Dr. Noopur Raje, MD
Massachusetts Cancer Center and Raje Lab

Interview date: January 17, 2014

Myeloma cells can't survive outside of the bone marrow. Dr. Noopur Raje, MD, of Massachusetts General Cancer Center tells us that the "soil" in which they are growing is an important target for new treatments. Dr. Raje describes her work to make the bone marrow neighborhood as unfriendly as possible to stop the growth of myeloma cells. She describes how current myeloma drugs can change the bone marrow environment: Proteasome inhibitors  boost new bone growth while the IMiDs  boost immunity and bump up natural killer cells. She then expands the capacity of those drugs using a new HDAC inhibitor called ACY-1215 with existing myeloma drugs. In one study, Velcade blocks the protein pathway while the HDAC inhibitor blocks another pathway and prevents the cells from becoming Velcade-resistant. She uses another example of combining this same new drug with  IMiDs to affect a commonly mutated gene called C-Myc. She describes a trial for older patients using a standard triple combination that can be modified for age by lowering the dosage (RVD Lite). She regularly performs genetic testing as part of her standard care and is looking to target specific genes, using the BRAF and MEK genes as examples. Her research suggests that treating the bone marrow environment can also help to heal bone lesions. Dr. Raje reminds us that the 9 new myeloma drugs in the last 10 years came about because patients participated in myeloma trials. She notes that when patients wait to join a clinical trial when they are out of options, it is not really helpful, and encourages patients to take advantage of early access to therapies that go beyond the standard of care. 

The live mPatient Myeloma Radio podcast with Dr. Noopur Raje

Jenny: Welcome to today's episode of mPatient Myeloma Radio, a show that connects patients with myeloma researchers to help us is, as Dr. Shah said last week, become better educated patients so we can receive better care.

Now, if you'd like to receive a weekly email about the past and upcoming interviews, you can subscribe to our mPatient Minute newsletter on the homepage of mpatient.org.

I'd also like to suggest that you join one or many of the new Facebook groups that we've created by myeloma subtype. If you don't know your disease biology, today you can find out. Just call your doctor or the research nurse or your coordinator and ask those basic questions and then join the groups where we'll be posting information about certain subtypes when we come across it.

One last suggestion, don't be afraid to ask questions. If you'd like to do this at the end of the call, we'll have caller questions. You can dial 347-637-2631 and press 1 on your keypad.

Today we are very privileged to have with us Dr. Noopur Raje of Massachusetts General Hospital Cancer Center and the Raje Lab, who has been researching multiple myeloma for many years and studying how the bone marrow environment affects the growth of myeloma cells. Dr. Raje, thank you so much for joining us. We're very pleased to have you with us.

Dr. Raje: Thank you, Jenny. It's a real pleasure to be here this morning.

Jenny: Well, let me give a little bit of background about you before we get started.

Dr. Noopur Raje is a physician scientist with a focus on the development of innovative therapies for multiple myeloma. As the Director of the Center for Multiple Myeloma at the Massachusetts General Hospital Cancer Center, Dr. Raje leads a dedicated clinical team engaged in investigator-initiated, multi-center national and international clinical trials all aimed at developing new promising therapies for this disease. She also leads the translational efforts at Massachusetts General with her laboratory's efforts focused on identifying cellular signaling pathways that contribute to the survival and proliferation of myeloma cells in the bone marrow environment.

Dr. Raje received her medical degree from B.J. Medical College, Pune University in India, trained in Internal Medicine at Massachusetts General, and completed a fellowship in hematology and medical oncology in the joint Mass General-Brigham & Women's Dana-Farber Program. She is an Associate Professor of Medicine at Harvard Medical School and the first incumbent of the Rita M. Kelley Chair in Oncology at Mass General. She is the recipient of numerous awards including the Multiple Myeloma Senior Research Award, the Leukemia and Lymphoma Society Clinical Scholar Award, and the Claflin Distinguished Scholar Award.

We are very privileged to have you with us.

Dr. Raje: Thank you so much, Jenny. Like I said, it is my pleasure to be here today. It's been an exciting time for us in myeloma. With the last several years, we've made a lot of headways. I think what's been really gratifying is the fact that what's going on in the lab has actually impacted patients and helped improve quality of life for patients. So it's been really reassuring from that standpoint.

Jenny: Well, it's exciting to see the progress that's being made. As a patient, it's great.

Dr. Raje: Sure, absolutely.

Jenny: Let's first start with just some basics. I know because these are patients listening, you might have to dumb it down for us. In the bone marrow environment, if you take myeloma cells out and put them in a Petri dish, they die. So the bone marrow environment is doing something to keep them alive. Can you explain the bone marrow environment itself and why it's important in myeloma?

Dr. Raje: Sure, absolutely. Part of what we focus on in my lab is trying to understand this interaction of the bone marrow microenvironment and myeloma cells. As you know and as most of your listeners probably know, myeloma is a bone marrow-related cancer and it's found in the bone marrow and likes to stay in the bone marrow with the myeloma cells multiplying in the bone marrow. Obviously, there is an interaction between these myeloma cells and the surrounding cells which we refer to as the bone marrow microenvironment.

