The Latest Myeloma Updates from ASCO Breaking News ...cdn.patientpower.info/p2docs/transcripts/MM062210.pdfThe Latest Myeloma Updates from ASCO Breaking News June 22, 2010 Paul Richardson,

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The Latest Myeloma Updates from ASCO Breaking News June 22, 2010 Paul Richardson, M.D. Sergio Giralt, M.D. Mike Katz Please remember the opinions expressed on Patient Power are not necessarily the views of our sponsors, partners or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. Please have this discussion you’re your own doctor, that’s how you’ll get care that’s most appropriate for you. Introduction Andrew Schorr: Can drug therapies be combined in new ways for multiple myeloma and dose differently to reduce side effects? Will experimental drugs make things better? Is the role of transplant changing? Coming up on Patient Power hear answers from experts based on the latest studies and how this disease is increasingly being seen as a chronic condition. Hello and welcome to Patient Power. Thank you for joining us. I'm Andrew Schorr in Seattle. I'm back from Chicago and the big American Society of Clinical Oncology meeting, and so are about 30,000 other people, and three of them are with us today. One patient who has been living with multiple myeloma for 20 years and is quite a leading patient advocate for people worldwide, and then also one medical oncologist from Boston, and another cancer who is a leader in transplantation for myeloma from New York. And we're going to answer your questions and bring you the latest. First, I'd like to introduce my friend who I've talked to many times about myeloma, and that's Mike Katz. Mike is 57. He has been a business consultant for years. He lives in New York City and has three children, 20 years ago diagnosed with myeloma and still going pretty strong, right, Mike? Mike: Absolutely. Andrew Schorr: You've been through lots of therapies, from thalidomide for many years to Revlimid, to steroids along the way and lately some maintenance therapy with Velcade. Did I get it right? Mike: Yes, leading into maintenance therapy with Velcade, yes. Andrew Schorr: And no transplant at this point although you've had your cells harvested?


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Mike: Sitting in a freezer since 1995. Encouraging News Andrew Schorr: Okay. Now, you went to ASCO. Just from your perspective as a patient advocate, what impressed you most this year versus meetings in the past and of course the big hematology meeting that's so focused on myeloma as well? Mike: I guess that right now it's an incredibly active time for myeloma research and a time that's been rich with success in terms of finding treatments that work for people in all stages of the disease and a real shift in thinking about how to manage the disease over the long term because there are so many people that are living so much longer with myeloma. So there's a tremendous amount of interest that we didn't see years ago from researchers and pharmaceutical companies in developing new agents, and there are so many new ideas out there that are actually working. So it's very encouraging. Andrew Schorr: You are encouraged. And so you lead two support groups at least and also with ACOR, the Association of Cancer Online Resources. You are a moderator of all the discussions there. What's your message, let's say, to somebody be newly diagnosed now? Certainly, it's very variable among people, but what's your overall message for somebody who may just be terrified about this? Mike: I think the most important thing is for people to realize that this isn't what it used to be 20 years ago. And I think just telling people that I've had the disease for 20 years, and when they look at me and see that you wouldn't really be able to tell that's there was anything wrong with me, I think that itself is just a very encouraging thing. I think also I just tell people that they shouldn't make any assumptions because, you know, things have improved so much, and they really should expect to get very good results with their initial treatment. And by the time that those treatments don't work there are so more things in the pipeline that all bets are off in terms of what's published in the literature about historical survival for multiple myeloma. Andrew Schorr: Right. Anything that's in a book, hopefully is becoming outdated and that has been the fact. And that's happened for you. Because you were on thalidomide, and then newer drugs were invented and brought to market, so you've lived it yourself.


