Learn about all myeloma happenings on the new Myeloma Crowd site: the first comprehensive site for myeloma patients and caregivers. Dr. Paul Richardson, MD Jerome Lipper Center for Multiple Myeloma Dana-Farber Cancer Institute Interview Date: May 16, 2014

 Dr. Paul Richardson, a key leader of significant national and international myeloma clinical trials, shares three platforms for today's therapies: targeting the tumor environment, leveraging the immune system, and targeting how and when myeloma mutates. The latest in immunotherapies includes fast-tracking new monoclonal antibodies like elotuzumab (targeting protien CS1/SLAMF7) and daratumumab and SAR (targeting protein CD38), re-activating normal T cell functions by affecting the PD-1 pathway, and using vaccines to impact the immune system. He describes a new clinical trial that is studying multiple questions at the same time: the DETERMINATION study (see link) will have 1300 patients (700 in France and over 600 in the US) to determine when transplant is best used in newly diagnosed myeloma patients now that newer therapies are available. The study will also look at how the Revlimid/Velcade/Dex combo works as initial treatment and how lenalidomide affects progression as maintenance therapy. He gives a preview of his upcoming discussion at ASCO on panobinostat; that its use with dex and bortezomib is better than dex and bortezomib alone. He describes a mind-body peace study at Dana-Farber that shows how stress activates cell signaling pathways and the proof that using relaxation techniques can make a difference in myeloma growth because of the NF-kappaB pathway. He recommends that patients should consider continuous maintenance therapy until progression and cites studies showing the importance. He also suggests that any time patients have a bone marrow biopsy, they should request cytogenetics and FISH tests at the same time to keep an overarching picture of their personal disease biology in place. The live mPatient Myeloma Radio podcast with Dr. Paul Richardson

Jenny: Welcome to today's episode of mPatient Myeloma Radio, a show that connects patients with myeloma researchers. This is our 31st show to help you understand more about the latest in research so you can make educated treatment decisions and learn about the importance of participating in clinical trials. If we were able to double the rate of clinical trial participation from 5% to even 10%, the talented researchers we are interviewing can make faster progress in finding a cure. In our last interview we learned that 80% of myeloma patients in Europe that are eligible for transplant joined clinical trials and in childhood cancers 85% of patients participate. So it's highly possible, we could make 50% or 80% participation rate a reality if we made that choice. I think the question for us as patients is, how long do we want to wait to find a cure? If you'd like to receive a weekly email about past and upcoming interviews, you can subscribe to our mPatient Minute newsletter on the homepage or follow us there on Facebook or Twitter. We have a new site called myelomacrowd.org that is the first comprehensive site for myeloma, and if want to find out where to go for a credible myeloma news or find out who to follow on social media, it is one of the items we feature there. We've done the searching for you. You can check out the "All Myeloma" news page. We also have a growing online myeloma specialist directory, current articles on relevant topics and much more. We are very privileged today to have with us Dr. Paul Richardson of the Dana-Farber Cancer Institute especially because he's presenting at the ASCO conference later this month, and he is intensely busy, so thank you Dr. Richardson for joining us today and taking time out of your very hectic schedule.

Dr. Richardson: Jenny, it's really my pleasure and thank you. It's my privilege to join you and I'm very grateful for the invitation. Thank you all.

Jenny: Well, let me introduce you, if you don't mind. Dr. Paul Richardson received his medical degree from the Medical College of St. Bartholomew's Hospital in London and the Royal Marsden. He completed fellowships in hematology/oncology at Tufts University, Baystate, and Harvard and Dana-Farber before coming on staff at Dana-Farber in 1994. He is currently the Clinical Director of the Myeloma Center of Dana-Farber since 2000 and is the newly appointed Clinical Program Leader. He is also the RJ Corman Professor of Medicine at the Harvard Medical School. Dr. Richardson holds leadership positions in many professional organizations and is on the Editorial Board of the Journal of Clinical Oncology, Journal of Oncology, The Oncologist, Clinical Cancer Research, and British Journal of Hematology. He is the prior Chairman of the MMRC and serves on the Steering Committees and he now chairs the newly formed Multiple Myeloma Committee for the Alliance for Clinical Trials in Oncology, which used to be called CALGB. His honors include many awards from Massachusetts General Hospital, Brigham and Women's Hospital, and Dana-Farber Partners in Excellence Awards; The Brigham and Woman's Hospital Teaching Scholar Award; The Tisch Outstanding Achievement Award for Clinical Research; and the Dana-Farber Cancer Institute's George Canellos Award for Excellence in Clinical Research and Patient Care. He also was awarded primarily for myeloma work, an honorary Fellowship of the Royal College of Physicians in 2009, and he was more recently the recipient of a Warren Alpert Prize in 2012. Dr. Richardson has published more than 260 original, as author or co-author, articles and more than 180 reviews, chapters, and editorials in learning peer-reviewed journals such as the New England Journal of Medicine, Blood, the Journal of Clinical Oncology, Leukemia and many more. He is a key contributor in constructing and implementing clinical trials both early and later stage. His primary research interest is in new therapies, and he was a leader in the clinical development of bortezomib, lenalidomide and pomalidomide. Besides these esteemed accomplishments, and when I posted that we were going to do this interview, the comments I received from patients was that he is a living angel. That speaks volumes from the patients themselves. Dr. Richardson, thank you for making time for us.

Dr. Richardson: That's incredibly kind and thank you very much. That's a very, very nice introduction. I would just emphasize that that is all the pure product of a fantastic team, and we are very fortunate at Dana-Farber to have an extraordinary group of myeloma researchers and clinicians. I just want to especially acknowledge my team at Dana-Farber, in particular my nursing team, as well as obviously my great colleagues at the MD level and across the board. None of what you so kindly described would have been possible without a wonderful group that I'm privileged to work with. Most importantly, you've nailed it so beautiful Jenny, it's the partnership with patients that is so important, and it has become I think one of the hallmarks of success and progress in myeloma, is that literally we're working in partnership to beat this dreadful disease. It has been really one of the most rewarding aspects of the last decade and it's a very real reason why we've made so much progress but thank you for your very kind words. Again, it's truly my privilege and I sort of view my patients very much as my friends, and it's a really lovely battle to fight in many ways , if you think of it in those terms, but it's never easy I'm afraid, that's the real challenge. But nonetheless, thank you for that very, very kind introduction.

Jenny: Well, we are very impressed with what you're doing and the work that's being done at Dana-Farber, it's very impressive. We have a lot to talk about with your clinical trials specifically. But I want to back up a little bit, and when we first started this series we did a show on the benefits of joining clinical trials. So maybe you could repeat for us because I think we need to hear the lesson again because you're a major contributor in creating and constructing these clinical trials. Can you begin by reminding us why patients should join clinical trials and what the importance is for you?

Dr. Richardson: Yes. I think for us as a whole, the importance of a clinical trial is creating a win-win situation where we bring to the bedside the best treatment we possibly can, recognizing that in research there is always an element of uncertainty, but having said that, increasingly with the information coming from our laboratories, which is so much better informed and so much more precise, we're no longer having to work with new drugs that are shots in the dark for want of a better term. They are much more targeted, they are much more rational, and they are much more biologically derived. Based upon that, the likelihood of benefit from new drug development is increasing. Unfortunately, it's never 100%. There's always the risk of side effects. There's always the risks of the drug not working. But I think the very good news is that we're seeing an increasing high number of shots on goal predicated on the information we're provided by the laboratory. What is, I think, also terribly important is understanding that in clinical research itself, you can have a very promising agent in the lab but if the clinical research isn't done correctly, again, that's not going to lead to a drug being shown to be effective and/or approved. So the whole chain and journey that this process involves is complex and long. But the good news is it's getting, I think, more and more effective because of the better agents that we have. Now, patient partnership in this is absolutely essential, and what I think is so good is that I view clinical trials when done properly with the very best standard of care, because patients are very carefully monitored, there's a real teamwork around treatment and this is where, to be frank, our nursing teams are so vital. They provide a fundamental platform of expertise, and as the clinician researchers, all we do is myeloma so that gives us a particular expertise because we simply only look after myeloma patients, and then I hope brings to the patient the benefit of working with people who really know this disease because it is so complex and challenging. So hopefully by patients giving us the privilege of participating in our trials, we can reciprocate by offering not only cutting-edge new agents but also the highest possible standard of care, recognizing that our work gets increasingly busy. I think everyone who is being treated for any kind of condition and especially in the setting of malignancies are recognizing that it's always very challenging and complicated. But the good news is that with clinical trials, and in particular in the context of well-organized clinical trials, outcomes hopefully will be better for everybody, most importantly the patient but also for the field. And then I think the sort of closing comment would be, I'm so impressed that my patients, a very strong part of their motivation is actually helping people in the future, and I think that to me is quite inspirational and it always amazes me that that is almost always the primary motivation behind a patient participating in a trial is to try and help people in the future so that this currently incurable disease can actually become curable in the long-term, recognizing that that's a goal that I still think is way off but I think it's getting closer. I especially will acknowledge patients who have the courage to do this because if we hadn't had patients doing this a decade ago Jenny, we wouldn't have bortezomib, we wouldn't have lenalidomide, pomalidomide, carfilzomib. We wouldn't have these drugs without the courage and commitment of our patients and families.