Now, in the old days which I would say seven, eight years back, we're not smart enough and we looked at all of those cells as a single component and called them bone marrow stromal cells. What has happened, I believe, in the last three and four years is we've been able to dissect out this so-called bone marrow microenvironment so that we know that there are different types of cells which live there. You have the so-called vascular compartment which is the androgenic cells, you have a small amount of the stromal compartment, then you have certain immune cells.

What my lab mainly focuses on is looking at the bone compartment. If you think about the bone compartment, generally you have two cell types there. You have a cell called the osteoclast which is typically involved in bone destruction, and then you have another cell type called the osteoblast which is a cell type which causes or helps with laying down new bone.

Now, typically, with multiple myelomas, as you know, and I'm sure a lot of your listeners know as well, one of the most important features of clinical problems in myeloma is the fact that a lot of myeloma patients actually will present with the bone disease or during the course of your lifetimes you will end up with bony problems along the way. A lot of the reasons for the bony problems are the fact that the so-called osteoclasts or the bone-destroying cells tend to work overtime in myeloma. The osteoblasts, the so-called bone-forming cells tend not to either exist or are inhibited by some of the factors which are either produced by the tumor cell or by some of the surrounding so-called bone marrow microenvironmental piece.

So in the last five, six, seven years what my lab has been trying to do is dissect how these interactions trying to figure out what are the proteins which either promote the growth of these tumor cells or what are the features which block the effect on the osteoblasts which then doesn't allow bone healing in myeloma. It's been interesting because we've been able to find certain cytokines, certain proteins in this interaction.

Along the way, other researchers have also looked at some of the other compartments I talked about; for example, the immune cells and so on and so forth. In reality, the reason when you take myeloma cells out of a bone marrow and try and put it in cultures, which you first described, it doesn't live very well. It doesn't live very well because it's taken out of where it's hosted; it's taken out of the environment it likes to live in and you've gotten rid of all these proteins. Now, if the same cell is taken out and we actually lay it down on, say, some of these accessory cells that are out there, these cells then begin to grow; then suggesting to us there are proteins involved which are secreted either by the tumor cells or by these accessory cells which help the growth.

Again, one thing for sure, we liked targeting the myeloma cells. It is something we want to get rid of for sure. But the other piece of it and I think that's the next step that we're looking into is we need to make this neighborhood unfriendly. We need to do exactly what's going on the Petri dish so that we need to make the neighborhood unfriendly so that that myeloma cell cannot survive in the bone marrow microenvironment.

Jenny: That might not kill the myeloma cells or decrease the tumor burden if you already have some, but it sounds like it will prevent additional growth. Is that correct or no?

Dr. Raje: No, absolutely. There are different strategies. There are some strategies which would actually prevent for the growth. There are other strategies which would end up actually causing killing of the cells also. So it depends on what you're targeting. And that's the part we try and tease out in the laboratory and figure out which one it is.

Jenny: That's a great way to describe this. Thank you for making it basic for us. We need that. Now, I read some studies that talked about the bone marrow environment changing over time. The word they used was it was "remodeled." Can you explain what this is and how it happens?

Dr. Raje: Yes. The bone itself models and remodels constantly. It's not so much the bone marrow, and that normally happens in the normal physiologic state when you're looking at bone disease. Now, this is pertinent to bone disease specifically. If you think about the organ, the bone, this is a very dynamic organ. It's an organ which is constantly modeling and remodeling as you go through the process of aging. That may be one of the explanations specifically with us women post-menopausally. A lot of us will develop osteoporosis and that's because those osteoclasts that I talked about earlier on start working a little bit overtime. And the osteoblasts, which are your bone-forming or bone-healing cell, tend to become lazier as we get older. So this constant modeling-remodeling continues to happen and those shifts tend towards more thinning of bones as we get older.

Now, if you think about myeloma, just look at it as if it's in a very extreme form of osteoporosis and to the extent where you get this classic lytic disease, which we all are very familiar with with myeloma which can lead to a lot of clinically significant problems. That happens because of that, as I've spoken to a little bit earlier, is those osteoclasts become active working over time, secreting a bunch of cytokines and those cytokines include things like RANK ligand. The newer ones we've looked are Activin A. We've looked at certain others such as DKK1.

So there's a host of those proteins that we’ve studied in the lab, and the hope is that we will be able to target some of these and reverse this process. While that is going on, the so-called bone-healing cells continue to either diminish in numbers or tend to -- even if they exist in certain patients -- don't function as well. This whole process tends to be towards complete bone destruction or bone thinning to the extent where we end up getting bone problems.

The other way of looking at -- and just taking a step back from bone disease -- but thinking about myeloma more as a whole, over the last, say, three and four years now we have focused a lot on what's going on with the tumor, with the myeloma cell. We've been fortunate because we have the tools now where we can look at the myeloma cell at the genetic level. For every patient, we can actually fingerprint that tumor cell. We've seen that as you go through your journey with myeloma -- you know this, Jenny -- you do have times when your disease is in remission then it does come back where you need treatment and so on and so forth. As you go through this whole process, we've been able to look to see how your myeloma evolves genetically, and that is pertaining to the tumor cell.

But more importantly, I think, we can't just focus our attention on the tumor. It's very important to see what the soil is doing as well. As the tumor is changing, so also is the soil changing. Although we haven't gotten there yet, but this is a work in progress as we speak, we're really looking at this microenvironment, as well at a genetic level, to see that as you go through your journey with myeloma, are there more genetic changes within this microenvironment which is then going to favor the myeloma cell and make it more resistant to some of the treatments that we have in clinical trials or in research as we speak.

