Dr. Rafael Fonseca of the Mayo Clinic Scottsdale discusses today’s and tomorrow’s myeloma genetic approaches

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Originally posted on mPatient Myeloma Radio<

Dr. Rafael Fonseca, MD, Mayo Clinic Scottsdale

Interview date: October 11, 2013

Summary

Dr. Rafael Fonseca describes his research focus on genetic markers for myeloma and how they can become predictors for disease type and progression. He shares his belief that MGUS starts quite early, possibly even as early as childhood and that other genetic triggers cause it to become myeloma. He explains myeloma tests and how he and the Mayo Clinic focus more heavily on the FISH test and the gene expression profile test to determine risk and prognosis over cytogenetics. He notes that half of MGUS patients have translocations (or places where chromosomes have swapped places) and describes how that translocation will never change, even if secondary genetic markets change after treatment. He predicts that gene sequencing will be the up-and-coming approach to help find what “triggers” inactive MGUS to turn into myeloma. He also describes how a gene-specific approach is still early in its use but cites a study example of where this has already been done (the Cereblon gene’s effect when using IMID drugs like lenalidomide).  He describes the patients’ need to educate themselves and specific questions they can ask to make sure their FISH test and gene expression profile are done correctly.  He shares the wide range of active clinical trials at the Mayo Clinic – from MGUS to smoldering and then to advanced disease stage using a variety of approaches including combination therapies, a monoclonal anti-CD38 study as well as an early gene-targeted study called CDK5. He also explains a study using NAB-Paclitaxel (an iteration of Taxol, a drug used for other cancers) that is used for advanced myeloma resistant to other therapies.   

The live mPatient Radio podcast with Dr. Rafael Fonseca

Full Transcript

Jenny: Welcome to today’s episode of mPatient Myeloma Radio, a show that connects patients with myeloma researchers so that we can accelerate the pace of discoveries by participating in clinical trials. There’s a lot we can do to help researchers reach their targets and it’s something we can do even when we don’t feel good or are in treatment.

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Today we have an interview with Dr. Rafael Fonseca who is a myeloma cytogenetics and genetics expert at the Mayo Clinic in Scottsdale.

Dr. Fonseca: Hello.

Jenny: Hi, Dr. Fonseca?

Dr. Fonseca: Hello. Yes, this is him.

Jenny: Hi, this is Jenny Ahlstrom. You are live on the mPatient Myeloma Radio Show.

Dr. Fonseca: Well, thank you. It is my pleasure to be on your show.

Jenny: Well, thank you so much for joining us today. I would like to give everyone a little bit of background about you before we start if that’s okay.

Dr. Fonseca: Perfect. Yes.

Jenny: Dr. Rafael Fonseca is a Professor of Medicine and a Consultant in the Division of Hematology and Oncology at the Mayo Clinic, Arizona and is also a Getz Family Professor of Cancer. He earned his M.D. degree at the Universidad Anahuac, Mexico; completed his residency at the University of Miami and a fellowship in Hematology and Medical Oncology at the Mayo Graduate School of Medicine in Rochester. He is a Clinical Investigator of the Damon- Runyon Cancer Research Fund

He has received numerous awards including the Young Investigator Award in Hematology from Celgene and the Damon-Runyon Walter Winchell Clinical Investigator Award. He is a member of ASH, ASCO and the American Association for Cancer Research and International Myeloma Society. He is part of several clinical trial cooperative groups and is a founding member of the MMRC, the Research Consortium of the MMRF. He reviews grants and is part of the SPORE panel. He also reviews for medical publications and has authored over 150 articles. In his lab, Dr. Fonseca leads a team with a focus on the cytogenetic nature of the clonal cells of plasma cell diseases including multiple myeloma.

Dr. Fonseca, we are so delighted to speak to you today. Thank you so much for joining us.

Dr. Fonseca: Oh, thank you. It’s my pleasure to be in the program.

Jenny: Would you like to give a broad overview of your research to begin and then we can begin with more specific questions?

