Preventing Disease Progression from MGUS and Smoldering Myeloma with Dr. Irene Ghobrial, MD, PhD, Dana Farber Cancer Institute

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Tell your musician friends to donate a song today on Songs For Life to raise funds for multiple myeloma research!

Dr. Irene Ghobrial, MD, PhD
Dana Farber Cancer Institute
Interview Date: October 30

Summary

Dr. Irene Ghobrial, MD, PhD of the Dana Farber Cancer Center shares several new compounds that make the bone marrow microenvironment unfriendly to myeloma cells so they can’t attach to bone, preventing painful bone damage. A new inhibitor by Noxxon blocks this growth by stopping SDF-1. Dr. Ghobrial describes how this works and shares that it is the first time a bone marrow environmental drug has shown great effect for a low tumor burden of myeloma cells. She shares a new center at Dana Farber called the Prevention of Progression for MGUS and smoldering myeloma patients with the goal to prevent disease progression and the discovery of a cure. She gives a preview of a way Dana Farber is approach this very small disease community of MGUS and smoldering myeloma – to offer future crowdsourcing blood and bone marrow samples, so that any patient at any location can donate their tissue samples in order to make discoveries for these early stage disease states. Another study will open soon at Dana Farber for high risk smoldering patients using elotuzumab and Revlimid. Her ultimate goal is to understand if smoldering patients achieve a cure if treated early enough. She explains another drug, similar to the Noxxon SDF-1 inhibitor called Plerixafor, which is called a CXCR4 antibody. It has similar activity and is being used with Velcade so the myeloma cells can’t hide in the bone marrow. She also shares another clinical trial with a drug called TH-302 that leverages the harsher myeloma therapies ONLY when it sees cells that are low-oxygen. Cancer cells grow in low-oxygen environments, so the goal is to spare healthy cells while targeting cancerous cells. She explains the common question of bone damage – do the bones every repair themselves?

The live mPatient Myeloma Radio podcast with Dr. Irene Ghobrial, MD, PhD,

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Jenny: Welcome to today’s episode of mPatient Myeloma Radio, a show that connects patients with myeloma researchers. I’m your host, Jenny Ahlstrom.

We would like you to get to know these amazing myeloma specialists and learn about their exciting work and their open clinical trials. As patients, we have the power to move myeloma research forward at a faster pace if we join clinical trials in greater numbers. Now if you’d like to receive an email with all upcoming and past shows, you can subscribe to our newsletter which we now call the Myeloma Crowd Newsletter and you can find links to do that on the myelomacrowd.org page and the mpatient.org page.

Now, before we get started with Dr. Ghobrial, we’d like to share a new music contest that we’re running called “Songs for Life”. Artists donate inspiring songs and through the contest, we will ultimately select 12 songs to be included on an album and all proceeds from that album will be donated to myeloma research. There are really some excellent entries so take a look at songsforlife.org and click the Like button on the ones you like the best. The top 20 by Facebook likes by November 30th will be selected by the judging panel so your Facebook likes matter. This has been a really, really fun contest so please be aware that you can share this contest with your musician friends and please consider donating to the Kickstarter Campaign.

We’d also like to invite you to become part of the Myeloma Crowd. If you would like to add a post or write an article about anything to do with myeloma whether it’s a life with myeloma or something that you’ve seen in the news, we welcome you to do that and you can find the link to do that on the Myeloma Crowd page.

We are very privileged today to be talking with one of the top myeloma researchers, Dr. Irene Ghobrial of the Dana Farber Cancer Institute. She just published a paper on a topic that’s greatly important to all of us about myeloma bone damage.

Now we are waiting for Dr. Ghobrial to be added to the call and while we are waiting, we are going to go ahead and tell you a little bit about her.

Dr. Ghobrial is an Associate Professor of Medicine at Dana-Farber Cancer Institute at the Harvard Medical School in Boston, Massachusetts. She is a physician Scientist who specializes in the field of Multiple Myeloma and Waldenstrom Macroglobulinemia — and she can say it better than I can — specifically in the precursor conditions of MGUS and Smoldering Myeloma. She is on many Dana-Farber and ASH committees and it’s likely she’ll be incredibly busy in the coming weeks as ASH approaches.

She reviews abstracts for the American Association of Cancer Research and top publications such as Blood, Lancet, and the Journal of Clinical Oncology just to name a few. She’s on the editorial board of the American Journal of Blood Research. Dr. Ghobrial reviews grants for the NIH, the Leukemia & Lymphoma Society and the MMRF and has won numerous awards including a Dana-Farber Clinical Investigator Award, the Robert Kyle Award for her work in Waldenstrom and the American Society of Clinical Investigation. She particularly focuses on the role of the malignant bone marrow niche in disease progression from early precursor conditions like MGUS/smoldering myeloma to active myeloma.

Dr. Ghobrial and her lab attempt to examine how myeloma can use a process of cell dissemination to determine biological changes that incur during progression in myeloma so she seeks to understand that progression process from inactive to an active state. In addition, her laboratory research data has been rapidly translated to innovative investigator-initiated clinical trials. This lab has conducted over ten phase I and II clinical trials. Their studies on myeloma cell trafficking have been translated to the first chemosensitization trials in patients with Myeloma.

In addition, she is the co-leader of the first consortium of clinical trials for blood cancers in collaboration with the Leukemia & Lymphoma Society to form the Blood Cancer Research Partnership which is a consortium for innovative clinical trials of 11 community oncology sites coordinated by Dana-Farber. Moreover, she initiated a new clinic for the Prevention of Progression in Blood Cancers where patients with precursor conditions such as MGUS, early MDS and early CLL will be monitored before disease progression to see how the clonal evolution happens during disease progression.

