Dr. Damian Green, MD
Fred Hutchinson Cancer Center and Seattle Cancer Care Alliance

Interview date: February 7, 2014

Dr. Green shares his deep research using a new and exciting approach by combing two very effective therapies: immunotherapy (or the use of monoclonal antibodies) with very targeted radioactive isotopes. It is well known  that radiation effectively kills myeloma cells. It is also well known that monoclonal antibodies provide an exciting way for your own immune system to kill myeloma cells. New monoclonal antibodies are now being developed to target the CD38 protein. He describes why the CD38 protein is such a popular target - it is present in almost all myeloma patients on the myeloma cells, it stays in one place and doesn't move around during treatment, it is present in bigger proportions on myeloma cells than other cells in the body, and they are a lot of them on myeloma cells (they are high-density.) With the CD38 target in mind, he shares why he is using a carefully selected radioactive isotope called Yttrium-90 to attack the myeloma cells. It was chosen because it delivers the radiation in a very targeted way but doesn't last long in the body, it gives a cross-fire effect, but it doesn't do distant damage. The approach is a one-two punch for the myeloma cells and leverages proven and effective therapies by combining them together. We look forward to seeing his research move into clinical trials in the near future.  

The live mPatient Myeloma Radio podcast with Dr. Damian Green

Jenny: Welcome to today's episode of mPatient Myeloma Radio, a show that connects patients with myeloma researchers.

If patients learned more about clinical trials and joined them in greater numbers, we could help the researchers come to their conclusions more quickly. Right now, less than 5% of myeloma patients participate in clinical trials but 75% of those cancer patients say they would want to. If we were to double the number, we could dramatically alter the pace of research and cut research time significantly.

So a few items of business before we get started with today's show. If you like to subscribe to the newsletter to get email updates, you can do that on the homepage of www.mpatient.org.

This week we'd like to share something exciting that we launched. We have a new site called myelomacrowd.org and this is the first ever all-inclusive site for myeloma.

It's taken me about three years to get really up to speed on this disease. As a patient, I wanted a place where I could find all the good being done in the world of myeloma on a single site. So here you can find information about diagnostic testing, myeloma trials, patient support groups, what to eat during treatment, and really links to all the best news, all the best foundation work, and everything that's being done in the world of myeloma.

Now, the Facebook groups that we created are listed here as well. These new groups include subset patients with your same genetic markers. For example, there is a 4;14 group and a gene-13 deletion group. We encourage you to join those so you can chat with others of your same disease type because as we've been told, myeloma is not a single disease.

Now one more item, to all those of you who cannot remember what you were going to ask your doctor at your next appointment, we now have a free smartphone app called My Doc Notes that's available in Apple and Android stores that lets you jot down text notes or voice memos to remember your important questions and can take notes during your visit and text or with a recording. I just used this in my last appointment and it was the first time I left really feeling like I remembered everything that I wanted to cover.

Now on to our show for today. We are very privileged to have with us Dr. Damien Green of the Fred Hutchinson Cancer Center in Seattle who is working on many exciting things and not just to control myeloma but to potentially eradicate the disease altogether.

Welcome, Dr. Green. Thank you very much for joining us.

Dr. Green: Well, thank you very much for having me. I'm happy to be here.

Jenny: Well, I'd like to introduction for you, if I can, before we start.

Dr. Damian Green is an Assistant Member of the Fred Hutchinson Cancer Research Center and Assistant Professor in Medical Oncology of the University of Washington School of Medicine. Dr. Green earned his medical degree from Ohio State where he also performed his residency.

Recently, Dr. Green has demonstrated great success in selectively targeting multiple myeloma cells with antibodies carrying small radioactive particles that can selectively destroy the tumor cells and spare the normal tissue. This breakthrough may translate into a completely life-saving new therapy and his most recently research findings were just published in the research journal Cancer Research.

He's also pioneering a new way to better capture a patient's own healthy blood stem cells to use later for a bone marrow transplant. The new approach is designed to more effectively treat the patient's cancer during the process of collecting stem cells. He joined the Fred Hutchinson Cancer Research Center, also called The Hutch, in 2011 and has reserved Research Awards from the American Society of Clinical Oncology, the MMRF, the Lymphoma Research Foundation and the MMORE Foundation. His current research is also supported by a Career Development Award from the National Institutes of Health.

With that, Dr. Green, let’s talk about your approach to look at myeloma not just in terms of controlling it but in curing it.

Dr. Green: Sure. I think that I'm certain is not just my goal but the goal of all of my colleagues and research scientists who are looking for new treatments that will, again, not only effectively control the disease. I think as probably all you listeners know, we have made dramatic advances in terms of the ability to better control myeloma in the last decade or so but that all of us share the goal of trying to find effective ways to actually get rid of every last one of those malignant cells and cure patients. And I think it’s not unrealistic. We can cure patients of their lymphomas. We can cure patients of leukemia, other cancers of the blood and bone marrow, and I think that the time is now for us to be focused on curing the disease.

One thing I just want to say about the introduction – thank you for the kind introduction. I’ve actually been here in Seattle since 2004 at the Hutch. I came here for training and I’ve been here since. And I was going to say actually it’s actually a beautiful sunny day today in Seattle which may surprise some of the listeners and I have my blinds down because there’s too much sun otherwise shining in on me here.

Not to test that analogy too much, but I'm happy to shed some more light on what we’re doing here at the center and what my research is focused on and in particular a major focus in my laboratory is trying to develop novel approaches using immunotherapy, so immune system based approaches to get after and ultimately eradicate myeloma by targeting every myeloma cell in the body.