Dr. Fonseca: Sure, of course. Again, thank you for the opportunity. I’ve been working in myeloma now for the past 16, 17 years in both my clinical translational activities as well as the lab. We have been focused on the idea that the understanding of myeloma cells, very specifically the understanding of the genetic markers associated with myeloma biology, we can better care for our patients.

There are multiple goals with this. One is can we find additional targets? Can we use some of that information to actually improve existing treatments? And also, can we establish various prognostic categories for the disease?

We have been very fortunate that alongside with these efforts, myeloma over the last ten years has seen a dramatic and almost would call it an exponential expansion in the number of treatments and options that are available for patients. We have had to adapt rapidly over the years to try to understand what we knew, how does that relate to what we currently know, and how does that relate to the new drugs that are available in the field?

That’s kind of in a nutshell what we have done. My lab, I would say, is primarily interested in doing things that have clinical value, that have some applicability and that is not to say that other avenues of research are not important, but in mine, there’s a very quick translational approach to see what we can learn that we can bring to the bedside.

Jenny: It’s very practical

Dr. Fonseca: Very practical, correct.

Jenny: I know you have research in the area of MGUS, and you have been studying how MGUS progresses to myeloma. Can you share a little bit about that?

Dr. Fonseca: Sure. First of all, I should speak about my pedigree because I’m only interested and fortunate to work in that area because of having to work with people like Dr. Bob Kyle and with my colleague as well, Vincent Rajkumar, up in Rochester. That’s a team that has historically defined the natural history and the clinical aspects of MGUS. We’ve tagged along trying to understand can we put a layer of some translational research into understanding MGUS? I think through their observations we know a lot more about MGUS than we actually previously knew.

For instance, a couple of seminal observations have been that we know that all myeloma patients have gone through an MGUS stage pretty much. This has worked on both in our center as well as in collaboration with other institutions where I think one of the most notable examples is a repository associated with army recruits where individuals were getting blood samples collected every year. It turns out, became a large repository and Dr. Brendan Weiss led some of these efforts. Over time they learned that 60 individuals in that cohort developed myeloma and because of this previous collection we have the samples. So the samples were tested and people found out that all myeloma patients essentially have had an MGUS before they were diagnosed. Now that was a fundamental observation.

Another work done by some of the group from statistics in Rochester had shed light on, well, we know that MGUS is present but for how long? Using some models they have developed for the assessment of other diseases like HIV, they were able to find that patients have had MGUS for many years. Now this is central to the core of what we’re studying because I have done work and my team has done work finding out that MGUS cells harbor the same genetic abnormalities as myeloma has. With that knowledge and also with the knowledge that those genetic aberrations are there, we know that they are not sufficient to cause the cells to become what we would call cancer cells so there’s a need of acquisition of other abnormalities.

We’re trying to put all of these together because we would like to, one, understand how this happens. I think most of us think right now MGUS is an accident in nature. I myself, I will go out and say that I think it’s quite likely that MGUS starts very early in life, perhaps even in as early adult years, maybe even in childhood. It almost takes a lifetime for those cells to very, very slowly grow to the point that in some cases they give rise to myeloma. So we again want to try to put a layer of the genetics on that. Can we predict better who’s going to progress? Again, a lot of this work has been done trying to understand what clinical biomarkers might predict. I have a particular interest in genetics as predictors. I think that’s something that we have some good signal that it might help although one needs very, very large studies to make those final determinations.

I am currently working in other biomarkers that might predict progression from MGUS. Specifically, we’re looking at the number of biomarkers to see if we can predict ongoing or impending bone destruction.

That’s kind of in a broad view of what we’re doing in the area of MGUS and pre-symptomatic myeloma.

Jenny: That’s wonderful. I know there are some new tests and you’re a cytogenetics expert and a genomics expert so maybe we can spend a little time talking about the tests.

In our last interview, we discussed briefly but I think it would be really helpful to talk about each of the categories of tests like the FISH test and the cytogenetics test and maybe the gene expression profile and get into a little more detail about which test tells us what information.