Jenny: We’re very, very excited to have you on, Dr. Ghobrial. I just read a bio for you so thank you very much and we’ll have you go back and listen to what I said about you but it’s all good.

Dr. Ghobrial: Oh, thank you.

Jenny: So maybe we start – you just recently published in a journal called Cell Reports, a publication about a new compound to prevent bone damage and many, many patients are very, very interested in this topic. And there was something mentioned in the article called SDF-1. So maybe if you give us a little bit of background on that research and then explain what SDF-1 is and a little more about that.

Dr. Ghobrial: Sure.

So we always think that multiple myeloma cells love to live in the bone marrow and we ask the question well, what is inside that bone marrow that makes them so happy to live there because we believe that the cancer cells don’t just live on their own. They need the microenvironment, they need the soil to be able to grow and proliferate. And there’s a lot of research being done on the cancer cells themselves but we ignore so many times the microenvironment or the soil around them.

And we ask the question, well can you use a drug that changes the soil and make it less receptive for the tumor cells to grow and if so, then can we potentially use it in patients in early disease like in early MGUS and Smoldering Myeloma and prevent progression to active Multiple Myeloma?

So we know that there is something called chemokine ligands and chemokines and chemokine receptors which are basically ways for cells to hone or to get into the bone marrow and adhere and stick to the bone marrow in that area. And one of the very well-known ones is this SDF-1 and it’s been known for years as it goes up inside the bone marrow, it increases when cancer gets there.

So we collaborated with this company in Germany to take from them a small molecule that inhibits SDF-1. And we tested it in multiple mouse models as well as patient samples of bone marrow metastasis not only myeloma but even other cancers that go to the bone marrow will SDF-1 be high in that area and the answer was yes in certain areas where the cancer cells and localized, the SDF-1 will be very high. Then we ask the question well if you prevent that SDF-1 from going up, can you change the bone marrow niche and prevent Myeloma from growing, and we found indeed that with different types of models of mice, we were able to prevent progression of Multiple Myeloma by just treating the bone marrow niche and making it less receptive.

So this doesn’t even attack the cancer cells. The cancer cells are exactly the same ones, we don’t treat them, but just by being in an environment that’s not receptive, that’s hostile for them, they cannot keep growing and cannot disseminate and cause Myeloma to progress. So it was the first time targeting the bone marrow niche drug for Myeloma or for bone cancer in general.

Jenny: I think it’s unbelievable. It’s really a new way of studying it and a new way of attacking Myeloma in a roundabout way.

Dr. Ghobrial: We’re very excited about this, we’re hoping to start developing with the company clinical trials for our patients and then this could be used in conjunction with so many other drugs that attack the cancer cells themselves.

Jenny: So a question about it. Is there more of this SDF-1 present based on either disease state like MGUS or Smoldering or by genetic feature like let’s say you have a deletion 17 or a 4;14 translocation, can you elaborate about that a little bit?

Dr. Ghobrial: Very good question.

So we don’t know a lot of answers to this. We know that SDF-1 increases where the myeloma cells are. We know that it keeps going up higher and higher as you progress from early MGUS to late stages of Myeloma. But what we believe is if you wait until there’s so much myeloma in the bone marrow microenvironment attacking SDF-1, at that point may be too late, so we want to prevent it from even increasing up by a drug like this. So I think the attack time for clinical purposes would be at its earlier stage, let’s say early Smoldering disease to prevent further increase.

We don’t know if genetic subtypes will allow stromal cells which are the microenvironmental cells to secrete more SDF-1. We’re still trying to scratch the surface of what happens genetically and epigenetically in the microenvironment and how that regulates certain clones to grow and others not to grow. So if there is a cell that has 17p deletion, will it tell the neighboring stroma to secrete more SDF-1 because that will allow it to grow more or vice versa or so on.

So we’re just getting to know all of this and for us to do all of these work, we developed a brand new clinic here at Dana-Farber called the Prevention of Progression Clinic. So we’re recruiting patients who have MGUS and Smoldering disease and asking them to be part of this sort of group of people together to understand clonal evolution and which clones like to grow or not but also microenvironmental effects and so many other questions we’re asking, plus developing trials specifically for them.

Jenny: Okay, I love that. I love it! Smoldering Myeloma patients and MGUS patients are going to love it.

So in your Progression clinic, who are you inviting? Is it just Myeloma? Is this other cancers or just hematology cancers or who is participating in that new clinic?

Dr. Ghobrial: So it’s for early precursor conditions for hematological malignancies and we said it’s the same idea like in solid cancers, breast cancer for example. A woman would have DCIS which is the early insight to point yet they go and get treated and get cured in that they don’t wait for metastasis to happen. So we said, well why don’t we also invite patients with early disease, MGUS and Smoldering Myeloma, early MGUS and Smoldering, Waldenstrom, early MDS as well as early CLL, the stage called MBL. And in those patients we know that all of those patients if we watch them long enough, they will all develop myeloma or leukemia or CLL, chronic lymphocytic leukemia.

So these are the patients that we’re looking for. So it’s only for blood cancers or precursors of blood cancers, the patients may never develop a blood cancer but we know they have that precursor cell already in them. And we know that if we watch them for 20, 30, 40 years, some of them would definitely develop it.

Jenny: And your goal is “Why wait?”

Dr. Ghobrial: Exactly.

Jenny: Why wait to treat.