So the approach that we are taking is using a system known as radioimmunotherapy whereby we attach onto antibodies a small radioactive molecule that can then be delivered. The antibodies are specific for a marker or protein on the surface of the myeloma cells, and they basically act as a carrier for the radioactive molecule to bring it and deliver it directly in contact or in close proximity to the multiple myeloma cells.

So in sort of a big picture sense that’s what we do. It’s probably important for me to explain the rationale for why we are taking that approach.

Jenny: That would be great.

Dr. Green: Yeah, so I think, first of all, historically we know that multiple myeloma is very sensitive. Those malignant tumor cells are very exquisitely sensitive to radiation. We know that for lots of reasons but one reason that we know that is when patients present with a plasmacytoma, a massive abnormal myeloma or plasma cells, when those cells are not in the bone marrow or elsewhere in the body and this happens rarely but it does occur, patients can in that instance be cured of their plasmacytoma, collection of abnormal myeloma cells or plasma cells through the use of external beam radiation.

So if it’s at a single site and it’s not in the bone marrow and we can irradiate it -- and I shouldn’t even say not in the bone marrow, sometimes it can be in the bone but just at a single location, we can effectively get rid of every last one of those cells and that’s well known. We’ve known it for a long time. It is used as the standard of care for patients with a solitary plasma cell collection.

We also know that among patients who have bony pain from their multiple myeloma that we can effectively control that pain a very, very high percentage of the time if it’s just at localized site and it’s amenable. If we’re able to use radiation to treat it, radiation can be very effective at controlling the localized pain. It does not get rid of the myeloma elsewhere, but we know it works directly against those cells when we can aim a beam of radiation from outside the body at the myeloma cells in a specific location.

And there are also studies in the Petri dish and other studies that have all demonstrated that myeloma cells are very sensitive to radiation, more sensitive than normal cells. That’s something that we have to take advantage of in order to preferentially get rid of them and destroy them. So we know that and we know other cancers, the cancers of the blood and bone marrow in particular.

Leukemias and lymphomas are very sensitive to radiation therapy and we’ve been able to effectively treat and cure patients using delivered radiation therapy, targeted radiation therapy to those cells. In fact, if we go way back, and I'm in Seattle where the first stem cell transplants were done; stem cell transplant was born here, if you will, and the physician who founded our center, Donnall Thomas, received a Nobel Prize for his work in developing and really discovering the role for stem cell transplant.

And if you look at his very early research here in Seattle -- and this has also been done in other centers as well -- we know that if you could – in those days, we’re talking about external beams, so radiation from outside of the body beamed in like it’s frequently done for different tumors including the bone pain situation I mentioned a moment ago, but anyway when that radiation is used, it can at high enough doses as part of before a stem cell transplant, what we call conditioning therapy, before the new cells come in and try to knock out as much of the cancer as possible, there was data which showed that the more radiation you gave, the better your chances were for a cure. But the problem was there’s just a limitation to how much radiation a person can tolerate both before the days of transplant and even with the use of stem cell transplant.

So that’s the feeling, that was the limitation, and that was partly what informed or what got people thinking about, well, how else could we deliver radiation in a more focused way so that we can get more to those tumor cells without doing damage to the rest of the body? And it was that thinking out of which radioimmunotherapy was born. It only really became possible, it was not until the mid-1970s when the first monoclonal antibodies – so producing antibodies in the laboratory on large scale that we could deliver specifically against a target.

Two guys, Kohler and Milstein, they got the Nobel Prize in 1975 for coming up with this idea for how we can generate antibodies. And in fact, at the time people thought, "Wow! This is the Holy Grail and once we can do that, we can use these antibodies to attack tumors." It turns out to be a lot more complicated, but that was the start of a new generation of research where we began to try to harness the power of those antibodies. And really through the 1980s and 1990s here at our center, a big focus was in leukemia and lymphoma and developing radioimmunotherapy whereby we could specifically target the tumor cells.

So I could go on and on but I’ll stop there for a second, Jenny, and see if you have questions or I can tell you more.

Jenny: Oh, I would love to hear more and I guess I want to know how you train those radioactive particles. Can you go through the process of how that works?

Dr. Green: Sure, absolutely. So yeah, let me walk you through that with respect to myeloma and what we’re doing. So the first step in that process, as you could probably imagine, is we have to find a good target on the myeloma cells. And that takes a lot of work to identify what is the best target. The reason it takes a lot of work is because we have to know that, first of all, the target is there in large numbers. If there is a very small number of them, it’s harder to specifically deliver something through the circulation to those cells that have the target on them, so high density, we call it, of expressing a target that we can go after.

And then we also really want a target that is unique to the disease cells so that we’re not giving an antibody that is distributing elsewhere onto normal cells because some of these targets, while they may be a disease cell, if there are also plenty of them elsewhere, we won’t get a specific delivery system. So we need it to have a high density, we need it to be unique or as unique as possible on those target cells, and we need it to be stable. So once it binds there it stays there; it doesn’t float off especially when we’re delivering radiation.

So we spend a lot of time looking at targets in the laboratory and we focused on CD38 because it has a high density on the surface of myeloma cells. It is not entirely unique to those cells, but it is much higher levels on the myeloma cells than elsewhere and almost all the other places where it is found is on the surface of other cells that are produced in the bone marrow. I’ll tell you why that’s important in a second, but the third thing I’ll say is it also stays on the surface stably. So we know it stays there, it’s high density, and it is there in much larger proportions than anywhere else in the body and that’s the CD38 target that we go after.

