Rafael Fonseca, MD
Mayo Clinic Scottsdale
Interview Date: May 22, 2019

The cost of healthcare is on the minds of every stakeholder including patients, provider and payers, especially when it comes to cancer treatment. Dr. Rafael Fonseca joins Myeloma Crowd Radio to share his insights about the complexity of myeloma, factors that impact the development of innovation in myeloma and the focus on getting the proper care to patients as other economic interests are balanced in the process. Dr. Fonseca addresses what is sometimes called "STEP therapy" and how costs issues may need to be balanced with the  wholistic factors of great care.

Thanks to our episode sponsor

 

Jenny: Welcome to today's episode of Myeloma Crowd Radio, a show that connects patients with myeloma researchers. I'm your host, Jenny Ahlstrom. We'd like to thank our episode sponsor Takeda Oncology for their support of Myeloma Crowd Radio.

Now, before we get started with this show, I'd like to give you an update on HealthTree. We now have over 4,200 patients participating. And we feel that we have enough patients to start answering really significant and important research questions. This week, we invite you to fill out your answers for three important questions that we have around family incidence of cancer and specifically with myeloma. So our first question will be, “How many myeloma patients have immediate family members with other forms of cancer?” We'll see any patterns in the types of cancer they have. I've been approached by several people at some HealthTree workshops and other patient meetings who have mentioned that they have myeloma in addition to another cancer like ALL or B-cell lymphoma. So we want to see if there are any patterns there. Secondly, we want to know if patients have any secondary cancers in addition – well, that's the secondary cancer question. We want to know if patients have other family members with myeloma or precursor conditions like MGUS or smoldering myeloma. So those will be the questions that we'll be asking. Then we'll be able to turn those around and give HealthTree insights and share those on the myeloma crowd and HealthTree site. So if you have a HealthTree profile, we ask that you answer those questions in the full health profile pages and you'll see we have a brand new design for those pages. Then next week, we'll follow up with results.

Now, onto today's show, the show is a very interesting one. And we will be discussing a hot topic called “step therapy”. We'll also be talking about cost of healthcare with Dr. Rafael Fonseca of the Mayo Clinic in Scottsdale. Welcome, Dr. Fonseca. 

Dr. Fonseca: Oh, thank you. Thank you for having me.  A pleasure to be here.

Jenny: Well, we're so happy you're here. Let me introduce you just for a little bit before we get started. Dr. Rafael Fonseca is the chair of the Department of Internal Medicine and Professor of Medicine at the Mayo Clinic in Scottsdale. He's also Getz Family Professor of Cancer in the Mayo Clinic College of Medicine and Science in the Department of Education Administration. He's a Distinguished Mayo Investigator since 2010 and is also a Consultant in the Divisions of Hematology and Oncology and Basic Sciences Research Laboratories at the Mayo Clinic. Dr. Fonseca is an Editorial Board Member for the publication Genes, Chromosomes and Cancer and is also on the Mayo Clinic Arizona Executive Operations Team and Editorial Board in addition to being the initiator of the idea of HealthTree. We are just thrilled to have you. Thanks for coming.

Dr. Fonseca: Again, thank you. Always a pleasure to work with you. 

Jenny: Let's get started by just talking about costs in general. I know there is a lot of debate about healthcare costs. Because myeloma patients are on multiple therapies, cost is definitely an issue for patients. But can you please help us set the stage in a more general way before we dive into step therapy or other issues. 

Dr. Fonseca: Sure. Well, we live in a very complex and difficult times. The complexity and some of the difficulties come because of a lot of the progress that has been made in the fight against myeloma. And I would say that anyone could say the same for other diseases where they're making progress. But myeloma, it’s a very, very unique situation given the very large number of drugs that have been approved for the treatment of the disease.

Just for background, when I was in training, no one really wanted to work in the area of multiple myeloma and primarily because we didn't have many treatment options. Most of the people with whom I trained, they wanted to go to lymphoma, or potentially leukemia. Little did we know we were going to have this explosion of innovation and new treatments available for patients. So effectively since 1999, we have 11 new drugs that are available now for the treatment of the condition. Of course, they are available because they have been approved through the regular process of approval, through the Food and Drug Administration. Associated with that, there's a very large body of clinical research that has occurred that has led to this approvals, clinical research in multiple ways, Phase I, Phase II Phase III clinical trials both by industry as well as NIH and other oncology cooperative group efforts that culminated in those approvals. The net result is that the treatment of multiple myeloma is much better than it ever was. And going back again to when I was in training, one could anticipate that a patient who was diagnosed with myeloma could have an expected survival of approximately two to three years. In fact, this comes out from published data. One particular study that I think often is the study that was published by Dr. Kyle that he compared myeloma being treated with melphalan and prednisone versus multiple other chemotherapy combinations. They showed there was not much of a difference when melphalan and prednisone was the only treatment.

