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Jenny: Welcome to another episode of mPatient Myeloma Radio, a show that connects patients to myeloma researchers. We as patients have an important role to play in determining the pace of research. By participating in clinical trials, we can help researchers come to conclusions more quickly. We all want to find a cure and this is one way we can help even when and may importantly, especially when we're undergoing treatment. I know that we all care about myeloma research because we now have over 5,000 listeners to the show. Just a note before we get started, we have two new ways you can subscribe to find out about upcoming and past interviews on the Innovation in Myeloma Series on mPatient Radio. We have a new weekly newsletter called the mPatient Minute where you can see all the most important posts [0:01:03] in the emails sent to you just once a week or you can subscribe to all the posts that we have posted [0:01:08]. You can do this on the right side of the homepage of our site, www.mpatient.org website. To simplify our show, this will now be the only way we'll notify you of upcoming shows. So I really encourage you to register today. We have the best and brightest myeloma researchers on our calendar and you don't want to miss what they have to say. Speaking of which, we have one of the best and brightest with us today. I'm very delighted to have a conversation today with Dr. William I. Bensinger. Welcome, Dr. Bensinger and thank you so much for joining us. Dr. Bensinger: Thank you, Jenny. Jenny: I'd like to give you a little introduction if you don't mind. Dr. Bensinger received his medical degree at Northwestern University in Chicago. He interned at Washington University in Saint Louis. He worked at the National Cancer Institute in Cancerology before moving to the University of Washington for his residency with a subspecialty in Medical Oncology. Dr. Bensinger is the Director of the Autologous Bone Marrow Transplant Program at Seattle Cancer Care Alliance. He is a member of the clinical research division at the Fred Hutchinson Cancer Research Center. He is a professor of medicine at the University of Washington School of Medicine. He's also a member of the National Comprehensive Cancer Network Myeloma Guidelines Committee and co-chair of the same Cancer-Related Infection Guidelines Committee. He's also a member of the International Myeloma Working Group clinical endpoints committee.

He has published more than 200 articles in reference journals, books, and in the field of stem cell transplantation especially how transplantation relates to the treatment of multiple myeloma. He studied the use of CD34 stem cells and other antibodies that we'll talk about today. In addition, he holds several patents including one as co-inventor of the avidin-biotin bead selection system which you're going to have to cover. His areas of research include autologous stem cell transplantation as well as allogeneic targeted radiotherapy and immunotherapy. Dr. Bensinger has been treating and studying multiple myeloma for over 25 years. Thank you so much for joining us and thank you for your dedication to treating and finding a cure for multiple myeloma. Dr. Bensinger: Thank you very much for that very nice introduction, Jenny. I guess, I'll start off today by talking about at least one of the newer drugs in multiple myeloma and how we're using it to hopefully advance the treatment and management of this disease. The drug is Carfilzomib. This is a secondgeneration proteasome inhibitor. It's a second drug that was developed after the drug Bortezomib first came on the scene about ten years ago. This drug has a similar type of action but appears to be more specific to a particular enzyme within the proteasome. And it is a more, if you will, a more targeted approach in terms of reacting against this particular component in cells. The advantage of this is that it has fewer toxicities. Because it's so targeted against the particular enzyme, it has less off-target, what we call off-target effects which lead to some of side effects associated with Bortezomib, one of them being neuropathy. This has several advantages because there is a little or known neuropathy [0:05:15] with this drug. You can give the drug for a longer period of time than might be tolerated. Otherwise, you can give the drug more frequently and you can give the drug in higher doses than would be possible to do if the drug had some of these side effects. We're studying this drug in combination with other drugs for two phases of the disease in multiple myeloma. We have an upfront trial designed for patients with newly diagnosed multiple myeloma in which we're combining Carfilzomib with two other drugs, Cyclophosphamide and Dexamethasone. As you know, Cyclophosphamide is an alkylating agent, one of the older drugs for the management of myeloma but a very active drug and then Dexamethasone, also a very important drug. We're actually conducting this as part of a multicenter Phase I study where we're actually giving higher and higher doses of Carfilzomib mainly designed to determine if, number one, if there is a maximum dose you can give but number two if the higher doses can more effectively control the cancer. So far, we haven't observed those limiting toxicities and we've given actually twice the initial dose that's used to treat patients with this disease, twice the 2