Jenny: And when you look at patients, because you're constructing clinical trials that are both at the early-stage trying out brand new drugs, and these large-scale hundreds of patients late-stage clinical trials, when do you suggest that patients think about joining a clinical trial as part of their treatment path?

Dr. Richardson: Well, I think the sooner the better. I think that what we've realized over the years is the reality is that the clinical benefits of myeloma therapy are best appreciated relatively early. In other words, by participating from diagnosis onwards, you can actually -- if you get best outcomes early, that translates into the longest survivals in the long-term, and then also especially if one can participate in trials where your side effects and so forth are very carefully monitored and managed, then the continuum of benefit is that much greater because not only are you getting the benefit of state-of-the-art therapies early, but also hopefully, you're getting the minimization of side effects and that in turn results in a better outcome. Having said that, we have clinical trials both at diagnosis, Jenny, during and around transplants, in maintenance, then at first relapse and then for the very vulnerable patients who remain exquisitely susceptible to all sorts of challenges are those who have relapsed and refractory disease, and that's an area on our own group where we're very busy as well because that remains a very challenging area and that's very important for us to have good clinical trials of patients in that setting. I think in the old days when we didn't have such good drugs, there was always a thinking that clinical trials should be used in the 9^th innings, to use the baseball analogy. I think that's a mistake. I think what that does is if the treatment fails the patient then unfortunately they've lost ground, and lost precious time, and the same time it's very challenging for that new agent to help someone who is in real, real, real trouble. So what we tend to recommend is earlier participation because not only our patients more likely to benefit from the newer agents but they are also for the development of those newer agents. You're more likely to see a real signal whether it would be favorable or negative versus what happens unfortunately in the 9^th innings where the disease is so rampant and so difficult. It's very difficult to tease out what's due to the new agent and what's due to the aggressiveness of the myeloma. So earlier participation I think is key but the good news is by participating early in a trial doesn't mean you can't then participate in subsequent studies at later dates. In our own program what we try to do is have a continuum of studies that patients can participate in.

Jenny: And kind of a comment about that because I know the disease does get more wiley, so I like that approach to be able to participate in clinical trials earlier on, and it speaks to the need for patients to become well-educated very quickly in their disease, and that's a real challenge for patients particularly when you have local practitioners not aware of clinical trials, not referring, and what's happening in Europe when we talked to Dr. Sonneveld is that they refer. And so, we have a unique challenge here -- how do you get patients as educated as quickly as possible so they can make possibly a clinical trial their first choice for their care? Do you have any thoughts on how to make that easier or what could be done to change that?

Dr. Richardson: Well, I think there are enormous efforts ongoing. I think what's been really exciting in the myeloma world, and one of the cornerstones of the success of myeloma research in the last decade because it's worth sharing for patients on the call, that in the last ten years there have been actually eight FDA approvals for either new drugs or new approaches with current novel drugs and their use for example. The subcutaneous administration of bortezomib to minimize neurotoxicity, combination approaches and so forth. That's unprecedented. In the previous 30 years, there was nothing. I mean apart from stem cell transplant which is a very important platform for benefit but is not curative, there was really no progress that was meaningful. And so to see eight new approvals as a barometer of a progress is remarkable. So clinical trial participation I think has substantially improved in the US and I think there are a number of reasons. Number one, of course, the availability of exciting new agents that are more likely to help and really the revolution that novel therapies have brought, and of course very, very importantly, the advocacy of the patient organizations. I especially want to acknowledge MMRF, MMRC and of course the IMF. All these organizations have been remarkably supportive and I think they've been vital to improving awareness on the one hand and at the same time encouraging participation. I think that's been a real strength in the myeloma community. I think the other part of it, of course, has been the partnership of the investigators. Before I really became deeply involved in myeloma which was around 1999, I previously worked in anhydrous pharmacology and in the area of experimental therapeutics in different disease entities, and frankly there was a lot more division in the academic communities of those various tumor types and there wasn't the same collegiality and cohesion amongst the researchers. I think what's been very impressive to me from the very moment I arrived in the myeloma sphere, having -- I'm dating myself now but when I first treated my first myeloma patients all the way back in 1986. But when I started working with Ken in 1999 really seriously as his clinical partner, that basically was the starting of all these changes, and I actually want to especially acknowledge my mentor, Ken Anderson, who has been really on the forefront particularly in the laboratory setting at these advances as well as others. But what I was so impressed by was the partnership that existed amongst myeloma investigators and that continues. I think that's why it's particularly important to enrich for that because that's key to success. Hence, we have a very international network of investigators in the field. In that context, in the US, we're learning from our European and x-US partners who have very big trials networks, and as you alluded to Jenny, in other countries participation in clinical trials is much higher. Well, one of the reasons for that and I think this is an important point is access to the newer drugs. The only way patients outside of the US could get access to newer drugs is through the clinical trials. I honestly am much happier in the US model having come from the British model, which is more of a centralized system, where basically in the US patients have choices and I think that's by far the better platform. The important challenge for us as US investigators is that we are organized in a way that we can enhance those choices through our collaborative incorporative groups. And that's why frankly it's my real privilege to be part of the Alliance, our newly formed Myeloma Community which is just a wonderful group of investigators. And in that context we've really sort of ramped up our activities in the Alliance, and at the same token it is also a great privilege to be part of the MMRC which is a similar organization geared towards delivering state-of-the-art treatments to patients. But I want to emphasize that it's a real team effort and it's multiple different groups. And of course, keeping us all organized so that people aren't sort of duplicating, work is vital too. But all of that is going forward and I think that what you'll hopefully see is to improve the discussion in clinical trials as years go by because I think that's the key to success. But the final comment I would make is that our pharma partners are absolutely vital, and that's another reason why the field has been very successful in the last decade, is we've been really so fortunate with extraordinary pharma partnerships that have really accelerated this process and the commitment to this group. This is an enormously resource intensive processes, and extraordinarily large amounts of resources have to be committed to make this work, and they've done that and continue to do it. So I think we're very, very fortunate that we have this kind of synergy of pharma, academia, FDA, patient advocacy and all of that comes together to make this all possible.

Jenny: Well, it's been really impressive, what the groups have been able to do and help initiate and spur and support has shown a great deal of willing collaboration, so I totally agree with that. Well, let's go to your approaches. So with all these new approaches, because there are so many, you may have a short list that you're working with that looked the most promising. So what would you like to begin with?