Dr. Ghobrial: Now, not all patients need treatment. So there are patients who will live the 30, 40 years and never develop cancer or myeloma or leukemia but some within one or two years they will develop it. And right now we don’t even know biologically who will progress and who will not. So we have numbers like the M spike is higher then yes you’re high-risk smoldering and so on.

But these are very rough ways of looking at the disease; they’re not true molecular ways of looking at the disease. So we’re asking the question well, are there certain clones that predispose you to allow myeloma to grow much faster and is this the patient that we should be targeting? Are there other features, epigenetic, or other features in those patients that will make them progress much faster and those are the ones we should target early.

The second question we’re asking in clinical trials is should we really treat certain groups of patients early and maybe you will achieve a cure at that point. Just like you do in early breast cancer, you achieve a cure. Maybe myeloma, we have the right drugs but we have been targeting the patients too late.

Jenny: I love that approach. And what I noticed in the introduction that I gave for you is that you’re doing this all prospectively. So you’re doing it before the disease evolves and not looking backwards but you’re looking forwards. You’re gathering this group of patients, you’re studying them early and you’re seeing who progresses when so you can make those kinds of determinations. And that really hasn’t been done. I mean that has been done a little but not on a really wide scale in myeloma.

Dr. Ghobrial: Right. I mean we’re trying to collaborate also with people who have some samples. The Mayo Clinic has been collecting for many years samples of MGUS and Smoldering but we never identified molecularly what’s happening. And some of those samples can be used retrospectively but I agree with you. It’s a prospective group of patients who will work together and try to understand can we prevent progression or not. And I’m hoping that that excitement translates to patients that they really are participating in this. We’re trying to take that not only at Dana-Farber as a clinic but even that can we extend it into websites and social media to really allow all patients from all over be part of this work that we’re doing.

Jenny: Well, we’ll certainly help spread the word on the sites that we have so —

Dr. Ghobrial: Oh, that’s great! That’s wonderful.

Jenny: I have a question for you about the word “metastasis” in myeloma. So some doctors use the term and some others that I’ve talked to don’t like this term. Can you define what it means to you and how it is relevant to the bone marrow microenvironment?

Dr. Ghobrial: Sure. In general, people don’t think of blood cancers as metastasis, they think of it more as solid tumors. Yet if you think about it more carefully, well myeloma has all those lytic lesions everywhere in the bone and they’re really discrete multiple plasmacytomas, that’s why actually it’s called Multiple Myeloma, multiple and then omas which are really cytomas.

And we ask the question. well how would the cells go all over the bone marrow like this? They don’t just spread through the bone marrow — I mean, they can but in some cases but they won’t keep going on from your femur to your tibia to your vertebrae just through the bone. They have to spread through the blood and then from the blood go back again into the bone marrow, creates their area of growth in that area and then keep growing. And if you spread through the blood by definition you’re using a lot of the mechanisms of self-trafficking of your white cells or other normal plasma cells do that, or mechanisms that also solid cancers will highjack.

So metastasis is really a word that has been used in solid cancers but it’s exactly the same mechanisms that normal white cells and normal and malignant plasma cells will use to traffic. So how are they able to exit into the circulation from a bone marrow site? They use certain chemokines and certain factors. How are they able to protect themselves when they’re circulating in the blood? How are they able to find a new bone marrow niche and go and grow into it? How will they change that bone marrow around them to colonize? And we think that by the time we have MGUS, there are probably all those little seeds of myeloma cells everywhere in the bone marrow yet they’re not able to grow further into an active myeloma that you see clinically. So that mimics what happens in solid tumors, something called micrometastasis where you have tiny little seeds of cancer cells that are not capable of moving on to develop big metastasis.

So it’s a biological question of mechanisms of trafficking of cells and I use the word metastasis because it makes us really think of it in a different way and it makes us then address it in a different way but it’s not that suddenly we’re changing the way myeloma spreads. It’s the same way myeloma spreads but we’re trying to address it through understanding mechanisms of metastasis.

Jenny: Okay. Well that makes a lot of sense that it’s spreading and finding friendly environments to lodge and grow.

A question about that. So most of the time, I understand that myeloma cells don’t survive for long in the blood but people who have this extramedullary disease found in the blood are considered kind of high-risk. But if the blood is the typically unfriendly environment, I guess that’s part of your study, right?

Dr. Ghobrial: Correct.

Jenny: Is why can’t myeloma cells typically survive for long in the blood I guess is one question.

Dr. Ghobrial: So it’s a great question. So one thing, myeloma cells love to sit in an area that protects them so that’s why the bone marrow niche is perfect. They love to adhere and stick to other cells and that’s how they grow. When they’re not sticking to other cells, they are very vulnerable so the time that they circulate in the blood is the most vulnerable for them.

Then once they become so aggressive and they pack the bone marrow so much and they’re capable of going into the circulation, this is when those cells are so cell autonomous and aggressive enough to be able to survive on their own without sticking to their neighbors and this is those end-stages of plasma cell leukemia.

Now even earlier on, in earlier stages of myeloma, there are tiny little number of cells that are capable of going out, circulating, going back in quickly into the bone marrow. And these are the ones that I think are causing this metastasis. While they’re in the circulation they’re vulnerable and the easiest time is to kill them then. Some of our drugs immediately kill plasma cell leukemia cells when they’re in the circulation yet they don’t get rid of the cells that are in the bone marrow.

We’re trying to still understand are there specific subclones of plasma cells that are capable of circulating more than others? Why would some of them like to go to extramedullary sites like liver or skin in late stages when we start having myeloma spreading outside the bone marrow? And we’re trying to also understand what happens inside the blood that protects them and helps them to survive there and can we reverse that.

