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Jenny: Welcome to another episode of mPatient Myeloma Radio, a show thatconnects patients to myeloma researchers.

We as patients have an important role to play in determining the pace ofresearch. By participating in clinical trials, we can help researchers come toconclusions more quickly. We all want to find a cure and this is one way wecan help even when and may importantly, especially when we're undergoingtreatment. I know that we all care about myeloma research because we nowhave over 5,000 listeners to the show.

Just a note before we get started, we have two new ways you can subscribeto find out about upcoming and past interviews on the Innovation inMyeloma Series on mPatient Radio. We have a new weekly newsletter calledthe 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 toall the posts that we have posted [0:01:08]. You can do this on the rightside of the homepage of our site, www.mpatient.org website. To simplify ourshow, this will now be the only way we'll notify you of upcoming shows. So Ireally encourage you to register today. We have the best and brightestmyeloma researchers on our calendar and you don't want to miss what theyhave to say.

Speaking of which, we have one of the best and brightest with us today. I'mvery 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 inChicago. He interned at Washington University in Saint Louis. He worked atthe National Cancer Institute in Cancerology before moving to the Universityof 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 researchdivision at the Fred Hutchinson Cancer Research Center. He is a professor ofmedicine at the University of Washington School of Medicine. He's also amember of the National Comprehensive Cancer Network Myeloma GuidelinesCommittee and co-chair of the same Cancer-Related Infection GuidelinesCommittee. He's also a member of the International Myeloma Working Groupclinical endpoints committee.

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He has published more than 200 articles in reference journals, books, and inthe field of stem cell transplantation especially how transplantation relates tothe treatment of multiple myeloma. He studied the use of CD34 stem cellsand other antibodies that we'll talk about today. In addition, he holds severalpatents including one as co-inventor of the avidin-biotin bead selection

system which you're going to have to cover. His areas of research includeautologous stem cell transplantation as well as allogeneic targetedradiotherapy and immunotherapy. Dr. Bensinger has been treating andstudying multiple myeloma for over 25 years.

Thank you so much for joining us and thank you for your dedication totreating 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 treatmentand management of this disease. The drug is Carfilzomib. This is a second-generation proteasome inhibitor. It's a second drug that was developed afterthe drug Bortezomib first came on the scene about ten years ago. This drughas a similar type of action but appears to be more specific to a particularenzyme within the proteasome. And it is a more, if you will, a more targetedapproach in terms of reacting against this particular component in cells. Theadvantage of this is that it has fewer toxicities. Because it's so targetedagainst the particular enzyme, it has less off-target, what we call off-targeteffects which lead to some of side effects associated with Bortezomib, one ofthem 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 timethan might be tolerated. Otherwise, you can give the drug more frequentlyand you can give the drug in higher doses than would be possible to do if thedrug had some of these side effects. We're studying this drug in combinationwith other drugs for two phases of the disease in multiple myeloma. We havean upfront trial designed for patients with newly diagnosed multiplemyeloma in which we're combining Carfilzomib with two other drugs,Cyclophosphamide and Dexamethasone. As you know, Cyclophosphamide isan 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 wherewe're actually giving higher and higher doses of Carfilzomib mainly designedto determine if, number one, if there is a maximum dose you can give butnumber two if the higher doses can more effectively control the cancer. Sofar, we haven't observed those limiting toxicities and we've given actuallytwice the initial dose that's used to treat patients with this disease, twice the

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initial dose of Carfilzomib. The drug combination seems to be very welltolerated 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 everyoneseems to have responded so far.

We're also studying this drug in a group of patients who have failed lots ofother therapies namely patients who have relapsed and are deemed to haveresistant disease. These are primarily patients who failed the drugLenalidomide, one of the widely used immunomodulatory drugs. Patientswho have relapsed and failed l Lenalidomide were put on a combination ofCarfilzomib-Pomalidomide, the third-generation immunomodulatory drug andDexamethasone. Again, this combination seems to be very active.

Excuse me. I'm getting some background noise. I think someone has theirphone off of mute [0:08:12] or something but I'm getting a lot ofbackground noise so if that's possible to mute your phone or something.