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Mike: Right. Well, I went from thalidomide to Revlimid and now to Velcade and, you know, I'm plotting my next, my next therapy when that stops working, and luckily there's some really good drugs on the horizon I'm sure we'll talk about very soon in this session. Andrew Schorr: Yes, we will. And you have your first grandchild now, so the object here is to dance at her wedding, right? Mike: Absolutely. I want to see a great-grandchild. Andrew Schorr: There you go. All right. Well, hopefully that is achievable. We have two wonderful physicians with us. One as I mentioned from Boston, and that's Dr. Paul Richardson who is clinical director of the Jerome Lipper Center for multiple myeloma at the Dana-Farber Cancer Institute in Boston. We also have with us Dr. Sergio Giralt, who is chief of adult blood and marrow transplant at Memorial Sloan-Kettering Cancer Center in New York. So we're going to talk about all the different sides of myeloma through the perspective of the latest news from ASCO. So let's start with Dr. Richardson. Dr. Richardson, let's start at the highest level for patients. So Mike was saying he's very encouraged. How about you? And then start to give us some evidence of why you feel that way, okay? Dr. Richardson: Well, thank you, Andy, and it's especially nice to join both Mike and indeed also Sergio and your good self on the call because I do agree that there has really been remarkable progress in the last 10 years or so in treatment options for patients with myeloma. And I think the very good news is echoed by Mike's very prescient comments. We have lots of options for our patients, and I think the sort of top line information is really that with those options come choices, but I think we need to recognize that myeloma is a heterogeneous disease. And what we mean by that is that there are various different biologies associated in each individual patient, which means that it's sometimes difficult to predict how any individual patient may do. And in that context some patients have done as well as Mike has done, which I think is a sort of shining light, but I think we also have to recognize that the disease can be very much more difficult and more aggressive to treat in other patients, making their course not nearly, unfortunately, so favorable. So I think we face some substantial challenges, but the good news is, the highest line, is that we have treatment options that we can offer to patients that can not only give them very high chances of response but also durable


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responses and, most importantly, start to minimize some of the toxicities that were typically associated with the more intensive chemotherapies that we used to have to use in the past. Andrew Schorr: So, Dr. Richardson, you touched on it a second ago. People may feel that the therapies now are working better than ever in fighting their cancer, but there's also a price related to side effects. Wasn't that part of the discussion, particularly this year at ASCO, is how could we use drugs differently, dose differently and see if we could limit side effects? Dr. Richardson: Right. Well, I think the key advances have been that we recognize that combinations of our novel therapies in particular can be given where we maintain response and activity but at the same time reduce some of the troubling side effects. Most importantly, when we administer bortezomib, or Velcade, for example, when we used to give it on the previous schedule of twice a week, whilst that was very active in most patients was also associated with high rates of what we call peripheral neuropathy. The very good news is that when you administer it on a weekly schedule, especially in combination, you're able to not only maintain activity, which remains obviously a key consideration, but very importantly for patients you also substantially reduce the risk of the neurotoxicity. Maintenance Therapy Andrew Schorr: Now, what about drugs being used in a maintenance way? Where are we with that? Dr. Richardson: Well, again, great progress was presented at the meeting. The emergence of thalidomide as a maintenance strategy has been clear for some years, although it's been troubled by cumulative side effects, most importantly again a neuropathy and fatigue, as two examples. Now with the new thalidomide derivative, lenalidomide, or Revlimid as it's called, we've had some superb studies showing that the benefit of lenalidomide as maintenance after transplant is also now very clear with dramatic benefits to patients in terms of what we call progression-free survival, although it remains early to interpret overall survival information at yet. At the meeting as well there was also evidence from other studies of the impact of bortezomib maintenance in different settings. This was not in the post transplant population, interestingly, but actually in the non-transplant population where a large trial from Italy showed the benefit of the combination of both bortezomib with thalidomide as part of maintenance. Mike: Well, Paul, I think what is encouraging is that the maintenance therapies that are being looked at now, as you said, are lower doses and much less toxicity, many fewer side


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effects than what had previously been considered. Because from a patient's perspective if the maintenance therapy really impacts your quality of life then the bar is much higher in terms of proving benefit. But when they're so innocuous, when they're so easy to take, then it becomes much more reasonable prospect. Dr. Richardson: Oh, I completely agree, Mike, and I think that's what was so exciting about both about the lenalidomide data and also the bortezomib plus thalidomide data per the Italian study. The lenalidomide data was I think particularly promising because it has the convenience of the oral route without necessarily having to attend to receive infusions. But having said that, the bortezomib maintenance strategies, especially when they're given every one to two weeks, also are relatively, you know, are relatively convenient. Of course, I mean, not as simple as an oral medication but still not too disruptive. And, Mike, I think you can probably speak to that yourself. How are you finding your bortezomib maintenance? Mike: It's really a pleasure compared to being on full therapy. You do have to go in, I'm on a once every three weeks schedule, so that's really pretty easy. Dr. Richardson: Yes, exactly. My patients who are similarly on an every two weeks schedule find it also relatively unintrusive, so I think you're absolutely right that we've got options now for patients in maintenance that are much better than we had before. Mike: I think the other development is taking steroids out of the equation for maintenance because dexamethasone and prednisone were so much harder and so much more troubling in terms of long-term side effects, and even the dose reduction of dexamethasone in full therapy has also been a big improvement for patients. Dr. Richardson: I completely agree, Mike, and thank you for mentioning that, because steroids are truly a double-edged sword. They can be useful initially in treatment and at certain other stages in therapy for patients, but long term are particularly challenging. And the other maintenance strategy that we had of old called alpha interferon only appeared to help a small subset of patients, if any, because the biggest problem were the side effects associated with its use. Andrew Schorr: Now I have a question, Mike. Excuse me one second. So we've mentioned these drugs that have made such a difference for people, lenalidomide, or Revlimid, and bortezomib, or Velcade. And I know there was a study about using them together. Now, that's an expensive proposition but what about as far as effectiveness, Dr. Richardson?


