TRANSCRIPT Multiple Myeloma Updates From the 2015 ASCO Annual Meeting and 20 th Congress of EHA

Transcription

1 Welcome and Introduction Joan Levy, PhD [Slide 1] Hello everyone! [Slide 2] My name is Joan Levy, and I am Vice President of Research at the Multiple Myeloma Research Foundation (MMRF). I d like to welcome you to this multiple myeloma update from the 2015 American Society of Clinical Oncology Annual Meeting (ASCO) and the 20th Congress of the European Hematology Association (EHA), both of which concluded in June of this year. This is a continuing medical education (CME) activity jointly provided by the Postgraduate Institute of Medicine, cancereducation.com, and the MMRF. First, I d like to acknowledge Onyx Pharmaceuticals, Inc. a subsidiary of Amgen, Inc. and Celgene Corporation for their support of this CME program. The MMRF was founded in 1998 and is the number one private funder of myeloma research worldwide that is focused on accelerating new treatments to extend the lives of patients and ultimately find a cure for this disease. Together with our affiliate organization, the Multiple Myeloma Research Consortium (MMRC), composed of 22 leading myeloma centers, we supported the development of highly innovative therapeutic approaches. Through the work of the MMRC, specifically, we ve opened 60 trials of over 30 novel agents. You will hear more about some of these trials during this webcast. The MMRF has also launched two online gateways one for researchers and one for patients. The MMRF Researcher Gateway is an open access platform that allows researchers worldwide to analyze clinical and genomic data from our landmark longitudinal CoMMpass SM study of 1,000 newly diagnosed myeloma patients being followed both at the genomic and clinical levels over the course of their disease. The MMRF s second gateway, our CoMMunity Gateway, is geared to all myeloma patients and allows each patient to access information, network, and learn about clinical trials that are specific to their type of disease. Beyond research, we re also the leader in educational programming for the entire myeloma community, offering live, online, and print programs for patients, caregivers, and healthcare providers. You can always check our website at to find the latest information on multiple myeloma and its treatments as well as information on our upcoming programs. [Slide 3] Today, we have two key presenters and contributors from ASCO and EHA joining us. It is my pleasure to introduce Dr. Jesus Berdeja from the Sara Cannon Center for Blood Cancer in Nashville, TN, and Dr. Saad Zafar Usmani from the Levine Cancer Center/Carolinas Healthcare System in Charlotte, NC. They will share with us the latest multiple myeloma information coming out of these two important conferences. Welcome doctors, and thank you for joining us today. Now I d like to open it up to you to discuss your perspectives and key takeaways from ASCO & EHA. Dr. Berdeja? Updated: August 25, 2015 Page 1 of 25

2 I actually thought that this was a very interesting American Society of Clinical Oncology (ASCO) and European Hematology Association (EHA) this year. I think there were a lot of interesting presentations and points that were made this year, which I think will impact our standard of care in the future. What do you think? I think you're right, Jesus. Surprisingly, ASCO is not usually heme malignancies heavy but we had some impactful abstracts being presented and being disseminated to the community oncologist in that way, EHA was the same way. There were some very interesting abstracts. Updated: August 25, 2015 Page 2 of 25

3 Smoldering Multiple Myeloma [Slide 4] Maybe we can discuss a little bit about the high-risk smoldering myeloma patients and some of the data that was discussed, especially in light of the recent changes in the International Myeloma Working Group (IMWG) definitions of the high-risk smoldering myeloma (SM). What are your thoughts? I think that it's definitely worth heeding. I think that one of the things I find talking to my colleagues in the community is there's a lot of questions about smoldering myeloma and active myeloma, and I think they're all trying to sort of embrace the new definitions. [Slide 5] I think it's always worth discussing that and see if there was anything new that has come out that might have changed that. I think we're so used to going out and telling people active myeloma is very easy. You just need a clone and a protein, and if you have any kind of active disease or end organ damage caused by the disease, you have active myeloma. If you don't, you have smoldering. I think that's sort of been turned on its head in the last year or so. [Slide 6] And, actually, a lot of it is because of publications from the Spanish Group (PETHEMA) from Dr. Mateos with the initial look at high-risk smoldering myeloma treating patients with lenalidomide versus not treating patients that I think really made us look into whether that smoldering group truly was all the same or if we were undertreating some of our patients. I agree and the Mateos paper certainly brought this issue to the fold. Trying to treat smoldering myeloma with the idea of potentially nipping the disease in the bud has been tried before with interferon, thalidomide and pamidronate in the late '90s but did not really pan out in terms of its efficacy and what it was trying to do. [Slide 7] Originally, the Mateos study wasn't aiming at trying to find survival differences. Its primary endpoint was looking at responses. Even though there are some limitations of the study with the number of patients that were enrolled and the concern whether all patients got adequate novel imaging to really see if there was bone disease in those patients, so perhaps some of those patients were really active myeloma. Despite those nuances, I think that the Mateos study certainly makes an important point and it's a good first step. [Slide 8] With the International Myeloma Working Group, Dr. Rajkumar had been spearheading this effort trying to find clinical variables that can predict for a high chance of progression from high-risk smoldering to active disease. And I think that the three that they identified, which were at the highest risk of progression, were elevated involved to uninvolved light chain ratio of more than 100, having more than 60% bone marrow plasmacytosis and having more than one MRI (magnetic resonance imaging) focal lesion on either an axial skeletal MRI or a whole body MRI. Updated: August 25, 2015 Page 3 of 25