Now, take a step forward to 2019. First of all, we don't even know what the median survival is for myeloma patient at this point who is treated optimally. Well, we have some early indicators that obviously those numbers are much, much better. In fact, for patients who are diagnosed now, there's a significant fraction of patients that we'll be able to be expecting a survival greater than five or ten years. In fact, I hold the opinion that there's a small group of patients, hopefully one that will grow into the future that can have their myeloma permanently controlled if not cured in a small fraction of cases. We have seen a dramatic improvement in our ability to treat myeloma. That is unquestionable. But because of all those efforts, these drugs don't come cheap. They're medications that have been developed through this process of clinical trials. Often, they incur significant expense both for patients as well as for health systems.

So we have those two things that we need to reconcile. We'll talk through this throughout the show. But I think it's difficult to say that anyone in particular has a clear answer of how this can be dealt with. Because on the one hand, we do celebrate this progress. On the other hand, we would like to find, that should be the case always, ways to do things more economically and things that are more accessible for patients.

Jenny:  A lot of times I think sometimes people focus just on the drug cost. Maybe not overall cost but I think overall have healthcare costs are approaching like 18-19% of our GDP. But that's not just all drug costs. That's everything related to healthcare costs. 

Dr. Fonseca: Oh, yes. That's a very, very important concept. I've actually gone down to some of the details to see how this works out. If you take an economy, that's the number we think about the 19% for GDP. But depending on the numbers and the conditions, they can go anywhere from 10 to 20% of that being expenses related to medications. But the rest is still quite substantial. That includes paying for doctors, paying for hospital stays, diagnostic testing, durable medical equipment, then all the other things that come along with expenses associated with healthcare.

Now, sometimes, the % is even higher for the contribution of drugs for the treatment of one disease. So in the case of myeloma, it can be up to 20 to 30% of the total cost of the care of patients. But we have to see this in a very, very comprehensive fashion. We have to see, “Okay, how are we spending the dollars? Are the dollars being spent on drugs? And if so, are there any savings that are occurring in other parts of the health economy that come because better treatment is being available for patients?”

Jenny: Right. Patients are living longer and doing better on the treatment combinations. In myeloma, it seems to be just a complicated cancer. You're trying to kill multiple clones at one time. It's not like there's a silver bullet -- one drug that's going to cure everybody in myeloma it seems.

Dr. Fonseca:  That is correct. It's a little bit interesting how this has played out. If you think about other forms of cancer, some of them have been very well controlled with one pill or one type of medications. The prototype for this is chronic myelogenous leukemia (CML). Some cancers have been treated effectively and cured with a single course of chemotherapy. There's a related blood disorder called hairy cell leukemia that with five or seven days of treatment, most patients are cured. This is with older forms of chemotherapy. There are other cancers where multiple agents of chemotherapy can be curative like in testicular lymphoma or Hodgkin's disease. But in myeloma, it seems that at this point, we don't have that single way of treating the disease. If anything, the more we go along, the more we are realizing that the treatment has to be highly individualized.

Now, there may be a future where we have something like that, something new, something that cuts across the board. To some extent, the treatments we use work for most patients, things like the pills that we call the IMiDs. That includes the Revlimid and pomalidomide as well as proteasome inhibitors including carfilzomib, ixazomib and Velcade. 

Jenny:  Right. So you're using different things. Do you want to go just explain a little bit about how each patient is diagnosed with certain clones when they're diagnosed? Then there is this clonal evolution process also that makes it just a little more tricky.

Dr. Fonseca: Sure. Well, myeloma has been also a prototype in how we understand, how the treatment of cancer needs to encompass all of the cancer cells. To your question, we have been working around this concept of the subclonal nature of myeloma. That is when the myeloma patient is being treated. We did realize that within the population of cells, if you take a thousand cells from someone with multiple myeloma, you start finding that there's subgroups or like little tribes if you may. Now, these subgroups, they’re all very, very similar, so they're almost identical to the next subgroup, but they just have enough little differences that might make one of those groups respond better to one treatment versus another. In fact, we have studied this and published on this that you may be treating a situation and then one of the subgroups ultimately predominates and that's maybe the nature of a relapse. And you have to think about a different treatment for that. So it's a challenge. But this is probably true for all cancers that if you are effective in curing a cancer and controlling a cancer, you have to be able to control all of those subgroups or subclones as we call them.

Jenny: And I think the Mayo Clinic in Scottsdale particularly is one of the most preeminent genetic testing organizations where you're doing a lot in understanding the genetics of the disease. Do you want to talk about the importance of knowing what kind of myeloma that you have? 

Dr. Fonseca: Oh sure. No, I think it's a great point. Not every myeloma is the same. We understand and understand more and more as we go forward that they’re different flavors and those flavors are dictated by the genetic makeup of the myeloma cells, dictate different characteristics for behavior of the cells, how they respond to the treatments, what kind of treatments we should be using and so forth. The more we know, the more subgrouping we're doing of the different approaches that you need for each one of these genetic subtypes.

Now, I should clarify for the audience. When I talk about the genetics of myeloma, I'm not talking about the genetics that you inherit from mom and dad. In fact, these are genetic changes that only and exclusively are occurring in the myeloma cells. We test for them. There's a number of ways through which we can test for them. Most commonly, the FISH (flourescensce in situ hybridization). But you can do other testing like gene expression (GEP), profiling and more recently what people will refer to us, next generation sequencing (NGS). But the bottom line is we're testing for genetic changes, mutations and other alterations that are occurring very specifically on the myeloma cells and not in the cells of the rest of a person's body. So if we did the same test them on the skin biopsy or their muscle cells, they would be normal. But those changes, again, help us plan for treatment. We discuss the myeloma situation differently according to the risk stratification. We choose agents and we choose strategies for the treatment of myeloma patients differently according to the knowledge that we have from those genetic markers. So I always stress for patients it's important that we have this information because it does have significant influence on how we conduct ourselves as we treat other condition.