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Dr. Richardson: Well, I think in terms of effectiveness what we've seen, Andy is that the novel therapies have really enhanced the existing platforms that we had before. In particular, the impact on improving transplantation has been really quite striking. And in the same context the use of combination therapies in older patients who are not eligible for transplant have also been seen, when, for example, drugs like bortezomib, lenalidomide and/or thalidomide are either combined together or combined with conventional therapies. And I think what was particularly for me exciting at the meeting was to see sort of advances on all fronts. The Sunday morning session was particularly enthusing, I thought, because it brought the whole thing together. You saw in the course of, you know, what, two and a half hours, three hours of presentation, actually, you know, the constellation of advances that have been made both from the standpoint of improving transplant, making transplant optional in some patients. There was early data from a randomized trial led by Dr. Palumbo which suggested no difference in the preliminary analysis of patients either going on to early transplant versus later, and very interestingly then the maintenance data that followed as well as our own data showing the benefits of the combination of bortezomib, lenalidomide and dexamethasone, or RVD as we call it, which has been associated with unprecedentedly high response rates. And whilst it remains early, and we have to be very careful in interpreting that because early information can sometimes be misleading, there didn't appear to be any major difference in patients who went under transplant versus those who did not, making the possibility of keeping the transplant option in reserve a reality for some patients. Transplant Andrew Schorr: All right. Well, that leads us, as we talk about transplant, to Dr. Sergio Giralt. Dr. Giralt, in your role at Memorial Sloan-Kettering you still have transplant happening of course for myeloma. We had talked over the last year or so and we said, well, what will the role of transplant be? Is it changing? How do you see it now for myeloma? Dr. Giralt: So, hi, Andy, and hi, Mike and Paul, and it's a pleasure to be here on Patient Power. I think I echo both Mike and Paul that it's, you know, it really is an exciting time to be able to be treating patients with multiple myeloma. As we experienced, you know, 10 to 15 years ago the options were limited, the conversations, particularly for patients undergoing primary therapy was, you know, not whether you should get a transplant but when were you going to get it. And despite aggressive therapy only, you know, three to four out of 10 patients would achieve a complete remission, and the average, you know, survival was around five years with most patients having to deal with their disease within two years.


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I think Sunday morning in Chicago in the American Society of Clinical Oncology, really, you know, I think just begins the dawn of a new era. We now, you know, a lot of efforts have been focused on induction therapy. For the last two to three years we've seen the bortezomib-based induction actually improves transplant outcome. We're now looking at a bortezomib-lenalidomide-dexamethasone, the VRD that Paul has pioneered, has response rates which are, you know, all as high as his patients got transplanted, which now lets us start asking the question about whether, you know, whether there is a benefit of early versus late transplantation. We still recommend everybody should have their cells collected. I remind everybody that there's still seven randomized trials that show that transplant has improved progression-free survival and in some cases improved overall survival, but I think it's reasonable now, and, you know, we're actually encouraging patients to participate in studies in which there is a question of whether you should get your transplant early or late in the course of the disease, which will help inform patients and physicians in the next couple years. The other thing that I think was a game changer and a practice changer was the two maintenance lenalidomide papers that were presented. And, you know, if you think about it, the patients were randomized to receive the placebo--so they were not getting the lenalidomide maintenance--you know, half of them were having to deal with their disease again within two and two and a half years, while almost 70 percent of patients, that's seven out of 10 patients, have not had to deal with their disease now with approximately one year medium follow up. But the expectation is that many of these patients will not have to deal with their disease five, six and seven years down the road, so--you know, on just taking a pill a day with minimal side effects. So that really does change the whole paradigm. I think looking forward, you know, as we think about it, the main goal of therapy now is to try to identify the group of patients who do very well with minimal therapy. So those are patients who you might think give them VRD then watched them, you don't have to do any maintenance. Or the group of patients that will require, you know, induction, transplant and maintenance for a long period of time. And then finally what, you know, we've been working on, how do we make all these treatments easier. So the bortezomib was a great story. It was given first, you know, as--it was given four days every cycle, one, four, eight and eleven, with neuropathy rates of about 14 or 15 percent, was very debilitating neuropathy. And now by giving it once a week the neuropathy rates goes down to less than five percent. Effective drug. We have been able to learn how to give it with minimal side effects. And in the transport arena we're also working, how can we make high-dose melphalan easier. And I think there are a variety of studies that will be coming out with strategies that are aimed at minimizing the toxicities of transplant, making it a total outpatient procedure with minimal disruption of life.