Jenny: That’s a great explanation.

I have a follow-up question for that. So if you prevent through some of these tools like this SDF-1 inhibitor the ability for it to expand and grow in the blood and you have these circulating cells. Can it go elsewhere and colonize up — that would be the worry, right? So you shut it down in the bone marrow and then you have it pop up somewhere else.

Dr. Ghobrial: Yeah, great question. And originally when we started doing some of the work we were doing on CXCR4 inhibition, we were asked this question, well if you prevent them from sticking to the bone marrow will they start spreading everywhere and you cause plasma cell leukemia?

And the answer is no. We tested that actually in the mice and we have clinical trials ongoing now with CXCR4 inhibitors that never do that. And the reason for that is the cells that like to circulate outside the bone marrow, the ones that really cause plasma cell leukemia, it’s because they have intrinsically something that makes them less adhere and capable of going and sticking to other areas like the liver, skin, and so on. It’s not because we removed from them their adhesion molecules on the surface. In fact when we remove the adhesion molecules on the surface and some of them just exit, it’s because they’re so vulnerable that they immediately can get killed on their own. So it’s not that you’re changing the clone or you’re changing the type of cancer you have to become a more aggressive cancer.

Jenny: That makes sense.

Another question. When you were doing these tests with this compound with this new drug and tell me the drug name or the German company name?

Dr. Ghobrial: So Noxxon is the company and NOX-A12 is the name of the drug. It has now a new name I think but I can’t remember it from the paper. I’ll look it up.

Jenny: I understand. They change and then they go from a number to something else.

Dr. Ghobrial: Exactly.

Jenny: So when you said it’s better to do this with a low tumor burden, when you were testing, did you test a variety of tumor burdens like a really dense tumor burden and a really low tumor burden to see the difference in the efficacy of that compound?

Dr. Ghobrial: Yes, we did. So we tested in early pre-treatment before there are a lot of tumor cells and can you change the niche before you put myeloma cells and this is when it worked. We also tested after you have a lot of tumor burden and then you use this drug and we don’t see a big difference when it’s used alone. But when you add to it another drug like Bortezomib then you start seeing an enhanced effect of chemosensitization.

Jenny: So have you used it or has it been tested in any way post-treatment in any way, would that be another strategy to use it early in MGUS or Smoldering and then also to use it in a remission status to prevent regrowth?

Dr. Ghobrial: Yes, excellent point.

So post-stem cell transplant, can you prevent that minimal residual disease from growing again? And absolutely this could be tested both pre-clinically and clinically and could be a great option for patients as a maintenance therapy post-transplant. So there are definitely a lot of options for using drugs like this.

Jenny: So can you talk to us a little bit about the status of it in clinical trials now? So is it just entering clinical trial, is it already in a clinical trial, is there one that’s open?

Dr. Ghobrial: So there are several clinical trials ongoing in Europe right now. They tested it in myeloma and in CLL but not in those settings of very early treatment or maintenance therapy like we’re talking about. They’re testing it as a chemosensitization method which is in patients with relapsed myeloma, can you give it plus Bortezomib and they have some of that data that they’re presenting already.

And that’s a good way of thinking, that’s like a chemosensitization way, can you make them less adherent into the stroma and then they become more sensitive to the bortezomib or other drugs. But what we’re hoping to propose to them and develop as a clinical trial is can we now prevent progression with a single agent early on.

Jenny: And have you had any experience with side effects if this is really early? Do you know that yet or no?

Dr. Ghobrial: So they know already the toxicity profile of the drug from all their other clinical trials and it’s a very well-tolerated drug. So we’re hoping that indeed you can use it in Smoldering Myeloma patients in this situation.

Jenny: And it would be given over a period of time or consistently it’s not just given once, right, I would assume or maybe that’s a valid assumption?

Dr. Ghobrial: Right, yes. So it’s given I think once a week. I have to go back to look at the exact timing of it but it’s not something that’s not… it’s very easy well-tolerated and it doesn’t take too long from the patients who come in so it doesn’t cause a burden to patients to have to come in to the clinic a lot.

Jenny: Okay, that’s amazing. Well, we’re very, very excited to hear more about this. Is there anything else you’d like to share about this study and clinical trial, questions that I don’t know what I don’t know about this?

Dr. Ghobrial: Well, we are opening soon a clinical trial on another combination, again in Smoldering Myeloma so that could be exciting for all the myeloma patients. This will be for high-risk Smoldering Myeloma patients using elotuzumab which is the antibody that activates the immune system with lenalidomide which is Revlimid that we use in our patients and the question will be, can we treat patients early just like we said, prevent progression, and even achieve complete remission or the question of cure. Can we cure patients if we treat them early enough?

This should be on clinicaltrial.gov in the next one or two days it will be opening in the next couple of weeks at Dana-Farber and we’re hoping to open it in multiple other places. And I would encourage all your listeners who have early precursor conditions like MGUs and Smoldering, email me, call me any time. We’re happy to discuss with them their cases.

Jenny: Okay. I know we have some Smoldering patients online that I’m sure will want to ask some questions at the end so we’ll open it up for them to be able to do that.

I think it’s very exciting for Smoldering patients to know, I think this watch-and-wait is very hard for them. They want to do something but they don’t want to have to deal with active myeloma. None of us do.

Dr. Ghobrial: I agree, absolutely.

Jenny: So you have some other open clinical trials at Dana-Farber. There was one with Plerixafor and maybe this is the drug name that we’re talking about but it’s AMD3100. Can you explain what that clinical trial and it’s also running at Brigham and Women’s and it’s being used with bortezomib.