Jenny: Going back to our topic, do you want to give an overview of what is step therapy, what’s the idea behind it and where is this idea coming from?

Dr. Fonseca: Sure. Well, first of all, let me just say thank you for the interest. This seems a little bit far off but I think it's important for people to be aware about this. Step therapy is also known as fail-first therapy. This is a strategy that has been proposed and has been employed in a number of situations where someone who provides insurance for patients or payer or it could be the government through Medicare could say, “Well, what we want this for patients to try medication A before they go into medication B.” At first glance, this makes a lot of sense if you're talking about simple conditions. Let me give you an example of one of those first glances. If someone were to come to a physician's office and they said, “Well, I have a cough and maybe have fever,” the physician might say, “Well, let's start with maybe just some Tylenol and some rest. Then if things don't go so well, maybe tomorrow, we'll try antibiotics and something like that,” which makes perfect medical sense.

Step therapy, when it is applied to patients who have a cancer diagnosis, this needs to be looked at very, very carefully because in its extreme form, what it might require is for people to go through a step of trying a therapy that may be perhaps less effective or maybe perhaps more toxic than the best available and the best treatment that's possible for patients. Now, fortunately, we don't see much of this yet implemented but there is certainly a conversation going on. There's a discussion going on regarding the implementation of step therapy through various payers.

And just to land that very specifically in the case of multiple myeloma, you could imagine that someone could say, “Well, we have found that maybe this particular drug is going to be less expensive for whatever reason.” Maybe this drug is already available as a generic medication or maybe this drug has been just, in general, less expensive. From a payer perspective, you might say, “Well, I would like, again, patients to maybe try this first. Then we'll move on to the next line of therapy.” And I actually personally have raised my hand with a little bit of concern there because I don't think that that's, without further consideration, always in the best interest of patients. So I do think that physicians and their teams, the rest of the healthcare providers need to be very attentive to this because I think our first decision should always be and unquestionably be, “What is the best treatment that's available for this particular person?”

Again, I think the step therapy or the step therapy approaches -- and in fact, I think better described by fail-first -- do make sense in other simpler medical conditions. Let me use another example. If you have high blood pressure, someone might want to say, “Why don't we try a diuretic for a month and see if that works?” But I think they have to be looked at with much greater caution when we think about situations such as cancer and specifically multiple myeloma. And the last comment maybe before I stop is that part of the reason for my concern is that time is a very important variable when one deals with cancer and certainly when one is dealing with multiple myeloma. Sometimes, you may try something and the situation gets more complicated. You're already starting from a not so good point when you're going to consider that second line of treatment and patients may not have the opportunity to reach that second point of treatment. In fact, I have been working with a group of collaborators trying to understand the patients that go through one line of therapy, how many of them are able to make it to the next line of therapy because someone who proposes step therapy might say, “Well, we can try this first. Then if that doesn't work, we can try that down the line.” Unfortunately, we know that there are a number of -- a fraction of patients who might go through a line of therapy who may not have the opportunity to try a second line of therapy because something happened. They maybe developed a toxicity or maybe they got tired from treatment or maybe their disease just got very difficult to control. That is why one has to be careful when we think about considerations like step therapy, particularly in the context of cancer treatments.

Jenny: I know some other countries like in the UK, there's an organization called NICE. There's a group I think in the United States called ICER. They’re focusing on the costs of healthcare and how to cut down the costs in healthcare. This is part of what they potentially think is part of the solution. But if you look at the cost of healthcare overall, is just the medication costs in constricting that going to really solve the whole issue? Then in cases like myeloma, in countries that have tried things like this, how does that work?

Dr. Fonseca: Sure. Well, there are a couple of components to that question. Obviously, one -- and I think everyone has to be mindful of resources. Resources are scarce. People have to think about, “How can we divide things in the best way, the most effective way, a way that is fair?” That's why people are interested in trying to think about frameworks just like you mentioned with NICE and ICER here in the United States. But one has to think about the whole equation. I would say for healthcare, -- and this is a conversation that is often not carried to conclusion. One has to think about everything. One has to think about the treatment costs with the medications. One has to think about the treatment cost associated with hospital stays, with complications. As an example of this could be there is a medication that maybe -- in fact, it's better the treatment of a condition, maybe better the treatment of myeloma, maybe less toxic but maybe more expensive. But then when you actually try to factor in everything -- and you can factor in not only the expenses but also the value that comes from this. For instance, people who can take pills now and can return to a productive life. That has to be taken into consideration if you want to take the macro perspective on this, if you want to take either regional or national perspective of how these interventions may or may not end up being economically beneficial because we know that sometimes, something that is on a unit price more expensive may have significant benefit downstream.