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Andrew Schorr: That is a great summary and very encouraging as we get into this more. We're going to take a quick break. When we come back, more from Mike Katz, more from Paul Richardson at Dana-Farber in Boston and more from Dr. Sergio Giralt at Memorial Sloan-Kettering in New York. Stay with us. Amyloidosis Andrew Schorr: Welcome back to Patient Power and our discussion with three experts. One is an expert patient, Mike Katz in New York, and then also Dr. Paul Richardson from the Dana-Farber Cancer Institute in Boston and Dr. Sergio Giralt from Memorial Sloan-Kettering in New York. So we've received lots of questions from the myeloma community. Thanks to ACOR, the Association of Cancer Online Resources, and all the members of the community there, and thanks also to our friends at the International Myeloma Foundation where Mike is the vice president. So here's a question that came in from Diane. Dr. Richardson, she is asking about amyloidosis, and she is wondering, she's concerned about that for herself, wonders does she need a specialist in that as well as an oncologist for her team. And maybe you could explain to people what amyloidosis is. Dr. Richardson: Well, that's a great question, and I'm very grateful for Diane raising it. AL amyloid is seen in a subset of patients with myeloma, and it represents a very difficult and challenging complication where a particular protein is produced by the plasma cells that has a tropism. What that means is an affinity for certain organs like the heart, the kidney and the nerves. And it also can present--patients can be aware of it themselves because it makes the blood vessels in the skin particularly fragile, so they bleed easily, so you can see easy bruising for example around the eyes. You can also start to see certain patterns of muscle wasting in the shoulders and in other distributions around the body, and the nerve endings can also become more affected. But the most dangerous aspects of it are that it can affect the heart and it can affect the kidney. It also in its more advanced form can cause the tongue to become very plump, changing the way patients speak. But I think she touches on a key point, and I personally think that AL amyloid can be very complicated to manage when it occurs, and I work in partnership with specialists in that area. For example, here in Boston I'm very comfortable referring my patients to my AL amyloid experts in town who include, for example, Dave Seldin and Vaishali Sanchorawala at Boston University Medical Center and my good friend and colleague Ray Comenzo at Tufts University Medical Center, when we have patients with particularly complicated amyloid type problems. So that's an example of what we would do. Having said that, the treatment of amyloidosis as a complication of myeloma really revolves around directly the myeloma itself. If you can treat that effectively then