4 I think all of those things are important because if you look at the higher bone marrow plasmacytosis and the MRI focal lesion, both of those tell us that something is brewing in the bone and a skeletal event may be around the corner. And with the elevated light chain ratio, maybe a renal event is around the corner. So, I think those do make intuitive sense and it will be important for us within the field to actually relay that message to the community. At the same time, also relay the message that really these are guidelines. There might be patients who have these features who may not have any clinical signs of progression and have been cruising in that phase for quite a while. And it may be reasonable just to watch them. What do you think? I think that's right. And I think the other thing that always comes to mind seeing patients referred from the community is sort of the way we approach these patients with smoldering myeloma. We've always been taught to, once you diagnose them, to just kind of watch and make sure that their creatinine and their calcium and their laboratories seem to be doing well. But I think now we do need to have a much stronger baseline and know where to start to kind of determine how to follow these patients. Like you said, it's no longer just about clinical progression, but now there is actual laboratory and study information that will actually now place a patient in the active myeloma category. One of the things I find that's difficult is the whole bone MRI. I have a hard time getting that in the community; getting it covered or even being done. [Slide 9] So, one of the interesting papers from EHA was the paper from Zamangni and Cavo which actually looked at doing PET (positron emission tomography) which I found was very interesting because that is a much easier study to not only interpret but also to get it covered. I don't know if you saw that study, but I thought it kind of reassured because I think most of us feel that it's not only whole bone MRI but probably PET can be substituted as well. I think that it's important to appreciate that the PET scan and the whole body MRI provide different pieces of information. So, that with the PET/computed tomography (CT), the CT portion of the PET is providing information about lytic bone disease earlier than you would see on X-rays and it also provides FDG (fluorodeoxyflucose) uptake or increased activity of potentially myeloma cells in certain lytic areas. Is there anything else that we need to discuss in terms of smoldering myeloma? There were several presentations at EHA, but more about looking at risk factors for confirming the PETHEMA and Mayo risk stratifications that I thought were important, but I'm not sure necessarily change the current recommendations at the time. Updated: August 25, 2015 Page 4 of 25

5 I agree with you. I think that, in terms of the ability to predict progression from the available clinical variables or the available cytogenetic or FISH (fluorescence in situ hybridization) markers, we've probably reached a limit to those particular databases. I think the next logical step would be to find out biologically how we can predict for progression in any given patient based on either the plasma cell biology or the bone marrow microenvironment or both. And there are groups in Europe and in Arkansas who are actually looking at that particular question. [Slide 10] I think the SWOG (Southwest Oncology Group) 0120 study was a good first step where gene expression profiling was done in a group of roughly 331 patients with MGUS (monoclonal gammopathy of undetermined significance) and smoldering myeloma. There was some evidence that disease biology trumps disease burden at least in that study. This was published in Blood maybe a couple of years ago. Dr. Dhodapkar was the first author. I think that there are certain investigators that are catching on to that theme and trying to find out what we've done the most that we could from the clinical variables. Let's try to figure out from the biologic perspective. So, I think that that's where we are probably going to see more data. But outside of that, the current abstracts do not add to how we're looking at this right now. I agree. We're hoping for that time when we can just send a test that will give us the answer and not have to necessarily continue to have this be a clinical diagnosis, which until now continues to be so. True. Updated: August 25, 2015 Page 5 of 25

6 Upfront Therapy [Slide 11] So, I thought we'd change gears, if it's okay with you. Sure. It looks like the FIRST trial was a monumental trial presented I believe was at ASH (American Society of Hematology Annual Meeting) 2013 was the first time it was presented at the Plenary Session. It has since been published in New England Journal of Medicine (NEJM). There were several presentations at this past ASCO and EHA that sort of updated us on that data which I feel was relatively groundbreaking and really set the standard of care for the nontransplant eligible patient. Any thoughts on that? [Slide 12] Sure. So, I think that the FIRST trial provided us with, at least within the US (United States) practice environment with information that actually would augment how we practice medicine in the US anyway. I think the ECOG (Eastern Cooperative Oncology Group) trial which looked at lenalidomide and dexamethasone, but with changing the dexamethasone dose to either low dose or high dose in a Phase III fashion, that trial began in the mid-2000s, I think 2004 or 2005, and helped the uptake of lenalidomide and dexamethasone as an induction regimen of choice for both transplant eligible as well as ineligible folks. So, the community became very comfortable utilizing len-dex as an induction regimen quite early compared to the European countries because access of drug was also an issue in those countries. So, the FIRST trial kind of tells us what we've been practicing in the US was the right thing to do. At the same time helps the European colleagues to bring lenalidomide and dexamethasone in use for their upfront patients. One of the valuable lessons that we learned from the study, obviously, was the idea of continuous therapy. [Slide 13] The longer patients can stay on treatment, the better their overall outcomes are in terms of PFS (progression-free survival) and overall survival, at least compared with the MPT (melphalan-prednisone-thalidomide) regimen in this trial. What Dr. Thierry Facon also alluded to were a couple of abstracts. So, Dr. Facon and Dr. Cyrille Hulin presented on updated survival and then also the effect of age. It appears that lenalidomide and dexamethasone is efficacious regardless of age and continues to have an improved PFS as well as overall survival over time. Updated: August 25, 2015 Page 6 of 25