Jenny: When you look at MGUS progressing to smoldering and smoldering progressing to active myeloma, do you see those changes in the bone marrow environment?

Dr. Raje: We certainly see those changes in the tumor cells and that's something we refer to as clonal heterogeneity or clonal evolution. It's not heterogeneity; it's clonal evolution. The microenvironment part is something we've still not published, but it's something we are studying as we speak. Certainly, I think we'll have to wait and see what the data looks like. But my guess -- if I have to guess -- is yes, the microenvironment is going to change because we know that some of the cytokines that we've looked at changed between what happens in a patient with MGUS or smoldering myeloma, was this active myeloma because some of these cytokines are markedly upregulated when you have active symptomatic myeloma.

Jenny: Is this consistent across various patient types? When you say you're studying the genetics of different patients as it relates to the bone marrow environment, are you finding the same proteins that exist across all patients or just across certain types or certain proteins for certain types? How does that work?

Dr. Raje: Again, that's a really excellent question and I don't think we have the answers to that. We do see trends towards increases in certain proteins in subsets of people. It's not an all or none phenomenon which is again the reason why one has to try and understand that not everybody's myeloma is the same. Whenever we talk to you, we always tell you myeloma tends to be a very heterogeneous myeloma. Your myeloma is probably not the same as, say, person x and there are differences. We are beginning to understand what those differences are.

The other thing is there is heterogeneity within myeloma and that may be a good reason why multiple myeloma was initially called. The word "multiple" was coined because of all the bone lesions that folks had. But another way of looking at multiple myeloma is within myeloma you have subsets of people with different genetic abnormalities, and you see that even when you get a bone marrow aspirate and we do the routine FISH testing and the genetic testing on your bone marrow aspirate. Not everybody has the same kind of genetic changes, right? That heterogeneity is going to exist and it's going to keep on getting compounded as the disease progresses as well.

It would be really neat, and I think that's a part of what we are beginning to do now, is we keep talking about personalizing cancer care and things like that. It's a great thought. It's a good idea. I'm not sure we're quite there, but we do have to start fingerprinting tumors. For example, at MGH, if a patient comes and we're getting a bone marrow done, we're routinely doing what we refer to as a snapshot test and that snapshot test is specific to the tumor cells. We are looking at genetic alterations in the tumor cell. Part of the reason to look at this, Jenny, is to see whether or not you have any specific mutations that can, in fact, be targeted by certain drugs because we have a lot of different drugs in clinical development right now which could, in fact, target that specific mutation.

I'll give you one simple example of this. This not only speaks to myeloma across different disease types, but I think what happens is when you look at cancer in general it speaks to different cancer types. For example, in myeloma, when we did the whole genome sequencing of the myeloma genome, what was seen and what was striking was, in addition to the routine protein synthesis pathway genetic changes, the one feature which was noted here was that about four in every 100 people or one in every 25 people had what was known as the BRAF mutation.

Now, this BRAF mutation is seen in melanoma patients; melanoma is a skin cancer. If you look at melanoma patients, 80% of melanoma patients will have the BRAF mutation. When they've seen that in those melanoma patients, they treated the patients with a drug called vemurafenib which is a BRAF inhibitor; and about 80% to 90% of these patients responded, not indefinitely, but at least for a significant duration of time.

Now, in myeloma, this mutation is a lot rarer. It's only one out of every 25 people. But unless you look, Jenny, you're not going to find it. And what we are doing here at MGH is we have a clinical trial for these folks who do have that BRAF mutation will go on to a study with this drug called vemurafenib. There's all the evidence to suggest that if you use this oral compound in people, you actually respond to this. So unlike using just lenalidomide, bortezomib, and the rest of what we used to using for myeloma, being smarter about how we treat your myeloma would also be the right approach going forward.

Jenny: I think that's an outstanding approach. I would love that. Does the BRAF mutation show up on the FISH test or do you have to the genetic test to find that out?

Dr. Raje: Right. It doesn't show up on the FISH test. What we do is -- the FISH test looks for your (11;14), deletion 13, deletion 17, the ones you're familiar with. While we do that same bone marrow, we take a small pull of extra sample and this is done on -- it's a PCR-based technology where we're looking at all of these mutations.

The interesting thing, Jenny, is technology is getting to be so good right now. The other piece which we are doing out here is the platform where we had about 200 genes now is increased; we can do even more so on that same bone marrow which we would send for FISH testing. In addition to the FISH testing, which is kind of standard of care for all our patients, we are also adding on this to our patient sample.

This is something which is, you know, right now even if we find mutations, a lot of them are not targetable, but the way the pharmaceutical or the clinical drug development world is working, the hope is that very soon we may have something where we could be more focused on how to treat some of this. They're not yet doing it. What I would really like to do is what we talked about a little bit earlier is not just look at the tumor cells. Can we look at the microenvironment? We're not quite there. We haven't done that yet, but that would be neat as well.

Jenny: But I think part of it is the patient education about your disease biology. We've created these new Facebook groups by translocation and some of the gene deletions. We're finding that very few people, I would say, maybe 10% of patients actually know their disease biology. So if I had a BRAF mutation and I had active myeloma, I would raise my hand for that study. You can't do that unless you know what mutations you have.