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basically the process that drives the amyloid is suppressed. But it nonetheless remains very challenging because the protein is difficult to reverse its deposition once it's got into the tissues that it affects. And one of the cornerstones of management of amyloid is transplantation in younger patients who can tolerate it, although Sergio can touch on this I think, the role the transplant in amyloid has become somewhat more controversial although I remain in favor of it, particularly for younger patients. Andrew Schorr: Dr. Giralt, you want to comment on that? Dr. Giralt: Yeah, I think, as Paul has mentioned, I mean, the problem with amyloid is that it is a very repair disease. I mean, you think about it, there's probably 3,000 new cases a year as compared to 15,000 new cases a year of myeloma. So any given physician might not have a lot of experience, and we certainly believe that at least in the transplant context amyloid should probably be treated in centers of excellence where they have experience transplanting these patients because of all the autologous transplants that we perform they're the most complex. The question that Paul was mentioning about the role of transport emerges from this same thing. The French had a randomized trial in which the patients who got transplanted actually did a little bit worse than the patient who didn't. But many of the transplant centers were only performing one amyloid transplant, and they actually had very high mortality rates, which are not seen here in centers of excellence such as the ones that Paul mentioned, and Memorial has also a very large program. The problem with amyloid is that you have people who are on the treadmill and within nine months they're in a wheelchair, and the only thing that can revert this process in a relatively fast way is high-dose chemotherapy with an autologous transplant. So I think with amyloid transplant remains a mainstay of therapy when possible. The problem is is that patients sometimes are not diagnosed until they are very, very, very far advanced, and then you can't perform the transplant safely. I think we as, you know, as physicians from the plasma cell disorder community have to do a better job of educating the primary care providers, that first line, of what are the signals that they should be--what things should trigger their mind to think, hey, this could be amyloid, and then do the test to be able to make the diagnosis. Mike: Doctors, one thing I'd ask, though, is to what extent have the new agents, the novel agents and the new ones that are in the pipeline been tested with amyloidosis, and is it likely to have an impact? Dr. Giralt: Bortezomib has definitely been shown to be effective both as induction, and there's emerging data that it may actually be excellent for maintenance therapy. And I think


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bortezomib is finding its place as the induction therapy of choice for amyloid. Dr. Richardson: Yes, I would agree, Sergio. And I think the other drug that's emerging to have a very important role in amyloid is also lenalidomide because thalidomide was dogged by the problem that it has both cardiac effects and also neuropathy as toxicities, which made it more difficult to use. But I have to say we've been very impressed by the performance of the novel agents, so I agree with you, Mike, in actually helping patients with either AL amyloid itself, which obviously is a distinct entity, versus those patients who have myeloma that has a component of AL amyloid complicating it, which is a subtle but very important distinction. And certainly what we have done is in the latter group of patients tried to exploit novel therapies early in their management and then obviously move towards transplant, but ideally move towards transplant with the best possible platform of therapy, giving them the best remission possible before going to transplant. Because I think that in the past it's fair to say, Sergio, without novel agents it's been the trend to simple take patients straight to transplant. Now with the novel agents your goal has been I think improved by the use of novel agents like bortezomib and lenalidomide first to try and get the kind of remission and disease control that we need and then go to transplant as a true consolidation step. Dr. Giralt: I think there's no doubt about that. The fact that we can take these patients now into a better shape actually makes the transplant experience a lot, a lot better. Listener Questions Andrew Schorr: Okay. I've got another question for you relating to sort of the other side of transplant, and that is what therapy would be indicated afterwards. That's a question from Pat in Shawnee, Kansas. So she's 71 years old, and she had induction therapy with Thal/Dex and then Velcade and Velcade/Dex, and she had an auto stem cell transplant, and she said she's doing good and she says now her doctor has changed her status to remission. She hasn't had any maintenance therapy, and she has good quality of life. She's wondering, with all the news about maintenance treatment, she's post transplant, should she be on a maintenance regime? Dr. Giralt, any comment on that? Dr. Giralt: And I'm glad she asked this question. I want to thank her for that. This is the question that, as many of us were presenting in that Sunday morning meeting at ASCO said this is the Monday morning question. What do you do with patients who are now out, you know, one, two, three years after the transplant and we come up with the maintenance therapy. And I think unfortunately here we have to tell people we don't have clear guidance. The