I'll give you a couple of examples. When I was in training too as well, that’s 20 years plus, about a third of the admissions to our hospital when I was in internal medicine were related to patients who had age-related complications. This was devastating because people were mostly younger individuals who had to quit work, who lost their jobs, who their caregivers lost their jobs. They had all this financial pressure. Unfortunately, we had terrible treatments. So a third of our admissions were for patients who had very, very advanced disease. So much so that we were actually seeing building of hospital wing specifically dedicated for patients who were going to be admitted for these complications. We had, at University of Miami, a specific building that was dedicated to that. Nowadays, the medications – again, the units are expensive but people who have age-related complications can go back into their productive lives and can lead very meaningful and oftentimes people now think perhaps complete lives. That is because of the advent of the medicines themselves.

So when we talk about this, you have to look at the whole equation. You have to do the wholesome approach. Now, obviously, there's different ways in which people pay for healthcare. In the United States, we have a mixture of systems, both government and private. But in other countries, for instance in the United Kingdom, they have NICE which tries to determine whether the price to be paid for a medication is something that they would consider cost effective or they would consider a reasonable thing to do. Now, how one goes about creating the formulas that derive these numbers is very, very complicated because there's many assumptions. In fact, some of those assumptions do require significant subjective interpretation. Some of them even border on areas where people get into debates such as the ethics of some of those assumptions. An example of this would be the use of QUALY  which we can talk more about that. Then they go on to get a number and they say, “Well, it doesn't seem like we want to pay this much.” The outcome of that is that, well, one might say, “Well, we are maybe protected if you may as a society from paying too much for something that appears not to give us that much benefit.” The downfall of that is if you're a patient that you have a need for some of those medicines, you may now be able to get it through the health system in which you're living.” So they are, as is always the case with questions like this, tradeoffs.

We see that it's not unusual for our European colleagues to have access to these drugs at a much later date than we have them at the United States. The tradeoff we have is because we haven't had that type of mechanism established here, we have much earlier access to medications, although we pay higher prices for the drugs that are used for the treatment of myeloma and most other cancers. We pay with a higher price but we have a much earlier access than many of the countries. We're just using NICE as an example. Of course, everyone tries to do their best with they have and the systems they have but there are other countries that use similar systems to try to determine the so-called cost effectiveness.

Now, I think from a physician perspective, I think physicians can wear a number of hats. Sometimes, we are educators. Sometimes, we are clinicians that are seeing patients in the clinic. Sometimes, people participate in advocacy efforts or want to be thought leaders in this. These are all different roles that a physician can play.

“But in my opinion, when a physician is in front of a patient and they're in their room, their only interest has to be in doing their best to try to provide the best treatment for that person in front of them. That's so-called fiduciary responsibility that physicians have to patients. It’s very, very important that remains focused.”

I'm quite critical. I don't see a lot of practical examples, but I do see this happening in conversation when people might say, “Well, what about society's considerations or the expense to society?” I think you can discuss that out of the room or you can discuss that if your role is being in public health or if a person works for the government or something like that. But when a physician is at the bedside, their only responsibility is that person in front of them. That's why one has to be very, very careful with value frameworks.

ICER is a recent iteration. It’s sort of a NICE-like structure that has been proposed here in the United States. They have done some analysis. I think it's worth looking at the details of some of those analysis, but I think in a possible future, they could play a role just as NICE plays. Again, there could be a future where a society or payers decide this is the right thing to do for them. But one must not ignore the fact that if we were to go through a system such as the one that we have with NICE, that results in delayed introduction of medications into the clinic. In general, from a patient perspective, that is not a desirable thing.

Jenny: Right. And patients want to be able to sit in front of their doctors like you were saying and understand their best personal treatment options.

Dr. Fonseca: Right.

Jenny: When you’re looking at earlier use of the Car T technology, which might fit under that category, what you were talking about earlier, can you get a therapy that might not have as many long-term side effects that's a one-time treatment or something with boosters potentially or even do 3D tumor modeling? Because we're funding one of those projects to see which treatment combinations are the best for your tumor at that particular time. And just being able to have the flexibility to do that seems like it would be absolutely critical.

Dr. Fonseca: Oh, absolutely. I am convinced we’re living in the golden age of medicine right now. I think the number of options we have, not only for myeloma but are coming forward for many other diseases, is fueled by this growth in biotechnology and models like you described. I think it's worth noting. This is quantifiable. It has been published, the particular contribution to all of this by scientists, physicians, patient, Patient Support Organizations from the United States and this frenzy of activity where everyone is trying to look for the next best treatment. But the reality is that this has resulted in progress. Progress sometimes is revolutionary that a new pathway or a new molecule comes along and sometimes comes in incremental steps. But even when it's only incremental steps, when you start adding this up over time, this is huge. If one, for instance, starts looking at the results of Phase III studies that have been published in myeloma and you start looking at the rates of response, you can see that over the last ten, 15 years, the % of patients responding goes up. Then people say, “Well, that's not good enough. How many patients are getting into complete responses and the % keeps going up?” And if you go to one of our meetings, the ASCO meeting, people are almost not caring about complete response because now, they want to see the minimal residual disease negative status associated with any one of those combinations in this clinical trial.