7 I echo those sentiments. I agree with you. I think the striking thing to me was how important the idea of continuous therapy versus a set number of cycles was in this patient population. Looking just specifically at the progression-free survival, it's interesting that the MPT and the Rd (lenalidomidedexamethasone) 18 cycles are very similar. It was really the continuation of the lenalidomidedexamethasone that really made the difference, which I think is something that we all still struggle in terms of leveraging toxicity of continuous therapy versus benefit. But I think with time it continues to show that continued benefit. From Dr. Hulin's paper, I was somewhat surprised at how well the elderly frail patients actually were doing and were still benefiting, but I think with the caveat that it is important to dose adjust the lenalidomide in these patients who are likely to have worse creatinine clearance and potentially more hematotoxicity. I completely agree with you. And many times, again, there are no data to support this but in our clinical practices many times we actually start with the dose reduced lenalidomide and dexamethasone and perhaps escalate based on tolerability of a given patient. Many times that strategy may actually help in controlling the disease and improving the quality of life of patients. What are your thoughts about that? I think you're right. I think one of the important things to look at here is one of the difficult parts I think about myeloma is that not one particular dose or schedule is appropriate for every single one of our patients. If you're in the lymphoma world and you have a diffuse large cell patient giving CHOP (cyclophosphamide-hydroxydaunorubicin-oncovin (vincristine)-prednisone)-rituximab as the standard of care, and there's very few things you have to really adjust. Whereas I think in our population, we have to be cognizant of the very variable population that we deal with and also keep in mind the drugs that you will be utilizing some will need to be adjusted and some won't. And I think it's important to actually start at a tolerable dose instead of inducing toxicities that may really compromise your ability to continue the therapy long term, which appears to be the most beneficial way to do things. I completely agree, and I think there was a poster by Arikian et al. [Slide 14] at EHA as well which actually looked at the patterns of cost and outcomes in patients who actually have dose adjustments to their lenalidomide along the way. And what they showed within their abstract is patients who actually have a toxicity-related dose adjustment to their len, instead of discontinuation of their lenalidomide, actually do better in terms of their outcomes. That was quite provocative, I thought, that many times if a patient is being treated at a higher dose, community oncologists may discontinue the drug thinking that the patient may not be able to tolerate it. But if you can dial down the dose, make Updated: August 25, 2015 Page 7 of 25

8 the drug more tolerable for the patient; you can still get good mileage out of that medicine for that particular patient. I think that that was the message from that particular abstract. What do you think? I completely agree. I think going on further with sort of dose adjusting and looking at the patient populations is important to keep all those things in mind. I think our goal should be to try and find the appropriate dosing that is tolerable to maintain the patients on therapy. [Slide 15] Dr. Dimopoulos also had an abstract from the FIRST trial looking at patients with various degrees of renal insufficiency. I think hitting that point; again, that lenalidomide-dexamethasone is something that can be used safely in patients with decreased renal function. But, again, it needs to be dose adjusted appropriately so that the patients can actually stay on the drug and maintain their therapy. I agree. I couldn't agree with you more. And then we do have some interesting abstracts that are evaluating carfilzomib in the upfront setting for newly diagnosed myeloma patients. And I just wanted to get your thoughts on those particular studies. Yes. I think they're very interesting and I think one of the things I've always been a big proponent of is when we're talking about patients who are transplant eligible, we talk about doing aggressive therapy and doing combination therapy followed by high-dose chemotherapy and autologous stem cell rescue. Then we talk about maintenance, the plus/minuses of maintenance, which we can discuss later. But I always felt that, actually, our therapy itself after the completion of all treatments seemed to be actually less aggressive in the young fit patient more so because of the duration. We've been discussing with the FIRST trial that addresses that continuous therapy. I'm actually very happy to see abstracts looking at augmenting our usual paradigm of induction times four cycles followed by transplant and looking at either changing to more aggressive regimens adding drugs, as Dr. Charlotte Pawlyn presented [Slide 16] an oral abstract at EHA using carfilzomibcyclophosphamide-lenalidomide-dexamethasone as a potential induction. Of course, Dr. Andrzej Jakubowiak's [Slide 17] carfilzomib-lenalidomide-dexamethasone, but also looking at the posttransplant setting and actually considering consolidation to try and sort of mimic that more prolonged therapy with the novel agents that we do with the nontransplant patients. And, as you pointed out, there were a few abstracts presented. Two with the addition of weekly bortezomib and dexamethasone for four cycles of consolidation, mostly from the British groups and European groups, that looked at not only response rates but also progression-free survival with benefits of just the addition of those four cycles following transplantation. Updated: August 25, 2015 Page 8 of 25