initial dose of Carfilzomib. The drug combination seems to be very well tolerated and so far, all of the patients that we have treated have responded. That's a small number. It's only about a half dozen patients but everyone seems to have responded so far. We're also studying this drug in a group of patients who have failed lots of other therapies namely patients who have relapsed and are deemed to have resistant disease. These are primarily patients who failed the drug Lenalidomide, one of the widely used immunomodulatory drugs. Patients who have relapsed and failed l Lenalidomide were put on a combination of Carfilzomib-Pomalidomide, the third-generation immunomodulatory drug and Dexamethasone. Again, this combination seems to be very active. Excuse me. I'm getting some background noise. I think someone has their phone off of mute [0:08:12] or something but I'm getting a lot of background noise so if that's possible to mute your phone or something. Anyway, this combination seems to be quite active even in patients who failed Lenalidomide and again, seems to be very well-tolerated. These are two important combinations. This is a drug that is, I think, going to have a lot of important uses in the management of multiple myeloma. These are just a couple of the trials that we have. We have actually quite a large number of trials that we're doing at our center. We try to select different trials looking at different drugs and combinations. In a big way, I'm trying to find new types of drugs that had different activities with the idea ultimately of combining therapies. I think some of the major advances that have been done in the management of other cancers and I think it applies very much to patients with myeloma, these combinations of therapies. I think in general we find that combinations work more effectively and faster than single drugs or even maybe two drugs when you can use a combination of three. Now we have to prove obviously, ultimately that three or four-drug combinations are better than two-drug combinations. But I think that as a strategy for managing the disease, these combinations seem to be better. Just a review of some of the trials that we're doing, we're actually participating in a large international trial using what is now a pretty standard drug combination which is Bortezomib, Lenalidomide and Dexamethasone. This is a study primarily designed to ask the question of the role of autologous stem cell transplant when these newer drug combinations are used. As part of this trial, patients received induction therapy with this threedrug combination and then have their stem cells collected. Half of the patients have a transplant, go on to an autologous stem cell transplant and that's followed by two more cycles of the same induction therapy and then a maintenance phase. The other group simply stays on this induction therapy for five more cycles and then maintenance. Basically, you're comparing a total of five cycles of Bortezomib, Lenalidomide, Dexamethasone, plus 3

transplant to eight cycles of Bortezomib, Lenalidomide, Dexamethasone without a transplant. This trial is being conducted in Europe mainly in France and they have had a large number of patients on this study. And then in the US, there is a fairly large number of sites now conducting this trial, probably about a dozen now but I think that's going to increase to as many as 40 or 50 sites around the US. Jenny: What are the results showing so far on that trial or is it too early to tell? Dr. Bensinger: It's too early. For very good reasons, they don't want to release any early results of this trial because it might affect the ability to put patients on. The other trials that we're doing for newly diagnosed patients involve -- mainly for patients who are not considered transplant candidates, a randomized trial of Lenalidomide and Dexamethasone with or without the drug Elotuzumab. Elotuzumab is a monoclonal antibody and I'll talk a little bit about monoclonal antibodies in a few minutes to try to tell you more about that. But basically, this is looking at a three-drug combination, the antibody, Lenalidomide, Dex or just the standard Lenalidomide-Dexamethasone alone. We are going to be opening up a trial in fact probably within the next month for newly diagnosed patients using a new drug called Oprozomib. Oprozomib is an oral proteasome inhibitor. As you know, both Bortezomib and Carfilzomib have to be given by injection, either as subcutaneous or an intravenous injection. Oprozomib is an oral form of Carfilzomib. It's a potentially a very exciting drug because it's simply a pill that you take. This is being looked at in combination with Lenalidomide and Dexamethasone. Again, this is a common combination of a proteasome inhibitor, an immunomodulatory drug and then a steroid like Dexamethasone. This promises I think to be a very active combination but the nice thing about it is it's all oral. Jenny: Yeah. That's great. Dr. Bensinger: Now, I mentioned that I would talk more about antibodies. Monoclonal antibodies are one of the next big types of drugs that I think we're interested in in multiple myeloma. This interest really developed with the discovery and development of the first monoclonal antibody that had activity in any type of cancer and that was a drug called a Rituximab. Rituximab targets a protein expressed mostly in lymphoma patients and some patients with a form of chronic lymphocytic leukemia. This protein called CD20 is a protein that is not only found on the surface of the cells but it is an important signaling for the cell. It signals growth and development and it's found that if you block this with an antibody, cells go on to die. 4

