Patient Power Knowledge. Confidence. Hope. Myeloma Myth Busters: Clinical Trials Recorded on December 8, 2014 Paul Richardson, MD Clinical Director, Jerome Lipper Center for Multiple Myeloma Dana-Farber Cancer Institute James Omel, MD Patient Advocate Please remember the opinions expressed on Patient Power are not necessarily the views of our sponsors, contributors, partners or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That s how you ll get care that s most appropriate for you. Andrew Schorr: Hello and welcome to Patient Power. I'm Andrew Schorr. Well, there are things that are true in multiple myeloma and things that are untrue. So here to kick off the first episode of something we're calling Myeloma Myth Busters are two wonderful friends, and that's Dr. Paul Richardson, who directs the multiple myeloma program at Dana-Farber Cancer Institute in Boston, and Dr. Jim Omel, a physician who has myeloma and is a leading patient advocate. Here they are. Dr. Richardson, thanks for talking with us today. You and I have known each other for a long time. I've had myeloma for 17 years and have certainly had the excitement of watching new drugs come to us. And, of course, we get those through clinical trials, and it's all because of you and so many researchers like you and the work that you do. I think if we could get more patients involved in more trials, and we have so many good agents today, that we could make this go even faster. There seem to be a lot of myths about clinical trials that perhaps we need to explain to patients, and they would be more excited if we could give them better understanding. So I'd like to kind of ask you some questions, so you could dispel some of those myths. Probably the biggest myth of all that patients seem to ask and this is not a good word but guinea pig. Everybody thinks, Will I be a guinea pig if I'm in a trial? Will they use me for experimentation? Can you kind of explain how that is really a myth? Yes, Jim, thank you. And first and foremost, may I say it's been a privilege to have known you for these many years and to work with you. And your advocacy for patients as a physician and myeloma patient and as someone committed to making myeloma history is remarkable. Thank you. And, just as I said, it's so nice to be with you.
And I think in the other context what you're saying, the questions you're raising is so prescient. Frankly, I understand why patient would imagine that guinea pig is a concern. The good news in myeloma today is truthfully that is far far from what is reality. We're blessed with really good science that informs new drugs. New drugs then come forward into the clinic, which are truly shots on goal. So they're not sort of shots in the dark. They're shots on goal. That's point number one. Point number two, any clinical trial we do we believe we must put the patient first, and if we put the patient first in other words, we build around them safety, measures of efficacy, careful monitoring that actually ensures that they get excellent care. So you combine good drugs built on good science with excellent care and careful quality control, and I would argue actually that it's the opposite of being a guinea pig. It is actually a situation where you are in the most controlled and quality-assured environment possible, and by so doing you can improve your outcome. And then the lovely thing, which always inspires me and I'm always struck at how consistent it is and you embody it yourself also in so many ways is what I'm struck with my patients is they say I want to do this because this is going to help people in the future. And I think that is one of the most remarkable things in clinical research, which is such a consistent theme. So on the one hand we take the best care we can of our patients, offering the best new therapies that are the best informed by the laboratory, and at the same time we have patients like you who are committed to doing you know, to making us do better for everyone in the future. So in a way it's the opposite of a guinea pig. It's a true win-win. Well, of course, I agree with you, but there are so many misconceptions about trials, but I agree. I think guinea pig is a term that shouldn't be used, but unfortunately it often is. Another concern I think that patients often have, and this might be why they're not so quick to join on to trials, is the placebo effect. So many patients are worried that about If I'm on a trial I might end up getting a placebo for my cancer. And I'm sure that's not the case, but maybe you could explain it and dispel that myth for us. Yes, critical, another critical misconception. So the use of placebo controls in the context of cancer care is actually quite uncommon. When it is used it's used in the context of where the treatment benefit may be truly marginal or additive as opposed to fundamental. So, for example, in myeloma we actually very in my experience it's uncommon for us to use placebos. Most of our trials are open label, which I personally am a strong advocate for. In the setting when we do use placebos, it is in a situation where we have a backbone of agents that is working. So we have two or three drugs that are working, and then we may add another drug. But because in the FDA's opinion, for example because obviously these trials are built and designed with input from the regulators, and in my experience the myeloma group at the FDA have been outstanding in the advocacy for patients, most importantly, but as well good science, so no one's fooled by anything that's where the placebo becomes important. Because what it helps us do is understand is there really benefit, and by so doing as well therefore for the future makes the likelihood of a treatment that may have an additive effect that much more valuable. Now, I think the important thing to know about placebo trials as well is they're very carefully monitored, so they have a rigorous data safety management team that oversees the conduct of the trial. So if for any reason there is something that emerges during the course of the study, that clearly shows that the placebo arm is performing less well, then there [are] early stopping rules that would allow not only further enrollment to the placebo group to stop but most importantly patients who are assigned to placebo to be allowed to get the relevant medicine that may be helping them. So there are these safeguards that are built in to minimize the risk associated with a placebo. Now, the converse could be true of course, that if you're adding on a drug, it may actually do more harm than good, and the same may also apply. In other words, the Safety Committee may look and see that the experimental arm is actually not performing well. So basically what you've explained is that both both arms will get good treatment, it's just that that placebo arm won't get the study drug and they won't be exposed to potential side effects, but they also will get good standard therapy that's standard of care.