So first we identify that target and say, okay, it’s there. Now what’s our next step? And our next step is to develop an antibody or obtain an antibody that will bind to that target and then attach a radioactive molecule directly to that antibody and make sure that that doesn’t change the binding ability of the antibody because it could. As you could imagine, maybe the radiation would affect the antibody so it didn’t work so well. So we’ve done all that to show that, no, the radiation doesn’t inhibit the binding and that the antibody can then distribute and bind specifically to the multiple myeloma cells. That’s the sort of initial development stages.

Another important aspect is what radioactive molecule do we use because there are more than one. There are a whole bunch of them that can be used and they have different features. The one that we use for our studies is something called Yttrium-90, and the reason we use that specific radioactive molecule is because it has some features that we really like one of which is a relatively short half life. In other words, it delivers its dose of radiation but it doesn’t stick around for very long, so its half life is 2.7 days and that means it’s giving off half the radiation at 2.7 days later and then another 2.7 days it’s divided by another half, et cetera, so there’s less and less ongoing exposure to radiation.

There’s the initial delivery and that’s the most important period. That initial radiation exposure to the cells is when you get your most potent effect. So we want it to get there but then we don’t want to stick around forever and so Yttrium-90 has that benefit. It also delivers its punch over a few cell diameters not just one so that if we don’t bind every last one of the myeloma cells with the antibody, that’s okay because if we have surrounded the myeloma cells’ colleagues, if you will, with the radioactive antibody, we get a crossfire effect that delivers radiation into the cells surrounding the one that we have targeted.

People I think sometimes have a hard time picturing this, but we’re talking about hundreds of thousands of receptors on these cells or at least – well, I should say anywhere from 10,000 to 200,000-300,000 targets on every one of these cells, but that just gives us a big target where it increases the chances that we can get the antibody there with the radiation, have it deliver the radiation into the cell right there and across to cells surrounding or nearby.

Jenny: Can I ask you a question? From what I understood CD38 is present for many myeloma patients. Is it present for all myeloma patients and are you using the FISH test to find that or what tests are you using to find the CD38?

Dr. Green: I’ll answer both of those. First of all, with respect to whether it’s there on all myeloma patients, I will say virtually all myeloma patients. I say that because we have looked at this and we have seen expression of CD38 on all the patients who we have looked at. Other centers have as well.

In fact, University of Arkansas published their pathology group some years ago. They looked at over 300 patients and they reported 100% expression. In other words, 100% of those patients had CD38 and the vast majority of them had high levels of CD38 on all of their myeloma cells. And that is consistent with what we have seen here and I think generally accepted. In fact, CD38 and CD138, those two markers on the cells are universally accepted as being almost always expressed. I won’t say always. Some place in literature or some researchers will say 95+% but we see them in virtually every one of these myeloma cells.

So it’s there I think and the way that we see it though is not by FISH or cytogenetic studies; we actually see it on the surface of those cells by flow cytometry. So basically, the cells are squirted in a very fine mist, a single cell at a time get fired across a laser, the laser bounces light off the cells and can detect what's on the surface of them. And so CD38 has a unique -- there’s a unique way that we can identify its presence there on flow cytometry.

There are other ways too, something called immunohistochemistry; it's a special staining you can do to see CD38. But the most common way is on flow cytometry and that’s done almost uniformly on patients. So it's not a specific test.

Jenny: On the flow cytometry, we were talking to one of the other researchers who said there was a pretty wide variance in the level of detection. Some flow cytometry, I guess, they're done in colors and some are eight and some are 12 and I think the Spanish group is using 23-color flow cytometry.

Dr. Green: Yes.

Jenny: And so can you explain the difference and then how a patient would know if it's getting to the right level of testing for them?

Dr. Green: Sure.

Jenny: We've been talking a lot about testing.

Dr. Green: Yeah. Well, I have to say that from the get-go I'm not an expert in pathology or flow cytometry, but I can tell you that it is true that some centers do 12 colors, 16 colors, more than 20 colors. In fact, our group here in Seattle, at the Hutch, we have a world-renowned flow cytometry expert here who does an amazing job with what we call multi-color high levels in the 20s – I can't give you the exact number of color flow but it's in that 20 range. That can be very useful to pick out certain nuance in various diseases looking for very subtle findings, maybe very, very low levels of disease looking for a whole bunch of different things at once.

But for the purposes of our discussion, in fact, one does not need those large numbers of colors to detect CD38, let’s say, or really for any standard flow cytometry. For research purposes, there can be a role for that. But for the listeners, I wouldn't be concerned or focused on the number of colors in the flow cytometry as a determination about, is it good enough for my diagnostic purposes?

Now, I will say that having very experienced pathologists to review your flow cytometry that is important not related to that color issue, the number of colors per se, but rather just because they may be more skilled or adept at picking up low levels, nuance, just because they do this more often. I think that's true for anything that we face in the care of patients with myeloma and other cancers.

Folks who do things more often will see more variance and have more experience with that. I'm not saying that everyone has to rush off and see the most expert person all the time. What I’m actually saying is that there are certain situations when things are very complex or unclear that it might make sense to pursue that kind of second opinion or judgment for many things; your oncologist, be they an academic center or in a community can be excellent and just fine. But in certain cases, when things are not clear, it makes sense to get additional opinions from those kind of experts. So hopefully, that answered the question.

Jenny: And we think it's important for pathologists to look at your results too. So we interviewed a pathologist on this series and he reviewed how they can help you review your myeloma labs because they're pretty confusing.

Dr. Green: Our pathologists are vitally important to me in the care of myeloma patients. I frequently see patients in consultation for second opinions and evaluation. I am reliant on the outstanding pathologists that we have to pick up nuance or to suggest something maybe a little bit different. Because you can imagine that it's not unusual for a patient to come here for a second opinion because there's some concern about what's going on, and then it's additionally helpful to have our pathologists sort out if there's something unusual on the pathology that they can find that might help guide us to make recommendations.