Dr. Richardson: It's probably worth just walking through kind of a schematic where we are with the new agents in myeloma. I think the important construct is that in the last decade there's been a recognition of several important platforms. One is that the tumor microenvironment in myeloma really matters, that the neighborhood within which the tumor lives is as vital a target as the tumor itself. The second sort of big paradigm has been the recognition that there is a profound immune paresis. Well, what that means is the immune system in the patient is profoundly suppressed when patients have myeloma even very early myeloma. It explains why coughs and colds and sniffles are such a common issue with our patients, and actually more seriously pneumonias and so on, and life-threatening infections are unfortunately a real concern in the disease. The biological implications of this are that the immune system in any patient with myeloma is profoundly compromised, so the whole new frontier of broadly what's called immunotherapies is becoming very, very important. So when we think of plasma cell biology, we think about the immunomodulatory drugs, the IMiDs, thalidomide, lenalidomide, pomalidomide. When we think about plasma cell biology we think about proteasome inhibition, really a breakthrough. The first in class bortezomib, then of course the very exciting data around carfilzomib, and now the oral classes of drugs ranging from obviously, ixazomib which is really showing promise. An earlier development and very potent with some side effect challenges that we're trying to work out, oprozomib. This is the oral equivalent of carfilzomib but again, very active. There are a number of other oral compounds, and then finally there's a third-generation proteasome inhibitor called marizomib that is a completely different class that seems to be the most potent of them all and that's in development right now. So there's proteasome inhibitors, there's IMiDs, all of them marching forward targeting plasma cell biology. The next question is then what do we have that's targeting mutational aspects of the disease? In other words, the genetic that leads to this incredible heterogeneity within patients and between patients, and there's some real excitement. There's the so-called histone deacetylase inhibitors, which unfortunately ran into some bumps in the road in the context of their development a few years ago with some side effect profiles that limited their use. But most excitingly there were some very good new deacetylase inhibitors that seem relatively devoid -- well, not devoid but have fewer side effects, far fewer side effects and this range from -- actually a very interesting new drug called rocilinostat which just targets HDAC 6, and then very exciting new data that we'll be presenting at ASCO around panobinostat which is a very potent histone deacetylase inhibitor that we'll be talking about in a couple of weeks. So those are some examples. I want to stress though what is being probably the most powerful new changer in the last couple of years has been the emergence of the antibodies as part of the construct of immunotherapy and that's what we see a very exciting area. So if you don't mind, Jenny, how would you like to break this up? But we could start with each of these and walk through them. How would you like to do that?

Jenny: Well, that's a great outline. Let's start with what you mentioned last. Let's start with antibodies or the immunotherapy approach with monoclonal antibodies, and then other areas like the vaccines because I think patients are very excited about those and then we'll work our way backwards.

Dr. Richardson: Perfect. Thank you. Well, I think basically the first thing in terms of monoclonal antibodies is that in lymphoma, our colleagues in lymphoma and patients who have lymphoma have been able to access effective antibodies for some time. In myeloma that journey has taken a lot longer but in the last couple of years we've drilled down to a number of classes of antibody that really do seem to show promise. Now, one of the leaders is a molecule called elotuzumab which targets a marker on the myeloma cell originally called CS1 but now called SLAMF7. And the important point is that this marker seems to be fairly unique to myeloma, although it is expressed on some other tissues but to a much less significant degree. Elotuzumab on its own didn't seem to do too much in advanced myeloma. It was relatively safe but best generated stable disease in the clinical trials that we did it. However, when you combine elotuzumab with drugs like lenalidomide, it's almost like you generate a super charger effect where basically the two drugs synergize and not only seem to modulate aspects of the immune system but also seem to have a direct, what we call apoptotic effect on cell signaling. So it's not just immunologically, it's immunological effects plus others that drive it. So the combination of elotuzumab with lenalidomide, the combination of elotuzumab even with bortezomib, all of these approaches have shown great promise, and in particular elotuzumab plus lenalidomide I think is going to go forward as an approval finding platform, hopefully, in a not too distant future, within the next year or so. So elotuzumab has been a big one. The next real big one -

Jenny: Elotuzumab is being used in a trial I know as a newly diagnosed approach, correct?

Dr. Richardson: Right. It's being done first in newly diagnosed disease and in relapsed disease because in the approval process, Jenny, you have to go through approval first and typically in the relapsed/refractory setting and then it jump starts the approval process into the frontline setting. So that being the case, elotuzumab plus lenalidomide has been compared in relapsed patients and that trial is finished accruing, and we're eagerly awaiting results which hopefully we'll have in the next year or so and that probably will provide the platform for FDA approval for elotuzumab. But it's one class of antibody with one target, the SLAMF7 as it's now called and used to be called CS1. It is going now upfront as well into newly diagnosed patients, and a very exciting study we've recently completed at Dana-Farber looked at elotuzumab in what we call smoldering myeloma, which is a whole exciting new area where the basic principle is a stitch in time will save nine. In other words, if you go in very early in this disease and try and shut it down, you can really help the patient in the long-term. Some really great data from the Spanish group led by Marivi Mateos, she showed that if you give lenalidomide upfront in smoldering disease particularly if it's high risk as they defined it in Spain, that resulted in survival benefits. So this was a landmark experience because it provided us with the evidence that going into smoldering disease really can confer benefit. I have to say in Marivi's trial, how she characterized the patients is very thoughtful. In the US setting, we would probably consider those patients, active patients to be fair. But having said that, it provided the platform for us to really start to explore smoldering myeloma more proactively and there are a number of important efforts underway. Now, elotuzumab is a very well-tolerated drug in this setting, and just as a single agent we've been very excited to see how it has performed. So the next step is to how we can combine it with drugs like lenalidomide and take it forward. So that's kind of where elo sits right now.

Jenny: And does it have any side effects? I'm wondering about these monoclonal antibodies because I know it's nothing like a melphalan or even a bortezomib. But can you share what you’ve found with side effects, if any?

Dr. Richardson: Yes. Well, obviously any drug that works unfortunately has side effects. I think the important point is they are manageable, just the same way as the side effects of bortezomib were challenging but done properly it's manageable, very much the same case with elotuzumab, with managing the infusions patients do report that they can sometimes get hot flashes, sometimes they can experience, in fact before we optimized the premeds that we used with elotuzumab, there were significant infusional reactions. But the good news is, now with the proper premedication strategies, we've been able to get the drug much better tolerated. I think what struck me about elotuzumab is its very favorable tolerability as a long-term therapy. It isn't associated with significant GI side effects. It's not associated with neuropathy. It certainly doesn't appear to be associated with any cardiac signal. There are various aspects to it but the point to its long-term tolerability being favorable. I think the critical thing is though, that as any drug that's not approved, the data remains early-ish and so constantly one always has to be careful about being too sort of board-brush about side effects. One always has to be on the lookout, but having said that, my impression of elotuzumab is it's a very well-tolerated drug.

Jenny: Okay. I'm just curious because as we think about maybe using some of these immunotherapy approaches either in smoldering myeloma, I know the doctors are trying to weigh the balance of what's toxic and what can be given early and for a long period of time, and then not impact things later but shut it down at earlier stage. So I know that's all weighed in the balance. So I was curious about that.

Dr. Richardson: Yes. I think that elo for example in that context would be a very attractive drug relatively early in the game. I think that because it goes with a side effect profile and they don't appear to be late side effects that we're aware of. But I think that all our patients know this is a very long haul. So the ability to use drugs throughout the course of a patient's natural history is really important and I think a drug like elo has the promise of that because it doesn't seem to have -- and it also appeared to be a very good dance partner with other drugs. They don't appear to be overlapping toxicities that make it more difficult to give. So I think in aggregate, Jenny, we're very pleased with the promise of elo. It looks exciting particularly as it will be a good drug to partner with other agents.

Jenny: Now, do you want to share what you were going to say before I interrupted you?