9 [Slide 18] I completely agree with your take on this. One of the things that I wanted to add was the fact that the overall schema for transplant eligible patients of induction transplant consolidation and maintenance was actually introduced by one of the giants in the field, Dr. Bart Barlogie, at a time when he did not have the novel therapy to play with. And it's actually good to see those principles being applied to this young myeloma patient population where we're now thinking of, "All right, we have these well-tolerated drugs. How could we best maximize survival outcomes for patients?" And we're doing induction with these novel agents. And from Dr. Jakubowiak and Zimmerman's papers it was clear that CRD (carfilzomib-lenalidomide-dexamethasone) induction and consolidation was fairly well-tolerated. And the depth of response that we're seeing with doing CRD induction transplant and CRD consolidation, it's quite phenomenal. We're seeing stringent complete response (scr) rates going into maintenance at 87% and a similar or high number of patients actually have MRD (minimal residual disease) negativity as well. That's quite striking. I'm really encouraged by this and truly hopeful that one of the new drug classes that we are going to be talking about a little later, the monoclonal antibodies, how they can potentially even push the envelope of good depth of response even further for those patients. I completely agree. And I think it's a very exciting time for us in myeloma that we are starting to see some of these therapies that lend themselves very well to augmentation of therapy and, hopefully, decreasing toxicity, or at least not increasing toxicity, which I think has been one of the caveats with Dr. Barlogie's concept, which I agree with you. I think it's great to see that this is finally coming to fruition. But at the time when he was proposing it, the drugs that we had were relatively toxic, and often the push for potential cure or at least prolonged remissions came with a significant cost. And I think as we're getting better, less toxic drugs, I think we can really push that envelope and, hopefully, get to that point as well. Agreed. Updated: August 25, 2015 Page 9 of 25

10 Maintenance Therapy So, to continue with the transplant eligible patients, there were some updates on the use of maintenance in the post-transplant setting. Any thoughts or caveats we should be taking from that in your mind? Are you referring to some of the maintenance of consolidation abstracts? I was thinking more the maintenance. [Slide 19] There was an update from the CALGB trial presented that basically continued to show improvement in progression-free survival and overall survival (OS) in the patients that received lenalidomide-dexamethasone, consolidation versus observation. But, interestingly, in terms of the secondary malignancies, that continues to sort of plague the maintenance group with increased secondary malignancies in both groups but significantly increased in the lenalidomide group. But I just wanted to mention it in the current discussion just because I think we all feel that maintenance is important. But, again, it comes back to sort of kind of trying to attenuate the potential toxicities that we see with maintenance to leverage that benefit. But at least from my standpoint at this time, I feel that the data with maintenance post-transplantation with lenalidomide still favors doing so as the benefits, I believe, outweigh the costs. And I was wondering what your take on that was. I'm on the same page as you are, Jesus. I think it's important to recognize that second primary malignancies are an important concern but they are probably relevant to a small proportion of patients. Anywhere from 6% to 8% of patients who are on len maintenance may develop it. The majority of patients who do get len exposure do not develop it. It's important to try to recognize which patients may be at risk and there are some groups that are actually looking at that particular question. But one of the striking things in Dr. Phillip McCarthy's poster at ASCO was the TTP (time-toprogression) curve continued to separate from each other over time. That just overwhelms things in favor of len maintenance as a way of improving survival in our post-transplant patients. I think it's extremely important to have that discussion with our patients, provide them with details. At the same time, share with them that, yes, there is a concern about second primary malignancies but it doesn't appear to be in epidemic proportions, for the lack of a better word. Updated: August 25, 2015 Page 10 of 25

11 I completely agree. One of the things I actually found from that update presented at ASCO by Dr. Holstein and McCarthy was, actually, the data with patients in CR (complete remission). The patients in CR at the time of randomization seemed to benefit just as much as patients who were not in CR. I think that's actually an important point as well as we struggle with what does CR actually mean and the need for continued therapy in those patients leveraging, obviously, the potential toxicities. Any thoughts on that? [Slide 20] I think that's an important point, that there are patients who continue to have an upgrade or improvement in their response depth after transplant if they are on maintenance therapy. I think Dr. de Larrea from the Spanish Myeloma Group presented a poster at EHA with that theme in mind that there are patients who actually improve their depth of response while on maintenance and their survival appears to be better than those who did not go on maintenance and had no improvement in their response post-transplant. I think that that's an important point that you bring up. I agree. I think, since we're on the maintenance topic, I think most of the data, at least right now, seems to show that there is a benefit of maintenance not only in the transplant setting, but in the nontransplant setting. I think the main question still left out there is what is the best maintenance therapy and also for how long? I think those are the open questions that I think will be important. Hopefully, newer data will come that will help us with that. I'm not sure we have any more data presented at these meetings that will help us solve that question. I agree. I mean, there are some other drugs such as oral PI (proteasome inhibitor) ixazomib, some monoclonal antibodies that are being evaluated in the maintenance setting as well. So, it will be important to see the results from those trials in the coming years to see how this particular space shapes out. Updated: August 25, 2015 Page 11 of 25