That's very well said, Jim, and I think the important point is that not only will they receive the gold standard but they will be very carefully monitored so that if for any reason they don't respond as well as one would hope with and/or they encounter other side effects, they can have those addressed promptly and quickly. So the advantage of being part of the control group, if you will, is you're getting the gold standard but plus with the careful monitoring of being part of the trial. And obviously if you're part of the study, typically what usually is offered is that if for any reason the study drug emerges to be positive and an advantage there is some form of access to that drug subsequently, be it with an immediate approval, which would obviously be fantastic for everyone, or what we call companion trials where access to that other agent is available, the new agent is available. That's really exciting. So that if it's showing good benefit Right. even if you're on the placebo arm, you'll get that drug. Potentially, exactly. So how that would work is as follows: In a randomized controlled comparison if it was clear that the experimental agent was adding clinical benefit, one, the trial would be stopped, because obviously it's not ethical to continue if one arm is doing better than the other, and at the same time those people on the control arm would have access to the new agent. Now, some studies call this crossover, which sometimes is discouraged because it can dilute the effect of the benefit seen. But what we've always done in myeloma traditionally where we've had an agent that we think is really showing promise is have things called companion trials. So in other words, if you're in the control group and for any reason it turns out that the experimental drug is doing so much better, you will have some form of access to it. The other way of thinking of it is this: That if a drug really shows promise in a randomized trial, the FDA [is] very quick to then approve it, and in that context of course with the approval, access to that drug Very good. will occur. Yes. In the support group that I lead, I have several patients. Several of my members are very interested in trials. One though is quite skeptical. When I mention a trial he always says, I don't know. That sounds like a last resort. You know, if I'm going to be on a trial perhaps my doctor just doesn't have any other any other ideas or plans for my care. So maybe that's a myth too, that clinical trials are sort of a last resort a last-ditch effort. Can you kind of explain that it's perhaps not that way, so patients understand it better? Absolutely, Jim. I think, you know, that was a historical phenomenon typically, and certainly in myeloma it was something which was you know, we would perhaps reach for 20 years ago. Now because of the explosion in new ideas based on good biology and good science, good understanding of biology and good science, we're in a very different place. Basically, we use agents at different times in the disease. As you know, Jim, we're now testing exciting new agents in smoldering disease with a gui idea of heading this disease off at the pass before it even becomes symptomatic. And so obviously these are not treatments of last resort. They're treatments where we use them appropriately for the favorable safety profile in the right context in a way in which also if for some reason the experimental therapy fails, there are fallback positions that can be usefully exploited. So I very rarely consider protocols a treatment of last resort.