Dr. Richardson: No, not all. No, absolutely not. I welcome you breaking it up, please do. You tell me when you need me to take a pause. The bottom line with the next group of antibodies is that they actually -- and I think it's important to sort of characterize this for patients. As we think of classes of drugs, we have to recognize that some are very different than their counterparts in the same bracket. So for example, IMiDs are remarkably similar; Revlimid, thalidomide, lenalidomide but they have very key differences in terms of their properties. In the proteasome inhibitor class they are distinctly different because they're just different compounds. The boronate peptides are reversible inhibitors, the epoxy ketones which carfilzomib is one is a very potent, powerful but irreversible, and the beta-lactone has a completely different molecular structure, and it too, is irreversible and very potent. In the antibodies the same kind of rule applies in the sense that elotuzumab targets the SLAMF7 or CS1 as it used to be called, and daratumumab and this new compound from Sanofi which I'll just call SAR for short, they hit CD38. So that a distinct antibody would hit distinct targets because sometimes people say, "Oh, well just think of an antibody, it's all one thing." It really isn't. They have very different targets. So it's important to think of daratumumab as a separate antibody targeting a very distinct target and the same for the SAR compound which is also targeting CD38. And interestingly, dara and SAR do have quality differences between them at least preclinically. We fairly don't know what to expect quite yet clinically. But the good news is that both antibodies are showing that the target would this particular technology or this particular monoclonal platform because CD38 has been targeted years ago by different antibodies and they didn't work. This current group of new antibodies targeting CD38 are phenomenally active and what we're seeing is that both with SAR and with daratumumab there is single agent activity which is a step up from what we saw with elotuzumab, and there's a lot of reasons for this we think. Number one, CD38 is such an important target in myeloma. The other thing is that CD38 is a very important receptor in growth of tissues generally speaking. It's a very interesting concept but when you're an infant or young, there's a lot of CD38 expression on a lot of different tissues. As you get older, CD38 expression goes broadly down, so hopefully at our age Jenny, there is very little CD38 going on. Unfortunately, when you get myeloma that changes and CD38 is expressed by the myeloma, and then the hypothesis is there's a lot of CD38 expression in the neighborhood as well that may be part of the reason why this is such an attractive target. Because as you may have noticed drugs that really work well in myeloma are those that hit both the neighborhood and the tumor. So for example, proteasomes do that, IMiDs do that, and dara and SAR hit both. And that I think is a real -- or perhaps hit both. We don't really completely know that but that's a good working hypothesis. So when you've got antibodies that do this and really shoot both sides of the coin, if you will, then I think there's a real promise to these especially if you can then combine them. So just focusing on daratumumab first, that antibody is now really moving forward in Phase III studies now actually as I speak, having completed very quick Phase I and II development, recognizing that the early Phase I of development to the antibody was necessarily very slow because this is a first-in-man experience. So based upon that, we are now accelerating very quickly and we have combinations of dara with lenalidomide, combinations of dara coming forward now with bortezomib, and basically there will be combinations of dara with lenalidomide and bortezomib, the so-called RVD plus dara, and these will be very powerful platforms for future treatment. The initial results from lenalidomide plus dara in our own center, these studies are being led by my colleague, Jacob Laubach and Jacob is phenomenal in doing a wonderful job with all of these. Basically what he's showing is that when you put daratumumab with lenalidomide, there's tremendous activity being seen. Hence, similarly daratumumab even as a single-agent, just like our partners in the same trial who are actually from Denmark and Holland are showing exactly the same thing, as part of the same study, we're all working as one team. But what we're showing is that dara really works on its own, and dara combined with lenalidomide is very powerful as well. And then larger trials are currently ongoing led by our partners here in the US, Janssen who are leading these and moving these across the country so that this drug can get as quickly as possible to approval. One very exciting thing about dara is that the FDA drawn to the breakthrough status because it's uniquely targeting a mechanism in myeloma that no other drug until dara came was. So it was given what's called breakthrough status. SAR, the Sanofi compound is hot on its heels and it too is showing really encouraging activity and this is being led by our colleagues at USCF and at Mayo; Dr. Tom Martin at UCSF and Dr. Joe Mikhael at Mayo have led trials with SAR alone and shown what we saw with dara, single-agent activity about half the patients responding. Then when you combine it with these other drugs you're seeing real synergy. So Tom and Joe's next step is to combine it with other drugs and go forward, and actually we're also going to be helping with pomalidomide in that same context, combining it with SAR and trying that move that forward as well.

Jenny: I have a question about that. When you're running a study like this that's exciting and it has single-agent activity, which is really unusual or very exciting, and you say half of the patients will respond. Do you ever go back and look at the genetic profiles of the half it's working for to kind of help you narrow it down and say, "It might be better for this group of patients with t(4;14) or t(11;14)" or whatever?

Dr. Richardson: It's a great question Jenny, absolutely the case because in fact as your listeners are probably gathering, clinical trials are full of variances and uncertainties no matter how elegant the science. Therefore, a necessity to build both the collection of information about patients and most importantly, if possible, tumor tissue from their bone marrow to better understand who benefits and who doesn't becomes really key and that's been a central part of myeloma studies for the last decade actually. What we obviously know is that study of genetics can help us. These are signals of mutation within the tumor but also much more sophisticated tools of gene expression profiling are now emerging which are really helping us better understand who might benefit from what and why. And also, frankly, disease characteristics, good old-fashioned clinical characteristics at the bedside can really help us too. For example, you're seeing that with the monoclonal antibodies, the hypothesis is that these are mutationally agnostic drugs. In other words, if a patient has del(17p) and extramedullary disease and so forth, these antibodies in theory should not worry about that, it shouldn't be a problem. They should overdrive those mechanisms and what's really interesting is we're seeing that. We're seeing that in high-risk settings these antibodies are working just as we're seeing that pomalidomide for example does appear to be a very good choice for high-risk disease, and of course, was bortezomib in the early days recognized being very effective against various cytogenetic abnormalities. So this ability to look and understand risk and who benefits from what and why has been a central theme of what we're doing. It's a big challenge though, Jenny, because myeloma is incredibly heterogeneous disease, not just between patients but within a patient. And there's this whole entity of what we call clonal heterogeneity and clonal tiding that we're beginning to understand and it explains why in the clinic we face this sort of ebb and flow of the illness, and at the same time, we can see patients particularly with more advanced disease respond and then lose response. And then what we have kind of almost like mixed responses where there's some evidence of benefit but not complete and it points to the fact that this disease is not linear. This is not just one bad cell that multiplies. The metaphor I sometimes use for patients, which I hope is helpful, is it's almost like a tree, an oak tree, you know with branches, leaves and roots, and whilst it's one oak tree, it's an incredibly complex organism in itself. What our treatments are trying to do is get around and put a net around this oak tree and really take it off at the roots but at the same time get the branches, the leaves, the trunk and all the bits caught within the net, and that's a big challenge.

Jenny: And we talked to Dr. Lohr also from Dana-Farber about that and he explained why it was so complicated. It is so complicated and it sounds like when it progresses it becomes more complicated. So it would be much more exciting to have these drugs that like you're saying are mutationally agnostic and that were just broad and it would be much easier, it sounds like.

Dr. Richardson: Well, I think what you'll deal with Jenny, is that we'll get a sort of platform and on that note I think we'll have an IMiD, a proteasome inhibitor, steroids of course whilst they can be a bloody nuisance, they are a cornerstone of management. So IMiDs, proteasome inhibitor, steroid, antibody, and then the question will be what do you rationally add to that? Histone deacetylase inhibitors, other drugs, other small molecule inhibitors, and then of course, when you achieve minimal disease how do you then go after it? And that's where some of these vaccine strategies are being so interesting. Obviously, there's been a lot of buzz about the measles vaccine and used amazingly in one extraordinary lady -- thank goodness we've gotten such benefit from it. I think it's important to share with listeners that as I understand, a 49-year-old lady who has had a ten-year history of this disease, has had a remarkable response to the vaccination strategy that's lasted about six months and as any myeloma patient knows that great, but it's early. And the other patient who was treated with the same platform unfortunately didn't get the same benefit. She appeared to have a little bit of a response but not complete, and unfortunately, had disease progressed. So that's very similar to some of the signals we've seen with some of our early drugs. As many people might remember one of the first patient's treated with myeloma with bortezomib got a complete response in the Phase I trial. That was fantastic, sort of a light bulb went off and we said this is clinical evidence of the promise of the drug. But I think what we quickly realize is that this disease is such that one size does not fit all and we will need multiple approaches like this to win. So I think the vaccine strategy is very promising. The idea of a SAR vaccine built around immunomodulation is incredibly interesting. And then what's, I think, really additionally exciting is the whole world of what we call checkpoint inhibition which goes back to a point that I made earlier, which is that the immune system in our disease is fundamentally compromised. And what we've learned is that tumor cells switch off T cells through basically a checkpoint mechanism in which a number of things are in play, but two important pathways appear to be PD-1 as it's called and PD-L1 are just pathways through which T cells can be turned off. If you inhibit those pathways you can turn the T cells back on again. This is actually a wonderful work originally done by a colleague at Dana-Farber by the name of Gordon Freeman who's really a brilliant PhD Immunologist. Gordon showed this about ten years ago and since then there's been tremendous efforts across the solid tumor world to go after this with great success, the drug Yervoy for example being one very good example in melanoma. Now we have PD-1 inhibitors that we can bring to the myeloma clinic, and there are a number under study of my colleague, Dr. David Avigan is leading this charge in our group with vaccine strategies and PD-1 blockade in the context of transplant, that's his primary focus, where a transplant achieves a minimal disease state and then you go after it with these immunological strategies. Very interestingly, the questions arising, do you need the transplant to achieve that? And in fact is the transplant essential to reset your immunology to make this more likely to work or given the toxicity of high-dose melphalan, are there risks? Are there patients in whom going into that extent of ablation, of both marrow and disease, actually is the right way to go? Or can you get there to the same minimal disease state with an immune system that's less passive and reset it using these inhibitory strategies and vaccines? And that's a huge frontier that we're going to have to fully explore for the next five to ten years where we can understand what's the optimal treatment strategy for each individual patient in this setting.