Dr. Raje: I think you brought up a really critically important point. As I said to you earlier before we went live on this is a lot of what has happened with myeloma is because of patient awareness, patient advocacy so we do rely on all of you to push the frontiers ahead. I think it's critically important that you understand all of this because in the future it might actually impact your care besides all of us are learning more about this and getting a little bit smarter about it.

A lot of times, out in the community, if you're being treated for every time the disease comes back because you have a known diagnosis of myeloma, not a lot of people will get that second bone marrow done. I do think it's important to do it if you're able to have access to testing like we do because it might actually impact -- it certainly teaches us a whole lot about the biology of the disease. But it also might be able to give us some insights into therapies which ultimately -- all of us are working in the lab as hard as we are to try and make a difference in terms of treatments for our patients.

Jenny: Well, I think from a patient perspective, if it's another pull during your bone marrow biopsy, that's okay. I mean you're getting it done anyway. When I was tested, the FISH test did not bring up any translocations but the gene expression profile found the (14;20) translocation for me. I think it's important to go to the deepest level that you can and the tests that are more available at more locations now. They're available so I think we should take advantage of it.

I have another question because I heard a few people say that myeloma could be metastatic in some sense. Can you explain what that might mean?

Dr. Raje: I don't like that terminology very much.

Jenny: You don't?

Dr. Raje: No.

Jenny: Maybe that's not accurate.

Dr. Raje: When you talk about metastatic disease, you're referring to solid tumors. When you think about metastatic disease, think about breast cancer. Breast cancer stays localized to the breast. And then when it goes outside the breast like the lymph nodes or like the bone or like wherever else, liver, for example; you call that metastatic because it's gotten out of where you have that cancer to elsewhere.

What happens with myeloma is it always starts out. If you do have actual symptomatic multiple myeloma, it is a systemic disease; it's not a localized disease, right? The only time when you have localized myeloma is we don't call it myeloma; we call it a plasmacytoma. That plasmacytoma is a collection of myeloma cells which have affected either a bone or some kind of an extramedullary site and oftentimes it's in the aerodigestive tract. That is a plasmacytoma.

Most times when we think about treating myeloma, the beginning of myeloma is a systemic disease where we always talk to you about systemic treatment. The reason we talk about systemic treatment is it is a systemic disease. From the outset, you have multiple bones involved. Just because you have multiple bones involved, does that certainly upstage your myeloma? No. There's a lot of people with Stage I myeloma who will have lots of lesions in their bone X-rays and still be a Stage I myeloma. So that's the difference between calling it true metastatic.

I think what we can begin to think and talk about is what happens as myeloma evolves. As myeloma evolves, absolutely it tends to become a more often aggressive disease. It becomes a little bit harder for us to control with every new relapse that you have. I think we've been very fortunate because with every year now we're almost kind of spoiled. We've still not done enough. I can never say we've done enough until we can sit down and say we don't need to worry about myeloma anymore at all. But we do have more and more drugs becoming available to us. Last year, we had pomalidomide. We had carfilzomib getting approved. So those are all good signs.

What happens is myeloma cells evolve over time. There are some researchers who will say that the metastatic potential increases and as people go through their journey or as people relapse, you can start seeing extramedullary disease, right? Plasmacytomas happening at different places. The way I look at it is your myeloma is becoming more aggressive, it's becoming independent of the microenvironment, and it's just a natural progression of what's going on with your myeloma. I wouldn't necessarily call it metastatic myeloma. That's not a word that I like using.

Jenny: Well, that's a great clarification. Thank you. Let me go back to the bone marrow environment and ask how treatment affects it.

Dr. Raje: The good news is some of the drugs we have -- and this is something we've all always done when we've tested it in the lab right from the IMiDs and this was right through my training I've been working with thalidomide first. Thalidomide never worked in the lab because it's a poor drug. When we used lenalidomide and pomalidomide way back in 2000, the nice thing about these drugs, when we do our drug testing we always test them against the myeloma cell, and then we test them in the context of this bone marrow microenvironment.

And we like drugs which work when your myeloma cells are in the context of this bone marrow microenvironment because that's truly was going on in the human body. We try to recapitulate that in the laboratory. The drugs which work only on tumor cells then we know that needs to be combined. So most of the IMiDs, the proteasome inhibitors like the carfilzomib, like the bortezomib, the IMiDs like lenalidomide, thalidomide, and now most recently, pomalidomide, tend to alter the microenvironment as well. The IMiDs, for example, have a whole bunch of effects on the microenvironmental cell; therefore, example is called immunomodulator drugs for a reason; they help boost up your immunity. They increase what we refer to as natural killer cells. These natural killer cells boost a person's immunity against your myeloma and help keep your myeloma under check.

Other cells like T regulatory cells are decreased. T regulatory cells are cells which can promote myeloma growth but by being on an IMiD, this can be suppressed. If you think about the proteasome inhibitors in addition to them having a great effect on the tumor cell itself, what it does in the bone microenvironment is mainly affects bone. What I talked about earlier was the fact that the bone healing cells, the osteoblasts don't work well in myeloma. These drugs, in fact, will boost up that osteoblastic compartment so they do regulate this bone microenvironment making it less friendly for your myeloma cells. All of these drugs which we have in the clinic right now do a little bit of both.