I totally agree with you, and I've explained to him that it's not that way, but coming from an expert it's nice to really hear that that's that we have that good backing. To be fair, Jim, no one could be more expert than the patient and the physician, and you embody both. I think the important message is though that communication with the provider is key. In other words, the patient needs to be armed with these key questions. These are very good questions, and your support group member would be absolutely right to say to his doctor, you know, to say to he or she, you know, Is this a last resort? And obviously I very much hope that what was being offered would not be in that context could be explained. There's another factor in trials that has probably had some reality in fact, and that's the cost. So many times in the past, at least insurance companies have not covered patients' costs when they're on trial. Now, I think that there's a national change in that. Many states have gone to that, and certainly with Medicare patients they're all covered with trials. So can you tell us a little bit how it works with costs on clinical trials? Yes, yes. This has been the coverage of clinical trials obviously has been a very hot topic for a number of years, and, in fact, in Massachusetts for example about 20 years ago, in fact longer, 25 years ago it was mandated that insurers should provide coverage for the standard of care around a clinical trial. And this is not you know this has been an ongoing But all states haven't been that way. That's true, but I would stress that I think that over the last 20 years or so there has been a real forward momentum Yes. in cancer care to ensure that that's not been the case. And it's not just been a phenomenon of the last few years. I think it's been a momentum that had a strong head of steam actually way before then. And I think, in fact, recent changes in healthcare delivery have in some ways challenged this, because the costs of care are becoming more and more challenging for both patients and providers alike. So in the clinical research community we're very aware of this, and what we're being very vigilant about is minimizing costs to insurers and patients alike and ensuring that, number one, our research agents are, of course, free of charge and that we ensure that sponsors of clinical trials take on as much of the cost of the trial as is reasonably possible. And so consequently there is a real advantage to the patient participating, and the least we can could is reflect that by minimizing any financial stress to the patient or their insurer accordingly. So I think that's very important because it is very real that in current healthcare economics these bottom lines matter. And as you know, Jim, in one of our favorite studies that you and you have advocated so passionately for, and I'm eternally grateful to you for it in our determination trial one of the biggest advantages of that up-front study is that our former partners have been very generous and provided free drug, particularly lenalidomide (Revlimid ), for as long as it's needed, which is amazing. And that for patients has been a huge bonus. So I think drug costs matter. And I would say in a similar way the cost of drug development matters because if we can keep that on to a reasonable level, then the cost to society of these exciting new medicines becomes much more tangible and much more realistic. And I'm always reminded that as we think about the cost of clinical trials that the total costs in healthcare of medicines and devices is only 10 percent. 90 percent is the rest. That's an important fact that sometimes gets lost in the debate. And the other thing is if you have drugs that really work, you dramatically change outcome. Patients live longer and better. The cost to the system dramatically falls. And I think as we think about that in our conversations about health economics it's very important to remember that research is a win-win in every possible way.
Unfortunately, the politics of it tend to be the other way around. It goes to the bottom of the agenda. I think that's something both you and I are very passionate about changing. And on that note I think it emphasizes why clinical trials are just so important for us and our patients more than anything Absolutely. and for society as a whole. I think as you mentioned something on the DETERMINATION trial that I should really emphasize again, and in fact it just says so much about costs. If patients are not on that trial, they have to pay for Revlimid. But if they're on the DETERMINATION trial, they get the drug free. Correct. So not only do clinical trials not cost patients more, it's just the opposite. Their personal costs are actually much less, aren't they? I agree. I think one has to be very careful though because in no way do we want clinical trials to be in any way coercive. I mean, the last thing we want is that. What we do want to see though is patients understand fully, objectively the value, and the value is both tangible in the practical sense of quality, of I mean of free medicines and so on, but also, differently, the value of the contribution that they make to the future for the fight against this disease. But at least we can break the myth that clinical trials are costly, and you lose insurance. That just isn't the case at all. Oh, absolutely. Absolutely not. Absolutely, and very well said. That is absolutely not correct. Another myth has to do with phases of trials. Obviously there are different standards, different phases. What about Phase I trials? There are the most exciting drugs, the most exciting offerings, but are they really safe. There is this myth perhaps that I shouldn't be on a Phase I trial. Is there is there something that you can explain that will tell people that that's not the case at all? Right. Well, I think understandably from, say, 20 or 30 years ago where treatments were less targeted and more nonspecific there was always the worry in Phase I that you would find unexpected side effects that would be really challenging. And, of course, that's not gone away completely, but it's much less. What we're seeing in Phase I is that we've got targeted agents that are biologically informed in the sense that they're derived from laboratory studies and they're premised on a real target in the mechanism of action that has been carefully teased out in not only laboratory bench work but also in in vivo models. In animal studies.