Anyway, this combination seems to be quite active even in patients whofailed Lenalidomide and again, seems to be very well-tolerated. These aretwo important combinations. This is a drug that is, I think, going to have a lotof important uses in the management of multiple myeloma. These are just acouple of the trials that we have. We have actually quite a large number oftrials that we're doing at our center. We try to select different trials lookingat different drugs and combinations. In a big way, I'm trying to find newtypes of drugs that had different activities with the idea ultimately ofcombining therapies. I think some of the major advances that have beendone in the management of other cancers and I think it applies very much to

patients with myeloma, these combinations of therapies. I think in generalwe find that combinations work more effectively and faster than single drugsor even maybe two drugs when you can use a combination of three. Now wehave to prove obviously, ultimately that three or four-drug combinations arebetter than two-drug combinations. But I think that as a strategy formanaging the disease, these combinations seem to be better.

Just a review of some of the trials that we're doing, we're actuallyparticipating in a large international trial using what is now a pretty standarddrug 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 areused. As part of this trial, patients received induction therapy with this three-drug combination and then have their stem cells collected. Half of thepatients have a transplant, go on to an autologous stem cell transplant andthat's followed by two more cycles of the same induction therapy and then amaintenance phase. The other group simply stays on this induction therapyfor five more cycles and then maintenance. Basically, you're comparing atotal of five cycles of Bortezomib, Lenalidomide, Dexamethasone, plus

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transplant to eight cycles of Bortezomib, Lenalidomide, Dexamethasonewithout a transplant.

This trial is being conducted in Europe mainly in France and they have had alarge 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 nowbut I think that's going to increase to as many as 40 or 50 sites around theUS.

Jenny: What are the results showing so far on that trial or is it too early totell?

Dr. Bensinger: It's too early. For very good reasons, they don't want torelease any early results of this trial because it might affect the ability to putpatients on. The other trials that we're doing for newly diagnosed patientsinvolve -- mainly for patients who are not considered transplant candidates,

a randomized trial of Lenalidomide and Dexamethasone with or without thedrug Elotuzumab. Elotuzumab is a monoclonal antibody and I'll talk a little bitabout monoclonal antibodies in a few minutes to try to tell you more aboutthat. 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 monthfor newly diagnosed patients using a new drug called Oprozomib.

Oprozomib is an oral proteasome inhibitor. As you know, both Bortezomiband Carfilzomib have to be given by injection, either as subcutaneous or anintravenous 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. Thisis being looked at in combination with Lenalidomide and Dexamethasone.Again, this is a common combination of a proteasome inhibitor, animmunomodulatory drug and then a steroid like Dexamethasone. Thispromises I think to be a very active combination but the nice thing about it isit'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 withthe discovery and development of the first monoclonal antibody that hadactivity in any type of cancer and that was a drug called a Rituximab.Rituximab targets a protein expressed mostly in lymphoma patients andsome patients with a form of chronic lymphocytic leukemia. This proteincalled CD20 is a protein that is not only found on the surface of the cells butit is an important signaling for the cell. It signals growth and developmentand it's found that if you block this with an antibody, cells go on to die.

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There is much interest in developing a similar type of antibody in multiplemyeloma. Unfortunately, myeloma cells typically do not express the sameCD20 protein but they do have other proteins. Among them a protein calledCD38 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 wereperformed. I was part of those initial trials and I have to say that the activityof Elotuzumab by itself was relatively modest. What I mean by that is thebest that you could see when you use the drug alone in patients withmyeloma who would relapse was stabilization of their disease. You didn't getreal responses in these patients.

However, when the drug was combined with Lenalidomide, thisimmunomodulatory drug and Dexamethasone, the responses were relativelydramatic. Typically for a relapse population of patients who are treated with

Lenalidomide and Dexamethasone, you'd expect to see response rates in the50%-60% range. When you combine this with Elotuzumab, we observedresponses 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. Butbecause of that, this drug has moved forward with the combination ofLenalidomide and Dexamethasone both as initial therapy and is continuing tobe studied in a relapsed setting. The neat thing about antibodies is they workby 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 serioustoxicities. There is usually some first dose effect in which you can get like aflu-like syndrome when you get the first couple of doses of the drug but afterthat, there don't appear to be serious side effects. So it's nice because this isa drug class that potentially can be used with other drugs and not add to theside 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 activedrug to date appears to be a drug targeting this protein CD38. CD38 isexpressed very heavily on myeloma cells and plasma cells and also to alesser extent, on some other blood cells. There are several forms of anti-

CD38 antibodies that have been reported to have activity in myeloma assingle agents. There is great interest in this antibody as well. One of thedrugs is called Daratumumab but there are at least two other forms that aremoving forward in development. We will be opening a trial for patients withrelapsed 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.