Dr. Ghobrial: Correct. So just like we’ve talked about SDF-1 which is the chemokine ligands, this is the receptor of SDF-1 so it’s exactly the same mechanism and this is a CXCR4 inhibitor. We actually tested it using Plerixafor or AMD3100 with bortezomib and the trial is almost done. I think we have ten more patients to accrue.

So we’re using it, just like I said, a chemosensitization. You prevent the cells from sticking to the bone marrow, you make them much more sensitive to Velcade and we’ve seen that even in patients who were resistant to Velcade because the cells are sticking to the bone marrow, now when you add these two combinations together maybe that will make them more sensitive.

And we’ve tested another antibody from Bristol-Myers Squibb also a CXCR4 antibody the same way and that hopefully will be presented in the American Society of Hematology. So that’s the same mechanism of trying to prevent that interaction of cancer cells with their bone marrow cells and by doing that you make them more sensitive to therapy. But these are in the relapsed setting, they’re not in that early smoldering setting.

Jenny: And it’s part of the goal to knock down the tumor burden with the chemo so you can use these different approaches?

Dr. Ghobrial: So the whole idea is that if Velcade is not working because the cells are hiding inside the bone marrow or it’s not working because the cells are sticking to the stroma around them and that makes them resistant, so sort of like when all the neighboring cells are protecting them, they prevent them from dying. Can you prevent that, can you take that cell out of that niche that’s protecting it and by doing that make it more sensitive to Velcade or Revlimid or other drugs.

Jenny: And if you’re setting the very beginning stages and it sounds like much of your work is focused on that, we’ve had some other interviews talking about these progenitor cells or these cells that aren’t killed through traditional myeloma approaches, either the stem cell transplant or the other drugs. Is there any way from your experience in drawing these cells out so they’re exposed or… I don’t know how to explain that but…

Dr. Ghobrial: Yes, it’s a great question!

So we were actually trying to figure out this but in this clinical trial, we may not be able to ask this question. Are we actually sensitizing the myeloma stem cell or are we specifically targeting a stem cell or progenitor cell that has a high level of CXCR4 on its surface? And that’s definitely a very important topic. We have not been able to test it in this trial because the patients have so many cells but it can be tested in a different model with minimal residual disease cells or with minimal cells where the leftover cells are indeed progenitor drug-resistant cells. And now can we make them sensitive again to therapy? Absolutely. And that could be for future trials and for future work as we’re doing in the lab. Absolutely.

Jenny: And do all myeloma cells have this CXCR4 expressed or do they all have the SDF-1 expressed? Is this like a really broad approach that applies to everybody?

Dr. Ghobrial: So great question. Some cells express it more than others and some express it in different areas more than others and we’re trying to even see if certain genetic subtypes of myeloma will have more or higher CXCR4 expression.

We know that in a different cancer, Waldenstrom for example, there is a mutation in the CXCR4 that makes it much higher level of expression and they’re able to resist therapy in this way. In myeloma we don’t have a mutation in CXCR4 itself but we have some studies that show that the expression of CXCR4 changes as they become more aggressive or they start going to areas like in the liver and so on, so can we prevent the extramedullary disease by using drugs that inhibit this pathway.

Jenny: Okay. And is there a difference between… so this AMD3100 is very similar to the Noxxon pharma product. Is there any difference between these two products?

Dr. Ghobrial: Slightly different. One is targeting the receptor, one is targeting the ligand and they actually work their pharmacokinetics and so on, it’s very different on stem cell mobilization. We actually tested them head-to-head in one of our mouse models of Prevention of Progression and the NOX-A12 looks slightly better than the AMD3100 but that was for specific sort of prevention of progression or the niche-dependency part. I cannot say that that will be the same if we use them on myeloma cells themselves. SDF-1 is usually not secreted that much from myeloma cells; it’s mainly from the bone marrow microenvironment.

Jenny: And how do you translate a discovery like this to other cancers? I know you’re working with other hematology cancers, is there a way of using it in other solid tumor cancers or does it not apply to those?

Dr. Ghobrial: It absolutely applies because bone metastasis happens in so many solid cancers so the question will be can we use the same drug to prevent bone metastasis in breast cancer, prostate cancer, other cancers that love to go to the bone marrow.

We are also trying to see will that also affect the bone lytic lesions or not, what is the effect on normal cells or the cells that have been affected by myeloma cells. It also is the same pathway that other hematological cancers, leukemia, CLL, and other cells, Waldenstrom cells, will use to traffic to the bone marrow. So this applies actually in general to so many different cancers.

Jenny: I know it’s sort of unusual to create clinical trials that include multiple cancers especially like a hematology and a solid tumor cancer together in one trial but are you considering doing that?

Dr. Ghobrial: It’s a great question and I think some of those drugs like this one that attacks the bone marrow niche alone could potentially be used for this. The end points may be slightly different so maybe different subcohorts of patients in different arms could be tested for different things but it’s definitely a great point that we should consider as we develop new, innovative ways of developing clinical trials. The old way of doing it the same way doesn’t work well and takes a long time for us.

Jenny: And there was someone that we interviewed that just said we have to stop thinking about cancer as a localized disease like a kidney or a liver or a bone kind of disease. So I think that’s a really unique way of thinking about creating a clinical trial and the more broad the appeal, the better.

Dr. Ghobrial: Yes, except that the endpoints might be slightly different. For breast cancers to prevent metastasis we’ll have to make sure that indeed we’re testing the right endpoints for them.

Jenny: Right. That would be a challenge creating the trial wouldn’t it, which is probably why it’s not done.