Exactly. Typically in myeloma in mice fortunately and in the sense of God bless the mice, but you know we don't usually have to go to dogs and apes and so forth, because it's always very challenging when one thinks of that as better than myself. I always find that a little bit difficult. But anyway that notwithstanding the bottom line is that when we come to the clinic the the predictive value of our previous studies for safety in particular have much improved. Now, we mustn't, of course, be complacent about that. Things can happen that aren't expected, and unfortunately in cancer care what we have learned is that effective drugs do have side effects. The good news though is that we're increasingly better at managing them, we're increasingly better at anticipating them. And also in the context of Phase I, we are very cautious about dose escalation and phenomena like it. I think what's particularly challenging in myeloma in Phase I is to remember the following, which is that the disease itself can be very, very challenging in what it does, and so drugs that fly into that storm can sometimes, you know, can be quite a challenging time as the treatment is delivered and as the disease is sort of wrestled to the ground, and side effects can occur in that context. In other words, they're not just due to the drug. They're due to the aggressiveness of the myeloma. So Phase I is perhaps and I say this carefully because it's always a you know, you never say never, but I would say Phase I is genuinely less risky than it used to be. And I think also as you move into Phase II you've defined the dose typically and then are able to just look at efficacy or activity. And then Phase III is the comparison, you know, this new cocktail versus the gold standard, how do they compare. And that paradigm still very much applies. What's interesting in the approval process, and I especially want to acknowledge the FDA in this, is the ability to get what we call accelerated approval. And I think we've been really blessed in myeloma that we have a very vibrant partnership with an excellent division at FDA where they're very interested. And if a drug shows a signal of benefit that we're able to move to this accelerated approval mechanism which then allows greater access to the drug for patients, and then at the same time further studies can follow before full approval. To me that's been a magnificent effort collectively to improve outcome for patients. It really is exciting how myeloma drugs are moving forward so quickly. Yes. And I think you know they begin in Phase I. Patients have to understand that there [are] lots and lots of study, lots of evaluations before any human ever gets the drug. So I think that myth should really be dispelled. I completely agree. There are some other things I wouldn't really call them myths, but as long as I can ask you these questions I'm going to ask. Some patients have concerns about giving extra tissue or extra blood. Could you explain to us why that's important? It's huge, because what it does is it provides correlates of science which can be very critical in assessing outcome both for what we call minimal residual disease as one example and also for assessing the effects of drugs that may not be obvious by the simple measurement of a particular blood test that's routine or a clinical exam or an assessment of how a patient is feeling. So we're able to also learn from these so-called surrogates an awful lot. For example, we night not see a huge clinical benefit to a drug, but we may see at the microscopical, tissue-based level that there is an impact on the disease, not quite enough to perhaps tip a response but enough to show that we're hitting the target. That informs us about what we intelligently might next do. The other thing is that we do what we call pharmacokinetics, which is where we look at the levels of drug in a person's bloodstream or in their urine or both. That's incredibly important because it helps us understand safety. So in both the terms of activity of drugs and in terms of their safety, the ability to have these correlative samples is vital.
So that extra tissue is really important. It's huge. And obviously what we try and do is simplify it, so blood and urine is easy. Bone marrow is more challenging, so we try and be as humanistic as possible in that context and structure the assessment of tissue in a patient-friendly way as possible. And for bone marrows for instance I think you try to do those at a time when a patient would normally have a bone marrow in evaluating their disease anyway. Exactly. And for example what many of my patients tell me is that the biopsy is by far and away the most uncomfortable and the aspirate done in expert hands is less so. So for example we often don't need to go to a biopsy with every bone marrow test. We need it initially because we need to know exactly how much disease there is, and we might need it to assess the depth and breadth of response, which is obviously to the benefit of our patient anyway. But the ones in between can sometimes just be simple aspirates, and that for example is is genuinely a little easier for a patient to tolerate. There is an aspect of trials that you know me quite well has been concerned about, and that's randomization. I know it's a difficult question, but many patients don't like the idea that they're not going to have some say-so in the arm of their trial. How could you explain to patients how randomization is a requirement for a trial, and how would you answer a patient that wants to be on an arm but is not going to be unless the coin flip puts him in that arm? Right. I agree. Randomization is challenging. I mean my personal favorite studies are Phase Is and IIs, which don't involve you know choices because at the end of the day both I and my patient know exactly what they're getting and what they're going to be assigned to. However, I realize that in the context of prospective studies an ability to be assigned to a treatment that may be the very best versus another that may be equally good but perhaps marginally better is a critical scientific question that we cannot possibly answer without randomization. So I think randomization should only occur when the difference is very subtle or may not even be known. We call that equipoise, and as long as there's equipoise in randomization I'm very comfortable with it and for the simple reason that both arms do get best care. But because we generally don't know which is the best, for that reason a randomization is appropriate. And I think the other piece of randomization is the concept that there's a loss of control. That really doesn't happen. As you know in our DETERMINATION study for example, to use it as a very tangible one, if you're assigned to the non-early transplant arm and there's evidence that your disease needs to be met by an early transplant, that will happen. Conversely, if you're assigned to the early transplant's arm and there's evidence that actually safety may be a worry and that the early transplant might not be in your best interest, that won't happen. So I call that adaptation. So in other words, in both arms there is the ability to adapt. And as long as that's there that puts again the patient first, and as long as that's part of your trial you usually can't go wrong. And that really makes trials quite attractive, just knowing that even if you're in one arm if the other arm is what your doctor thinks is best for you, you will get that treatment. Right. It gets back to this concept, Jim, of equipoise. You know no randomization should involve, in my view, you know, A-plus versus Z. It should be A-plus versus A-plus or minus, but both A. And I think if you think of it in those terms, that's truly what we call equipoise.