Dr. Fonseca: It’s been now since the mid-1980s when the first observations were made about cytogenetics. For those in the audience, it’s the study directly of the chromosomes, which requires that you put the cells in a culture media, the cells divide, and we can put substances that will arrest that division so you can actually look at the chromosomes as they are depicted in textbooks. That proved to be a very useful technique for the study of patients with myeloma so that one could establish prognosis, could link that to outcomes. Unfortunately, that’s a test that doesn’t work for most patients because in most cases you don’t get the information.

We moved on to the FISH test, which has been used over the last 15 years. We can establish actually with better ability to predict what’s going to happen. We can establish prognosis that we did with clinical variables alone. We’ve been using that to determine the myeloma category whether it’s high risk, it’s not high risk, et cetera. That has again been done routinely in the clinics. For those in the audience who are not familiar with this, FISH is a way where we actually can put some probes against the myeloma cells, and we look at them under the microscope. Looking at them in the microscope, we can count the number of chromosomes; we can look for translocations and the like. It’s a very, very practical tool that has been used in the clinic.

Now more recently, there is the thought of using gene expression profiling and without a doubt, a lot of this pioneering work has been done by the University of Arkansas which have applied this technology to myeloma samples. They can, even better than FISH, predict outcome for patients. There’s some technicalities on why one test may be preferred over the other in some circumstances, but more and more I think patients will see this type of approach as we study their bone marrows and try to establish prognosis and then hopefully, in the near future, help us in therapy selection.

You’re going to see more in the realm of next-generation sequencing, high-throughput sequencing where we might be able to associate mutations with specific therapy. Some of the members of the audience may be familiar with some of the work that Keith Stewart is doing where there’s this gene that’s called Cereblon that appears to be very important for response to the drugs we call IMIDs, the lenalidomide and thalidomide. That still is being developed, but it’s quite likely that tests like that will allow us to say, this is a go or no go for this drug. And if it’s no, then what might be the other options for the treatment of patients?

So that’s how we’re trying to bring genetics into the clinic. I think people are now accustomed to use this as routine of care and for those in the audience I guess you’ll see more and more of this.

Jenny: One question about that. At a patient conference, I asked the group, which was probably 200 people, if they had had the gene expression profile test done and only about 10% of them have. If our target ultimately is to treat myeloma at a gene-specific level or a cytogenetics-specific level, I think we all need to be getting this test. Is that a correct assumption?

Dr. Fonseca: Well, one could clearly make the argument for that, although primarily it’s been used right now for prognosis. It’s not being used quite yet universally for therapy selection, that’s the gene expression profiling.

We do think it’s a very important test as one that helps you provide a little more precision. The reality is that there is not going to be a test that is absolutely perfect for prognosis determination. So it gives us an approximation of what we may be dealing with, but it doesn’t necessarily give you a full answer. To some degree you get an approximation, a very good one when you do the FISH test alone, and you can improve a little bit on that with the use of the gene expression. But for all practical purposes, I think one or the other is sufficient for patient management at this present time.

Jenny: We’ve had this conversation with a few other doctors as well, and that’s kind of a consensus. But where I see it going in the future is more specific and even though it sounds like it’s not possible today to treat based on these profiles, I think unless we have these profiles that we can’t ever get to that point. As an expert, what do you think? Should we be encouraging patients to seek this test out?

Dr. Fonseca: I think patients should be encouraged to have this testing. Certainly, they should discuss this with their physicians. I would say, at the very least, FISH — in our center, we don’t really use cytogenetics anymore, but FISH would be necessary. And if they can and that’s part of the workflow in the physician’s offer the are seeing, I would definitely have them go for gene expression profiling.

As I mentioned, right now we’re still mostly using it for prognostic. I think we need to get to the point that it’s predictive. What I mean by that, let me say — you might say, if you’re going to look at the street race for cars, you might say, prognostic might be — I’m going to say something bizarre — maybe you’re going to bet on German cars more than Japanese cars if you’re looking for performance. So if you’re making an estimate of what you think the aggressiveness of the disease would be, that’s prognosis. Predictive would be if you have the same cars, some cars will run on diesel, some cars will run on gas and you won’t change that. There’s many reasons why a German car might lose on the race, so that’s the prognosis variability. But you know that a car that is diesel can only take diesel.