I just want to go back for a second to the CD38 radioimmunotherapy. Is that okay, Jenny?

Jenny: Sure. I have some follow-up questions for you too.

Dr. Green: Okay. I just wanted to sort of round that up by saying that -- so we got to a point where I say we attach an antibody. We attach the radiation directly to the antibody to deliver it to the myeloma cells, and we envision using that as part of conditioning for a stem cell transplant at least initially.

The reason I say that is because we had experience doing that with lymphomas and leukemias and in that way, we can deliver very high doses of targeted radiation right to those cells and then rescue the rest of the bone marrow even if other bone marrow cells have some CD38 on them. And so we're getting a little bit of radiation to those cells as well. It's okay, relatively speaking okay, because we can still come back in and rescue the bone marrow with a transplant. Through this approach, it lets us give a lot more treatment in a targeted way to the myeloma cells.

So at least at first we envision it in that context.

Jenny: So if you were to do it by itself, you're just worried that you couldn't give enough of it and then you'd have other complications because your body wouldn't recover from -- or you'd either get too low of amount or you'd give too much and the body couldn't recover from it?

Dr. Green: Well, I think we have to learn more to know what effect there might be, let's say, on the bone marrow. And there may certainly come a time we could take this approach without necessitating the rescue of a bone marrow transplant. But I think that having a bone marrow transplant at least initially gives us the opportunity or the reassurance that we could rescue and protect the normal cells of the bone marrow or at least have them recover after the targeted therapy.

But in lymphomas, for example, there are FDA-approved drugs that target CD20 with the radioimmunotherapy and deliver radiation to the lymphoma cells and those are not used -- sometimes used as a part of a transplant regimen. We've done that here but also in isolation, without requiring a stem cell rescue. And I think that that is not outside of the realm of possibilities for the CD38 approach as well. It's just having the stem cells.

Some research studies have actually been designed where you just have those stem cells. You don't necessarily use them but at least they're in the bank so that if you see that you need to give them in order to rescue the bone marrow, that they're there. Does that make sense? And I could envision that as well as a trial design whereby one would at least have those cells in reserve if you need them.

Jenny: Let me ask this question because I know when you say the word radiation or radioimmunotherapy, that's a combination but the word radiation sometimes -- I mean I even get nervous going into my PET scans when I get the shot. Can you talk about the dose of radiation and how you determine that and if there are any other things that people need to be concerned about or not concerned about?

Dr. Green: Sure, absolutely. I think we are very sensitive as well to concerns about radiation exposure and how we administer the radiation that we use. I think it's reasonable for folks to be concerned about radiation exposure in general, radiation from CT scans, even from standard X-rays although that relative radiation for the X-ray is very low in fact. Nonetheless, when you get to your dental X-ray, the staff step out of the room and I think that's because for them we're talking about maybe hundreds and hundreds of exposures cumulatively.

So I think that we have a lot of respect for the power of the radiation that we use, but we also recognize that the way that we are administering it, there are different types of radiation. So external beam radiation which delivers radiation from outside of the body and beams it in in a focused way still exposes more of the body and tissues to the radiation, just the tissues even in the path of that radiation as it’s passing through the skin, et cetera, towards the target tumor cells.

The type of radiation there is different. That approach is very different from the way that we’re delivering the radiation and the type of radiation we’re delivering. As I mentioned before, Yttrium-90 that we use which is what’s called a pure beta emitter, so it emits beta energy, beta radiation over a very short distance. And that’s important because it means that that radiation, unless it’s in direct contact with something like the target cells that we’re speaking of, it doesn’t do any more distant damage. Now, it still goes in the circulation and while it’s in the circulation, yes, the body is exposed to that radiation; but we actually have designed specific approaches to protect and to try to improve our ability to protect and reduce exposure of the rest of the body to radiation.

I can also tell you that because now we’ve been doing this for years, many years since the 1980s with patients with lymphoma, we’ve looked very closely at what are the complication risks. One of the big concerns with radiation is a risk for secondary cancers of the blood and bone marrow particularly developing something called MDS, myelodsyplastic syndrome, which is a precursor to leukemia.

Now, even when we give very high doses of the radioimmunotherapy for stem cell transplant and then we give much bigger doses than the doses that are recommended for the FDA-approved agents not used for transplant, but when we give those much higher doses the incidence of secondary complications in the bone marrow right where we’re delivering that radiation to is very low. Some groups have reported an increased risk and I think there may be a small increased risk of secondary cancers or leukemias, but that has to be viewed in a bigger context of the overall survival of these patients.

So when one looks at how they are doing long term and the percentage of patients who are treated effectively or cured from this approach, the benefit is still there, meaning that there may be some low-level risk of a second cancer sort of like the concern with Revlimid, let’s say, in myeloma where there’s some concern about a low-level risk especially if one had Melphalan in the past from Revlimid causing a second cancer. If you look at the overall survival data for patients, they are still doing better on Revlimid than not on it for everyone.

So unless we can pick who is at the highest risk for getting a second cancer of the blood and bone marrow for an individual walking in the door, the benefits outweigh the risks and those risks for radioimmunotherapy really has been very low. We’ve actually had a hard time teasing out, is it really the radiation therapy or is it the other prior treatments that also predispose people to getting a secondary cancer that is the root cause?

So I won’t say that there is no added risk from radiation using this approach, but it’s different from the X-ray radiation that folks receive from a CT scan or an X-ray. It’s targeted; it’s delivered locally. And I think the other important thing to address your question how we do this to protect other organs, we use something called dosimetry, so we give a test dose. Before we give that Yttrium-90 that I'm talking about, that’s the therapy dose, we actually give a surrogate radioactive particle that doesn’t do any damage to organs or tissues but we can see it on something called a gamma camera.