There is much interest in developing a similar type of antibody in multiple myeloma. Unfortunately, myeloma cells typically do not express the same CD20 protein but they do have other proteins. Among them a protein called CD38 and there's another protein that doesn't have a number but is referred to as CS1. Elotuzumab is one of the first drugs to move forward in this field. Elotuzumab targets the CS1 protein. Phase I studies of the drug alone were performed. I was part of those initial trials and I have to say that the activity of Elotuzumab by itself was relatively modest. What I mean by that is the best that you could see when you use the drug alone in patients with myeloma who would relapse was stabilization of their disease. You didn't get real responses in these patients. However, when the drug was combined with Lenalidomide, this immunomodulatory drug and Dexamethasone, the responses were relatively dramatic. Typically for a relapse population of patients who are treated with Lenalidomide and Dexamethasone, you'd expect to see response rates in the 50%-60% range. When you combine this with Elotuzumab, we observed responses in the 80%-90% range, really dramatically different. Jenny: That's stunning. Dr. Bensinger: Yeah. It was quite stunning and unexpected, I have to say. But because of that, this drug has moved forward with the combination of Lenalidomide and Dexamethasone both as initial therapy and is continuing to be studied in a relapsed setting. The neat thing about antibodies is they work by a totally different mechanism of action from most of the other agents that we use. It's a unique class of drugs. They typically don't have serious toxicities. There is usually some first dose effect in which you can get like a flu-like syndrome when you get the first couple of doses of the drug but after that, there don't appear to be serious side effects. So it's nice because this is a drug class that potentially can be used with other drugs and not add to the side effects. That's one of the reasons they're such interested in antibodies. There are some other drugs that look promising in this class. The most active drug to date appears to be a drug targeting this protein CD38. CD38 is expressed very heavily on myeloma cells and plasma cells and also to a lesser extent, on some other blood cells. There are several forms of antiCD38 antibodies that have been reported to have activity in myeloma as single agents. There is great interest in this antibody as well. One of the drugs is called Daratumumab but there are at least two other forms that are moving forward in development. We will be opening a trial for patients with relapsed disease using one of these antiCD38 antibodies. We're also looking at several other combinations in the relapsed setting. We're looking at a form of histone deacetylase inhibitor called ACY-1215. 5

Histones are proteins that bind to DNA of cells and result in modification of how the cells can grow and develop. What happens is these proteins will bind to the DNA and essentially field the DNA from its ability to make other proteins that promote growth and development. It's found that these histones are much more active in certain types of cancers. If you can inhibit the action of these histones through an inhibitor of this enzyme, histone deacetylase, you may get activity in myeloma. This is a particular histone deacetylase that seems to be very well tolerated and is used again in combination with Lenalidomide and Dexamethasone. We're studying it as part of a dose-finding study. Groups of patients receive increased doses of the drug with Lenalidomide and Dex. So far, it appears to be very well tolerated and with good activity. Jenny: I have a question about the histone inhibitor. I've seen different numbers, like the ACY1215 that you're talking about. I have seen other numbers. Are those just different kinds of histone inhibitors? Dr. Bensinger: Yes. There's a whole variety. In fact, there are some approved for the treatment of cancers. There's one called Vorinostat which is widely used for the treatment of T-cell malignancies. Unfortunately, it was studied in myeloma and had very, very modest activity and it's probably not a very important drug in this disease. But there are other types of histone deacetylase inhibitors and they are likely to be specific for different types of cancers. This is where you get into this issue of a more personalized approach to the treatment of cancer. We can talk more about that later. Jenny: Yeah. I'd like to. Dr. Bensinger: We're also studying in a relapsed setting the use of another oral proteasome inhibitor. This is one that's a little further along in development called MLN9708. It also has a name, Ixatomib [0:22:05] and I honestly have trouble pronouncing it. It's one of these odd spellings, I-X-A-TO-M-I-B or something like that. But I refer to it by its name before it was given this special name, MLN9708. This is an oral form of the proteasome inhibitor Bortezomib. It's much further along in development. It's also being studied not only in a relapsed setting but in an early treatment setting. It's also being studied or soon to be studied as a form of maintenance therapy. We can talk more about the role of maintenance therapy in a few minutes but that's yet another study that we're doing. Then, we're studying several other interesting compounds that I think have quite a bit of potential. One of them is a drug called Ibrutinib. What it is is an inhibitor of a specific B-cell signaling pathway inside B-cells called Bruton's Tyrosine Kinase. This is a signaling pathway whereby cells are stimulated to grow and develop. If you block this pathway, cells die. It seems to be a very 6

