Myeloma Myth Busters: Clinical Trials

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When it comes to understanding clinical trials, it is often difficult for patients to separate fact from fiction. In the first in a Patient Power series dedicated to debunking medical myths, myeloma expert Dr. Paul Richardson joins patient advocate Dr. Jim Omel to explore commonly held misconceptions about participating in research studies.

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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.

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. 

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? 

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.  

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. 

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. 

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.  

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… 

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? 

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. 

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…

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. 

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. 

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 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. 

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.

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Page last updated on April 2, 2015