And if there really is equipoise, patients will buy into that because if we don't know what's best we have to do the trial to find out. Exactly. And this is where again I want to emphasize to patients this mechanism of the signal from a single-arm, historically controlled study. This is a very important tool, because there are certain situations where you have very high mortality and no effective therapy, and it's very clear that randomization in that setting is not appropriate. And there, there are clear mechanisms by which we can establish a clinical signal and at the same time use historical control data to be able to say this is a clinical benefit and then subsequently confirm it in different settings where equipoise is present. One last thing. Thanks so much for explaining this. We're at ASH today. Can you tell us what [are] the most exciting things that you're looking for, the most exciting things that are coming down for myeloma patients here at ASH? You're very kind, Jim, to ask. I think there's an awful lot at this year's ASH, again mainly around the antibodies, on the one hand, the excitement around daratumumab, around elotuzumab. I think one of the most exciting trials of all though is the carfilzomib (Kyprolis )-Revlimid-dex study compared to Revlimid and dex alone, the so-called ASPIRE. ASPIRE. And this is a large international trial which has shown that the combination of carfilzomib-lenalidomide-dexamethasone (Decadron ) results in disease control of around 26 months or so, which is remarkable in the relapsed setting. That's over two years. And by comparison lenalidomide and dexamethasone do very well at about 18 sorry, at about 18 months, so the actual difference is about eight months between the two. So 26 months for the carfilzomib-lenalidomide-dex arm and 18 months for the lenalidomide-dex. And why that's so good is because on the one hand lenalidomide and dexamethasone perform so well 18 months is better than we've will seen and on the other hand, the addition of carfilzomib takes it that next step up and makes it even better. And it sort of builds on the success of when we can put bortezomib and thalidomide and dexamethasone together versus thalidomide and dex where we showed the 6-month difference in favor of bortezomib. And now with Revlimid and dexamethasone and now carfilzomib, Revlimid and dexamethasone that difference is even bigger at eight months. So these are all incredibly important positives that show disease control is improving. So I think the excitement is monoclonal antibodies, the success of the ASPIRE trial, the ongoing research into new drugs, lots of new agents, the further refinement of existing studies that show or rather existing regimens to show tolerability and efficacy. And at the same time, it's great to see at ASH that one of the key lectures is given by a myeloma expert, Dr. Jesus San Miguel. And it's also fun that at the educational session we're debating exactly what you and I have talked about, which is where does transplant belong so a very, very timely and very exciting ASH. And certainly exciting from patients' standpoints to think that there are 855 abstracts dealing with myeloma. Myeloma is just such an important aspect of ASH that from our standpoint it's just great news. I completely agree, Jim, and it's particularly nice to have the chance to be together as well. It was great meeting you. Absolutely. Thank you so much for all you've done for us for so many years, for explaining the myths around clinical trials because both of us agree that patients should really get involved in get excited about trials. It's what we need to get our therapy even better.
Completely agree, and thanks so much, Jim. Good. Thank you. Andrew Schorr: Thanks for watching our first episode of Myeloma Myth Busters with our friends Paul Richardson and Jim Omel. We'll be back with more. Send us questions anytime if you're wondering is something true or is it a myth. Be sure to be signed up for alerts on our website, so you'll know whenever we post something new. I'm Andrew Schorr. Remember, knowledge and truth can be the best medicine of all. Please remember the opinions expressed on Patient Power are not necessarily the views of our sponsors, contributors, partners or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That s how you ll get care that s most appropriate for you.