important pathway in a variety of B-cell cancers. Ibrutinib is already been shown to have tremendous activity in chronic lymphocytic leukemia and a form of lymphoma called mantle cell lymphoma. The drug will likely be approved before the end of the year for these diseases. There is little data in myeloma and we don't know yet what the activity is going to be but it could be a very important drug. We just started a trial with a number of patients in this group. You're looking at this drug Ibrutinib. It's too early to tell how useful it's going to be in myeloma but I think it is a potentially promising pathway. We're actually studying a very unique drug combination. I'll be honest with you. It's going to be a little difficult to explain in layman's terms but what we're studying -- the drug is called SNSO1-T and it's being studied in B-cell malignancies. It's yet another B-cell pathway based on inhibition of a molecule known as eukaryotic translation initiation factor. We just call it EIF5A. Again, this is a protein that's been implicated in the regulation of cell proliferation, inflammation and cell death and appears to be very active in BCell malignancies. The protein is modified in cells with another protein that I won't even mention the name of that basically turns the protein on or off from being a protein that promotes cell death to a protein that promotes cell growth. What we're studying actually is a small DNA molecule [0:26:09] which is called a plasmid DNA and an interfering RNA. So it's actually two components to this and it's given intravenously. It gets into these cells and modifies this protein to make it a more of what we call pro-apoptotic protein which the idea is it promotes cell death. It's a totally different approach from other types of drugs because this is a form of DNA that we're trying to get into cells. It's interesting because I was just to report in the New England Journal of Medicine looking at a form of amyloidosis targeting it with a type of RNA and showing that you could target this and effectively control the development or the progression of amyloidosis. I think this approach may have some real promise for this type of treatment for patients but it's a very early study and we don't have any kind of results to report at this time. Jenny: But this is still in the immunotherapy family would you say or no? Dr. Bensinger: I wouldn't call this immunotherapy. More of the immunotherapy approach is the antibodies and then some of these studies that are starting to be done with modified T-cells and then of course the oldest form of immunotherapy that we use is donor transplants or allogeneic stem cell transplants. To that end we have a study where we're using a unique regimen to treat the myeloma in patients who have high-risk myeloma. It's well-known that there are certain features of myeloma at diagnosis that are called high-risk. What that means is patients who have 7

these high-risk features have a more aggressive form of their disease. They can respond to treatment but they generally have shorter remissions and the disease comes back much more quickly with the same therapy that might control the disease for a longer period of time in patients who do not have these risk factors. Some of these risk factors are an elevated Beta-2 microglobulin which is a protein that's a marker of the disease in the blood. And then certain genetic abnormalities that are seen by chromosome analysis of myeloma cells either with conventional chromosome analysis, for example, deletion of Chromosome 13 or with physionalysis deletion of chromosome 17 or a translocation which means a piece of the DNA from one chromosome has been switched and swapped out onto another chromosome, in this case, translocation 4-14. That means, a piece of chromosome 4 has come off and been attached to chromosome 14. That translocation is also associated with high-risk features. What we're doing for this is we're looking at a unique way to deliver more aggressive therapy as part of the treatment for patients who are having donor transplants. In this case, it's a substance known as Yttrium-90 attached to an antibody, CD45. Itrium90 is a radioisotope so it's a radioactive substance. It's very high energy but it's what we call a pure beta radioactive substance. What that means is it doesn't have any gamma rays or x-rays. The energy from the radioactivity has a path length of only about roughly a third to half an inch in distance. You can give this isotope to a person and it acts across several cell diameters but does not become dangerous to anyone standing next to the patient or anything like that. What we do is we attach this isotope to an antibody called CD45. CD45 is an antibody that binds to blood cells in general. What this does is it guides the isotope to the cells in the bone marrow and the cells in the lymph nodes and spleen. These are the sites of blood cancers in general but also the sites of the disease multiple myeloma. The idea is you get a dose of this isotope. It's given intravenously. It travels to the bone marrow, it travels to the lymph nodes and spleen and radiates those areas with this Yttrium-90. Yttrium-90 has a half-life of about two and a half days. After about ten days, the isotope has disappeared from your body. It's decayed away. After this treatment, patients are then given some chemotherapy primarily designed to assure engraftment of the allogeneic stem cells. They receive Fedramine [0:32:26] and then some immunosuppressive drug. And then they receive bone marrow or excuse me, not bone marrow but peripheral blood stem cells [0:32:36] from a suitable allogeneic donor. This donor is most commonly a brother or a sister but may also be an unrelated donor if we can find a suitable donor in the registry.