So we attach that to the antibody first and usually a couple of weeks before we give the therapy dose we give the same antibody but labeled with something called Indium-111 which is a gamma emitting, so not the beta emitter that has this high energy that kills the cells but a gamma emitting radionuclide that we trace label on the antibody and we inject basically just to follow where it is going.

So we can see where it is with a camera and it’s sort of like a PET scan or some of the other imaging scans that we do, but this one is directly attached to the same antibody we're going to use later on with the therapy step to make sure that we're not delivering too much of it to the wrong place; i.e. if it's all getting caught up in the liver or the lungs or somewhere else, then a patient wouldn’t be a candidate for the treatment. More likely though, almost always that's not the case but rather just let us know how much is going to each of those sites.

And then based on a huge wealth of experience that we have historically, we can calculate what the maximum dose we can give when we give the therapy step because we know how much is going to get there from the dosimetry imaging step. How much, let's say, will be in the liver, and we can then calculate. Okay, when we give the treatment dose, this is the maximum amount we can give. We know if we gave more than that, it might be damaging to the liver. So the liver may define what we call the dose-limiting organ. And once we know how much is going to go there two weeks later, we can then determine what dose we're going to give of radiation two weeks later so that we're underneath the level that would do damage to those organs.

So we spend a lot of time focused on ensuring that we're not going to be delivering too much dose to normal structures. I can't tell you that that means 100% of the time, there's no toxicity to those organs. I can tell you that we're very good at limiting that risk and that we take that very seriously.

Jenny: I think that's really helpful for you to clarify because when you hear the word "radiation," you just picture old school radiation, and that's just what you imagine. So I think it's very helpful for you to describe it in more detail.

Dr. Green: Sure. I think you're right.

Jenny: This has been used in other cancers like leukemias and lymphomas. What phase is this in your studies in myeloma? Is this something that's really early? Is this something you've been working on for quite a while?

Dr. Green: We've been focused on this and like I mentioned before, identifying the target, going through all these processes and steps to make sure we’re looking at the right target in the right way. We've been doing that now for about five years and have made a lot of progress. As you mentioned I think in the beginning, we just published some of this data in the journal, Cancer Research, showing how effectively in what we call pre-clinical models. Frankly, this is in animal mouse models of myeloma where we can eradicate the myeloma cells in a significant proportion of the treated animals.

We are continuing now to further look at different myeloma models to demonstrate the effect. We don’t do that because we're in any way want to slow down getting this to patients but rather quite the opposite. In order to go through all the regulatory processes to get this kind of approach to patients, it requires convincing folks that this is an effective approach. But I think we're definitely making good headway on that front. We're at a place now where we would begin to start considering how we can produce adequate amounts of the antibody and the specific reagents or steps to administer to patients safely for a clinical trial.

But those things, in order to produce something and have it be available takes a huge amount, not just of time which is what we’re putting into this actually, but also of resource and funding in order to produce what's considered good manufacturing product grade, clinical grade agents that we can then deliver to patients.

We have a facility here. We actually produce our own agents here at the Fred Hutch that we can administer to patients, which is a huge blessing to us so that we can actually produce things that we can give to patients here at the center. But for us to be able to do that, the next steps will really be securing adequate funding support to produce these things.

Jenny: I'm not sure how you say it -- Yttrium study?

Dr. Green: Yttrium.

Jenny: What phase is that in and what kind of patient are you looking for in that study?

Dr. Green: So that study in the Yttrium – the approach that I'm describing to you is not yet in a clinical trial approach. Now, there is a clinical trial here at the center that we’re doing that does use Yttrium-90 for patients with multiple myeloma, relapsed treatment / refractory multiple myeloma that is as part of conditioning for an allogeneic transplant so a donor transplant, sort of mini or nonablative transplant we call them.

That study though does not target the CD38 I’ve been talking about. It actually targets something called CD45, and CD45 is very rarely expressed on myeloma cells. So your listeners may wonder, "Well, if it’s very rarely expressed on myeloma cells, why are you delivering radiation to that cell that has CD45 on it?" And the reason is the crossfire that I described earlier. The purpose of that study is to take advantage of the crossfire effect even though the myeloma cells won’t have it on their surface.

CD45 is expressed by many, many other cells within the bone marrow. It’s called the pan-leukocyte antigen I think and it’s highly expressed in the bone marrow. So it is there on the surrounding cells with the idea that you would deliver the Yttrium there, and those cells would be in close proximity to the myeloma cells and the radiation would get to them from their neighbors.

That is the study that we do have open here and certainly in the right context we put patients on that study, in particular patients who have relapsed treatment refractory disease and an identified stem cell donor, allogeneic donor.

Jenny: Okay. So it’s kind of like using a portion of it, but your research of the CD38 specifically is still a little early?

Dr. Green: The CD38 research is not yet in the clinic. As you probably know and I'm sure your listeners know, there’s been a lot of excitement about CD38 antibody in the last couple of years. There are at least two, maybe three pharmaceuticals that are producing a CD38 antibody.

One of them, daratumumab, has been fast tracked by the FDA for approval also for relapsed multiple myeloma and I think it's very exciting. In fact, I think that from our perspective is proof of the principle that CD38 plays a role, although our approach is to pack a big extra punch with that CD38 and not just try to take advantage of the antibody alone which tries to use the immune system basically to attack those myeloma cells, but instead we put a payload on there that sort of delivers an extra punch I think maybe understating it but delivers something in a targeted way designed to destroy the myeloma cells that the CD38 binds to.

But your right that that is not yet in the clinic. Our hope is to get it there and really as fast as we can.