We live in this very active or let me call it effervescent time in development of clinical options. Certainly, myeloma, it’s a great example for this. There is a possibility that at some point in the future, as one of my colleagues once said, “We maybe a combination or we maybe a drug away from being able to cause MRD negativity in a large fraction of patients.” Then were that to be true, could we think that there is a future – we don't have that yet -- but could there be a future where all of this development culminates in some form of combination that allows for myeloma to be treated for a rather shorter period of time, safer, with less toxicity? We can only hope so. 

Jenny: All patients would hope so. That'd be fabulous. Amazing. You hear these different conversations. You go to these conferences and people are starting to talk about this step therapy. So where are they being driven from or where is it coming from? And then maybe you want to explain what that QALY is. 

Dr. Fonseca: Yes. Most of the push for step therapy is coming from payers. And payers, whether they’re government payers or private payers, they have to look after their business so they're trying to look for models that would help them spend less in the services that are provided. And I think that's where that comes from, I think just taking an approach of, “Well, where could we potentially be saving money?”

I'd like to make reference to a recent report. This was released just a couple of weeks ago from an institute called IQVIA. It’s IQ, then V-I-A. They looked at pattern of utilization of drugs in the United States. They looked at the number of drugs that are being prescribed, the cost, et cetera. It's a public report by the way which is quite interesting. But one of the questions they ask is as follows: “If a patient can get a generic medication…” -- which by the way is 90% of what's prescribed in the United States. “If a patient can get a generic medication, how often do they actually get a generic?” So in other words, there's a generic drug. That means that we should probably try to use that generic drug because they're going to have a lower expense. They call this generic efficiency. The number is an astounding 97%. So there's not a lot of room for improvement which is – it’s a common line that you hear from people to say, “Well, maybe they're using the latest and the greatest, but maybe there's a drug that is cheaper. It's going to be ‘just as effective.’” There's almost nothing that is cheaper that is just as effective and without some incremental value for the drug you're paying for.

Let's use an example. You look at a family of drugs, the IMiDs. When we first started using them, we used thalidomide. Thalidomide was a medication that was revolutionary because it gave a whole new class of drugs for the treatment of myeloma. But that came with a steep price of toxicities. Almost every patient developed peripheral neuropathy back then and also a much lower efficacy than what we see with the new drugs. Then the next step, second generation, was lenalidomide Revlimid where patients actually had a much lower, in some clinical trials, minimal rate of neuropathy and increased efficacy over thalidomide. Then subsequently came the third generation pomalidomide which was so much more potent that we go from 25 milligrams of Revlimid down to two to four milligrams for pomalidomide. If you see the molecules, they look almost identical. You might say, “Well, they’re just changing a couple of things here chemically.” But it turns out pomalidomide works in patients where Revlimid had stopped working. For instance, in our laboratory experimentation, we find that it's clearly a much more powerful IMiD than Revlimid. The chain of progress doesn’t stop there because now, there's a clinical trial of this drug, the CC-220, which actually has activity at even lower doses and even in patients who have failed prior IMiD. So there's an incremental value of more potency. We don't see the toxicity of peripheral neuropathy anymore that we used to see with thalidomide. It all comes with a tradeoff. That's why when I started with this IQVIA, 97% utilization of generics, that means they're used when they need to be used. There's not a lot of opportunities. But something like step therapy, they might say, “Well, maybe we’re going to try thalidomide. If a person doesn't develop neuropathy, we're going to continue.” In my opinion, again, I don't think that's the right approach.

The second part of your question was the QALY. The QALY is a metric that is used often by economic analysis of drug costs. By the way, if I could say just parenthetically, I published a few papers on this. But I've taken the approach of -- every time I do this, I'd like to include, and have done so far in every one of the publications, an economist just to make sure that my statements make sense because I think they have a very unique way of looking at the use of resources. I'm trying to learn from them, but I still want to have them as sounding board for some of the statements. But the QALY, it's a metric that is used by economists where they tried to measure the value of an intervention. It stands for Quality Adjusted Life Year. What it stands for, if you have a drug that gives you % improvement -- let's say a drug now gives you one extra year of life. That would be a life year. But the Q and the A is an adjustment that is made because the quality of life after diagnosis is felt to be reduced. In other words, if because of that treatment you have some toxicity or you cannot do things that you used to enjoy doing like walking or playing sports, et cetera, that might result in that life year being adjusted at 50%. Folks who are using this as an analysis will say, “Well, that life year, yes, you've got a year but we're going to count it as half because it was not a full year. It's not as when you were able to do sports or engage in activities of the living.

There's been a number of people, myself included, who have remained critical of that being a metric to be used because in ways that whether they're intended or not, they diminish the quality of life of someone post -- the value of the life of someone post diagnosis because they're saying, “Because of your symptoms, we're going to count that extra year only as if it was half of a year.” We've heard loud and clear. If you have a cancer diagnosis, be that myeloma or any other cancer, I think people who have experienced this know this that every single day counts and your attention to what you do with your life is so much more precious than anything. A cancer patient would argue that a year of life post diagnosis is more valuable than it was before they even realized that one may be dealing with a disease that may result in a life ending diagnosis. I think that Q and the A is problematic for a number of people. Certainly, it is for me and other people who are interested also in bioethics. Therefore, I think it's difficult to accept frameworks that use QALY because of those limitations.