So we want to get to the point that genetic markers allow us to make those type of determinations where we say, we shouldn’t waste time with this treatment. We need to go to the next one or we need to go to a combination. Will we ever get to that point? I think we’re going to get it close, I don’t know if it will ever be perfect, but we certainly can do better than what we’re doing right now.

Jenny: I see a lot of new drugs that are cell inhibitor drugs like the HDAC inhibitors and the kinase inhibitors. Are we able to look at studies for those types and ultimately maybe we can get to this point where we have studies that are for a particular subtype of myeloma patients that are studying an HDAC inhibitor because — I don’t think it’s possible today but could they be specific to a subtype of patients?

Dr. Fonseca: I agree and I think we might even see that in the future there might be studies that target specific a genetic lesion irrespective of the tumor. So you might say, well this mutation is rare in myeloma. Maybe, let’s say, it’s present in 5% of cases. But if it’s also present in bladder cancer and it’s present in lung cancer, you might see a clinical trial where that drug is used for any patients who have that mutation irrespective of their tumor type.

We’re thinking more and more along the lines of what are the molecular defects and therefore the molecular targets more than necessarily the anatomic location of a specific cancer. So that would be one of the solutions. You might see some trials that may target just a subset of myeloma patients because it’s very specific to myeloma, and patients will have to fulfill some criteria for a biomarker or something else that makes them be in that category.

Jenny: Now I was doing some reading about some of your research about IgH translocations. Can you explain what those are first and then what you have found?

Dr. Fonseca: Sure. One of the things that we have found in the cells of myeloma and also in the cells of other patients with lymphoma is that they can have abnormalities that involve the site where actually we produce our immunoglobulins. This site we also call the IgH and stands for the heavy chain of the immunoglobulin. It turns out during the normal development of B-cells, that is a genetic part of our body that has to undergo rearrangements. That’s just a word we use to say that there are little pieces that are cut out, that are excised. There are normal physiologic mutations and that is a gene that gets rearranged. Usually, we can produce a perfect immunoglobulin that help us fight off infections from bacteria and viruses.

So if we look at a perfectly healthy baby, that baby is actually undergoing mutations in its B-cells. Usually, it can generate the necessary antibodies to form immunity. You can imagine, if you’re dealing with chopping off DNA bits and so forth, it’s sort of a risky proposition because if something goes wrong, then that could actually lead to a cancer. Well, it turns out the system is very, very unforgiving. Any mistake is immediately detected and those cells die so our bodies in general are well-prepared for dealing with those typos. But every now and then, one of those typos does not get recognized and then just stays there.

Normally, what happens with the translocations and that’s where we have worked. You have a strand of DNA and that’s where you have your genes. A little cut is introduced and when you have that cut, you have those free ends that normally should be together. They can actually go and exchange partners, sort of interchange of segments of chromosomes, and that’s what we call a translocation. It’s kind of like a partner exchange between two different chromosomes, and that we think leads to about half of all myeloma cases. In fact, those translocations are seen in patients with MGUS as well too. About half of patients with MGUS have those translocations.

I think from what we know, they’re found in their lesions so that’s probably one of the very first hits that occur in B-cells that ultimately become myeloma cells. But we know we have patients again with MGUS who may have these translocations for decades and don’t have progression. As I mentioned previously, they appear to be necessary but perhaps not sufficient for imprinting the full cancer behavior to those cells.

Jenny: So there’s some other trigger?

Dr. Fonseca: There must be another trigger. We think they collaborate with other genetic abnormalities that are subsequently acquired on those cells. It turns out actually that the different translocations imprint a different variety of clinical behavior to the myeloma. For instance, two translocations, one between chromosomes 4 and 14 and the other one between chromosomes 14 and 16 so we call them the t(4:14) or the t(14:16) are associated with a more aggressive form of myeloma, whereas the translocation 11:14, in general, is associated with a more favorable version of the disease.

So that’s how we’re studying translocations. Obviously, they’re ideal targets if one had a way to shut them down, but it turns out they’re very powerful genetic changes. So there’s not, as of yet, a good system whereas you can “just shut down the production” of the genes associated with translocations in the hopes of treating a tumor, although people have tried.