Jenny: Well, that's excellent. Is there more that you'd like to talk about with the immunotherapy group?

Dr. Richardson: I think the immunotherapy point is really one that is one of great hope, I think, for patients, but to understand that it's most likely to work in a setting of minimal disease states, because at the end of the day for an immune system that's already not functioning on all cylinders against the huge bulk of disease is less likely to be effective than going after it when it's in a minimal disease state however that's achieved, be it through proteasome inhibitor, an IMiD, steroid, an antibody or all of the above plus the transplant and that's, I think, a critical construct for patients to understand in the context of immunotherapies.

Jenny: And is it something that could be used as preventative whether, let's say, you're in a state of remission or at a smoldering stage? I know it's being thought about in smoldering, but even in the state of being in remission. I know patients don't really care for the watch and wait kind of approach. They want to feel like they're being proactive.

Dr. Richardson: Well, I completely agree with you and I think that my patients know in my smoldering practice we've always tended to be proactive. We've looked at all sorts of various strategies. If anybody has a sniff of osteopenia, I've always been in favor of going after that with bisphosphonates. Interestingly bisphosphonates aren't just bone strengtheners. These patients may or may not know they do much more than that. They have anti-myeloma effects. They also have effects on certain components of immune system including T cells. So there's a sort of rationale to bisphosphonate use that perhaps goes beyond just simply bone strengthening but the fact of the matter is that early intervention in smoldering disease beyond simply watchful waiting is becoming a very important and active area of research. In our own program we have a fantastic vaccine strategy that's being developed in this area and this immunotherapeutic approach is here and have been developed by a number of colleagues and my colleague, Dr. Nikhil Munshi, has been exploring this. Also, we have as well that, the building on the platform of lenalidomide with the addition of elotuzumab. That's another program we're moving forward with, and my colleague Dr. Irene Ghobrial, will be hopefully taking that further as we go down the road. And in the same context actually, at a much different level, Jacob, my partner is a leading a mind-body study in partnership with the Mass General where we us simple mind-body techniques and relaxation, and sort of holistic approaches to try, and reduce inflammation and improve lifestyle strategies to reduce the risk of disease progression. I mean that may sound incredibly fanciful but it's actually not because what we've found is that with certain techniques and strategies you can reduce inflammatory signaling through this very interesting immunological access that does appear to have a strong endocrine and emotional base. And in collaboration with our colleague, Herb Benson, at the Mind Body Institute at Mass General, we're looking at this as a real strategy. So there are a number of really interesting avenues where people can be doing more than watchful waiting, if you see what I mean Jenny.

Jenny: I think it's terrific and I would love to learn more about that approach. Emotion does cause inflammation, so I could see a big connection with that. Well, that will be interesting to see.

Dr. Richardson: Yeah, it's actually quite interesting because what we did was, in a normal volunteer study, they used relaxation techniques and looked at the expression of inflammatory markers and what we found is that with specific relaxation techniques, downregulation of inflammatory markers could be achieved. And one very important clue emerged with an important switchboard that's relevant to the biology of myeloma and that's NF-kappaB. And what that was shown to do was be downregulated by using these mind-body strategies, and NF-kappaB is a very key switchboard to myeloma. So that in a nutshell is the hypothesis behind this ten-week program that we're doing. So there's range of approaches. I must say I think it's not going to be one. I think it's going to be all of them put together that will give us the best outcomes but that's how I would see it, yes.

Jenny: Well, that is great that you're thinking about other aspects that affect those markers because I've heard about NF-kappaB quite a few times as being a really important pathway.

Dr. Richardson: It is but I think the other point is that in managing this disease, a very holistic approach is relevant because we you recognize quality of life really matters and side effects are cumulative as well as potentially long-term. So this kind of multifaceted, multidisciplinary approach to disease management is really essential. And that sort of brings me to one thing I really did want to emphasize because it's such an important trial I think nationally, is a study we're doing where we're trying to best understand where the place of transplant is in younger patients who are eligible for it because in Europe it is very much a philosophy of kind of one-size-fits-all when it comes to this and that's primarily driven, I think, by resource issues as well as others. In the US we've been blessed with more choice. The question is: I'm quite sure that transplant to younger patients has a definitely role and helps a significant proportion of them. The question is does it, and if everybody, and when is it best deployed, particularly now that we've got these really exciting new ways of agents that are coming through that are generating such exciting results. And what we're learning is that transplant is truly a critical modality but it can be a double-edged sword and to the point of these issues of side effects. So the question then becomes, at what point do you best deploy it? When do you use it? I think what, at Dana-Farber, we've been working very hard on over the last four years or so is what we call the DETERMINATION Trial which is delayed versus early transplant and setting up lenalidomide, Revlimid maintenance with triple therapy, that's where the acronym comes from. The name DETERMINATION captures it quite well actually. It's a study we're doing in partnership with the Clinical Trials Network, the CTN, and with the Alliance and it's a national study. And it's again run in parallel with the French effort led by colleagues at the IFM. They've done a superb job. They enrolled their 700 plus patients already because the only way you can get RVD therapy in France is through that trial. In the US, obviously, patients have choices which I've said earlier is very, very important and I fully, 150% support that. The point about the DETERMINATION Trial in the US though is that we hope that it will provide just the sorts of choices patients need in the context of a randomized trial. And what that means is no straightjackets, no placebos, but patients are assigned to each treatment arm and if it's the right choice for them go to transplant for any disease-related reason, the trial is adaptive in that sense and we'll allow that if the patient, for example, is assigned to the later transplant and the disease moves in the wrong direction, they can automatically go to a transplant conversely if they're assigned to an early transplant and as a clue that, for example, a transplant may not be safe, they can similarly step back. But the construct is basically the same that you look at very effective initial treatments, RVD in this case combined with zoledronic acid, early stem cell collection, and then once arm receives transplant relatively early, the other, it's kept in reserve and then used later. Both arms essentially result in the same sandwiches of therapy, if you see what I mean and very, very importantly the actual maintenance in both arms of the trial is the same, and it's until progression. It's continuous lenalidomide until it runs out of benefit. This is terribly important because what we're hoping with this study is to best understand who gets most benefit from transplant early versus late, and very importantly understand how RVD as induction, consolidation, and then lenalidomide maintenance until progression benefits patients. Because in the European trial for regulatory reasons, the French are stopping at one year with lenalidomide maintenance and I think I personally have real caution about that because in the US we've shown that there is survival benefit continuing lenalidomide until progression. And so, in the US we felt very strongly for our patients that the trial had to be until progression. The FDA were fully supportive of that and that's what we're doing. This will provide us with a fantastic opportunity to do several things, most importantly understand the role of maintenance; two, where a transplant best belongs; three, to your point earlier Jenny, built into this trial on numerous scientific surrogates to help us understand from one patient to another really tailoring that treatment, who benefits from what and why. And I especially want to acknowledge my colleagues on the qualitative side, led again by my partner, Nikhil Munshi, who is leading this with Herve Avet-Loiseau in France. There's some very complex genetic look at this disease in this very large trial. So the trial itself will be about 660 patients in the US, about 700 in France. Right now we're almost at 300 patients in the US. We've activated half of our sites and another half to open, and we really hope to finish the trial by the end of next year early 2016, and this will be such an important platform for all that we just talked about because what it will do is not only provide a trials network to continue to do this kind of seminal work and provide access to patients across the county but also it will be the platform, as you can see, Jenny, we're adding these new immunotherapies, adding these new antibodies. All of that will start to flow because it will make sense from this platform study which helps define where we are kind of now and where we best need to be going. So the DETERMINATION trial is very important with Dana-Farber, and we've got a fantastic team working around it who've really worked tirelessly to get it to where we hope it will be and it's, I think, also hopefully going to be an example of how the US is rising to the challenge of participating in trials that help everyone, a sort of win-win for everybody, and at the same time can provide global guidance as to how we should treat the disease, which was previously something only the folks in Europe could do. We're hoping that now we can do that with this trial. And only the final point I would make is that it's 70 sites across the country, so hopefully accessible to many patients, but most importantly, and I'm particularly grateful to our pharma partners for this. It is, by the way, an investigator sponsored trial. It's not what we call a pharma sponsored trial, it's an investigator sponsored trial but we have a great partnership with our pharma partners. And our pharma partners are providing us with free drug for as long as it's needed, be it Revlimid or Velcade. These are provided without charge. Right now the current sort of craziness around the health care reform, this is incredibly helpful to patients, so just an important side. Jenny: Oh, that's very important and what's really impressive to me about this trial is that number one, it's flexible and it sounds like you're looking at it in a very fluid sort of way, an adaptive sort of way but also that you're testing multiple things, and that's what I was going to ask about because in Europe, I think, they're constrained and they can gather large numbers of patients. And so, I noticed that they tried to test for multiple outcomes at the same time while they have all those patients. And it sounds like, in this trial, you're trying to do the same thing.