Jenny: Well, I'm not a very violent person but I like words like “destroy myeloma cells”.

Dr. Green: I feel the same way.

Jenny: So when you look at the patient who expresses CD38 and you’re targeting that, do you look at the other genetic or genomic factors for that patient profile or it’s just too early to try to do that yet?

Dr. Green: Well, I think it’s a great question. In terms of selecting which patients would be appropriate for this kind of therapy, we do not make that distinction based, let’s say, on high risk versus standard risk cytogenetics. There does not appear to be, as far as I'm aware, any big difference. There have been some data in the literature which suggests that patients with higher risk myeloma actually may express more CD38. And if that’s the case, I guess you could think that might be a good thing from the perspective of those who are higher risk patients and maybe there’s more target on them so this may be particularly beneficial in that setting.

I can tell you, one thing that we do know about radiation and high-risk cytogenetics, way back in the beginning I mentioned those plasmacytoma, the collection of plasma cells outside of the bone marrow that we can cure with radiation. And they’ve gone back and looked to see what about higher risk cytogenetics in those myeloma cells? Do they respond less well to radiation just like they respond less well often to other therapies than standard risk cytogenetics? And at least so far and there is limited data but the published literature on that point suggests that no, they are every bit as sensitive to the radiation as are the cells without the abnormal cytogenetic findings.

So that’s encouraging to us suggesting that maybe we can by delivering radiation to those cells it doesn’t pick and choose or it doesn’t – the radiation is delivered to the cell independent of whatever is going on in that cell’s DNA and nucleus. And we’re hopeful that that might let us overcome some of the limitations related to the cytogenetics, the high risk cytogenetics that limit the effectiveness of other treatments.

Jenny: Well, maybe you want to talk about high risk for a minute because on our interview with Dr. van Rhee from UAMS, he was saying this is really the group that might need the most attention. So maybe you can touch on where we’re making progress for high risk disease.

Dr. Green: Sure, absolutely. And we are making progress definitely with high risk disease. I think the most exciting findings in recent years has been the data from the HOVAN Group where they showed really for the first time a significant impact from novel therapies on patients with high risk cytogenetics in particular, the deletion 17 or p53 subgroup which is probably the highest or amongst the very highest risk group of patients in terms of a cytogenetic finding and demonstrating that the use of bortezomib proteasome inhibitors, in particular bortezomib, both up front and then as part of maintenance after a stem cell transplant significantly improved response rates and survival rates among those patients.

Now, it wasn’t a huge number of patients but I think we’re seeing clinically, myself and my colleagues, that yes, in fact the proteasome inhibitors play a very important role for those patients and overcome some of the down, of the negative side or the increased risk that we’ve seen historically with cytogenetics.

The same is true for (4;14) translocation. We know that that translocation is historically generally considered high risk. There’s kind of an intermediate risk category among patients who don’t have anemia when they present and have (4;14) and it gets into some complexities, but it’s generally considered to be a high risk finding. And yet those myeloma cells are also very responsive to the proteasome inhibitors and now not only bortezomib but also carfilzomib being available. We don’t have as much data on that, but I think that there is reason to be optimistic that carfilzomib as well will have enhanced effectiveness with high risk disease.

So I think that’s one place where certainly we’re having some advances, and I think there’s probably going to be more to come in that regard.

Jenny: Well, it’s nice to see those approaches especially the monoclonal antibody approaches start coming out. It’s really wonderful as a patient to see so much being developed.

Dr. Green: And on the monoclonal antibody, there have been dramatic advances in that approach not only in myeloma but other cancers of the blood and bone marrow. But in myeloma, as I mentioned, the CD38 antibodies, there’s also elotuzumab which is also the anti-CS1, a different marker on the surface of myeloma cells that looks to be quite effective when combined with Revlimid. So I think that immunotherapies are very exciting. And frankly, the other advantage to them is they have limited toxicity. Patients don’t have the same toxicity from this approach that they do from lots of other chemotherapy approaches. So it’s definitely promising.

I also just want to tell you just in brief that there’s another step – I described this approach that we take with CD38 and attaching the radioactive molecule to it, but our most effective approach has actually been – and bear with me because it’s going to take a second to explain this – but we actually administer the antibody against CD38 without the radioactive molecule on it. But first we prepare that antibody. We change it a little bit by tagging it with something which is called streptavidin, a naturally occurring substance -- actually, avidin is found in egg white -- and we attach streptavidin to the antibody and then we inject the antibody and we let it distribute to those myeloma cells, but it's going there with no radiation involved, right?

So it allows that window of time where the antibody travels through your system and bind specifically to the target site, no radiation step, no exposure of any normal organs to the rest of the body to the radiation. And usually that takes about 24 hours. We’ve studie this extensively. So it takes 24 hours to distribute and it goes there.

Next, we administer another agent that clears from the blood any of the antibody that doesn't bind. It doesn't pull it off to target cells, but if it still sitting around in the blood that we call the excess amount of the antibody, it clears it, remove it out through the liver so it's gone.

So now we've primed the myeloma cells with the antibody with that little streptavidin molecule sitting there. The reason we do that is that allows us to let it distribute slowly and only then do we deliver a very, very small molecule biotin connected to the Yttrium-90 radioactive molecule. That is so tiny that it can penetrate throughout the body and distribute to those target sites within minutes.

So now it quickly goes to and binds onto the antibody streptavidin that's on the myeloma cells. Any of the radioactive molecules that doesn't do that is cleared out through the urinary system within 30 minutes. That way, there's no prolonged exposure to the rest of the body of the radiation. It's gone within 30 minutes.