Jenny: Yes. I would agree with that statement. I think when you have a cancer diagnosis, you actually live more fully than you did before. There's a heightened awareness, appreciation. 

Dr. Fonseca: Yes. People are so much more aware of what's ahead of them. I usually ask people, “What are you doing six weeks from now?” They take a pause, “Oh, well, I don't know if school year is going to finish.” But oftentimes, when you deal with a patient, they're talking, “I want to make it to the graduation which is on May 17,” or, “I need to be at my son's wedding, et cetera,” because those landmarks have an extra sense of urgency and significance than you did have -- not that you didn't have any, but of course, you didn’t have before the actual diagnosis.

Jenny: Yes, absolutely.  Well, what can patients do to influence this conversation?

Dr. Fonseca: I think patients need to remain engaged and alert to this. I think one of the things that they should always ask is, “Is this the best treatment that is possible.” Now, one could envision situations, both here in the United States and abroad, where one person might not have access to a treatment for a number of reasons because of the economics, the insurance coverage or what have you. But I think the conversation needs to start, “Okay, what is the best treatment that is available? And can I get that?” I don't think that -- I can't imagine that from the physician’s side, people would bring this to the bedside instead of in a deliberate way to say, “Well, I'm just going to use these things because I don't want to stress the system or I don't want to stress the payers.” I want to think that's the case. But I can't imagine that the conversation could very suddenly and almost imperceptibly could start making its way to the bedside where people will start questioning these things.

I'll give an example that it's somewhat a good illustration for this. There is a national campaign. It's a WISE campaign, but it's a campaign that it's called Choosing Wisely that has looked for many years at things that physicians do that they should not be doing because they haven't been proven to be beneficial or they're harmful and they're just adding expense to do healthcare. I think physicians agree that everything that comes out in this particular campaign is good. Patients should not be doing that. But in a quick second, you can start seeing that the campaign is only about not doing things. It’s not about doing things. And doing things is very important. Then there's a report and this has been put out in the literature. I don't even know what the current quantification is for this. But there's a significant delay of introduction of a novel therapeutics into the clinic just because people are not doing good things. So just as it is important not to do the wrong things, it’s just as important to do the right things.

There's a recent study in lung cancer where people looked at patients who have lung cancer and who had the genetics tested for their lung cancer. The investigators asked the question, “Okay. If you have a patient with lung cancer that has a mutation that will benefit from a specific treatment, what are the odds that that treatment is going to be given?” Surprisingly, it’s likely under 50% of cases. So even when patients had the testing and the oncologist should have known that that particular drug should have been added to their treatment regimen, it only happened in about one and two patients.

Jenny: Why is that?

Dr. Fonseca: Well, we don't know. I think this was a first study. It could be a number of reasons. One is that maybe the pace at which oncologists are moving through the clinic. I think some of this could be prevented by having more informed patients. Maybe we can talk a little bit about how something like HealthTree could help in that regard. It may be that there are some administrative issues with how healthcare is conducted in the sense that you could see a patient who sees an oncologist and report comes back two weeks later. This patient is now seeing someone else in the team that is caring for this group of patients. And that's just filed under the medical record but no one acts on that. So those are the kind of things that I think need to be solved and need to be helped. That's part of what -- of course, the team under your leadership with the HealthTree is trying to change some of that so that patients think about these things. I think the bottom line is just being a more informed patient will make you a better patient.

Jenny: Yes, I agree because I think if you're educated as a patient, you can write down your notes and ask your questions and make sure you get everything answered. You do realize that everybody's so busy. The doctors are pushed really to the max in my opinion in terms of what you're expected to do. Sometimes, things just get missed just because everyone's so busy.

Dr. Fonseca: I play a role here at Mayo as you mentioned there in the introduction. I have an administrative role chairing the Department of Medicine. We're very fortunate in a system like Mayo Clinic where we have what we call the unhurried appointment. For me, that means that if I see a new patient, I will get an hour to see the person. If you see someone in return, you get 30 minutes. That's considered very generous. You have health systems where patients are seen every ten to 15 minutes sometimes with people running between the rooms. I think one of one of the antidotes to those things falling through the cracks, it’s still being a very informed patient.

Jenny: Yes, I completely agree. That's one of the reasons that we're creating new things like HealthTree University. That would be coming soon for patients so you can really get up to speed. Well, you mentioned innovation at the beginning. I want to go back to that and see what your ideas and thoughts might be about innovation because if you look at the market, there are lots of different companies who are developing different medications in myeloma. I think we're so lucky like you were saying at the beginning that we have such interest from all these different groups. I think that's what shocked me the most being at the last ASH meeting, watch just the number of companies that are jumping into the space. How do you encourage greater innovation especially with such a lengthy approval cycle? I know the FDA has a job to make sure that we have drugs that are safe. But are there things that could be done (and I know myeloma has benefited from this accelerated approval process), but how does that process and the regulatory side impact the innovation in your opinion, from a clinician’s perspective? 