Dr. Ghobrial: Yes, yes. So there are other problems other than just the scientific rationale, absolutely.

Jenny: And in assembling this data that you’re working on assembling in the clinical trial that you have to gather these groups together and gather tissue samples and you’re working with the Mayo Clinic, I just wonder as a patient in myeloma if there’s a way to create this on a national or an international basis so all our samples are going to the same place and everybody has access to those?

Dr. Ghobrial: That’s a wonderful idea. And actually yesterday we were thinking about can we create a crowdsourced clinical trial basically where patients who have MGUS and Smoldering disease can go online, consent and submit their information, and you submit samples, get your genetic testing done. As we get more and more into these methods of social media I agree with you. Why are we limiting it to one area where some patients can have access and others cannot, why can’t we open it into a national and international effort?

There are many limitations to this of course, it’s not as easy as we say it — IRB approval, patient confidentiality, funding for all of these things for resources for gathering of information for where the samples can be tracked and submitted. But the idea is absolutely very exciting and this is the way to move forward in the future.

Jenny: Well, we would love to help with that as much as we can.

Dr. Ghobrial: Absolutely! Maybe after this call, we can talk more about it.

Jenny: That would be great.

Now you have another trial, I don’t know if you want to go into it or not, that’s TH-302 and I wasn’t familiar with it so I thought I would ask you while we have you on the call.

Dr. Ghobrial: Sure. So we’re very excited about that, we will be hpresenting the data in ASH also.

So this is another way of targeting myeloma cells and we know that inside the bone marrow there is less oxygen levels so this is called hypoxia and again, cancer cells in general can grow very well in a hypoxia environment. So we said, well if we use an alkylating drug just like Cytoxan or Melphalan and switch the drug so that it’s only active when the cells are hypoxic and it’s not active when the cells are not hypoxic so you avoid all of that other side effects from an alkylating drug. The loss of hair, the mucositis, the stem cell damage and so on.

So this company developed this TH-302 which is a hypoxia prodrug and it gets activated only in hypoxic cells. So we’ve been working with them and we have tested the drug either alone at first and now in combination with Bortezomib, we’re seeing interesting, very exciting results even in patients who have very bad aggressive disease because these are those cells that are very hypoxic.

So we’re looking forward to develop this drug more and more in myeloma but also in other cancers. This drug is being used in pancreatic cancer in large phase III trials and we’re seeing very promising results. But this is our first trial in hematological malignancy and we’re excited to see that it’s working so well in multiple myeloma.

Jenny: And who provides this drug?

Dr. Ghobrial: So the company is called Threshold and the drug is called TH-302.

Jenny: Well, I think it’s just brilliant and exciting how many new approaches are coming out for myeloma. It’s like myeloma’s being attacked from all sides which it deserves to be attacked from all sides.

Dr. Ghobrial: Absolutely, yes.

Jenny: So for whom is that trial appropriate? For relapsed/refractory?

Dr. Ghobrial: Yes. So this is open for relapsed refractory myeloma.

Jenny: And it’s only at Dana-Farber right now?

Dr. Ghobrial: No, it’s open in multiple sites so not only it’s open at Dana-Farber and other academic centers but also we opened it through a new consortium that we created at Dana-Farber with the help of Leukemia and Lymphoma Society called the BCRP, Blood Cancer Research Partnership, with the idea that a lot of our trials that are available, can we extend them to the community so that patients have easy access to them.

So the BCRP is available in 11 community oncology sites throughout the US. And we have a website for that so people can see which trials are open where.

Jenny: That’s a great idea, opening it up to local centers because a lot of myeloma patients go to local centers either don’t have access or they don’t know that they have access to academic centers where many of these studies are being run.

Dr. Ghobrial: Exactly.

Jenny: That’s a great approach, I haven’t heard about that before. Is that relatively new?

Dr. Ghobrial: It’s been open now for one year so that was another initiative that we developed at Dana-Farber which is the BCRP. And again, LLS has helped us a lot for both, for the precursor initiative as well as for the BCRP.

Jenny: Fantastic. It sounds like you’re doing a lot of innovative things for myeloma.

I have two more questions that are kind of more broad general questions and I want to leave plenty of time for caller questions because we have several. So you do much grant review looking at different approaches in myeloma, what are the key factors that you use to determine what are the most exciting opportunities in myeloma today?

Dr. Ghobrial: So we have sort of four criteria that we evaluate grants for. One of the most important ones is innovation as well as will it translate to clinical practice in the future? So is that something that will make a difference for patients?

So innovation is making sure that we’re not funding just “me too” trials or “me too” research that it’s been done already in one place, we’re just repeating it again and we’ll do the same thing. Because then you’re not moving the field forward.

And then translation and really taking it to the clinic is important because we don’t want to spend research money on things that may never lead in the future. Now again, you have to balance it. Science is very important and a lot of the early work in science may not be known to translate to clinic until later on you figure it out. So you have to always be careful, is this a scientifically good question and then will it be translatable or not. But you always have that in mind, what is the end goal, what is the purpose of this? Will it help some day in the future understand better the disease or develop trials or develop drugs for the disease or prevent the disease in a way?

Jenny: And not just science for science’s sake.

Dr. Ghobrial: Yes. There is definitely that question but if you do a lot of science, really what is your purpose, what’s the goal and will that be important research or not? That’s very important to look at.

And then of course other things will be the investigator. Is this someone who will be able to do the research they are proposing to do and all of the other factors, but the most critical ones are innovation and is it an important question to be asked.

Jenny: And then my last question is what is the benefit of clinical trial participation for you as a researcher?