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Histones are proteins that bind to DNA of cells and result in modification ofhow the cells can grow and develop. What happens is these proteins will bindto the DNA and essentially field the DNA from its ability to make otherproteins that promote growth and development. It's found that thesehistones are much more active in certain types of cancers. If you can inhibit

the action of these histones through an inhibitor of this enzyme, histonedeacetylase, you may get activity in myeloma.

This is a particular histone deacetylase that seems to be very well toleratedand is used again in combination with Lenalidomide and Dexamethasone.We're studying it as part of a dose-finding study. Groups of patients receiveincreased doses of the drug with Lenalidomide and Dex. So far, it appears tobe very well tolerated and with good activity.

Jenny: I have a question about the histone inhibitor. I've seen differentnumbers, 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 approvedfor the treatment of cancers. There's one called Vorinostat which is widelyused for the treatment of T-cell malignancies. Unfortunately, it was studiedin myeloma and had very, very modest activity and it's probably not a veryimportant drug in this disease. But there are other types of histonedeacetylase inhibitors and they are likely to be specific for different types ofcancers. This is where you get into this issue of a more personalizedapproach 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 anotheroral proteasome inhibitor. This is one that's a little further along indevelopment called MLN9708. It also has a name, Ixatomib [0:22:05] and Ihonestly have trouble pronouncing it. It's one of these odd spellings, I-X-A-T-O-M-I-B or something like that. But I refer to it by its name before it wasgiven this special name, MLN9708. This is an oral form of the proteasomeinhibitor Bortezomib. It's much further along in development. It's also beingstudied not only in a relapsed setting but in an early treatment setting. It'salso 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 minutesbut that's yet another study that we're doing.

Then, we're studying several other interesting compounds that I think havequite a bit of potential. One of them is a drug called Ibrutinib. What it is is aninhibitor of a specific B-cell signaling pathway inside B-cells called Bruton'sTyrosine Kinase. This is a signaling pathway whereby cells are stimulated togrow and develop. If you block this pathway, cells die. It seems to be a very

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important pathway in a variety of B-cell cancers. Ibrutinib is already beenshown to have tremendous activity in chronic lymphocytic leukemia and aform 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 theactivity is going to be but it could be a very important drug. We just started atrial with a number of patients in this group. You're looking at this drugIbrutinib. It's too early to tell how useful it's going to be in myeloma but Ithink it is a potentially promising pathway.

We're actually studying a very unique drug combination. I'll be honest withyou. It's going to be a little difficult to explain in layman's terms but whatwe're studying -- the drug is called SNSO1-T and it's being studied in B-cellmalignancies. It's yet another B-cell pathway based on inhibition of amolecule known as eukaryotic translation initiation factor. We just call it

EIF5A. Again, this is a protein that's been implicated in the regulation of cellproliferation, inflammation and cell death and appears to be very active in B-Cell malignancies. The protein is modified in cells with another protein that Iwon't even mention the name of that basically turns the protein on or offfrom being a protein that promotes cell death to a protein that promotes cellgrowth. 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 twocomponents to this and it's given intravenously. It gets into these cells andmodifies this protein to make it a more of what we call pro-apoptotic proteinwhich the idea is it promotes cell death. It's a totally different approach fromother 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 ofMedicine looking at a form of amyloidosis targeting it with a type of RNA andshowing that you could target this and effectively control the development orthe progression of amyloidosis. I think this approach may have some realpromise for this type of treatment for patients but it's a very early study andwe 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 theimmunotherapy approach is the antibodies and then some of these studiesthat are starting to be done with modified T-cells and then of course theoldest form of immunotherapy that we use is donor transplants or allogeneicstem cell transplants. To that end we have a study where we're using aunique regimen to treat the myeloma in patients who have high-riskmyeloma. It's well-known that there are certain features of myeloma atdiagnosis that are called high-risk. What that means is patients who have

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these high-risk features have a more aggressive form of their disease. Theycan respond to treatment but they generally have shorter remissions and thedisease comes back much more quickly with the same therapy that mightcontrol the disease for a longer period of time in patients who do not havethese risk factors.