Dr. Fonseca: Sure. Well, I mean this is a very complicated question because you could take a couple of approaches. You might say, “Well…” I think everyone agrees with the statement that innovation is good. It would be hard to argue against. But the level of evidence that sustains what we consider innovation is different for different people. You can take an approach where someone might say, “Well, I could envision a situation with regulatory authorities, be that the FDA or other authorities abroad.” It could take more of the view of saying, “Our purview is more focused on the safety than it will be on the efficacy.” Then we can let things play out down the line with regards to efficacy in what's called now the real world. There's actually some good precedent for that. An example for that would be things such as -- let's use a medication, Frydak, or panobinostat. Panobinostat, many in the audience will probably have not heard about it even though it's an FDA approved drug for the treatment of myeloma, which in my eyes, was a fairy tale in how it was developed. The preclinical work from the group at Dana-Farber identified this as a potential target for a drug in myeloma. They designed a clinical trial. This was a Phase III clinical trial that if it was any other disease, if it was being used in, say, pancreatic cancer, it would have been a blockbuster medication. But it turns out it didn't have the efficacy and certainly had significant toxicity so that -- number one, it’s the medication. First of all, the company Novartis that developed this clinical trial (which was very well conducted and it was subsequently published in procedures journals), decided to stop promotional activities because doctors were not using panobinostat because the data was not supportive of its use. Most recently, I just heard that the drug was sold to another company to see if they would have interest in that. But the reality is that the market didn't support that drug being a good tool for the treatment of most myeloma patients. There some patients who will respond very well. If some have taken it I’m hearing in the audience, then that is great. It's just that at large, it was not a good medication.

So that would be the approach of saying, “Well, the FDA is only focused on safety.” But even if you take that approach, you could say, “Well, if you treat 200 patients, what if there was a drug that caused a serious side effect, let's say blindness, in one in 10,000 patients. You would never know that from clinical trials.” So part of that still comes as a real world experience afterwards. On the other hand, if you take an approach that you say, “Well, no. What the FDA should be, not only safety but it should also do extensive studies for efficacy and should only approve drugs once it's very clear that these drugs have a very significant impact on overall survival and we have very large cohorts that we know is safe,” the net result will be that you will have drugs that are going to be better tested by the time they reach the market. But unfortunately, they may be reaching the market five or ten years later than would you have been able to use before with a more liberal approach to approval. An example of this is pomalidomide. Pomalidomide was approved before there were large Phase III clinical trials. Arguably, there were a lot of patients that gained benefit from pomalidomide.

There are no easy answers. In fact, one might say that if you lengthen the approval process, because that's going to erode into the time that the drugs will have patent protection, any company that launches a product like that will have to ramp up the prices because they need to recover the investment whatever time remains of their patent protection. There's no easy answer. I tend to more biased and skewed towards the idea of approving early because I think that also fosters competition. If you have a drug that works against the target, then another company could more quickly develop another drug against that same target and maybe compete. Some of that, for instance, was seen with a case of hepatitis C. 

Jenny: Yes, well, I think I would agree that because currently, it's very hard to close that loop right now, right? There is not a system that's capturing all the real world data from all the myeloma patients who have been on all these different lines of therapy (HealthTree.org can do this today). You're not actually quite sure how everybody responded. You see the clinical trial results faster than the ten or 20-year outcome data from that. It seems like having a data system to capture it all is really important. Then can you give patients an idea of how the costs that it takes for a pharma company to get through a Phase I or Phase II or Phase III study? Because you were saying earlier that if you're participating in a Phase III study with hundreds of patients and you're comparing it to the standard of care, which maybe you could do in a different way, if you just had a data system that was capturing that data, you wouldn't have to do it necessarily in a Phase III clinical trial to keep the costs down, to let more pharma companies jump at the space and try it out and see what they can do.

Dr. Fonseca: Again, this is an important point because there is no question that the process of drug approvals is incredibly expensive and perhaps even getting more expensive.  When you look at the efficiency with which clinical trials can be run to ultimately lead to approval of these drugs. The numbers vary depending on how the computations are made. The most comprehensive analysis has been done by a group, Tufts University. They came up with a number of around $2.6, $2.7 billion per drug. Now, that is disputed. Some people don't like the algorithms that are used. Some people dispute the number because the group has been funded. One of their funders includes sectors from the pharmaceutical companies. But to the best of my knowledge, no one has been able to actually refute that number with as comprehensive an approach. Part of what they have is they have proprietary methods for the analysis of this. Now, I'm aware of two other individuals who have done an analysis similar to this. Merrill Matthews and then also a reporter from Forbes, Matt Herper, who actually came to very, very close numbers looking at the expenditures in R&D versus revenue.

Now, at the very least, I think some of the numbers that could be thrown would be close to a billion dollars in the low end. It’s $1 to $2.7 billion. It takes a lot of money. It’s the same goals. That first pill costs $2.6 billion. The second pill is going to cost cents to be produced. It is the process of innovation. It’s important, so is intellectual property protection and the period that these drugs will have on their patent. Again, I don't think anyone has the right answer. Obviously, there's a lot of conversation about the duration of patents and in particular, the transition of medications from patented to generic, which I think everyone agrees that that should happen. But there a period of time and a number of sales that occurred during that period of patent protection. That is what determines the revenue for these companies.