Dr. Richardson: Exactly. The idea is that by combining best therapies with how to best integrate modalities, we then take very strong steps towards that, what we can then mix and add on. Because you can imagine the RVD platform, and what's being validated by carfilzomib and Revlimid as well has very, very high response rates and that provides us minimal residual disease platform that we're talking about. And then the question then becomes, do you need the transplant to derive that? Or in some patients, do you not? And then when you come in with these new antibodies and these new vaccines, can we spare people increasingly? The three to four-week hospitalization in high-dose melphalan, recognizing that that's an incredibly important approach. But having said that, there were some patients who know it's not only very tough but they can also have serious setbacks. And so as a result of that, are there patients we can spare that side effect profile? And I think what's also very exciting as well is that these kinds of trials are not just being pursued in younger patients. Right now in the Alliance we're in the midst of organizing and putting together a very important new platform built on lenalidomide and dexamethasone with one of the new really exciting antibodies, daratumumab. And for older patients who obviously can't tolerate transplants, they're too toxic for them, can we offer the same platform without the intensity of chemotherapy? The reason, in fact, we're looking at Rd plus dara in a way that we are is because of the success of the DETERMINATION trial, and the fact we've been able to do that has actually encouraged people to say, "Well, let's look at Rd and dara," and this is a work in progress and we've very much hoping it will come to fruition but it gives you an example of how we're approaching it.

Jenny: Well, it's also a great example of personalizing therapy or trying to segment people out, so I really appreciate your approach to it. Now, I know we're running out of time but I'm going to keep you over, if you don't mind.

Dr. Richardson: It's pleasure. Not a problem at all.

Jenny: If you don't mind talking about -- if there's anything else you want to talk about in immunotherapies, of course we can, but helping us understand kind of where the HDAC inhibitors are playing a role, or if there are other things you would like to talk about first, like the panobinostat that you're discussing in ASCO. I guess I will let you prioritize what you feel is the most important.

Dr. Richardson: Thank you, Jenny. I think obviously at ASCO there will be a number of very nice presentations of various different studies. And it's exciting that ASCO has become more myeloma-enriched than it did in years gone by for sure, which I think is great. A flip of that is that at this year's ASCO we'll be presenting our results of PANORAMA 1 which was a large international randomized Phase III trial where we sought to define the clinical benefit of adding panobinostat to bortezomib and dexamethasone in both relapsed and relapsed/refractory myeloma patients. The reason this was so compelling is that there had been some very important laboratory work led by my colleague in the laboratory, Teru Hideshima, had shown that when you put panobinostat and bortezomib into preclinical systems, there was evidence of synergy and that applies to other histone deacetylase inhibitors as well. The question was how we could translate this clinically? And then there was some very nice work in Phase I to safely combine bortezomib and panobinostat clinically and establish a schedule that could be tolerated. And then we did a study called PANORAMA II where we showed that in a multicenter trial of patients who are not just relapsed and refractory but were truly resistant to bortezomib, that a third of them would then respond and what was really interesting even though bortezomib would fail them and not just fail them previously but their disease had grown right through it, so-called refractory to bortezomib. And then what we also showed in that trial was that in the high-risk cytogenetics group, 43% of the patients responded which told us something about the way these HDACs work. Again, it gets back to this what we call Mutational Targeting. These drugs are epigenetic. They're not just working on the proteasome apparatus. They also work on the genetics of the myeloma. And so, what we do is kind of shut down some of the genes that are being turned on that can drive mutation. That's a really important property of these drugs. And so, consequently this trial Panorama 1 was very important because it hoped to build on the previous experience with the vantage program where vorinostat has been combined in the same platform. But unfortunately, for various reasons I think not least of which were the absence of steroid, some perhaps challenges with the dose and schedule of use. These are all pitfalls that we can all run into in clinical trial development, had really failed to show benefit. I mean it showed a minimal benefit in terms of progression-free survival; some response rate benefit but unfortunately not enough to really justify continuing. The really good news with the PANORAMA program is that we've been able to show not only a substantial response rate difference but also a substantial progression-free survival difference in favor of the three drugs versus the two. So panobinostat plus bortezomib plus dex, those three drugs are better than bortezomib, dex and placebo. This is all on the actual website. It's in the abstract so I'm not saying anything that isn't already out there. The important point is I will be obviously framing out those details when we present the talk at the meeting itself. But suffice to say within the limits of what -- because obviously there's the ASCO embargo, you can't talk specifically of your presentation until the day of it. The bottom line, that it's a meaningful clinical difference, it's not a trivial one and I think it therefore opens a real avenue, not only for panobinostat itself but also for frankly drugs that are successors of it potentially, who have fewer side effects potentially and at that same time may be as potent, or if not more potent. So that's a real opportunity.

Jenny: So a question about the HDAC inhibitors, you said they had a few bumps in the road. So at what point as an investigator, do you know "Hey, this is really where it's going after" or "We really need to move forward with this"?

Dr. Richardson: Jenny, that's a great question and I would say that that bumps in the road with vorinostat were driven mainly around side effects, that you couldn't keep people on the drug because the side effect profile was too challenging. And what we've learned with myeloma is that you need to continue treatment because if you can't continue treatment, the disease resurfaces again and can arguably sometimes be even tougher. So you need the ability to able to continue therapy. That was the challenge with vorinostat and I would also say that it happens in other trials too. We recently had a real disappointment with an Akt inhibitor called perifosine which had shown great promise in early phase development, but when we took it into Phase III and used it at a dose that we thought would be very well tolerated and it was actually, but we didn't see a big clinical benefit. And with the benefit of hindsight there were lots of reasons why the perifosine trial had to terminate early not least of which because of resources. There just weren't any resources available to continue the trial. But what we know and learned is that probably we weren't high enough in our dose, that perifosine probably should have been at a high dose. Now, we based on dose decision on minimizing side effects and maximizing tolerability, and because we'd seen an encouraging signal in Phase II even at these lower doses, but only when we went into Phase III could we really see that possibly we had done too low a dose. And in that context, if we'd had the resources to be able to adapt to that and then go into the next step, that might have been a different thing, but we didn't unfortunately, and so the program had to be closed. Having said that, the good news about perifosine and drugs like it is that there are other compounds in the same class that are coming forward. So it's very analogous to vorinostat and panobinostat. Vorinostat sort of pushed in the right direction but unfortunately didn't cross the goal line. Panobinostat has and now opens the door, and I think in the area of Akt inhibition, perifosine show great promise but didn't quite get across the goal line and other compounds like it are probably moving in a stronger direction. So it's such a good question you asked, because I think it's important to appreciate that you can have the best data in the lab but if the clinical trials are not done right, you can be truly led down the wrong path. But in fairness to anybody who knows about clinical trials, it's incredibly challenging because there are so many variables. And for example, doing good PK (pharmacokinetics). When patients come to the clinic and you do a good PK and they're saying, "Oh my goodness, I've got to wait here for six hours until the blood draw." It's a darn nuisance, but at the end of the day, you're really helping because if the PK isn't done right, we don't know if you're getting the levels of the drug you need. It's really sometimes as simple as that. So I think that your question raises a very good one. But the good news is that, certainly when it comes to myeloma at least, if you look at the number of Phase III trials that are being done that are successful versus the number that have failed, there have been some failed Phase III trials but fortunately they are not too many and they far outweighed by successful Phase III's. So in myeloma at least, we've been fortunate. Our track record has been better although I wouldn't for a minute suggest that we haven't got lots more to do.