Some of these risk factors are an elevated Beta-2 microglobulin which is aprotein that's a marker of the disease in the blood. And then certain geneticabnormalities that are seen by chromosome analysis of myeloma cells eitherwith conventional chromosome analysis, for example, deletion ofChromosome 13 or with physionalysis deletion of chromosome 17 or atranslocation which means a piece of the DNA from one chromosome hasbeen switched and swapped out onto another chromosome, in this case,translocation 4-14. That means, a piece of chromosome 4 has come off andbeen attached to chromosome 14. That translocation is also associated withhigh-risk features.

What we're doing for this is we're looking at a unique way to deliver moreaggressive therapy as part of the treatment for patients who are havingdonor transplants. In this case, it's a substance known as Yttrium-90attached to an antibody, CD45. Itrium90 is a radioisotope so it's a radioactivesubstance. It's very high energy but it's what we call a pure beta radioactivesubstance. 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 athird to half an inch in distance. You can give this isotope to a person and itacts across several cell diameters but does not become dangerous to anyonestanding next to the patient or anything like that.

What we do is we attach this isotope to an antibody called CD45. CD45 is anantibody that binds to blood cells in general. What this does is it guides theisotope to the cells in the bone marrow and the cells in the lymph nodes andspleen. These are the sites of blood cancers in general but also the sites ofthe disease multiple myeloma. The idea is you get a dose of this isotope. It'sgiven intravenously. It travels to the bone marrow, it travels to the lymphnodes and spleen and radiates those areas with this Yttrium-90. Yttrium-90has a half-life of about two and a half days. After about ten days, the isotopehas 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 bonemarrow or excuse me, not bone marrow but peripheral blood stem cells[0:32:36] from a suitable allogeneic donor. This donor is most commonly abrother or a sister but may also be an unrelated donor if we can find asuitable donor in the registry.

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The ideas here is to facilitate the graft but also to eradicate as much of themyeloma as possible prior to the introduction of the graft. What that does isit makes it easier for the graft to, if you will, clean up any residual myelomathat's left behind. This is one of the advantages of a donor transplant. Thisnew 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 havedisadvantages. 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 usingyour autologous stem cells. That's because these allogeneic cells replace thebone marrow and the immune system in the patient. It takes up to a yearbefore a patient's immune system recovers from this. During that time,

patients are more susceptible to infections and can develop quite seriousinfections during this time. In addition, the cells have the capacity to damagenormal organs in the body. It's basically a form of rejection where theimmune system is rejecting the body of the patient. Primarily, this affects theliver or the skin or the GI track.

We call that graft-versus-host disease. This has to be controlled or preventedby giving these immunosuppressive drugs. Patients need to take these drugsfor a minimum of six months but sometimes, they have to take the drugs foras long as a year or two if they have any graft-versus-host disease. One ofthe 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 requiresa kidney transplant because their kidneys are failing, those patients have totake these immunosuppressive drugs for the rest of their life. Their bodynever develops tolerance to the kidney graft and so they're always at risk ofrejecting it. That doesn't happen with a bone marrow or a stem celltransplant. Most patients eventually -- the graft becomes tolerant to them.

The bottom line on this is that allogeneic transplants while they have agreater 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 muchgreater risk of complications. There is a risk of dying from this type oftransplant in the range of 15% to 20%. That's the reason it's not more widelyused because of this risk. If you can contrast that to an autologous transplantwhere you're using your own stem cells, the risk of dying from that type oftreatment is very low in the range of only one two percent.

