collaboration with the Broad Institute and MLRS and some of the companies to create a website where patients will potentially also get their information in aggregates, not as a single personal level because that will be clinical information but in aggregate. You know, every 100 patients or every 200 patients we sequence, we put all the data out there so that they can see what’s going. And hopefully, that can help us understand who truly will progress in their lifetime from MGUS or smoldering myeloma to real myeloma, and what are the mutations and changes that happened in those early stages of the disease.

So if I’m 40 years old and I have MGUS or smoldering, likely I will develop myeloma in my lifetime, and I want to know my chances of progression. Will it happen next year, in five years’ from now, or will it happen 30 years from now? And how do I prevent that from happening and what’s going on with my disease? And these are all those questions that we’re doing with the PCrowd study.

Jenny: Well, I think that study is really unique, and I think what’s so unique about it is that patients can participate no matter where they are. They don’t have to come to your facility and they can just ship you samples on a regular basis. So a question about that, is this something that you could translate to the cfDNA where patients could get a sample taken and send it to a central facility or something, so someone could look at the test results? Because patients would gladly do that.

Dr. Ghobrial: Yes, absolutely. I mean this is exactly why we’re doing the cfDNA on all the samples because we can get information even before we get a bone marrow biopsy. So whenever patients are sending us blood samples, it gets routinely part of that cohort of information. And we would love to send that not just to PCrowd but also to other myeloma samples and other trials. Again, in the sense we cannot do that without a purpose, how many samples, what’s the endpoint; otherwise, this becomes very prohibitive cost wise. But as part of research, this is what we’re trying to do.

Jenny: Would the samples travel well? I know sometimes myeloma cells are taken out of the bone marrow or microenvironment. And then once you get them to the lab, half the cells or more died and so it’s not really helpful. So is this something that will stay in the blood sample so you can actually track it, or does it have to really be done well locally?

Dr. Ghobrial: No, it can be shipped and actually there are specific tubes that can keep the DNA completely perfect for us to take it up to even one week after getting the sample done. These are called track tubes, and we’re getting even better tubes in the future. But these track tubes that we’re using now in many of the trials are perfect for that. It can be shipped without any issues.

Jenny: Amazing. And you mentioned that you’re using it in clinical trials right now. Do you know or have an estimated time frame where this could be used in other clinical trials or in expanded clinical trials where people could send you samples or things like that? I know it’s hard to say that, but I’m just kind of wondering, are you looking at a year from now or five years from now? Just to give people an idea of how fast it is progressing.

Dr. Ghobrial: I think we need to have a plan of how can we get this approved by the regulatory group so that insurances can cover it. And based on that, how many sample need to be done and go from there. And that would require specific amount of funding for that question. So we’re working on putting together a proposal to go for this specific question. If we get it done in a year or two depending on, of course, accrual of the trial because we need the data of sequential samples. So it needs to have the followup of two or three years based on that trial.

Jenny: Well, I think that’s something that patients might want to help you fund, because I know I am not the only one that has developed probably a fear of the bone marrow biopsy. I had a friend who has had 38 and it just — yeah, just the thought of that is no good.

Dr. Ghobrial: Yes, absolutely.  I totally agree. If I was a patient too and getting bone marrow biopsies 30 times, I would not be happy.

Jenny: Yes I know, that’s not good. How can patients, in your opinion, help accelerate the progress of this and the adoption of this?

Dr. Ghobrial: Well, I mean maybe we can propose that we work together on creating that idea of how can we take that to the next step of clinical approval, right? How many patients, what are the requirements, and what’s the funding required and we can just get that done together. And patients will be part of it to get it approved. And that’s the beauty of this.

Jenny: Yeah, I think it’s a great ideaI just know that patients are — at any time like with your study, patients have been very willing to send you samples, and they’re very happy to answer researcher questions when asked, because we all want to help accelerate a cure for this disease. And this test, not only is it more convenient but it gives you so much more information that I think a lot of patients would be really motivated to help make it a reality. So I think we will have a follow-up conversation about that.

Dr. Ghobrial: Absolutely.

Jenny: So do you have any other thoughts on the bone marrow or these liquid biopsies that you’d like to share with the patient community?

Dr. Ghobrial: No, I think as we develop newer technologies, this will become even better and better. I just said we’re trying to develop a new way for getting the translocations. There is a new technology called Sherlock which just came out a few months ago where potentially these could be just on a piece of paper, we can transmit the information and get all the sample — you know, put there and then you get this genomic test done. So blood biopsies will explode more and more and we’ll get more information. What we’re lacking is exactly what you said: bringing it to the patients immediately and not waiting years and years because people are asking research questions that are not truly clinical questions. And I think this is the power of patients in moving things forward much faster.

Jenny: Well, I think it’s something we could sort of be pushy about because no one likes to get the biopsies.

Dr. Ghobrial: Yes.

Jenny: They’re really bad. Well, I would like to open it up for caller questions. So if you have a question for Dr. Ghobrial, you can call 347-637-2631 and press 1 on your keypad. And we will start with our first caller. Go ahead with your question.

Caller: Hi, Jenny. Hi, Dr. Ghobrial. It’s Dana Holmes. It’s so great to talk to both of you today. Thanks, Dr. Ghobrial, for everything that you’re doing. Looking forward to this blood biopsy for sure.

Dr. Ghobrial: Absolutely. Hi, Dana. How are you? It’s great to talk to you.

Caller: I’m doing great. As you know, I’m a happy long-term PCrowd study participant.

Dr. Ghobrial: Yay.