12 Stem Cell Transplantation [Slide 21] I agree. Actually, just changing gears a little bit, the question in everyone's mind, of course, these days to transplant or not to transplant, right? That is the question. I was wondering if you would take us through, I think there were two papers that were discussed at ASCO with very different results. I was wondering if you could take us through them. I was thinking of Dr. Francesca Gay's and Dr. Suzanne Lentzsch's papers. [Slide 22] Sure. I just want to preempt this by making the statement that within the United States myeloma space, only about 13% or so of myeloma patients actually go on to receive stem cell transplant. And there are several factors associated with that, access being one, access to a stem cell transplant center, and then comorbidities in the real world also appear to be important. So, when we talk about transplant eligible patients, I think it means something different at a center that sees a high volume of myeloma patients and it means something different when you are out in the community. Community docs probably see patients who have a higher comorbidity and their decision making may be a little different. So, with that in mind, there were a couple of studies that actually looked at the role of stem cell transplantation. Historically, we've recognized from the two pivotal studies in the '90s, one by the French Myeloma Group and the other by the MRC UK (Medical Research Council United Kingdom) group that compared to standard of care, stem cell transplants do improve progression-free and overall survival. In terms of PFS, you can get roughly a four and a half year mileage of PFS out of your autologous stem cell transplant for your patients. But with the novel agents, we had been questioning the role of autologous stem cell transplant. Dr. Antonio Palumbo provided us with an answer to that question in the setting of len-dex induction therapy. His paper was published in American Journal of Medicine (AJM) where after len-dex induction therapy patients were randomized to either receiving autologous stem cell transplant or receiving melphalan-prednisone-revlimid (lenalidomide) (MPR) before they go on to be randomized to len maintenance versus observation. And what he showed was that patients who are receiving autologous stem cell transplant have a superior PFS and overall survival in that setting. But having said that, the main question is whether you can still utilize autologous stem cell transplant in the first relapse if you haven't given it upfront. What's the value of giving it upfront if you can get similar sort of mileage out of it in first relapse? I don't think that any of the current abstracts provide us with an answer to that particular question. It's important to wait for the Dana-Farber IFM trial which is trying to examine that question. Hopefully, we ll have some data from the French Myeloma Group in another year, maybe at ASCO 2016, but we don't have an answer for that yet. Updated: August 25, 2015 Page 12 of 25

13 I do want to discuss the Dr. Suzanne Lentzsch abstract [Slide 23] a little bit only because it's important to appreciate how to interpret that data. So, it looks like this study was a randomized Phase III study with roughly 60-odd patients. So, the statistical assumptions for that kind of a study with that small of an n has to have huge chances of error or findings that would otherwise be attributable to chance alone. The primary endpoint for this particular study was looking at response rates of patients who are receiving len-dex with or without upfront autologous stem cell transplant. What the study found was that there was no difference between the two arms in terms of statistical difference between response rates as well as outcomes. But we have to take these results with pinch of salt. It's a very small study. The statistical assumptions are pretty huge, and I don't think you can make a lot of interpretations from these data. They do provide us with some food for thought, but there are larger more statistically impactful trials that are underway that will help examine that question. I completely agree, and thank you for kind of going through the history of this. I think it's very important and some of the caveats in terms of when we talk about patients who are transplant eligible because I think you hit it right on the nose that it isn't clear who this population is in reality. But having said that, I agree with your assessment of Dr. Lentzsch's paper. I think it's provocative but, at the same time, it's a very small trial looking at these outcomes that I'm not sure they're able to actually achieve unless they saw a very large difference, which so far they have not. So, I think it's an interesting paper. It's unclear of what to make of the actual outcome. [Slide 24] If you look at Dr. Gay's paper sort of kind of giving us an update, a much larger study, 389 patients, the same induction as with Dr. Lentzsch's paper, but in this case patients then going on to, again, the nontraditional approach, which is patients who got transplant got a tandem autologous transplant mel 200 versus a consolidation of six cycles of lenalidomide-cyclophosphamidedexamethasone. And I believe there was no maintenance here. And in this scenario, which, again, it's not quite what I would consider the standard approach for either transplant or nontransplant patients, there was a four-year benefit in both progression-free survival and overall survival. So, I think you're right. I think we need to wait for that randomized study that really is treating patients similar to the way most of us would approach them with our current standard of care. [Slide 25] Another trial to watch out for, again, it's a very important study, the BMT CTN 0702 study which is actually a three-arm Phase III study. It finished accrual about a couple of years ago, I believe, in late 2013, early So, the data will probably be shared at ASH of 2016, so in another year and a half from now. But that trial is a trial of single autologous transplant either with or without an RVD consolidation compared with tandem autologous transplant. And all the three arms get len maintenance afterward. So, there's an arm that gets an autologous stem cell transplant and then Updated: August 25, 2015 Page 13 of 25

14 goes on to len maintenance, there's a second arm that gets autologous stem cell transplant times one, then gets RVD (lenalidomide-bortezomib-dexamethasone) consolidation and then len maintenance, and the third arm gets tandem transplants and then len maintenance. I think that particular study will be extremely important in the grand scheme of things and probably make the case of RVD consolidation. I'm just putting my bet on that. But let's see what the results show. I agree. I think we have two very large trials that, hopefully, will be helping us quite a bit in answering or at least kind of. They probably won't settle the question necessarily but at least will help guide us on how to approach these patients. Updated: August 25, 2015 Page 14 of 25