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We're trying to improve on the ability to do the allo [0:36:38] transplantsbecause we think it has a greater chance of cure. In the interim, in theabsence of that, many of us are trying to work on trying to make myeloma ifyou will a chronic disease. I hesitate to use the analogy to something likediabetes 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 forsome patients who don't have high-risk features, they actually can have theirdisease managed as a chronic form for sometimes ten years or more. That'sone of the things we're trying to do in the absence of the ability to cure thedisease. 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. Ourultimate goal is to try to improve the overall treatment and outcomes forpatients with myeloma.

One of the things that we do is look at Maintenance Therapy. Maintenancetherapy 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 anautologous stem cell transplant. An autologous stem cell transplant we knowhas a much better chance of producing remissions. The remissions tend tobe more durable and in some studies patients who have transplants livedlonger than patients who don't.

Autologous transplant is not a cure for a majority of patients. The disease willcome back. So now we're looking at drugs for maintenance as a way toimprove how patients do, keep the disease under control for longer periodsof time and hopefully result in patients living longer. There has been

progress in this. Lenalidomide has been shown in several trials to improvethe length of disease-free interval. It can nearly double the length ofremission when it's used after an autologous transplant. At least in one oftwo trials, patients who had maintenance lived longer than patients who didnot.

But it's not a cure. Patients, the disease does come back. We're looking forother strategies. We're studying other types of drugs for this. Bortezomib hasbeen studied and it looks promising as another way to do maintenance andthen of course, some of these new oral proteasome inhibitors like the one Imentioned, 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 improvethings for patients. One of them of course is what's the best initial therapy. Italked about that earlier about two drugs versus three or perhaps even fourdrugs. I think that ultimately, antibody combinations are going to beimportant with two or three different drugs but we've got to prove that andthat'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'sany other areas you wanted me to touch on.

Jenny: With a wide variety of trials that you're running and a lot of differentapproaches that you're taking, I know you specify that some are for newly

diagnosed patients, some are for high-risk myeloma patients, some are forrefractory myeloma patients. But a patient looking at all the trials that arerunning at your facility, how do you choose one that is personally the mostrelevant? What do suggest to your patients?

Dr. Bensinger: That's a good point. Well, I'll tell you, of the trials that we haveopened now, say for a newly diagnosed patients, two of them are designedfor patients who are not really going to consider autologous stem celltransplants. They're really designed for patients that are, say older than age70 or patients who might be younger and have core [0:41:41] morbiditiessuch 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 trialsthat I would recommend to patients who might not be transplant candidates.

The other two trials, one of them I mentioned is the Bortezomib-Lenalidomide-Dex trial, that's asking the question of an early transplantversus delaying it to later in the course of the disease. The other trial is theCarfilzomib-Cyclophosphamide-Dexamethasone trial, that's just an inductiontrial. After that, patients can have a transplant or not. Depending on thepatient's wishes, I may stir them to one or not. If the patient says they don'twant to have a transplant, they're not interested in a transplant, I might stirthem 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 butagain, they're not sure about it, they might be a suitable candidate for thistrial in which there's a randomization between the two.

It sometimes not possible to say one trial is better than another becausethey're all asking different questions. But I think you can narrow it down to achoice of one or two after discussion with the patient and really trying to findout what they want, what they're interested in for their goals. I think that'san important part when you're talking about things with a patient. You dowant to personalize the treatment. You do want a treatment that the patientis 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 geneticcharacteristic of the tumor whereby you can use drugs that might exploit aspecific pathway that is most active in that patient's type of myeloma. If youhave a drug that can attack that particular pathway, that might be a betterway to go for the patient. I don't think we're quite there yet but it is certainlyan area that we're moving toward more and more.

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Jenny: Okay. Dr. Bensinger, it's terrific. Let me open it up just for callerquestions and I will shut your [0:44:36] phone. Anyone who is interested inasking a question can press 1 on their keypad and we have one question. Letme 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 canyou do to identify the different types of myeloma and how many types ofmyeloma 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 varietyof specific tests that look at certain types of signaling and growth andreproductive pathways in the cell. They look at things like signaling forApoptosis which is the cell death pathway. They all deal with aspects of cell

regulation and growth. Broadly speaking the studies that have been doneclassify these into about four to six different broad groups, types of myelomabut it's really a simplification I think to help us understand broadly whatthings are active. If you have a particular type of pathway that's beenactivated, this is where ultimately, it may be possible to pick a drug that canblock that pathway in your cells.