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studies, both studies that were done, both the French and the American study, had patients starting maintenance therapy within two to three months of their transplant. And in this study the patients that got the maintenance therapies did significantly better than those that didn't. I think we could use common sense which will guide us. If she's in a complete remission and she's greater than one year out of her transplant, the reality is that as long as she's followed carefully and that, you know, they can intervene the moment they see signs of some early progression, that would probably be okay in common sense. Likewise, if there's still evidence of disease as measured by the paraprotein peak and she had features of high risk at presentation, meaning bad chromosomes or very high tumor mass, it may make sense to put her on lenalidomide maintenance and see if we can reduce the tumor burden and therefore she will gain some benefit. But I think the core question is as we address the maintenance issue is that we need to remind that it's, you know, it's not one or the other. There are three possible strategies that now emerge. The first strategy is you do nothing and you wait until people progress clinically, which I think is now not the strategy that many of us would recommend. The second strategy is you put everybody on maintenance, and you just keep them on maintenance until progress. Or the third strategy is that in patients with what you would call as low-risk disease, who have had a complete remission to the transplant, you observe them carefully, and at the moment of initial signs of disease reactivation you intervene, let's say, preemptively with lenalidomide therapy as if they were doing maintenance. Now, those strategies have not been, you know, tested in a prospective randomized trial, but I think outside of the protocol setting they, you know, they are common-sense strategies. They are what Mike would like to see as a patient perspective. I mean, here you are in remission. Would you want to be on a drug for three years without knowing that it's working? And from Paul, what did he get or what did he feel from the discussion on Sunday? Mike: Well, I think you mentioned something that's very important, common sense, because the good news about having all these new therapies and people living longer and so many things in the pipeline, it's great news, but it also means that it's much harder to answer these questions. If you don't have a lot of options and people don't do very well, then it's very easy to test out the options you have and figure out what's better. But now I think we're moving into an era where there are going to be more questions we don't know the answer to, so it just makes it much more important for patients to be informed and to have a good myeloma specialist, maybe more than one, that they can ask these questions to. And then ultimately you have to use common sense and figure out what's right for you.


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Andrew Schorr: Paul, do you agree with all that? Dr. Richardson: I absolutely agree with you, and I think that Sergio framed it very nicely that there are several frameworks that one can think around. I think that in the CLGB trial, which we are actually one of the leading enrollers to at Dana-Farber, for those patients who have been randomized to the placebo group I think very correctly they were given the option to go on to lenalidomide even if they had been several years out from their transplant, and in fact and certainly in our practice the vast majority elected to take, to start the maintenance therapy, understandably in the context of the trial. I think it's much more difficult for patients who are not part of the clinical trial and who have remained in complete remission and doing very well, because I whilst I think lenalidomide is a well-tolerated medication generally I think it would be a mistake to convey to patients that it's without side effects. It certainly has manageable side effects, but they are real and they are there. So I think that there is a potential price to be paid if patients simply adopt the maintenance strategy without necessarily really thinking the process through very carefully. So I think Sergio nailed it in terms of the three options. One could look at a patient who has residual paraprotein after a transplant. That's someone I would strongly favor the introduction of a maintenance strategy. A think a patient who is in complete remission, has an excellent quality of life and really has reservations about going on any form of additional treatment over and above what they're receiving, such as periodic bisphosphonate or similar, they could reasonably be watched, and a watchful waiting might be a reasonable approach. And conversely if a patient has real concerns about relapse and does want to start treatment even if they are in remission as a clinician I certainly wouldn't object to them starting because I think in both trials, Sergio, it's true to say that unlike the thalidomide experience where benefit was only seen in patients who still had disease, what was striking to me was that in both trials those patients in very good remissions as well as those in less good remissions all appeared to benefit. Andrew Schorr: I have a question, moving on. Roseanne has a question about steroids. And so often we talk about dex or dexamethasone. Some people are taking others and have less side effects, or it's different for them. For instance, what about Medrol or other drugs like that? So, Dr. Richardson, tell me about that. If steroid is part of it, how do you decide which one? Dr. Richardson: Well, I think it's a great question. I thank the patient for the inquiry because it touches on a point that Mike made earlier, which is that steroids are an absolute menace as well as a savior. And I personal find Solu-Medrol in patients in whom dexamethasone becomes an increasing challenge a very useful alternative. It's not a pure glucocorticoid,