Jenny: Thank you for making it understandable for us. Does any change in the bone marrow ever create drug resistance?

Dr. Raje: Absolutely. Some of these features, the bone marrow environment produces cytokines. Once we've learned about with myeloma for many, many years now are drugs like Interleukin-6, IGF-1, which is the insulin growth factor 1, then the newer ones which we've described more recently like the Activin, RANKL. All of them promote myeloma growth. With progression we've seen that these cytokines which are largely produced by the microenvironment compartment actually tend to go up in people. These high circulating levels of these cytokines can predispose patients to developing resistance.

When we design trials, one thing because -- there are two things: one is because of the genetic heterogeneity of the myeloma in itself, where everybody's myeloma is different and within a person's myeloma also, not all myeloma cells express all the genetic alterations. But in terms of the microenvironment also, there are certain cytokines which are up or down and so on and so forth. So the goal has been with myeloma for us to be able to combine some of these drugs, and with combinations are the idea being that we could then overcome some of the genetic heterogeneity as well as the heterogeneity and these protein expressions within the bone microenvironment.

Jenny: Well, I have sort of an off question -- you talked about three areas in the bone marrow environment. I have a curious question because I've heard about the VEGF, how it's a growth factor in the bone marrow environment. Maybe I have this wrong, but I think it tells new cells to grow or create new blood vessels. I was curious about this because I think my disease started during pregnancy. I think when that growth factor is being supported because you're trying to create this new life, and I'm just wondering if that's related at all to what you study.

Dr. Raje: I specifically don't study angiogenesis but there is data, on angiogenesis in myeloma. There has been some evidence to show that increased VEGF levels can actually promote myeloma growth. When we first used thalidomide and lenalidomide, they were considered kind of anti-angiogenic drugs. That's how they were first discovered. The idea was maybe by us giving people thalidomide and lenalidomide, we are blocking this pathway. We've not necessarily been able to confirm that completely in the clinical setting and the data with kind of this VEGF and all does exist, but it's not as strong as with some of the other cytokines that we've seen.

Certainly, some amount of angiogenesis might play into the development of myeloma but I don't believe it could be the whole story. Ultimately, it's an interplay of a whole lot of host factors, environmental factors which might, in fact, contribute to the development and even the progression of the disease.

Jenny: Thank you for answering that. It's a little bit off topic. Let's go back to your studies and your active trials that you're working on as they relate to your research.

Dr. Raje: Sure. Obviously being in Boston, being at MGH, we work closely with Dana-Farber. Programmatically, we work very, very closely together and we really shared quite a lot of trials. We do have a lot of trials which are spearheaded through the MGH and vice versa and both institutions participate in each other's. I will highlight some of those which are part of what we've spearheaded. We have a lot more which are accessible to patients.

I really do think part of the issue having clinical trials is making sure that patients are aware and having access to them because a lot of what's happened in myeloma is because of (1) patients having access to some of these drugs; and (2) patients actually agreeing to participate in our clinical trials. If it hadn't been for that, there's no way that we could have gotten nine drugs approved in the last ten years. So it's really commendable that people like yourself with what you're doing her today help bring about this awareness, and then the rest of your listeners who actually participate in these trials. We really, really are grateful for this because we could not have made that progress.

We've done simple studies where we've used combinations in one situation. We've used RVD which is the lenalidomide, bortezomib, dexamethasone combination. It's absolutely been used in people who are younger and transplant-eligible patients. But for some reason in older patients at least the community oncologists have not necessarily come on board with using triple combinations.

If you think about myeloma and think about the epidemiology of myeloma, 70% of myeloma is about the age of 67 or 70. So you really have to have a treatment which is applicable to that vast majority of patients. Part of us doing this RVD Lite protocol so to say is just to teach the community that even in the older patients we want to see the same kinds of responses as in younger patients, but they do need to adjust the doses of these medications so that our patients can tolerate them better and still get the benefits of new drugs. It doesn't matter if you're 84. You should still have access to these drugs. They would need to be modified in how we give them.

So that's a very straightforward trial that we are doing. We've done quite a few patients already. We have a few more slots there, but that's an idea where we hope that even the older patient is just going to do just as well as the younger patient. That's kind of the standard of care approach.

In terms of treatment for myeloma, we have a whole bunch of different combinations that we are investigating; one of them being with the HDAC class of drugs. In this case, we are using an oral one called ACY-1215. We've again studied this in the laboratory and now have moved it to the clinic where we are combining it with either bortezomib or with lenalidomide or with pomalidomide. What we've seen is that it's extremely well tolerated. Patients have no problems being on it. More importantly, we're seeing fantastic responses with it. That to me seems like a very promising target.

We have another target. This is a bromodomain inhibitor like JQ1, which was published a couple of years back. These bromodomain inhibitors target what's called c-Myc. It's a protein in your myeloma cells which can make the myeloma grow. By targeting this, we are just still on the verge of beginning this trial or with these bromodomain inhibitors called CPT-001, I believe. I may be off on the numbers because I never remember the numbers of these drugs.

So that's for the treatment for your myeloma. We have a whole bunch of others. We've used CDK inhibitors. We've used mTOR inhibitors and they all had different impact on myeloma. Most of them have been used in combination.