15 Relapsed/Refractory Disease [Slide 26] So, given the time, I thought, actually, we would talk about the relapsed/refractory setting because I think a lot of the important studies that were presented were in that patient population. Is that okay with you to move on to that population? Sure, absolutely. [Slide 27] So, I thought especially at ASCO there were three large, randomized Phase III studies that were presented that, I think, may have an impact in our standard of care and potentially lead to some new FDA (US Food and Drug Administration) approvals. And I thought maybe we could talk about those three. And I was particularly thinking about Dr. Lonial's presentation on daratumumab and Dr. Lonial's presentation on the Phase III, randomized, open-label trial of Len/Dex (lenalidomidedexamethasone) with or without Elo (elotuzumab) in relapsed or RRMM (relapsed/refractory multiple myeloma) ELOQUENT-2 (CA ) study with len-dex plus elo versus len-dex and Dr. Dimopoulos with the ENDEAVOR study looking at carfilzomib-dex versus bortezomib-dex. I think we should discuss those three studies. Agreed. I think that they're very important studies, especially in light of how the myeloma therapy landscape is looking. We can perhaps talk about each of those studies one at a time. Should we start with Dr. Dimopoulos s study since these are drugs that are FDA approved at this time? Sure. [Slide 28] Obviously, that was the ENDEAVOR trial. A very large trial with 929 patients. Patients were relapsed, had to have had one to three prior therapies, and they were randomized to receive carfilzomib-dexamethasone versus bortezomib-dexamethasone. And I think it's important to point out that carfilzomib-dexamethasone is not what is the FDA approved dose for carfilzomib, which is 27 milligrams per meter squared. In this case, the dose was 56 milligrams per meter squared Updated: August 25, 2015 Page 15 of 25

16 intravenously twice weekly, three weeks on, one week off. So, standard schedule, but a higher dose with dexamethasone. Bortezomib-dexamethasone was standard dosing of bortezomib 1.3 milligrams per meter squared IV or subcutaneous days one, four, eight, 11. Basically what was found in this study, which actually, I thought was quite impressive and almost surprising how well the study arm did. But the progression-free survival of the carfilzomibdexamethasone arm was 18.7 months compared to 9.4 months for the bortezomib-dexamethasone arm. Overall survival is not statistically significant at this time. It's still early. And there were definitely an increase in overall responses and the depth of responses favoring the carfilzomib arm. Comment? I think that this is an extremely important study. I think one of the things that has weighed heavily on our minds is which is the better proteasome inhibitor especially in light of the fact, sure, carfilzomib doesn't have any significant peripheral neuropathy issues, but there were concerns about a cardiac signal. So, doing the study was important to do. They also, the study sponsors and investigators, were quite stringent in following the cardiac toxicities. They were actually doing serial echos and EKGs (electrocardiograms) and looking at this extremely closely in both arms. And what they found was a higher incidence of cardiac events perhaps in the 4 to 5% range depending on which way that you look at it. But those are similar to what have already been published and known about carfilzomib. So, there's a signal but it appears to be a class effect because you do see similar signals at a lower rate with bortezomib as well. I appreciate the fact that you highlight the dosing of carfilzomib. They did utilize the higher dose of carfilzomib at 56 milligrams per meter squared and I think that their rationale of trying to deliver maximal proteasome inhibition in this setting was reasonable. And the fact that this particular drug can be given in that kind of dose and is tolerable is also appreciable. One of the caveats to this study is that about a little less than half of the patients who went on study did have bortezomib exposure in the past. So, they may have received a bortezomib-based treatment in the past. They haven't progressed on it actively, so they are exposed but not refractory to bortezomib. So, there were patients on the bortezomib arm who had prior bortezomib exposure who may not necessarily get the same mileage from bortezomib this time around. So, even with those caveats, I think the doubling of the PFS is quite remarkable. The number of patients was very high so the statistical assumptions would weigh in more in favor of this being the right outcome for this particular trial. Yes. One of the interesting things about carfilzomib, for those of us who have been kind of working on studies with the higher doses, is the FDA approved dose starts at 20 milligrams per meter squared the first two doses. If tolerated, it goes up to 27 milligrams per meter squared. But it's given almost like an IV push over two to three minutes. I think what the realization was that just by altering simply Updated: August 25, 2015 Page 16 of 25