Jenny: Well, that's part of the process. It's just part of that process to flush things out. It's just the nature of it. Now, I don't want to take all the time because we have a few caller questions. So let me go to that and then we can come back to a few emailed questions as well. So if you have a question for Dr. Richardson, please call 347-637-2631 and press 1 on your keypad.

Caller: Hi, Jenny. Hi, Dr. Richardson. What an outstanding opportunity to speak with you. Thank you for taking my call. I'm a smoldering multiple myeloma patient and we really a very betwixt and between group of patients. I have two questions for, if you please. I was very interested in hearing your thoughts about early treatment invention trials and some of the ones being developed by your group. Elo with Revlimid is one example you spoke to. I wanted to ask about the OncoPep peptide vaccine, PVX-410. I met your colleague, Dr. Munshi at a recent MMRF seminar and he indicated the next step would likely be to couple it with a few cycles of lenalidomide. In an earlier interview that Jenny did with Dr. Orlowski of MDA, he also stated a similar thought to couple an antiPD-1 with Rev. So I guess the hypothesis is now to try to knock back the clonal activity and then allow the immune system to keep things stable with the help of these MoAbs and a vaccine such as the PVX. Will your group participate in this PVX Rev vaccine?

Dr. Richardson: Oh, I'm so glad you asked it, and in the interest of time, I sort of skipped over that. We very much are and just to explain that because it's led by my colleague, Dr. Noopur Raje at Mass General. But obviously the science from it has come from the laboratory. So how we've had to work this is very hard, is that I'm on the clinical side and I am very deliberately firewalled off from the laboratory side of this particularly project because it's generating a vaccine that's actually part of a company called OncoPep. So I have to be very walled-off from it. You can understand why, for obvious reasons. I mean that's perfectly fine. What we've done is we've done that successfully. Like all these regulatory things, it takes an enormous amount of time and a lot of committees and so on, and we've worked our way through that. So the very good news is -- it's funny you just raised this, because I'm actually leading that trial at Dana-Farber now. We just had an initiation with it. And you're quite right. It is going to be this vaccine plus Revlimid just for short period of time to see how it works. And the important point is that it's just three cycles of Revlimid but it's not enough to compromise your ability to go on to another trial for a newly diagnosed myeloma because obviously what you don't want to do is burn a bridge now that you might not be able to then access a clinical trial in the future. But the really good news is you get three months of lenalidomide treatment plus this vaccine which I think is fascinating, and it's a very elegant work built out at Nikhil's lab with his colleague, Dr. Jordan Bai (?). And the bottom line is that you do have to however have a very specific HLA type, HLA-A2 which occurs in about 40% of folks, so not everybody unfortunately will be able to do this trial because the vaccine is specific to that particular marker. But to your broader point, the use of a drug like Revlimid or lenalidomide, as I prefer to call it, is basically just like it is with elo. It's a super charger. It gets everything going. It's an immunomodulator. We've learned about the IMiDs that they are revolutionary actually, as immune-modulating drugs. They truly do these fascinating things and particularly when you partner them with drugs like proteasome inhibitors, they synergize, and in the same way with the vaccines, immunomodulatory strategies help the vaccines work better. So the idea of bringing lenalidomide-like drug plus the vaccine into smoldering disease is truly attractive. So I'm delighted that you asked that question.

Caller: Thank you. Could this be a curative approach at the smoldering stage because the tumor burden is low or is it likely just to delay progression?

Dr. Richardson: That's a great question again. The more I work in myeloma and the more I have over the last 20 years or so, the more careful I am with that word because the disease is so clever and so deceptive. I personally think that the old metaphor, a stitch in time saves nine, does apply. I think the likelihood of intercepting this disease -- I guess the metaphor to use and be best of visualizing this is, is by the time the disease becomes an enormous oak tree with all the leaves and branches, et cetera, is a damn hard work to get it down. When it's sort of a baby oak that's -- I have nothing against oak trees by the way. It's probably the wrong analogy. They're lovely trees but anyway, that aside. But a small tree basically is an easier thing to deal with. I'm not much of a gardener. My wife just tells me what to do in the yard. But I know that sometimes taking down one of those small trees is a hell of a lot easier than trying to sort of de-root something and get it out of the ground when it's really established. Caller: Right. You don't need the big machinery for that.

Dr. Richardson: Yes, quite was and then needless to say, you know a day of work, it's a couple of hours. So anyway, the bottom line is that if you can intervene earlier and intercept with the disease earlier, the likelihood of clonal heterogeneity and a clonal tide emerging is that much less. You touch on such an important point because that's also a part of the rationale for optimizing therapies early, is that if you optimize therapies early not only do you shut the process down but at the same time you then give the patient the best platform for quality of life and not only longevity but at least compromise to functional status as possible.

Caller: So you could perhaps intercede before the disease becomes more complex, I see. Thank you.

Dr. Richardson: Absolutely.

Caller: How important is it, Dr. Richardson, for us to know our tumor biology at the smoldering stage? This is a confusing issue because we understand that it actually does change and become more complex as the disease progresses. So do we wait to have those tests or should we find out now? If we should find out now, how do we do that? Do we need to have FISH tests or do we need to do the next level of gene expression profiling? Is it important for smolders to know that?

Dr. Richardson: Yeah, I think broadly it's a great question because it applies across the disease. I think that any additional information is helpful but one has to be very careful how you use that information, and I think that I'm always reminded by an old saying that, "A fool with a new tool is still a fool." Until you know how you use a new tool be it gene expression profiling, until you know how to really make sense of these gene signatures. You can be led to make decisions that ten years from now we will realize were misplaced. So I think gathering the information is very important. I think synthesizing the information and putting it together in terms of a treatment strategy is highly individualized and I think that there are certain things that you need to look for. For example, I mean we've looked for in the old days; we used to look at some of the genetics of smolders and MGUS patients and realized that you could see some pretty awful genetics in the tumors themselves and the plasma cells themselves. But oddly enough that wasn't what predictive who would do badly, that actually there were other clinical features that were much more likely to tell you what direction the patient would go in, free light ratio being an obvious one for example as well as the amount of tumor in the bone marrow. So obviously there are other factors not just genetics at play. So I think what I do is trying to distill a whole constellation of features. In our own program we have a very aggressive approach led by Nikhil again in tissue banking where he banks tissue for gene expression profiling and so on. And we, and other groups, are looking at more commercially available gene expression profiles to at least be able to provide you the information. The question of what you do with that information is a very measured one and I think you have to be very careful. Again, I think that's a nice discussion to have with your doc. What makes sense here based upon what we know? That's how I would approach it. I think one message you raised though that's really important, that the testing of disease with marrow and the look at side of cytogenetics during the course of illness, throughout the natural history of the disease is vital because what your side of genetics look like now is not what they will look like down the road. They will change and that's why it's so important to remember when you do have a bone marrow, always remind your caregiver, "I'd like cytogenetics and a FISH please." Again, not because it necessarily would change your decision per se but it would certainly add to the tapestry of what you're looking at.

Caller: Very good. Thank you so much Dr. Richardson. It was a pleasure.

Dr. Richardson: My pleasure. Thank you. Jenny: We have another caller. Go ahead with your question.

Caller: Hello, I assume that's me. At what point, a person that has the whole oak tree, everything, qualifies for the vaccination treatment? I understand that that is more by company that produces it, but you say you will work in conjunction. Would you be able to tell me? And where is that treatment available? Only through your clinic or you guys communicate with other centers throughout the country?

Dr. Richardson: Thank you. The daratumumab studies are available broadly across the US. The challenge is when drugs are not approved, of course trials are at various difference stages. Some are open, some are opening, some are closing or have already closed to enrollment. So it's always a bit tricky sometimes getting the exact place and time to participate. But I would actually suggest talking to your own medical oncologist and then hematologist and finding out, nearest you, where a site usually one of the antibodies, be it daratumumab or the SAR compounds, Sanofi compound exist and exploring participation in their trial there. But the program is nationwide just to be clear.