But as I was talking to you earlier, I'm certainly interested in the bone marrow environment. In addition to what we do to the tumor, one of our goals both in the laboratory and in the clinic is to really modify the bone marrow microenvironment or to remodulate that bone marrow microenvironment so that we make it unfriendly to myeloma. By doing so, whatever we've done in trying to make myeloma a chronic disease, our hope would be that we would create an environment so that those myeloma cells can never go back into that microenvironment and live there.

So we do have certain drugs that we are using to target the bone compartment specifically. We have VEGF hepatocyte growth factor inhibitor. That's XL-184. We have another inhibitor called ACE-011 against a cytokine called Activin A. We're also studying another antibody called DKN-01, and this is against the cytokine called DKK-1.

And the hope that some of this is that the lytic lesions which you see with myeloma right now, our hope would be -- we've always told you when we treat you, your myeloma is going to get better but your X-rays are probably going to keep looking the same. We keep you on drugs like the bisphosphonates or zoledronic acid as Zometa and Aredia for pretty much your entire course of your treatment.

Now, some of these drugs which I just mentioned, our goal is to see whether or not you get healing of those lesions also. We're doing these studies as we speak. We're doing interesting imaging studies with these clinical trials. So you get PET scans, you get FDG fluoride bone scans to see whether or not us treating this microenvironment, in fact, is going to impact what happens to the outcome of myeloma.

These are smaller studies but I'm very excited about this because this is the first time that we are using kind of bone anabolics in this setting. Even in the bone world, we've obviously used zoledronic acid and pamidronate for many, many years now and denosumab, which is a much easier drug which can be given under the skin for reasons which we presented it at ASCO last year is not yet approved for the treatment of myeloma. It's been approved for breast cancer. It's been approved for prostate cancer. The reason it wasn't approved for myeloma was that there was a slight hint towards an increased mortality despite the fact that the bone disease was well controlled.

When we went back and looked as to why that was happening and whether we should just forget about the drug, and what we were struck by was the fact that it's really the patients who got zoledronic acid versus the denosumab were quite different in terms of their risk factors and to try and get rid of that and because this can be a very useful drug specifically in people with myeloma who have kidney problems as well because as you know, one can really not quite safely give some of the bisphosphonates in that patient population.

So we are doing a study where we're comparing zoledronic acid with denosumab or Xgeva, and we'll see if that pans out. I'm pretty sure as far as the bone piece of things that are concerned, it's going to look the same or maybe better. But if you can have a subcutaneous shot instead of you going into an IV infusion every month or every couple of months, I think that will be so much better for your quality of life as well.

So those are some of the clinical trials that we have, but I'd be -- if you have questions on any other, because I'm working in this field, I am familiar with others around, I'd be happy to talk about them.

Jenny: Well, let's go back to the ACY-1215 because that's an HDAC inhibitor, and that is part of the cell signaling pathway, correct?

Dr. Raje: Correct.

Jenny: Can you explain how that works, to affect those proteins?

Dr. Raje: Sure. The way to think about this, this is an epigenetic regulator. But part of the reason why we first wanted to use ACY-1215 is simple; it's an HDAC inhibitor. If you think about what drugs like bortezomib or even carfilzomib does to myeloma, these are proteasome inhibitors so they block your protein synthesis pathway; and by doing so, they kill the myeloma cell. But the myeloma cell tries to outsmart that, right? And one of the resistance mechanisms there is, what it creates is a different pathway which is the agrosome pathway. It creates agrosomes and then the cells tend to survive through that.

Now, what happens with the agrosome, the agrosomes are regulated by these HDACs, these enzymes and a very specific enzyme there is called HDAC-6. What we are using here is ACY-1215 is more selective towards HDAC-6 which is a class 2b HDAC inhibitor. By doing so, most of our ACY studies in combination -- right now we have it in combination with bortezomib, for example, and what it's doing out there is bortezomib is blocking the proteasome pathway, the HDAC-6 inhibitor is blocking your agrosomal pathway so it's not allowing for bortezomib resistance to develop. Together, they're doing a better job at getting rid of your myeloma cells.

We also combining it with IMiDs and in addition to it acting on, say, the agrosomal pathway. Because it's an epigenetic regulator, it actually affects the expression of certain proteins, and one that we've seen in myeloma is that it affects the protein called c-Myc. C-Myc, we all know, is actually very important in multiple myeloma pathogenesis. Most people will have high c-Myc levels and those high c-Myc levels predisposed to more myeloma growth. Using drugs like ACY-1215, we can block that pathway.

So our understanding of the biology allows us then to combine these drugs with certain other drugs with the hope that they're going to work synergistically in people, and you're going to see better responses as opposed to using the IMiD or the proteasome inhibitor by itself.

Jenny: Does everybody have the c-Myc?

Dr. Raje: Most people will. These are very generalizable. These are unlike what I talked about earlier on where you have very specific mutations. The majority of patients or combinations such as using an HDAC inhibitor with, say, a proteasome inhibitor or an IMiD should be applicable to patients in general because here we're not drilling down on the genetic mutations which your cancers depend on.

Jenny: You're beyond the point just using an HDAC inhibitor alone. Now, you're trying to combine it with lenalidomide and dex in one and Velcade index maybe in another?