The ideas here is to facilitate the graft but also to eradicate as much of the myeloma as possible prior to the introduction of the graft. What that does is it makes it easier for the graft to, if you will, clean up any residual myeloma that's left behind. This is one of the advantages of a donor transplant. This new immune system with the donor cells can more effectively attack and destroy the myeloma cells and get rid of them from the body. Allogeneic transplants have these major advantages but they also have disadvantages. This is more -Jenny: I'm wondering if you can still [0:33:38] talk about that. Dr. Bensinger: Sure. It's a more difficult approach to go through than using your autologous stem cells. That's because these allogeneic cells replace the bone marrow and the immune system in the patient. It takes up to a year before a patient's immune system recovers from this. During that time, patients are more susceptible to infections and can develop quite serious infections during this time. In addition, the cells have the capacity to damage normal organs in the body. It's basically a form of rejection where the immune system is rejecting the body of the patient. Primarily, this affects the liver or the skin or the GI track. We call that graft-versus-host disease. This has to be controlled or prevented by giving these immunosuppressive drugs. Patients need to take these drugs for a minimum of six months but sometimes, they have to take the drugs for as long as a year or two if they have any graft-versus-host disease. One of the good things is though that eventually, the graft develops tolerance to the patient. Patients are able to come off these drugs eventually. It's not like if you, just to give an example, if you have a patient who requires a kidney transplant because their kidneys are failing, those patients have to take these immunosuppressive drugs for the rest of their life. Their body never develops tolerance to the kidney graft and so they're always at risk of rejecting it. That doesn't happen with a bone marrow or a stem cell transplant. Most patients eventually -- the graft becomes tolerant to them. The bottom line on this is that allogeneic transplants while they have a greater chance of long-term disease control and a greater chance actually of curing the disease, they're much more difficult to do and there's a much greater risk of complications. There is a risk of dying from this type of transplant in the range of 15% to 20%. That's the reason it's not more widely used because of this risk. If you can contrast that to an autologous transplant where you're using your own stem cells, the risk of dying from that type of treatment is very low in the range of only one two percent.

We're trying to improve on the ability to do the allo [0:36:38] transplants because we think it has a greater chance of cure. In the interim, in the absence of that, many of us are trying to work on trying to make myeloma if you will a chronic disease. I hesitate to use the analogy to something like diabetes because it's clearly not -- that's not a cancer. But the management of myeloma has improved tremendously in the last ten years. I think that for some patients who don't have high-risk features, they actually can have their disease managed as a chronic form for sometimes ten years or more. That's one of the things we're trying to do in the absence of the ability to cure the disease. But I think we're not ignoring approaches to try to cure the disease. It's just that we're trying to do all these different things simultaneously. Our ultimate goal is to try to improve the overall treatment and outcomes for patients with myeloma. One of the things that we do is look at Maintenance Therapy. Maintenance therapy is essentially low dose drug treatment used after some initial treatment. That can be an initial course of therapy to get the disease control [0:38:12] or it could be an initial course of therapy followed by an autologous stem cell transplant. An autologous stem cell transplant we know has a much better chance of producing remissions. The remissions tend to be more durable and in some studies patients who have transplants lived longer than patients who don't. Autologous transplant is not a cure for a majority of patients. The disease will come back. So now we're looking at drugs for maintenance as a way to improve how patients do, keep the disease under control for longer periods of time and hopefully result in patients living longer. There has been progress in this. Lenalidomide has been shown in several trials to improve the length of disease-free interval. It can nearly double the length of remission when it's used after an autologous transplant. At least in one of two trials, patients who had maintenance lived longer than patients who did not. But it's not a cure. Patients, the disease does come back. We're looking for other strategies. We're studying other types of drugs for this. Bortezomib has been studied and it looks promising as another way to do maintenance and then of course, some of these new oral proteasome inhibitors like the one I mentioned, MLN9708, are being studied as a form of maintenance. I think there's a lot of exciting strategies that we're all working on to try to improve things for patients. One of them of course is what's the best initial therapy. I talked about that earlier about two drugs versus three or perhaps even four drugs. I think that ultimately, antibody combinations are going to be important with two or three different drugs but we've got to prove that and that's what these studies are aimed at right now.