Jenny: Or put them back where they belong, basically?

Dr. Fonseca: Oh, think that would be too complex. It would be very, very hard. I don’t know if that would be possible because every single cell has a translocation. So you’d almost have to just make sure you can give a drug that targets the effect of the translocation.

Jenny: Interesting. That’s the heavy part of the chain and then there’s a lighter part of the chain. From what I understand, the IgG kappa or IgG lambda or those types are the light part of the chain, and they don’t have necessarily a prognostic effect or do they?

Dr. Fonseca: The translocations there are uncommon. For the audience, I’m going to make a distinction. There’s a difference between a translocation, so we’re talking about that in the kappa and the lambda. But then we have the same terminology applied to the proteins we measure so that you have the kappa and lambda proteins and the free light chains. It is probably familiar to most people. Those don’t have a very strong prognostic significance. However, if you were to say anything about them is that the lambda ones have a slightly higher association with the high risk version of myeloma although we don’t really use that as a prognostic marker in the clinic.

Jenny: Okay, that helps my understanding. The heavy chain part, is that a new test?

Dr. Fonseca: We’ve always measured the heavy chains through the serum protein electrophoresis, the immunoglobulins. We can now measure for the last several years, as you know, the free light chain which is the unbound fraction of the light chains that are supposed to be associated with heavy chains so that’s proven to be an, I’m going to say, incredibly useful test. It’s something that I can’t imagine how our practice would be now without it because it’s a very reliable and sensitive form of detecting monoclonal proteins.

There’s a proposal now for a new test that is sort of like the free light chain, but it measures at the same time the heavy chain. This is still undergoing clinical trial testing, but it also looks quite promising.

Jenny: It seems very complicated that you really need an expert in your corner to be able to perform all the tests and then analyze all the results. Beyond choosing a specialist, which I highly advocate, what else could we do to help patients better understand their lab results?

Dr. Fonseca: It is complicated. First of all, the fact that there’s people listening to this program is already a reflection of their interest. We work with the various grassroots organizations, foundations, Leukemia and Lymphoma, MMRF, IMF, et cetera to disseminate some of this information. But there’s no question, it’s a very, very complex process. Ultimately, I think in time — I’ll speak for my patients — I think we’ve spent quite a bit of time explaining the testing so that they become familiar with what we’re looking for. I think one just needs to really focus on education.

One of the things we have learned is that obviously, as you said, we advocate and could we construe this self-serving, but we advocate that people visit with a myeloma specialist at least at some point so they can help them plan out the long term. But as they work with the community doctors, there are two things that I think are important for patients to know. First of all, the risk stratification. I think we talked previously you can do that for the FISH and gene expression. But I think it is important for patients to have that discussion with their physicians. It gives you a different hue to what you plan, how you plan for treatment, what to do after transplant if transplant is on, et cetera.

For them I would just have them, instead of think about all the genes and the different tests, just remember if the FISH shows either 4:14 or a minus 17, it’s high risk and everything else I would call not high risk. It’s a very pragmatic and simple approach just to make that determination, and I think most oncologists in the community should be able to at least recognize the importance of the two categories.

The second one which creates a lot of confusion is the free light chain which you already alluded to. I tell my patients and I know there are more technicalities, but I want to make it very simple. Once you know which one of the two free light chains is the abnormal, so the kappa or the lambda, you don’t ever again have to look at the ratio. You just focus on the total amount of that free light chain, and that’s never going to change. If myeloma is IgG lambda, then that myeloma is lambda and then we could almost, almost — and again, I’m going to leave those out the technicalities — forget about the kappa. I would tell my patients forget about the ratio, forget about the kappa. We’re just going to be measuring the lambda, and that makes our life simpler because then we can just measure how the lambda goes down with therapy. We want it to stay down. If it came up, then we would be concerned about disease activity and so forth.

Those are two things where I think patients can help the providers because admittedly again for a community doctor where myeloma could be 3% of their practice, 5% of their practice, they don’t necessarily know all the nuances of the management of this.

Jenny: I agree and I really advocate having a specialist even if you need to get your treatment somewhere else and you can’t access one on a daily basis or a monthly basis or whatnot, I still think it’s important.