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which is what dexamethasone is. It is a steroid which also has mineralocorticoid effects. What that means is is it helps the body to hang on to certain key chemicals, particularly sodium and other electrolytes, that actually make patients feel better. So I actually find it a very useful substitute for dexamethasone. However, traditionally dexamethasone has been used because it is the most potent steroid, and it is the most active against the glucocorticoid receptor in myeloma. But I have to say that there are no studies that prove qualitatively that there is a difference between the way Solu-Medrol targets the glucocorticoid receptor in dexamethasone, but, Sergio, perhaps you can comment more. Dr. Giralt: So I agree with Paul and Mike that steroids is the bane of our existence in the fact that it is one of the most active agents but it's also the one that produces a significant amount of side effects that patients have actually found intolerable and changed their quality of life. And unfortunately we don't have a lot of good ways of modulating or altering the side effects of steroids. One of the ways that we did it successfully with lenalidomide was reduce this four days on, four days off, four days on, four days off, to just the 40 milligrams once a week, which makes them a lot more tolerable. But particularly in older are patients or patients with co-morbidities, diabetics, these are not easy drugs to give. Unfortunately I think there is only the rare patient in which you can get away from giving them the dexamethasone to giving--because you still--I mean, it's not necessarily the steroid itself, it's the doses that we're giving. So to be able to give an equivalent dose of 20 milligrams of dexamethasone you have to give around 60 milligrams or 80 milligrams of Solu-Medrol, which although may be associated with less toxicities than dexamethasone, they're still significant, they still retain fluid, they still have all the mood swing abnormalities, so they're still associated with significant side effects. One of the things that I think we're lacking is a concerted effort of saying why do some people get side effects to steroids, why do other people don't, and how can we address the issue of steroid side effects in a more concerted effort. Mike: One thing that we don't seem to be looking at is maybe using the combinations of the drugs without dex. It seems like when we add some of the novel agents together we're very reluctant to remove the steroids. Why is that, guys? Andrew Schorr: Paul? Dr. Richardson: Actually, Mike, it's an excellent point, and if you look to our first study when we combined lenalidomide and bortezomib, the so-called Rev-Vel trial, the first doublet was just Rev plus Vel, and what we found was that when we added dex to it, just to echo Sergio's


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point, it improved the response rate over the two drugs alone in a significant proportion of patients. Having said that, a substantial proportion of patients just benefitted from the Rev and the Vel alone without the steroids. So I think the ability to try and be dex-sparing is now feasible with the novel agents, but I think we do have to recognize that the addition of low doses of dex can in fact improve not only activity but in some cases also improve some of the side effects themselves, in particular fatigue and, interestingly, we think with some aspects of bortezomib, neuropathy. Some aspects, I want to stress, dexamethasone with its anti-inflammatory properties may help. The Future Andrew Schorr: Dr. Richardson, so we look for an even brighter day in myeloma, so there was data presented about new agents. Any comment to help people? We were talking about with Mike, you know, new things coming along that have helped him over the years. What about looking forward from here? Dr. Richardson: Well, Andy, I think you're absolutely on target there. The thing that was so exciting about the ASCO sessions was that not only do we have this framework of refining currently available novel agents but also looking into the pipeline and seeing what's coming. I think there were a whole barrage of exciting studies. I think one of the first to be presented was data on carfilzomib, which is a second-generation proteasome inhibitor, which does act very differently to bortezomib in terms of its activity to the proteasome, and importantly seems to have significantly less neurotoxicity as a side effect, which is very important. It's not that it doesn't have any neuropathy, it does, but it's substantially less. And I think what was particularly exciting is it was seemingly able, certainly in bortezomib-intolerant patients, to work very effectively in reducing tumor burden and seeing some very durable responses as well, which I thought was particularly exciting for that particular drug. I think what was also very striking was the combination of bortezomib with other new agents like the histone deacetylase inhibitors, and there was a particularly nice presentation on the combination of bortezomib and a new histone deacetylase inhibitor, so-called panobinostat or LBH, and this actually was further reflected by updates on work with vorinostat, which is another histone deacetylase inhibitor, both in combination with bortezomib as well as, interestingly enough in a separate study in combination with lenalidomide.