Dr. Ghobrial: So I think the most exciting time for us is seeing patients improve or have response on a drug we didn’t have before or we didn’t know that this will happen. It’s the best thing ever for us, right? We go into this practice to see that indeed we can help.

And we can’t do it alone, patients can’t do it alone and I think the only time you see that interaction between everyone is when you’re seeing responses and data in clinical trials that the patients are excited because they’re having access to a great thing that we didn’t have before. We’re excited because we see amazing responses in patients who would have otherwise not done very well. And I’m sure the pharmaceutical companies will be excited too and the FDA will be very excited so it’s that interaction between all the work that comes at the end with one time point which is seeing a patient improve on a drug that you didn’t have before.

Jenny: We’re big believers in participating in clinical trials because it’s what’s going to change the phase of myeloma treatment.

Dr. Ghobrial: Absolutely. Thank you.

Jenny: So thank you for all you’re doing.

Dr. Ghobrial: Thank you.

Jenny: I’d like to open it up for questions so if you have questions for Dr. Ghobrial, you can call in to 347-637-2631 and once you are in, press 1 on your keypad. And I am going to go ahead and start with our first caller, please go ahead.

Caller: Hi Jenny!

Jenny: Hi!

Caller: Hi, Dr. Ghobrial, it’s a pleasure to speak to you. Thanks for interviewing with Jenny today. I’m a smoldering multiple myeloma patient, so obviously very, very interested in hearing about your clinic. Loved the idea of a crowdsource trial too which could enable patients regardless of location to actually participate. I think that’s probably one of the biggest issues with trying to participate as a smoldering or an MGUS patient in some of the prospective trials that are available to us. Now the University of Penn, the NIH, the travel consideration is an issue and I think that that probably limits the accrual in some of these. So even thinking of this is just really an incredible asset to all of us so I appreciate that.

Dr. Ghobrial: Absolutely.

Caller: I have a Smoldering Facebook group of about 200 members and several MGUS Facebook groups as well so we would welcome the opportunity to share your interview and any other info that you’d like with the members.

Dr. Ghobrial: Oh, that’s great.

Caller: Oh, it is great. I mean, trust me. We are a band of folks who have come together with a commonality of having this smoldering diagnosis and we’re just trying to inform each other, educate each other and offer each other insight from our specialist and from whatever we research so it’s really been a good experience. We share readily about any of this information and Jenny’s been a terrific resource for us and support to our members as well.

A question concerning your clinic. I know Dr. Weiss at UPenn has a prospective MGUS and Smoldering progression risk trial and Dr. Landgren had one as well. He was at the NIH. Will your clinic utilize testing that they’re using now or have used or will you employ additional novel techniques to track evolution?

Dr. Ghobrial: So great question and we work very closely with all of them. They’re wonderful physicians and I collaborate with them a lot.

What we’re hoping to do is extra things so it’s really trying to look at all of the potential things that can happen in early disease and during progression. So not only the clinical information and not only sequencing some of the tumor cells but we’re also looking at epigenetics regulation. We’re also looking at the microenvironmental cells which I had said before, we ignore them a lot. So we’re asking the question, what happens to the immune system as you progress.

We know that the immune system gets worse and worse and that’s why that could be part of that progression yet we’ve never really examined that well. We’re looking at the peripheral blood at something called exosomes which contain a lot of information about us that we have not even explored before and that’s an easy thing, just peripheral blood sample, we’re looking at so many other things. So it’s more than what has been done before and we’re hoping this keeps growing more and more and we can actually have collaborations with Ola and with others that this becomes a national effort and not just a Dana-Farber effort.

Caller: Great! At this stage, if a patient wishes to participate in this and have all of this testing done, we would actually need to travel to Boston, to your clinic, right?

Dr. Ghobrial: Not necessarily yet. We’re hoping like you said that we will have this as an online tool and people can just send us the peripheral blood sample and then a bone marrow sample as it comes along.

For now, yes, it’s just open at Dana-Farber but very soon we’re hoping to have it accessible at other places. Already we’re talking about opening it in that BCRP consortium so that physicians all over can have it. This is where I would love to maybe talk more with your group of people and see how we can move this along very fast. We don’t want people traveling all the way to Boston just for this.

Caller: Yeah, absolutely. The Smoldering population would definitely welcome something like that. I mean if it were as simple as something as a blood sample or the next bone marrow sample, it’s just an extra aspirate perhaps or something along those lines. That’s really wonderful.

My next question to you. We’ve seen the newly published International Myeloma Working Group updated guidelines outlining specific myeloma defining events as significant criteria for early treatment intervention, we do understand that it’s subject still to clinical judgment. How close are you or the community defining, in your opinion at this point, who will truly and likely progress?

Dr. Ghobrial: Great question and we don’t know that’s why we actually asking this question.

So we’re trying now to look retrospectively at Smoldering patients who had the same tumor burden, same exact numbers by risk criterias that we have — the Bob Kyle criteria, Mayo, Spanish criteria. But as biologically and molecularly, are here genomic studies that can differentiate them, are there microRNA studies that can differentiate them and so on. And until then, we really don’t know who are the progressors and the non-progressors and that’s part of the big study that we’re doing now for the precursor clinic.

Caller: Great! So it’s really critical to get the message out there that if we could participate and help you out that it will benefit us obviously greatly. So that’s terrific, thank you for that.

If a patient wanted to come up to your clinic now and not wait for the crowdsourcing, can they do that and do they need to register as a Dana Farber patient? How would that work?