Caller: Yep. My serum sample number nine will be on the way next month to your brilliant researchers, so they can keep doing what they’ve been doing, because I honestly feel that we have the simple samples to send you. It’s such an easy task for a patient to participate in PCrowd, and they already have access to my vein. All I need to do is just hand the phlebotomist my three little vials. They hand it back to me. I package it up and ship it on back. It is the easiest way to really become empowered as an MGUS and a smoldering myeloma patient.

So if any of my fellow MGUS and smoldering patients are listening, sign up because it is the best thing to do on behalf of our patient cohort. Because if we want answers, we’ve got to get them these samples so that they can test them and really figure out who is going to progress and who is not. So that may be the rest. Some of us can really sleep more peacefully at night than wondering if we were going to wake up full-blown myeloma the next morning. So I definitely encourage that.

Dr. Ghobrial: Thank you, Dana. Again, the patient power, like you, makes a huge difference. And I can tell you now we’re starting to get the fruit of what you have been doing. All the collections for the last couple of years, we’re starting to get all those samples sequence with their answers, with how patients are doing so that we can show all of these data. So we have at least three or four manuscripts almost ready. I cannot give you the exact details, but I can simply share some of the information when we have our own, the PCrowd group getting together. As we possess some of those and they’re available for publication, I’ll share it with everyone, absolutely.

Caller: Fantastic. I’m so looking forward to it.

Dr. Ghobrial: We’re working with the Broad right now on developing a new website where every 100 or 200 patients will get sequenced. We can share that before we even get to publication, and hopefully that’s not an unbearable problem. As you know, many of the times, we’re not allowed to share the exact research information because the journals bar us from doing that. So we’re trying to get around it so that patients immediately get that information as we get it done.

Caller: I think that’s brilliant. That was the aggregate data sharing that you were talking about. That’s just really a welcome end point for us to actually start seeing the fruits of what we’re doing. But you know, some patients think like, oh, I’m sending a blood. I’m not hearing anything. It’s like, well, research takes time. Just keep giving them the material that they need to study, and eventually we’ll start seeing some answers. So I’m grateful to you and your researchers for bringing this easy study to us because it really is truly such an easy thing to participate in.

Dr. Ghobrial: Absolutely. And I totally understand how patients feel. Well, it’s been two years and I’m sending samples. What’s going on? Because we need that followup. In fact, we may need five years of followup to see some progress or some not, who is doing what, who is on treatment. Just like I said, if Jenny wants to do something to get approval, we may need two to three years of followup on patients on trial to see if they have progression-free survival response rates, and then we can use that information to go to approval. So it’s not an immediate answer because we may not get the immediate answer. We need the long-term followup in many cases.

Caller: Absolutely, absolutely. Well, we will continue to be patient patients for you and keep sending you guys your samples. Dr. Ghobrial, I did have question because I do realize that you and your team are working on this blood-based biopsy. But there are many other myeloma groups and teams working on similar biopsies from what at least I have been reading. Is that the main goal for each of these groups the same? Will these blood biopsies be similar? Will they be looking at something totally different? How do we kind of get everybody to coordinate and collectively bring all of their research together to really bring us, the patients, this blood biopsy which everybody is keeping their fingers crossed to someday be able to use?

 

Dr. Ghobrial: Yes, absolutely. So recently, there were a couple of papers that came out: one from the Canadian group, one from the Australian group. We all work well together. There was one from us here at Dana-Farber. So we all know each other. We all work together, using slightly different technology, asking different questions, but at the end of the day, it’s all one idea that we are trying to get, exactly like you said, blood biopsies to our patients.

Caller: Fantastic. Well again, thank you to you and your researchers for everything you do. And we’ll keep encouraging our members to participate in the PCrowd study. Hopefully, someday we’ll have answers and everyone will be very, very grateful that they participated in this wonderful research. And Jenny, thanks for all you do and for continuing to bring all of these forums to the patients where we’re able to actually have these wonderful discussions with the researchers. Appreciate that very much.

Jenny: Oh, sure. Thanks, Dana, for your questions.

Caller: Bye now.

Jenny: Well, Dr. Ghobrial, unless you have other thoughts about the liquid biopsies, I want to thank you so much for participating. I apologize that we couldn’t add the other doctor on the line, but you did an excellent job giving us an overview of what this research is all about. It sounds so incredibly exciting to me.

Dr. Ghobrial: Well, thank you so much Jenny for putting this together. Again, maybe we can follow up, all of us, to really make this come true for our patients.

Jenny: Oh, I think it’s fabulous. Yes, we will for sure. So I would like to thank everyone for listening to Myeloma Crowd Radio, and tune in next time to learn more about the latest in myeloma research and what it means for you.

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About Author

Myeloma survivor, patient advocate, wife, mom of 6. Believer that patients can help accelerate a cure by weighing in and participating in clinical trials. Founder of Myeloma Crowd, Myeloma Crowd Radio and the CrowdCare Foundation.

1 Comment

  1. Dolores Pederson on

    I would like to know why so many doctors fail to mention or test for Amyloidosis when a patient has been diagnosed with Myeloma. Since the two can sometimes go together it would seem that once there is a Myeloma diagnosis there should be a test done for the Amyloidosis. Especially if the patient has something going on with the heart, kidney, colon, etc. It seems that this is overlooked all the time. When my husband was finally diagnosed with Myeloma and continued to have heart and colon problems, we asked his hematologist/oncologist about the Amyloidosis and all he said was that it was a cousin of Myeloma. My husband’s father had died from Amyloidosis of the kidney so that should have made the doctor look into it further. When my husband was not getting any help from the doctors he was seeing in this area we went to The Mayo clinic in Rochester where he was diagnosed with Amyloidosis also. He died in 2009. I see so much about the Myeloma, but not about the Amyloidosis sometimes being with it at the same time. Patients and their families should be made aware of this!

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