17 the infusion time to 30 minutes the toxicities that were seen in the initial studies with the previous dosing were not there and the higher doses were very tolerable. So, I think that's important for people to realize is that if this ever comes to fruition and becomes an FDA approved indication dosing, that it is infused differently than what most of us are used to doing in the clinical setting currently. Having said that, there was, actually, a paper by Dr. James Berenson looking at carfilzomib doses up to 70 milligrams per meter squared but given intravenously once weekly instead of the twice-weekly dosing used as standard therapy. And so, even at those high doses, over 30 minutes, the carfilzomib appeared to be very well tolerated. And, again, no significant increase in cardiotoxicity was seen. So, I think that is an important thing to realize that probably the dosing of carfilzomib will need some adjustment in the future. I agree with you. So, another thing that I wanted to add to this discussion was when we were doing some of the early carfilzomib trials in late 2009, early 2010, was that specific fact. We were seeing some cardiopulmonary issues. And one of my ISTs (investigator sponsored trials) when I was still at the University of Arkansas, we had changed the infusion for doses above 27 to 30 minutes at bedtime and had noticed an appreciable decrease in the cardiac signal. And that dosing was eventually adopted. The 30 minutes was adopted for subsequent studies and we saw the same thing. And it was an intuitive move, but I think it's important to appreciate the fact that despite the PK/PD (pharmacokinetic/pharmacodynamic) data that would suggest carfilzomib would be most potent as an IV push, it does have significant clinical benefit, as you can see, even with the 30-minute infusion. Right. And, I guess, before we leave the study, obviously, at ASH 2014, the [Slide 29] ASPIRE (Carfilzomib, Lenalidomide, and Dexamethasone versus Lenalidomide and Dexamethasone for the Treatment of Patients with Relapsed Multiple Myeloma) trial was presented there and that, of course, is a randomized trial with carfilzomib-len-dex versus len-dex that greatly favored the carfilzomib-lendex arm with quite impressive progression-free survival for both arms actually, but in particular for the carfilzomib-len-dex arm. And at these meetings there were some updates from the data that basically continued to show us that there's a significant benefit. Even when you stratify the patients by having had one prior therapy or two or more therapies, the benefit of the addition of carfilzomib continues to be present. So, I think the reason I bring that up and I just wanted to end here, I found that the progression-free survival in this study was help me out here. I can't remember what it was. I want to say it was 25 months for the carfilzomib-len-dex arm. You are right. It is around 25 versus 17. Updated: August 25, 2015 Page 17 of 25

18 17, yes. So, quite impressive. And the reason I brought this study up is just I think now we have two large, randomized studies with carfilzomib as part of the treatment in patients sort of earlier than what were FDA approved. So, a lot of the questions that I've been getting now are in light of this, where do you position carfilzomib in standard practice? I was wondering if you could comment on that. I think this is extremely an important piece to discuss and it's probably relevant to the ASPIRE, the ENDEAVOR, as well as the ELOQUENT studies because they're kind of vying for a position in a similar space. And this is where it becomes important to actually look at what were the patient characteristics on each of these studies and how did they differ in trying to make that relevant to your patient? So, in my mind, the way that I would think of this is patients who either got a bortezomib-based regimen or a lenalidomide-based regimen as their first line of therapy, what kind of response they got from it. For example, in a patient who got a lenalidomide-based regimen, if you're considering a proteasome inhibitor as the next line of therapy, then the ENDEAVOR trial data may be what you need to consider in making that choice. Similarly, if you had a patient who had a bortezomib-based initial therapy and you're considering lendex as the next line of therapy, then based on the data from ASPIRE, you may opt for carfilzomib-lendex as that next line of therapy. [Slide 30] ELOQUENT it's an interesting study. Honestly, I want to get some sense from you about the elo-rd data or elo-len-dex data. But I honestly was hoping that we are probably going to have a higher PFS on the elo-len-dex arm compared with what the trial actually reported. I was hoping that the immunomodulatory angle, the mechanistic augmentation of the NKMP cell clonal expansion against myeloma cells with anti-cs1 or anti-signaling lymphocytic activating molecule (SLAM)-7 activity would be higher, but I don't think there was activity, but it wasn't as impressive as seen, in say, the ASPIRE or the ENDEAVOR studies. I think that's true. I asked you unfairly, before we even discussed the ELOQUENT-2 study. But, I guess, just to refresh people's mind, Dr. Lonial presented the ELOQUENT-2 study which was a large, randomized trial with patients randomized to lenalidomide-dexamethasone versus lenalidomidedexamethasone plus elotuzumab. And just as a reminder, elotuzumab is a monoclonal antibody against SLAMF7 and doesn't have much single agent activity but at least in the early Phase Ib and II trials, in combination with lenalidomide-dexamethasone, it showed very impressive responses. But, really, what was most impressive was the progression-free survival that elotuzumab seemed to stabilize the disease and patients appeared to receive more benefit. So, that was the premise, I guess for this trial. Updated: August 25, 2015 Page 18 of 25

19 And these were patients, again, in the same population, one to three prior regimens. What's interesting to note in this population, just with the point you made or at least driving the point you made earlier was to look at those patient populations because in this case, most of the patients that were recruited were outside of the United States. And so,hey only had 6% of patients that actually had prior lenalidomide. So, I think it's important to keep that in mind as you apply it to your own patient population. But, basically, the results were the progression-free survival favored the elotuzumab-len-dex arm. The progression-free survival was 19.4 months versus 14.9 months for the lenalidomidedexamethasone arm. The overall response rate also was improved, although not to a huge degree, 79% versus 66%, although that was not completely unexpected. But, I think what was really impressive to me was the lack of toxicity. If you look at the toxicity tables for both arms, they're basically identical. Except for a few grade 1/2 infusional toxicities from the antibodies, especially in the first dose, there was really no added toxicity from the elotuzumab to this combination. So, I agree with you that I think the differences in the two arms are more impressive in the two studies previously mentioned. But, I think they're statistically significant and with an added drug that really has no excess toxicity that lends well to, hopefully, even more important combinations. I think in that vein, I would argue that it's going to be difficult to find what would these results look like in the setting of patients who had been previously exposed to lenalidomide that relapsed that were still considered sensitive to lenalidomide? Would we have seen a bigger difference in this similar to what you mentioned with the difference in the carfilzomib-dex/bortezomib-dex study looking at patients that had prior bortezomib. Agreed. I think that that's an extremely important point that you're making. And if I remember correctly, there is a study looking at that specific question. So, patients who have had len exposure in the past, can you add elotuzumab to get better responses in PFS in those patients? I mean, that's where we can potentially prove that particular concept. Now one of the things that Dr. Lonial did specify in his presentation was the patients who do have a good response, there is a subset of patients that continues to maintain that response for a long period of time. And that kind of speaks to the mechanism of action of this combination, which may be very different from what we're seeing with car-rev-dex, for example or car-dex by itself. I think it's all very exciting. I think that they're important tools but, again, I go back to your point that you really need to look at which population was tested to really make that decision of about how to sort of juggle these combinations and position them for your own individual patient. Of course, none of these are FDA approved at this time in the United States, so I suppose we'll have to wait for that to occur before people have to start to think about this; but likely in the near future. Updated: August 25, 2015 Page 19 of 25