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Let's see. I think I've covered about all I wanted to say. I don't know if there's any other areas you wanted me to touch on. Jenny: With a wide variety of trials that you're running and a lot of different approaches that you're taking, I know you specify that some are for newly diagnosed patients, some are for high-risk myeloma patients, some are for refractory myeloma patients. But a patient looking at all the trials that are running at your facility, how do you choose one that is personally the most relevant? What do suggest to your patients? Dr. Bensinger: That's a good point. Well, I'll tell you, of the trials that we have opened now, say for a newly diagnosed patients, two of them are designed for patients who are not really going to consider autologous stem cell transplants. They're really designed for patients that are, say older than age 70 or patients who might be younger and have core [0:41:41] morbidities such as bad lungs or a bad heart that might make it more dangerous for them to undergo an autologous transplant. Those trials would be the trials that I would recommend to patients who might not be transplant candidates. The other two trials, one of them I mentioned is the BortezomibLenalidomide-Dex trial, that's asking the question of an early transplant versus delaying it to later in the course of the disease. The other trial is the Carfilzomib-Cyclophosphamide-Dexamethasone trial, that's just an induction trial. After that, patients can have a transplant or not. Depending on the patient's wishes, I may stir them to one or not. If the patient says they don't want to have a transplant, they're not interested in a transplant, I might stir them to the trial that involves just the induction therapy because transplant in that is optional. If on the other hand, the patient wants a transplant but again, they're not sure about it, they might be a suitable candidate for this trial in which there's a randomization between the two. It sometimes not possible to say one trial is better than another because they're all asking different questions. But I think you can narrow it down to a choice of one or two after discussion with the patient and really trying to find out what they want, what they're interested in for their goals. I think that's an important part when you're talking about things with a patient. You do want to personalize the treatment. You do want a treatment that the patient is in tuned with. I don't think we're quite at the point of what we call personalized medicine yet. Personalized medicine implies a treatment that is based on specific genetic characteristic of the tumor whereby you can use drugs that might exploit a specific pathway that is most active in that patient's type of myeloma. If you have a drug that can attack that particular pathway, that might be a better way to go for the patient. I don't think we're quite there yet but it is certainly an area that we're moving toward more and more. 11

Jenny: Okay. Dr. Bensinger, it's terrific. Let me open it up just for caller questions and I will shut your [0:44:36] phone. Anyone who is interested in asking a question can press 1 on their keypad and we have one question. Let me bring them on. Okay, go ahead. Participant: Hi, Dr. Bensinger. Thank you so much for taking your time today. The question I have is around personalized medicine. What kind of test can you do to identify the different types of myeloma and how many types of myeloma are there? Dr. Bensinger: There are several tests that are out there that involve gene [0:45:13] active genetic pathways that are seen in myeloma cells, a variety of specific tests that look at certain types of signaling and growth and reproductive pathways in the cell. They look at things like signaling for Apoptosis which is the cell death pathway. They all deal with aspects of cell regulation and growth. Broadly speaking the studies that have been done classify these into about four to six different broad groups, types of myeloma but it's really a simplification I think to help us understand broadly what things are active. If you have a particular type of pathway that's been activated, this is where ultimately, it may be possible to pick a drug that can block that pathway in your cells. I do want to tell you that you have to be a little bit careful about that because one of the hallmarks of myeloma is what we call genetic instability. What that means is the cells don't have a uniform, common genetic signature among themselves. You have multiple groups of cells or what we refer to as subclones of cells. Each subclone has a little bit different genetic signature. What happens sometimes is if you use a drug that favors one particular group of cells, you effectively control that group but what happens is the other group that has a different genetic signature maybe allowed to survive and grow and proliferate and that's the group of cells that grows back. It's a little bit complex just talk about truly personalized treatment of a particular type of cancer. Does that help you? Participant: It's a little disappointing. The answer, I was hoping it would be a simpler answer. That there's [0:47:35] certain subtype. Dr. Bensinger: Myeloma unfortunately is not like a disease such as CML. CML, chronic myeloid leukemia, there's a single genetic abnormality that is seen and that is the dominant feature of the disease in most patients. Myeloma is not like that unfortunately. That's why it's been more difficult to approach and treat this disease in a personalized way. Participant: A couple of weeks ago, I listened to one of the shows. I think Dr. Landgren and he's from Sweden. He talked about the more sensitive test 12