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And the message from all of these combinations was similar, that the combinations dramatically enhanced activity even in patients in whom bortezomib for example had failed them previously. And very importantly the side effects profiles were manageable, so that was positive. And I think one of the most exciting presentations that then followed that in the new drug section were actually two. One was on pomalidomide, which is the third generation IMiD, the sort of third in line, if you will, after thalidomide, lenalidomide and now pomalidomide. And Dr. Lacy I think did a super job of showing the results from the pomalidomide studies done at the Mayo Clinic which reflected activity even in patients in whom not only had bortezomib failed but also lenalidomide as well. So that I think was very good news. And finally the other presentation that certainly caught my eye was by Dr. Sagar Lonial, looking at the new agent milatuzumab. In fact there were two presentations on milatuzumab, one by Sagar and the other by Dr. Andrzej Jakubowiak, where he showed the combination of milatuzumab with bortezomib, and both elo with bortezomib and elo with lenalidomide showed very encouraging activity. And I think milatuzumab may be the first antibody we have that is coming close to the type of signal that for example the lymphoma doctors have benefitted from with the introduction of rituximab. Andrew Schorr: Wow. Quite a lineup. So, Dr. Giralt, you obviously are involved in transplant across many illnesses, but it's been questioned about the role or the changing role of transplant for myeloma. With this big array of drugs is it possible that maybe you'll be doing less myeloma transplant and focus on other illnesses more? Dr. Giralt: Well, you know, it's always interesting. We're in the business where we want to put outside out of business, but so, you know, I always tell patients that transplant is a choice, it's not a necessity. It's a choice patients make based on the recommendations physicians give them and based on their priorities. So, you know at this moment in time--and I'm a transplanter, but, you know, I think we need to remember that high-dose melphalan with autologous stem cell support remains the single most effective strategy for myeloma and achieving a complete remission. And we shouldn't throw the baby out with the bath water. I mean, this is--it's actually in many cases this treatment now is one of the cheapest treatments we have to offer because, you know, as Paul has mentioned before in this day and age of cost containment, you know, cost is an issue. So I think as we think about where the myeloma spectrum is and where is it going to go over the next five or 10 years, I think we are going to be able to carve out a fraction of patients in which we say the risk of--you know, the chances of getting what we want for patients, which is always the longest life with the best quality of life with the minimum burden of treatment. So there are going to be fractions of patients where transplanting them makes no sense because we can give them long life with good quality of life with a


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combination of novel therapies and some form of maintenance for maybe one or two years, and transplant can be used as salvage in case the disease comes back. We would have to plan collection of the cells. And then there's the other group of patients in which one transplant may not be enough, where we actually might have to do the total therapy approach, which is intensive consolidation, two transplant s, maybe a donor transplant, followed by immunotherapy, and, you know, we're not--myeloma is now at the same place where leukemia was 15 to 20 years ago, where we're starting to recognize that it's not one leukemia. It is a variety of leukemias that are defined by different cytogenetic abnormalities, and each of these cytogenetic abnormalities will require specific targeted therapies. So I think myeloma is that at that dawn, and thank god the pipeline is full of therapies, and now it's just for us to figure out which patients need what strategies to be able to give them the longest life with the best quality of life. And yes I can, you know, I would have no trouble focusing my efforts on something else. Andrew Schorr: Okay. Well, this is a great point in time. I'm going to give the last word to Mike Katz. Mike, you go to these meetings, you interview so many, you've been living with it. Your cells are in the freezer, as you say, have been for years. What would you want to leave patients with from your perspective? Mike: I would say live your life well, work hard to make sure that you're taking good care of yourself and your myeloma, and look forward to a bright future. Andrew Schorr: Well, I sure hope so. And I want to thank our M.D. experts who are with us today from two of the top institutions. Dana-Farber Cancer Institute, Dr. Paul Richardson, thank you for being with us. Dr. Richardson: Oh, it's my pleasure. And I just want to thank you, Andy, and especially thank Mike and Sergio for participating and also most importantly the very nice questions from the patients. It's really my privilege to be part of the discussion this evening. Andrew Schorr: Well, thanks. You keep working on a cure for us. And Dr. Sergio Giralt from Memorial Sloan-Kettering Cancer Center in New York, thank you. And maybe we'll put you out of business at least as far as myeloma goes, but thank you for helping us understand really the vast array of presentations of myeloma, and we're glad you're there for myeloma patients who need it. Thank you for being with us.


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Dr. Giralt: And I thank the people from Patient Power who have given me the honor to be here on the call with Mike and Paul. And, you know, we really do hope for the day where, you know, all patients with myeloma, you know, will look at this as a nuisance more than anything else and that we will be able to have treatments that will give, you know, all patients long life with good quality of life and minimum burden of treatment. Andrew Schorr: All right. Thank you both for being with us. I want to point out that we did a video with Dr. Richardson right at the ASCO meeting, and that is on the Patient Power website at patientpower.info/ASCO. Mike, all the best to you. Doctors, thank you. Thanks to our audience for being with us. I'm Andrew Schorr. Remember, knowledge can be the best medicine of all. Please remember the opinions expressed on Patient Power are not necessarily the views of our sponsors, partners or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. Please have this discussion you’re your own doctor, that’s how you’ll get care that’s most appropriate for you.

Documents

The Latest Myeloma Updates from ASCO Breaking News ...cdn.patientpower.info/p2docs/transcripts/MM062210.pdfThe Latest Myeloma Updates from ASCO Breaking News June 22, 2010 Paul Richardson,