I do want to tell you that you have to be a little bit careful about thatbecause one of the hallmarks of myeloma is what we call genetic instability.What that means is the cells don't have a uniform, common geneticsignature among themselves. You have multiple groups of cells or what we

refer to as subclones of cells. Each subclone has a little bit different geneticsignature. What happens sometimes is if you use a drug that favors oneparticular group of cells, you effectively control that group but what happensis the other group that has a different genetic signature maybe allowed tosurvive and grow and proliferate and that's the group of cells that growsback. It's a little bit complex just talk about truly personalized treatment of aparticular type of cancer. Does that help you?

Participant: It's a little disappointing. The answer, I was hoping it would be asimpler 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 seenand that is the dominant feature of the disease in most patients. Myeloma isnot like that unfortunately. That's why it's been more difficult to approachand 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

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that are out there right now and had been able to get greater specificity inthe control path of[0:48:27] the disease. You think that's helpful, thedoctors 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, Idon't this we're at a point now where we have really targeted therapeuticsthat are going to be able to exploit those pathways. I don't think we're thereyet.

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 thatas 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 westart looking at what we were talking about before the call, crosscoordination between diseases and can we treat with potentially alreadyexisting drugs for that type of genetic expression? Did you think we're stillquite far away from that as well?

Dr. Bensinger: I mean, I think we're starting to do that. An example isIbrutinib. Ibrutinib is this drug that is very active in two types ofmalignancies, chronic lymphocytic leukemia and mantle cell lymphoma.We're studying it now in myeloma because the same pathway maybe activein 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. Butwe don't know yet. I mean, that remains to be seen about this activitybecause 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 eventhough it seems like it's at the beginning of that type of discussion. We haveone more caller,[0:50:31] for a question. Okay. Go ahead.

Participant: Hi, doctor. I was wondering what is it about autologoustransplants that makes them less effective in curing the disease and ratherjust bring the patients into remission for a temporary period of time.

Dr. Bensinger: One of the problems with myeloma is drug resistance. Whenyou treat a patient with chemotherapy and even with high dose therapy likeMelphalan, there is a small residual group of cells that are resistant and

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survives the assault, if you will, with the chemotherapy and with the highdose therapy. Those cells basically survive and eventually grow and lead to arelapse of the myeloma. So it's this drug resistance that is the hallmark thatmakes it more difficult to cure this disease. I will tell you that we do have asmall 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. Bylong-term survivor I mean more than ten years. Some of these patients mayactually be cured but the problem is the majority of patients they have theseresistant cells that survive this treatment and ultimately regrow.

A donor transplant has the advantage in that they -- this is a form ofimmunotherapy. These new donor cells have a limited capacity to seek outand destroy these residual cells that may have survived the therapies thatare given. Autologous cells by their very nature because they're your ownstem 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. Ihave a follow up question about your response. When you say 10% to 15% ofpatients are potentially cured that have gone through an autologoustransplant or potentially other therapies, has anyone taken a look to seewhat kind of either physiokinetic[0:53:13] or cytogenetic testing that theyhad or to see if there similarities with their backgrounds. Are we curing asubtype?

Dr. Bensinger: They're generally the good-risk patients that don't have thesehigh-risk phys[0:53:28] features such as deletion 17 or 4-14 or deletion 13by 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 tenyears in remission after auto transplants. We think that some of them mayactually be cured but 10% to 15% maybe an overestimate of the actualcurability there.

Jenny: Thank you for the clarification.

Well, Dr. Bensinger, we are so grateful that you joined us today. It's been avery informative interview. You've covered a lot of things for us to thinkabout. 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 thankfulfor your participation today.

Dr. Bensinger: Thank you very much. I enjoyed doing it and it's really beenfun for me too.

Jenny: If you like to contact Dr. Bensinger and ask him about his trialsindividually, he is located in our doctor directory on the www.mpatient.org

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website. If you send him a message via that method, he will receive that andyou 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 themPatient Myeloma Radio Show. Join us next Friday for another episode tolearn more about how your participation can help push faster towards a cure.

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