It's either binding specifically to the target sites or it's gone. And we've been able to show that we can deliver much more radiation safely that way because the rest of the body isn't being exposed to significant degree to that radiation. That's called pre-targeting and that's pre-targeted radioimmunotherapy, and it's the major focus of ours because it lets us give more radiation in a targeted specific way just to the myeloma cells.

Jenny: Oh, it sounds great. That's sounds wonderful to be able to target specifically and not affect other things going on your body. It's ideal.

Dr. Green: Exactly. When I was a kid, it's the kind of thing where I would sort of muse about these kinds of things and say, boy, that's a science-fictiony kind of thing to do and yet we are able to and can effectively do it.

Jenny: Now, I know we're running out of time, so I want to be quick with some of my last questions so we can have time for caller questions as well.

We were talking on one of the shows and one of the researchers was telling us that waiting until the end when you have no other options is really not a good time to be joining a clinical trial. So can you share with us your opinion on when is the best time to join a clinical trial?

Dr. Green: Absolutely. In some ways, it's complex; in some ways, it's simple. My short answer is that there is no bad time to join a clinical trial. For some clinical trials, it's appropriate once all other options have been exhausted and those would be things like Phase I trials where they're trying to determine what the best dose is and nobody knows if the therapy is necessarily going to work. But as an individual patient, one might say, "Well, gee! This is something new. They are trying to initially learn about it. Maybe it will work for me." And that kind of Phase I trial for relapsed refractory disease nothing else has worked is entirely appropriate.

But on the other end of the spectrum, there are certainly trials that are available for patients up front early at the beginning or after diagnosis; perhaps transplant trials, perhaps trials for patients who have tried one therapy and it's not working or one or two and now need something else to be more effective. Those can be Phase I, more often Phase II or Phase III three clinical trials.

But I think that it is vitally important for patients to be aware of some factors. Number one is that all of these trials have to go through a process of close scrutiny in terms of making sure that patients are not being offered something that is below the standard of care. In other words, if we know something works well and it's a standard of care, you should not be asked to and you shouldn't be involved in a study that doesn't give you the standard of care plus something else. In other words, you wouldn't want to come in at the beginning and get a treatment that nobody knows if it works very well or not while we know we have effective therapies from the get-go.

And so I think sometimes there's a misconception that that might be out there, but that is not the approach of these clinical trials. The approach might be we'll give you the standard therapy plus this other agent or in cases, let's say, where patients have high-risk cytogenetics or some finding where we know nothing is working particularly well, there isn't a good standard of care, that might be a place where a new agent is reasonable to try.

But I agree with the assessment that waiting to be involved in a clinical trial after all other options have been exhausted doesn't really help to answer all of the questions that we have about can we do things better? Can we improve outcomes for each individual patient, but also for the future?

And there are some benefits to being in clinical trials in terms of close scrutiny, being watched closely; in terms of being aware of and having the opportunity to get a new treatment, being aware of new treatments that are coming along. So often the trials will say that there's no promise of a benefit to individual and that's true. The whole reason why we're doing the trial is we don't know. There is a scientific basis for these trials rooted in experience and other prior studies, but we don't know for certain that any individual trial is definitely going to work. Otherwise, of course, it wouldn't be a trial.

So there's an advantage to the field. There can be advantage to individuals enrolling in these studies and I think, as you mentioned before, 75% of patients, they want to be enrolled but only 5% of patients are, and I think there's some disconnect there. Perhaps also, I think patients sometimes worry that if they agree to a clinical trial that they're committing themselves to it without an opportunity to get out of it. And really, nothing could be further from the truth, which is to say, for any individual, you can sign up for a clinical trial. And if, for any reason, you decide, "Hey, I'm not going to do this trial. I don't like the side effects. I changed my mind," any number of reasons, you're not signing a lease for a house or a car or anything along those lines. You have the power and the right to say, "Done. I don't want this. Instead, give me this other treatment. That's what I prefer." I think that's important for folks to be aware of.

Jenny: It's very important. Once you know that, you can be an empowered patient and make good choices about your care. Well, I have taken a lot of time, and I want to open it up because we have some caller questions.

If you have a question for Dr. Green, you can dial 347-637-2631 and press 1 on your keypad.

Caller: Doctor, thank you so much for your time today.

Dr Green: Sure.

Caller: My question is, has radioimmunotherapy been used for leukemia or lymphoma?

Dr Green: Yes, it has. We use it for leukemia and lymphoma, in fact. And again, in the case of lymphoma, there are two FDA-approved agents, actually: Bexxar and Zevalin. Actually, now just Zevalin I think is commercially available, but it is used for both of those diseases. And we've had lots of experiences here in Seattle and in other places as well using that approach.

Jenny: And maybe I can ask a follow-up question to that. Is it just used for allogeneic transplant patients or is it used for autologous also?

Dr Green: It has been used for both. Most patients with leukemia in general will undergo allogeneic transplant because unfortunately autologous transplants aren't really sufficient for leukemias to be effective. But in lymphoma, it has certainly been used for autologous transplants with excellent rate of response and cure rate using the radioimmunotherapy as part of the transplant conditioning, and also in – well, I think, remind me again, your question was whether it's used for – was that your question, for auto and allo transplants?

Jenny: Right.

Dr Green: So yes.

Caller: Well, thank you so much, doctor, for your time and for and for answering my question.

Dr. Green: Sure, certainly.

Jenny: We have another caller. Please go ahead with your question.

Caller: Hi, Dr. Green. Thank you. Thanks so much for taking my call. I just want to know if -- being diagnosed is pretty overwhelming and I just want to know how does someone who has just been diagnosed find a clinical trial that is right for them?