It's pretty complicated. That's why I probably shouldn't go out and venture to say much more on the finance sciences. It’s not my area of expertise. But I was looking at the list of the most profitable companies last year. It turns out Lilly lost $200 million, Lilly which is the company which is at the forefront right now of the conversation regarding insulin. I think that is probably true for most human endeavors. Things are far more complicated than they seem at first glance.

Jenny: I'm just wondering because it seems like myeloma has been really fortunate in its development of the myeloma drugs where you have drugs like daratumumab and carfilzomib and pomalidomide that according to some researchers that I talked to on Saturday, they said those were benefited by this accelerated approval process. They almost got approved after the Phase II study instead of waiting for all the Phase III results to come out. Then you can, like you were saying, get them used earlier in the clinic and help people using them. Maybe an earlier approval, like you're saying, after a safety assessment and then letting the market decide what's better if you have a system that can capture the outcomes, it might be less expensive and then really drive innovation. 

Dr. Fonseca: Absolutely. A way that I think is of good to everyone in the myeloma community is that we have the interest from investors in biotech. Because absence of this interest, the money probably could be going to some other things: telecommunications, laser technology and other things. But the fact that myeloma has been a path by which several companies have been able to get their drugs approved, it encourages even further interest in myeloma. People saw that there were approvals for thalidomide and then Velcade and Revlimid. That stirred a lot of interest. People actually brought money to the table so to speak.

And you see what's going on right now with other diseases such as Alzheimer's where many companies have lost a tremendous amount of money. There is a big worry that people will not want to invest anymore in clinical trials that are targeting Alzheimer's disease, which is obviously a huge problem when it comes down to human health and longevity. But these companies are failing there. Just recently, a large company, Biogen, had a huge clinical trial fail. The billions of dollars that were lost in that will not be recouped. Unfortunately, that sends a signal that that may be an area where you may not want to be doing a lot of clinical research, which is quite the opposite of what we have seen in multiple myeloma. And what we want, of course.

Jenny: Do you think earlier testing would be less expensive and over the long run, if more testing is done -- because I know there's data that shows that if you're diagnosed with, let's say, MGUS or something, one of the early precursor conditions, you actually do better over time just because you're watching it more carefully and you're able to intervene when your numbers start going up. Do you think more testing would be better? Or do you think that's just an extra expense that we shouldn't be spending? 

Dr. Fonseca: Well, I think it needs to be tested a little bit further through population-based studies. Some of them are going on through the Scandinavian countries. But I think there could be a future, a better future where people could do early testing. Then if you have someone who has indicators of early myeloma in the form of smoldering or in advanced MGUS, then maybe you keep a close eye on things. Certainly, you want to intervene before people would have lost either kidney function or they would have developed bone lesions that would lead to pain. In the ideal world, you could even think about treatment. In fact, we are starting treatment earlier than we used to based on some of the revised criteria now for treatment initiation for multiple myeloma. The ideal world would be someone gets treatment before they have complications, maybe with highly effective therapy, with regimens that it can cover most of the subclones and ideally also with a time-limited duration. I mean right now, we see that maintenance is very, very important.  But it would be even better if we could treat myeloma for, say, two weeks or four months or some defined period of time that would allow people to return back to their lives without having to require treatment anymore. 

Jenny: Yes. Patients would love that. My final question would be how do you see a data system like HealthTree (www.healthtree.org) helping with this, helping on the innovation side and also helping to overall help reduce costs?

Dr. Fonseca: Well, I think that first of all, the ability to understand better treatments and their side effects and things to be looking out for and how they provide durable responses in patients with different conditions or with different genetic makeups would be probably the path for the future. A personalized medicine approach where the patients get what's often stated as the right treatment at the right time would be ideal so that maybe patients with certain genetic markers could get group of drugs that is going to be effective and other patients without those markers will be spared the toxicity and the expense of those medications.

A great example for this -- and I know this is on pause. I'm not going to use this as a venue to say people should go into this medication but it was Venetoclax. Venetoclax turned out to be highly effective and active against a subgroup of patients, namely those who have the translocation 11;14. We just need to go back and understand what were the issues related to the combination with Velcade. But it's not farfetched to imagine that once everything gets cleared that maybe drugs like Venetoclax would be used even into additional myeloma patients or perhaps even for maintenance. But we have to get all the safety signal cleared before we do that. But I think that is one example where things will go into the future.

Jenny: I think what's happening in myeloma care is so exciting and so promising. It's just encouraging to see what's happening. Our goal is to help find the right treatment for the right patient at the right time and fund research that's going to be doing that. So we're just -- we're excited. 

Dr. Fonseca: Thank you. It's very, very exciting time obviously. As I always say, today's best is simply not good enough. We need to keep going. But things are moving in the right direction.

Jenny: Thank you so much for participating and for joining us on this really important topic about costs in myeloma care. You have a lot of things you think about when you’re a patient and cost is definitely one of them. Thank you very much for joining us today.

Dr. Fonseca: Well, it’s always my pleasure. I look forward to our next conversation.

Jenny: Okay. Thanks so much.

Dr. Fonseca: Bye.

Jenny: Thanks for listening to Myeloma Crowd Radio. We invite you to tune in next time to learn more about the latest in myeloma research and what it means for you.