Dr. Raje: I don't think HDAC inhibitors should be used as single agents at all because as single agents, they're going to do a whole lot. If you understand the complexity of the tumor and then the microenvironment, if you're just blocking one single signaling pathway, your tumor cell is going to try and outsmart it very quickly. So as a single agent, we're going to see very little effect. That's why a lot of the clinical trials which we have going forward are generally clinical trials where we use combination strategies.

Jenny: Next, could you further explain the zoledronic acid and what is does and how it works?

Dr. Raje: Sure. Zoledronic acid has been around for years now. We've been using it for more than, I want to say, 15, 20 years now. Pamidronate started off, but what zoledronic acid does is, you know, the osteoclasts that I talked about earlier on, these are the cells which help bone destruction. Zoledronic acid kills those cells. By killing those cells, it's going to prevent further bone problems, and it's also indirectly going to affect your myeloma growth because these osteoclasts feed myeloma cells. It blocks osteoclasts, directly has nothing to do with myeloma cells, but by blocking osteoclasts, it will inhibit myeloma. But more importantly, it actually treats bone disease.

What it does not do is the other part which we're beginning to look at is the osteoblast compartment. It has no impact on that. It would be nice to have drugs like zoledronic acid and denosumab, both of which block the osteoclasts but simultaneously, if you can have something which is going to increase the function of those osteoblasts or the bone healing cells, then you want to get the bone marrow microenvironment modulated to a point where your myeloma cells are not going to be able to live in that environment.

Jenny: It looks like a two-pronged approach where one is going crazy and one is not working, and now you have two different targets for both sides.

Dr. Raje: Correct. Absolutely. You got it.

Jenny: Well, I want to leave some time for caller questions. So let me ask you just a final question. You talked about patients being in clinical trials. What could you accomplish if we doubled the number of patients in clinical trial, because right now that number is pretty small?

Dr. Raje: Like I said earlier on, where we are today is because of patients participating in these trials. We've been fortunate to be able to do trials that are fast-paced. But if you doubled that number, we'd have a lot more drugs approved and that's going to be a benefit to everybody. I cannot underscore the importance of -- I think one piece of education for patients is when you think about clinical trials, they're afraid. They think they have no options left and that's when they should be looking at clinical trials.

I would argue that, again, myeloma is where it is because of clinical trials. Again, if you see my practice, a lot of times I will tell my patients, most of it, as I said to you, are drugs we are using in combination so I would be using, for example, that Velcade in any case. If you can have access to a new drug while you're using Velcade which would be the treatment for you at that point in time, nothing wrong with that, if you're able to come to your clinic visit and so on and so forth. So I cannot underscore the importance of clinical trials because I think they're going to be able to get a lot more done much, much, much faster.

The other thing is don't wait for clinical trials until there are no options left because doing a clinical trial at that point in time is really not helpful. I think you should be doing clinical trials when you're actually feeling well, when you can access them. And then you've probably gotten some of these trials at the time when you would not have been able to get them. Now, they're approved and available to all, but that certainly may have changed the natural history of your disease as well.

The last thing I will say with clinical trials is as you just heard me speak, in the myeloma community, I will tell you that we are very rigorous about the pre-clinical development of some these drugs and we do not bring them to the clinic unless we really have a strong rationale, strong pre-clinical evidence to take it forward clinically. And that's why when we offer you these clinical trials, we do think that they are really, really going to work quite well in people. So I would absolutely encourage people to participate in trials.

Jenny: So you're already seeing benefit and maybe opportunity for someone to have early access to a new therapy that might work better than standard of care.

We'd like to open it up for caller questions. So if you have questions about Dr. Raje's research, you can call 347-637-2631. And once you're on the call, press 1 on your keypad.

So caller at 557-6827, please go ahead.

Caller: Hi, Dr. Raje. I just have a question for you. Are there other blood cancers like leukemia where these new bone marrow drugs are working well?

Dr. Raje: Again, that's a good question. It depends on what the blood cancer is. In certain lymphomas, for example, certainly some of these drugs. And we share a lot of what's working in myeloma tends to work in the lymphomas as well. For example, drugs like lenalidomide which has effects on the tumor cell as well as microenvironment we've seen working quite well in certain subsets of lymphomas. So yes, in certain types of cancers. Yes. Others where it's more often acute leukemia-like picture, it's less likely to be the case because that's a very different disease and that's where chemotherapy tends to be more effective.

Jenny: Great. Thank you for the question and for your answer. Okay, caller at 204-6956.

Caller: Hi, good morning. Hi, can you hear me?  Just a general observation on clinical trials. I wonder if, I guess, for lack of a better term, selling the idea of the importance of participating in a clinical trial should also rest with the treating doctor because I think oftentimes we patients aren't really well versed on the effects and the importance of clinical trials and the physician should be. And yet, again, just a general observation, when I was first diagnosed, no one ever even talked to me about clinical trials. I'm just wondering what your thoughts are on that.

Dr. Raje: You bring about such an important point and I could not agree with you more. The same thing which I talked about in terms of a little bit of hesitancy to be on a clinical trial because a clinical trial is almost viewed as if it's something which is experimental and people don't want to do it. A lot of physicians share that same feeling and I do agree with you 100%. We, as clinicians, need just as much education and a hope that more of our clinical community will also be able to provide patients with access.