Dr. Green: I think that is a terrific question as well. In part, there is a geographic component and let me start by saying I know that it is a lot to face and deal with it. There's so much information that one has to try to assimilate at the time of your diagnosis. But I also want to tell you that the prospects for patients with myeloma really have never been brighter and advances have really made a huge difference in terms of our ability to project for patients a much better course. So we're doing great in that regard and I think we're just going to keep doing better. That should give you hope.

In terms of finding a clinical trial, I think it's important to -- a couple of things need to be taken into consideration. It really depends on where you live and what's close to you. Most often, clinical trials or the largest number are usually available at academic centers. So if you live near an academic center, university or affiliated center, those may be the best places to find out about clinical trial options.

There is also online a route by which you can find out about all the clinical trials that are available nationally. We can probably work to get you information on how to get to that. Jenny, I don't know if you have links to the clinical trials site, but I imagine it wouldn't be hard for us to get you that information so that you can look at trials nationally. But it's important also to recognize that while I strongly advocate for clinical trials, I also advocate for people to live their life and to be at home and close to their family. It is rare I tell someone to travel long, long distances because often these trials require frequent check-ins, blood draws, et cetera.

So it's important to try to find trials that are close to you for the most part, let's say, outside of a stem cell transfer plant where one may have to travel. But if it's an ongoing kind of trial, looking close makes a lot of sense and probably the best place to start is at the closest academic medical center. There are other trials for US oncology, other private groups but the largest collections are usually at the academic centers.

Caller: Thanks, Dr. Green.

Dr. Green: Sure. Do you live somewhere -- I don't know if you want to say where you're at. I might be able to tell you where it's close to you but...

Caller: There's quite a few places locally that I can find I believe.

Dr. Green: Sure. So yeah, I think it makes sense to look around at those places. And sometimes it makes sense to call them and ask a number of places, what kind of trials do you have available? And make sure they give you all the information about the trial to read through so you get a sense of what sounds reasonable to you.

Caller: Definitely. Thank you.

Dr. Green: Sure.

Jenny: Okay. We have time for one more caller. Caller, please go ahead.

Caller: Thanks for taking the call, Jenny and Dr. Green. Dr. Green, I first heard about you from Nancy Kaufmann at the MMORE Foundation.

Dr. Green: Nancy is terrific and so is the MMORE Foundation.

Caller: They are. We've been out to their fundraisers for a couple of years now.

The question I have -- well, I have several but I was told not to take much time because we're short. A friend of mine has -- he has been diagnosed with myeloma. He did tandem transplants. He was in remission a short period of time and now he's fallen out. So when he went to look for medical trials and he's actively looking for trials, the feedback that came was, "Well, you've fallen out of a tandem transplant after a year. You don't really qualify for anything. So the only thing you can do is a third party stem cell transplant."

And I'm just curious if you have any other ideas because that seems -- I thought that would be the point where you would actually -- he's not refractory to anything. So why wouldn't he qualify for a typical medical trial? I don't know all the details of the situation, but it just seems kind of odd that the only option that they're giving him -- and these are really distinguished medical centers I’m not going to say their name.

Dr. Green: Sure.

Caller: A third party transplant is the only thing you can do right now.

Dr. Green: Yeah. In fact, I would say that we have trials here that are available to patients who have had prior autologous transplant, even two transplants. Some trials do not accept those patients onto the trial, but that's certainly not the case for all the clinical trials. And in fact, some of the ones I mentioned like the one with the third party transplant that you mentioned, the one that we're doing here using Yttrium-90 against CD45, that's open to patients who had prior transplants, prior autologous transplants like you're describing or tandem transplants. We have other trials as well. There are fewer of them, but there definitely are a fair number so may be worth looking further into that as an option.

And I think in answer to the question about the responses, the reason perhaps some of those trials are not available to your friend – and I'm not saying I agree with this – is because if the disease comes back shortly after the second, let's say, autologous transplant, then prognostically that is worse than not – an obvious point then if that were not the case -- and so some of these studies they're designed first to ask the question amongst patients, let's say, who aren't a very highest risk of progressing. And again, I'm not citing a perspective.

Caller: Yeah, because a high risk, that could hurt the trial and I understand that so -- yeah.

Dr. Green: To give them sort of fair benefit of the doubt, sometimes it's not so much that they are trying to exclude or make their data look better because they have to report who they put on to these trials but rather are first trying to answer the question the group of patients who have the best likelihood of doing okay for longer rather than a shorter period of time so they can follow those patients out and tease out responses, et cetera.

But again, I'm not endorsing that approach and I would say I think that your friend should keep looking because there are such trials and we do have some here and I would be happy to offline we could follow up and look at that or you could advise your friend to get in touch with us.

Caller: I will send an email to Jenny and send the name along so maybe if she can make the introduction to you.

Dr. Green: Sure, that's fine. And also, if Jenny doesn't want to be in the middle, Nancy Kauffman as well, however you want to do that is fine with me.

Caller: All right, thank you very much.

Dr. Green: Sure thing.

Caller: All right, bye.

Dr. Green: Take care.

Jenny: Well, Dr. Green, thank you so much for joining us today. We are very grateful that you're working towards a cure and we are grateful that you're doing amazing work and for looking at completely new approaches for myeloma. So thank you.

Dr. Green: Well, thank you. It was a pleasure to talk to you and to the callers. I think we all share the same goal which is curing this disease and doing everything that we can to find new and effective approaches to do it safely and improve everyone's quality of life.

Jenny: Well, absolutely. Thank you very much.

Dr. Green: Sure thing. Take care.

Jenny: Thank you for listening to another episode of Innovation in Myeloma. Join us next week for our next mPatient Radio Interview as we learn more about how we as patients can help drive to a cure by joining clinical trials.