Dr. Ghobrial: Yeah. So again, email me anytime. My email is irene_ghobrial@dfci.harvard.edu. It’s a long email but if you Google my name, you’ll find my email. Please email me any time. It’s very easy and we even offer next day patient consults so I’m happy to talk to anyone who’s interested in this.

Caller: Very good. Well, Dr. Ghobrial, thank you so much. Appreciate your time and look forward to more great things.

Dr. Ghobrial: Absolutely! And email me so I know your Facebook information if you want me to work with you guys more.

Caller: I definitely will. My name is Dana Holmes so I’ll email you. I’ll put my name in the subject line for you.

Dr. Ghobrial: Perfect! Thank you, Dana.

Caller: Terrific! Thanks so much. Bye now.

Jenny: Okay. Thank you so much for your questions. Okay, our second question.

Caller: Yes, hi!

You indicated that this SDF-1 inhibitor drug might be useful as maintenance therapy potentially. So that’s a situation I’m in. And I’m kind of wondering if it were useful as maintenance, could there be a clinical trial designed to test that? It’s sort of by analogy to your approach as preventing progression, people on maintenance are also in that situation where they want to prevent progression.

Dr. Ghobrial: Exactly, absolutely.

So it’s all about developing the right trial and the right tools for those patients and absolutely this could be a very nice design where we can ask the question should it be used alone or with Revlimid because a lot of patients are on Revlimid maintenance right now. The endpoint could be prevention of myeloma progression still so it’s exactly the same point as in early MGUS. Can it also be used in post-transplant or post-remission to prevent progression? Absolutely.

Caller: Okay. Well, I’d encourage you to design such a trial or encourage other people.

Dr. Ghobrial: Yeah! I mean right now it’s a very small company so they are not —

Caller: People on maintenance basically can’t get on to any clinical trials.

Dr. Ghobrial: We know that and we’re trying to design trials for maintenance. The problem with trials of maintenance is they take a very long time and some companies are not interested to do that because they want to see very fast responses. I’m not saying that’s right or wrong but I’m just saying why there haven’t been too many trials. And a lot of them will have to compare to Revlimid or add Revlimid to it so that’s why it’s so hard to design trials in maintenance and you need the support of pharmaceutical companies and the financial support is not easy if some of those are very small companies.

Caller: I wonder people like the MMRF could help on that, it would be nice.

Dr. Ghobrial: Right, right. So we’re working with MMRF and LLS especially for some of those small companies to see if they can support them.

Caller: Okay. Thank you very much Doctor. Sounds very exciting.

Dr. Ghobrial: Absolutely!

Jenny: Thanks for your question. I think that’s one question that keeps coming up over and over again in these interviews is there seems to be this blank area for people who might be in remission and want to prevent relapse or who are on maintenance and want to prevent myeloma growth. It’s an area that patients really are interested in finding a solution for.

Okay. We have another caller , please go ahead with your question.

Caller: Hi, good morning, Dr. Ghobrial. My question is can myeloma bone damage be repaired? I’m not sure if the bone can heal itself or not.

Dr. Ghobrial: Yeah, great question.

So we know that the bone, there are two different cells that control it. It’s much more than that but there is something called the osteoclasts, the bone and osteoblasts which make it a bone. And unfortunately in myeloma, the osteoblasts are decreased in myeloma and they still decreased even after treatment. So even after remission we don’t repair the bone. We’re trying to actually ask this question, well, why not and can you use new drugs to develop bone to enhance those osteoblasts.

So there are already some drugs in development or in early clinical trials, DKK1 inhibitors and so on that indeed enhance osteoblasts. We’re hoping to see if these will completely reverse bone lytic lesions which I’m not sure they will. The other question of course is can you prevent bone lytic lesions from happening? So again, early intervention and not waiting for things to happen and then you try to reverse them. So can you use those drugs early on to prevent progression?

And we’re looking at the lab right now in our research is if you enhance those osteoblasts, those bone-forming cells early on, can you even prevent them from allowing myeloma to grow? So using a drug like the DKK1 inhibitor or SDF antibody and so on in clinical trials early, can you not just prevent bone lytic lesions but also myeloma from growing because that interaction between the osteoblast and myeloma is not very well-defined.

Caller: Okay. Thank you.

Jenny: Great answer. Thank you for your question. So just a follow-up question for that, how far along is that?

Dr. Ghobrial: So the DKK1 inhibitors are available already for many patients with myeloma and I would encourage many of you to look them up on clinicaltrials.gov.

SDF antibodies I don’t think they’re available yet but the drugs are being developed rapidly and I’m sure they will be in clinical trials soon and there will be more of them. So I don’t think this is hard to find and hopefully we will get more and more of those in the future.

Jenny: Great! Well, wow! There’s so much that we talked about today that is so exciting. We are so grateful for having you join us today.

Dr. Ghobrial: I’m grateful, too.

Jenny: Well, we’re thankful for your great work and dedication to eliminating this disease and preventing it from beginning in the first place. So thank you very much for joining us.

Dr. Ghobrial: Thank you again and hope again I can hear more and more from many of you to work together so that we have this instead of watch-and-wait like you said, we can prevent progression.

Jenny: Oh, I think it’s the wave of the future and we’re happy to help.

Dr. Ghobrial: All right. Thanks again.

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

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2 Comments

  1. This is fantastic. It amazes me that there is so much support out there for a disease that affects so few. If you have a newsletter or a notification blurb of upcoming events, I am including my name below. If not, I will be checking back frequently. I find these sites like yours and others on my own, and am becoming educated in my stage 2 MM (diagnosed in November of last year), and sites like this are imperative in my quest for education. Thank your for what you do.

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