20 Agreed. And I think we're actually running out of time, but maybe we can talk about what most of us think is one the most exciting drugs coming our way which is daratumumab. Do you want to go a little bit through the study presented by Dr. Lonial at ASCO? [Slide 31] Sure. So, the study that Dr. Lonial presented was a Phase II trial of daratumumab in patients who have had at least three or more prior lines of therapy or are considered double refractory to both lenalidomide and bortezomib. And this was a multi-institutional study. It was a registration study. It was designed in two Phases where the first Phase the study team was examining the efficacy of the 8 milligram per kilogram dose compared with the 16 milligram per kilogram dose. They found that the 16 milligram per kilogram dose was better and then had an additional 90 patients go on the 16 milligram per kilogram dosing. And in terms of overall responses, I believe the study quoted a response rate of around 29% and this is in patients who have had a median of five prior lines of therapy. And in terms of distribution of patients in the US and the European centers, it was kind of equal. It was 50/50, if I remember correctly. What was important in my mind was just as we observe with elotuzumab, there were some infusionrelated reactions in about 40 odd percent of the patients the first time that they were receiving the daratumumab. They were only grade 1, grade 2. They were managed with the standard of care measures and then those infusion-related reactions did not recur with subsequent infusions. One of the things that he also highlighted in his presentation was the fact that the first infusion takes about six-and-a-half hours, but subsequent infusions can be dialed down to about three or three-anda-half hours. So, that was important. I thought that this is our first monoclonal antibody drug class, the anti-cd38, which is showing singleagent activity in myeloma so it's really exciting. I agree. I think I would just make some comments about sort of the infusional toxicity. I think most of our community colleagues are used to giving things like rituximab for patients with lymphoma and some of the antibodies for the solid tumors. So, I think the whole idea of sort of a slow infusional infusion in the first cycle is sort of a well-known process. So, hopefully, that will not sort of attenuate the importance of this therapy, because, I think it should be able to be given safely in the clinic just with some safety issues. I think as we get more comfortable with it, it will be less of an issue. Updated: August 25, 2015 Page 20 of 25

21 What I was also very intrigued by was the patient population that we're looking at. This is a very refractory population all basically refractory to their last prior therapy being exposed to proteasome inhibitors and IMiDs (immunomodulatory drugs). We're used to thinking of patients who are double refractory to bortezomib-lenalidomide, which in this case was 95%. But they had a very large percentage of patients that were what we call quadruple refractory which is refractory to all the FDA approved PIs (proteasome inhibitors) and IMiDs bortezomib-lenalidomide-carfilzomibpomalidomide. So, a very refractory population and still very impressive responses. So, I think this is a therapy that is definitely going to change significantly how we practice. I think it will be intriguing to see where it would be positioned if and when it gets FDA approved. So, that would actually be the last point of discussion, would be if this were FDA approved, where do you see it in terms of its usage at this time? I think it will probably be approved in that particular setting, three or more prior lines of therapy or double refractory, exactly how the trial was designed. I, honestly, would really like this drug to be utilized in early lines of therapy only because it's so well tolerated and it will probably end up improving the efficacy of any available platform. That's how the drug is now being developed. It's being combined with available platforms for upfront or first line of therapy, as well as first-line relapsed setting. But that's the space that I would probably see it used. It will probably be utilized in two to three prior lines of therapy setting first. It does have good single-agent activity. Based on some of the Phase I/II data that may be available in the next year and a half, at least in the US market, there's a potential for it being utilized with other novel agents as well. I completely agree. I mean, I think we've always been looking for the rituximab of myeloma and I think this is probably as close as we get and potentially even much more active as a single agent than rituximab in the lymphoma setting. So, I think it's quite intriguing. And I agree, I think with time, hopefully, it will be something that can be utilized as an adjunct therapy kind of looking again, going back to augmenting therapy in the patient that can tolerate more aggressive combinations to really try and get to that holy grail of cure in our patients. I think we've covered a lot of material in several different spaces. Obviously, we haven't covered everything, but I think we have highlighted the most important findings from ASCO and EHA and try to bring it into the clinical context and that will probably be helpful to our clinical colleagues. Updated: August 25, 2015 Page 21 of 25