Caller: If a patient is in what they call total remission, would you say a person should try to go into a treatment like that or just let it be for the time being?

Dr. Richardson: That's a great question. If you're in complete remission or in remission, unfortunately these drugs, obviously in a process of a clinical trial, disease has to be usually advancing because then you can, number one there's a need. Because always remember until a drug is approved or there's an uncertainty of risk and side effects. So you have to justify the risk of exposing the patient to the treatment. So if you're going to do that, disease has to be worsening. And so, if a disease is worsening, then treatment should follow as part of a clinical study. But if you're nicely in remission and stable, usually studies don't look at that particular population of folks unless there is a strategy like a vaccine which is specifically targeting patients in remission to see if they can continue their remission for that much longer. For example, my partner Dr. Avigan is doing that but he does that as part of a transplant. So what happens is you have a transplant then your disease achieves remission, and then the vaccines get given during the remission post-transplant. But to participate in that trial you have to be newly diagnosed and about to go into a transplant early, and for various reasons that's obviously a very select population.

Caller: Right. So obviously if a person is in remission, it means that still, the illness could be active or could be getting worse, what you just said?

Dr. Richardson: Right, it can be. So what we do and what we typically recommend in that situation though, and this is part of an important area that I'm glad you raised, is that there's this real importance of what we call continuous therapy which is why, for example, in the DETERMINATION trial we feel so strongly about the lenalidomide continuing until it runs out of benefit versus stopping it or stopping it a predefined end point. What we recognize is that this disease needs continuous treatment, and be it bisphosphonate plus lenalidomide, bisphosphonate plus bortezomib, or some form of treatment strategies like that. Some form of continuous therapy appears to really be important. And you may say, "Well, what's the evidence for that?" Well, probably the most compelling most recent evidence on that was the so-called first trial that was presented by Dr. Thierry Facon at ASH in December. Well, he showed that if you continue lenalidomide and dexamethasone continuously compared to the controls in this large -- I think it was about 1500-patient international trial, and patients who did not undergo transplant that there was actually not only a very big progression-free survival benefit in favor of the continuous therapy, there was also a survival benefit. So I think that when you see data like that it does strengthen the arguments for some form of continuous treatment as long you're tolerating it, being part of your treatment strategy.

Caller: Would you say two years is a reasonable time to be on that treatment, if apparently it is being tolerated?

Dr. Richardson: I think two years is fine. In our own group we recommend until progression actually because the evidence that we have from the ALLIANCE study led by my colleague, Dr. Phil McCarthy, actually continues to show survival benefit to continuous therapy, and with even the most recent updates, that survival benefit is getting stronger not less even though patients who are originally assigned to the placebo arm have been now quite rightly permitted to receive lenalidomide and that's what we call crossover. When that happens that usually dilutes the clinical benefit signal which is why sometimes regulators get jumpy around it, and I find that thinking ludicrous, if a patient is benefitting from treatment they should get it period, in my view. In any event, crossover was limited mistrial as it should have been, and guess what, even despite crossover that survival benefit is continuing to amplify. So telling us that stopping treatment and starting it again, unless there's a side effect is probably not a good idea. Some form of continuous therapy, if you can is probably a good idea.

Caller: So whatever then, for as long as possible, okay.

Dr. Richardson: I think for as long as possible is probably a better way rather than forever because the key thing is are you tolerating the drug? Because obviously medicines work if they're not giving you side effects, they're tricky. One of the interesting things I wanted to share with the listeners actually, Jenny, is that one of the side effects we find from lenalidomide continuous therapy is diarrhea. It's a big challenge. This irritable bowel that occurs with lenalidomide related use post-transplant, and we found really fantastic results with using a simple supplement called colestipol, which you take as a bile acid binder and in about two-thirds of patients we're seeing that it actually can really shutdown this irritable bowel, which we nicknamed Ready Belly for short, that can be such a nuisance for patients. It's not typically dangerous but it's very, very annoying with the tremendous urgency and what we call “hurry”, where a patient literally has to rush to the bathroom. And what we find is that if you use this colestipol with meals and you've talked to your doc about it obviously before doing it and get properly evaluated, but we found it an incredible benefit to about two-thirds of patients. So just a shout-out with everyone because it's not necessarily that well-known and it's one reason why some people do stop lenalidomide is because they get this irritable bowel and we found strategies like colestipol can really help.

Caller: Okay, thank you very much. I appreciate it.

Dr. Richardson: My pleasure.

Jenny: Thank you so much. Now, if I may add a comment to her comments. I know that's kind of a sticky wicket because when you look at continuous therapy versus maybe a vaccination or something. For example, when I talked to the doctor who was doing a MUC1 vaccine, he was commenting that you had to have a very low tumor burden and that the vaccine would work more so over time than with a high tumor burden. And so, I don't know if it would be possible for you to construct a clinical trial, that would be a suggestion I would make I guess as patient, I would choose a vaccine over a long-term forever maintenance therapy, just personally. But I don't know if that's even possible because typically those trials are never constructed. Could there be a different approach to that?

Dr. Richardson: Jenny, I think that's a great question and I think there's great research. I think the question is excellent because there is a research tool that we can use that hopefully will help us with this which is called MRD, Minimal Residual Disease assessment. So what you can do using MRD and MRD negativity is trying to understand who is truly an MRD negative state and who isn't. And so, tailor therapy again. I agree with you obviously if there was a way to just have a shot and then not do anything going forward that certainly would be a miracle. The snag with myeloma is that it's a little too clever for that and it loves to exist under the waterline, sort of iceberg-like and the reason for continuous therapy probably being so important is because it's this clonal heterogeneity and clonal tiding that's just so dangerous for myeloma. And what we realized as one of the biggest questions was, well if you put people on continuous therapy, aren't you going to breed resistance? And the very interesting observation is that with the right drugs, not every drug, but with the right drugs that resistance doesn't appear to be the case. And some beautiful work from my colleague, Dr. Antonio Palumbo in Europe has shown that when he put, for example, bortezomib and thalidomide together as maintenance for older patients, not only did he show survival benefit compared to the control group. He also showed that there was a substantial improvement in the time to next therapy when even though progression occurred. So if the disease progressed on the Velcade and the thalidomide combination, the time to next therapy was about a year later because the tempo of the relapse was that much less. Interestingly, they had a fixed-duration of treatment, Velcade and thalidomide continued for three years and then stopped. Unfortunately, once that happened, the tempo of relapses and the way they behaved became more like the control group again. So what that tells you is that continuous therapy probably does matter, and it's our job then to find the best tolerated Velcades, the best tolerated thalidomides to do that. And obviously lenalidomide, pomalidomide, these are drugs that in my view are generally better tolerated than thalidomide, although I have some patients who do extremely well on Thalomid, but there are others who obviously do not. So I think generally speaking I think everyone accepts that len and poma are probably better drugs. In fact they most certainly are. Similarly bortezomib now has become ixazomib as an oral form, which is just a pill once a week, so that's a remarkable breakthrough. Because now what you might be looking at, Jenny, is a pill once a week, perhaps a vaccine. Hey, an antibody every month with your bone strengthener and perhaps a daily IMiD taking like an aspirin once a day, and I’m not saying IMiD is an aspirin. No. But you get my point that it's an acceptable cocktail that you, Jenny, as a patient can tolerate, have a great quality of life and have an insurance policy that really protects you completely. Because my thing about the vaccines is I think they're great, but at the end of the day, you're banking on a lot with one modality and what you probably need is more than one modality because myeloma is expert at turning off the immune system. That's what it loves to do. Therefore, it's probably expecting an awful lot of just one vaccine to do that job.

Jenny: Well, that's very understandable, a very good description. You always hope for the best as a patient and the reality is a little more complex than that. Well, we've taken quite a bit of your time today and our show will be ending in two minutes, a hard stop. So I have to just thank you so much for joining us today, for taking the extra time. We are so fortunate that there are such caring and highly intelligent people like you working on this disease. So we really are so very grateful for your significant contributions to myeloma.

Dr. Richardson: Jenny, it's truly my pleasure and thank you. Thank you to everyone listening on the call. I really appreciate everyone taking their time to listen, so it's really my privilege. Thank you so much, Jenny.

Jenny: Oh we appreciate you, so best wishes for ASCO.

Dr. Richardson: Thanks a lot everybody. Have a lovely weekend.