One thing I will say though, when you are seen by a practice which does not have the same volume of myeloma patients, remember myeloma is not that common a disease. The lung cancers and the breast cancers are a lot more common than multiple myeloma. We are in a minority. We have 22,000 patients diagnosed on a yearly basis. Remember, some of those treating oncologists have seen maybe two myelomas in a whole year and in their busy practice do not have time to think about it.

So one thing I usually will urge most of my patients at least or most patients when I give these patient talks is seek out a program which is close to you which focuses on myeloma. It doesn't mean you have to get treatment there, but stay in touch with that group ever so often so you are made aware of what's new, what's available. Most treating oncologists, we like care to be local but most treating oncologists appreciate that relationship as well, specifically if they're not completely up to speed with the latest and greatest of what's going on in the myeloma world. It's physically impossible for everybody to keep up.

So I think you're absolutely 100% on track here. We need to have education on both ends of the spectrum.

Caller: Okay. Thank you.

Jenny: Thank you very much. To try to address that, we wanted to create a myeloma specialist directory that we've sent you over an invitation for. We hope you'll participate in, Dr. Raje, and that is the myeloma specialist directory that has a little bit more information than a name and a phone number and a face so that patients can find myeloma specialists, because as a patient, I think it's absolutely critical that you have a myeloma specialist working on your care. Even if you get treated by a local oncologist for a big portion of your care, I think it's still very important. Actually, I just flew to go see my specialist. I got back yesterday because I think it's important enough to travel for.

Dr. Raje: I'd be very happy to be part of your group of experts, and I couldn't agree with you more.

Jenny: Okay, we have one final caller at 400-3656. Go ahead.

Caller:  Dr. Raje, thank you for your time this morning.

Dr. Raje: You're welcome. It's my pleasure.

Caller: Thank you. My question is what tests do I need to get to tell if these cell signaling drugs will work for me?

Dr. Raje: Again, a good question. I don't think you specifically need a test for some of those which I have talked about because a lot of the signaling pieces are true to all myeloma in general. So I don't think we have any specific test where we look, for example, when we use CDK inhibitors. In fact, these are all expressed in the majority of myeloma patients and we don't go around looking.

I think more importantly we are tending to be doing more of like the BRAF inhibitor story, for example. We are looking at people who have, say, the BRAF mutation. We are also looking at other mutations such as the NRAS and the KRAS mutations. These tend to be more common and we are just in the process. So right now we don't have drug just as yet but where we would be combining certain MEK inhibitors in combination with BRAF inhibitors and hope that we see an inhibition.

So just for the cell signaling drugs so to speak, there's no specific test but for mutation of drugs which can target certain mutational aberrations with the myeloma, I think doing things like the platform we have is a snapshot platform, the one which is Foundation Medicine has their own platform. There are lots of platforms which are available around the country which can be accessed and I would urge most people to do that.

If you find that you have a mutation, you know, there's the clinical trials website and I believe, Jenny, you have something where you have -- am I correct in assuming you have compiled trials, et cetera or at least you can go to places to look, to see whether there's a clinical trial which could be targeting your specific mutation. I would at least look at those resources and see whether you should be hooked up with somebody who has those trials available.

Jenny: You find those tests through the genetic expression profile typically, right?

Dr. Raje: That's the extra test that you need to do.

Jenny: How many patients are on the BRAF study that you're running? How many patients are you looking for?

Dr. Raje: It's just a small cohort. We're looking at ten, and I believe we already have four people so there's still room for more. That's the most designer specific kind of a treatment. And soon to start, we're going to do a combination study. We're going to look at the BRAF inhibitor with the MEK inhibitor. And in that patient population, we're not just going to look at BRAF mutated patients because that's a rare mutation, but we're going to look at the other mutations which I talked about, the NRAS and the KRAS mutation which we believe signal through the MAP-kinase pathway and using a MEK inhibitor in that situation is going to be helpful for these people.

Caller: Thank you for clarifying that, Dr. Raje.

Dr. Raje: You're very welcome.

Jenny: Well, we are very grateful that you've joined us and helped us. Maybe our Facebook groups should be by mutation and not by translocation. I don't know. If you're trying to recruit for -- if you're trying to find patients for specific genes, then that might be another way of doing this.

Dr. Raje: Yes. We shouldn't forget translocations because they've taught us a lot. But this is just one more step where, because of the availability of technology, we're going to be able to do this. So I wouldn't say that you ever do this instead of that. I do think you have to do the center of care testing and then if you can add on no further -- and the other thing I will tell you is that insurance companies are paying for it. It's not an added burden financially either. The more information, like you said at the beginning of your show, the better. Even if it's not applicable today, our hope is maybe you're down the line or two years down the line we'll have more information on the biology of things. Maybe it would become then applicable.

Jenny: I completely agree. I think if you're prepared and you're ready and you know more about yourself, then you can pick and choose at a deeper level things that might be more appropriate to you personally, and just be prepared and ready.

Thank you so much for joining us, Dr. Raje, today. It's been a very helpful and a very informative and a very patient-friendly description of how this bone marrow environment works. We wish you the very best in continuing your wonderful and great work.

Dr. Raje: Thank you, Jenny, and likewise. I wish you the very best as well. Thanks so much for having me on.

Jenny: Thank you for joining us today.

To our listeners, thank you for listening to another episode of Innovation in Myeloma on mPatient Radio. Join us next week for our next interview as we learn more about how we can help drive to a cure for myeloma.