that are out there right now and had been able to get greater specificity in the control path of [0:48:27] the disease. You think that's helpful, the doctors in treating this? Dr. Bensinger: I think it's hopeful for understanding some of the pathways that are involved in the growth and progression of the disease. But again, I don't this we're at a point now where we have really targeted therapeutics that are going to be able to exploit those pathways. I don't think we're there yet. Participant: All right. Well, thank you. Great interview today by the way. Dr. Bensinger: You're welcome. Jenny: Well, kind of a follow up question that I might have about that is that as we see gene expressions with different types of cancers like a lung cancer or just any [0:49:12] cancer that has a particular gene expression, can we start looking at what we were talking about before the call, cross coordination between diseases and can we treat with potentially already existing drugs for that type of genetic expression? Did you think we're still quite far away from that as well? Dr. Bensinger: I mean, I think we're starting to do that. An example is Ibrutinib. Ibrutinib is this drug that is very active in two types of malignancies, chronic lymphocytic leukemia and mantle cell lymphoma. We're studying it now in myeloma because the same pathway maybe active in a group of patients with myeloma. We're hoping that this drug will have cross activity in myeloma as it has in these other types of blood cancers. But we don't know yet. I mean, that remains to be seen about this activity because we just started this trial recently and we don't have enough results. Jenny: Okay. So I hope that -Dr. Bensinger: We're trying to do that. Jenny: Yeah. I think so. I hear a lot of people starting to talk about that even though it seems like it's at the beginning of that type of discussion. We have one more caller, [0:50:31] for a question. Okay. Go ahead. Participant: Hi, doctor. I was wondering what is it about autologous transplants that makes them less effective in curing the disease and rather just bring the patients into remission for a temporary period of time. Dr. Bensinger: One of the problems with myeloma is drug resistance. When you treat a patient with chemotherapy and even with high dose therapy like Melphalan, there is a small residual group of cells that are resistant and 13

survives the assault, if you will, with the chemotherapy and with the high dose therapy. Those cells basically survive and eventually grow and lead to a relapse of the myeloma. So it's this drug resistance that is the hallmark that makes it more difficult to cure this disease. I will tell you that we do have a small number of patients perhaps in the range of 10% to into some case as high as 15% that are long-term survivors after autologous transplant. By long-term survivor I mean more than ten years. Some of these patients may actually be cured but the problem is the majority of patients they have these resistant cells that survive this treatment and ultimately regrow. A donor transplant has the advantage in that they -- this is a form of immunotherapy. These new donor cells have a limited capacity to seek out and destroy these residual cells that may have survived the therapies that are given. Autologous cells by their very nature because they're your own stem cells don't have this immune reactivity against the myeloma. Jenny: Okay. That's so great. Thank you for the question and for the answer. I have a follow up question about your response. When you say 10% to 15% of patients are potentially cured that have gone through an autologous transplant or potentially other therapies, has anyone taken a look to see what kind of either physiokinetic [0:53:13] or cytogenetic testing that they had or to see if there similarities with their backgrounds. Are we curing a subtype? Dr. Bensinger: They're generally the good-risk patients that don't have these high-risk phys [0:53:28] features such as deletion 17 or 4-14 or deletion 13 by conventional cytogenetics. So they are from among a group of patients with these good-risk features. Just to clarify, I don't want to tell you that 10% to 15% is cured. What Im saying is 10% to 15% are surviving more than ten years in remission after auto transplants. We think that some of them may actually be cured but 10% to 15% maybe an overestimate of the actual curability there. Jenny: Thank you for the clarification. Well, Dr. Bensinger, we are so grateful that you joined us today. It's been a very informative interview. You've covered a lot of things for us to think about. We will be posting this interview as a full transcript so people can go back and refer to it because I know they would want to. I'm just so thankful for your participation today. Dr. Bensinger: Thank you very much. I enjoyed doing it and it's really been fun for me too. Jenny: If you like to contact Dr. Bensinger and ask him about his trials individually, he is located in our doctor directory on the www.mpatient.org 14

website. If you send him a message via that method, he will receive that and you could contact him about individual trials. Dr. Bensinger: Well, thank you very much. Jenny: Thank you so much, Dr. Bensinger. Thank you for joining us for another episode of Innovation in Myeloma on the mPatient Myeloma Radio Show. Join us next Friday for another episode to learn more about how your participation can help push faster towards a cure.

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