In one of our other interviews, we were talking to one of the specialists and they were saying that there is right now at least in flow cytometry, there was a hundred times variance in the level of sensitivity of testing. As a patient, that might be in any spot in the United States or in the world. How do we know as a patient or how can we know, what questions can we ask to make sure that our tests are being run with the sensitivity level that we need?

Dr. Fonseca: I think it’s important to actually inquire about this. For instance, let me use an example. If you do the gene expression, you must insist that it’s a good aspirate and that the results are reliable and the company does very high quality work. But they do rely on the quality of samples that are submitted for testing.

If a person is to have FISH, the patient and their families — and I know some of this is going to be archived — but they have to look for FISH that is done in either what we call selected cells so they have to enrich for the myeloma cells or they have to use a secondary marker, something we call the CIG. In the absence of those, the test becomes highly unreliable.

When it comes down to flow cytometry, if it is to be done which doesn’t necessarily have to be done in every patient, but if it is to be done, it has to be done with a laboratory that has a competency to do this and venture out to say most of what’s available right now for commercial flow cytometry just doesn’t quite cut it for what we need for a minimal residual disease. It’s become complicated.

I probably would insist on the first two. And if they’re going to do flow cytometry, I would say that probably I would take that still with some reservation.

Jenny: What can we tell patients about where we can get the test or what questions do they need to ask their lab, I guess, not even their doctor, maybe the lab?

Dr. Fonseca: It is complicated because usually what happens is hospitals and physician offices will have various sets of systems and contracts to work with the various laboratories. Usually, this will cover a range of tests, not only the myeloma test. They can inquire and they can — I’ve not done this myself, but I would imagine if they inquire, they can get probably some detailed information regarding the test that is being done; what are the outcomes, what are the probes that are being measured.

The major commercial labs now are doing this as routine, some of these tests we mentioned, but I would definitely engage with a doctor’s office just to see what the specifics for the testing are.

Jenny: Well, wonderful. Before we leave testing, I guess I want to ask, how often should the testing be done? Because I’ve had a friend who actually came to you as a patient and thought you were wonderful, and her markers changed.

Dr. Fonseca: It is a very tough question. I have this friend I will use as example who. He describes himself as a hypochondriac. He says, “I’m not comfortable unless I have my daily CAT scan.” Of course, that’s a joke but it really reflects the difficulty that we have in measuring things.

For patients who are undergoing active treatment, I would say that at least monthly determination of the values is important. We do that on a monthly basis where we gauge progress or lack of. The idea has been that as patients complete therapy and they’re stable, this can be spaced out every two to three months. This is a discussion I have with patients because some patients might say, “Well, I’m not very comfortable,” and I know some physician office test every two months, sometimes every month. You can even ask the question, why not every two weeks? It’s become sort of a pragmatic aspect of how you want to manage patients. There are some patients who prefer the higher frequency.

I think we run into some problems where it gets more complicated is in the pre-symptomatic stages of the disease. There are many, many patients with MGUS and smoldering myeloma that we follow. These patients are followed at somewhat regular intervals. Some of them could be followed once a year; some of every three months. I can’t come up, as of yet, with a perfect algorithm that should tell you for this or that person this should be this frequent.

I think because of experiences where we have seen someone who has an MGUS or a smoldering and then the next thing we know we’re seeing progression of the disease for the younger patients. I know some of the audience may laugh, but I’m thinking well anyone under 65 who has this. Maybe we should do it every two to three months, and that’s where I’m moving right now with my practice just because of the potential of years lost.

Again, if you’re 70 and you’re not comfortable with every three months, you may want to discuss this with your doctor. But there’s really not a perfect timeframe for this and it becomes a bit of a practical one.

We do have some indirect markers that will tell us about risk of progression. If I had a patient with MGUS who had a low free light chain who had a normal creatinine, normal hemoglobin, a perfectly normal bone scan and a low level plasmacytosis — I’m going to use an example, 15% — I think the risk for that patient is really minimal so I would be very comfortable with extended periods between testing although I don’t have a crystal ball and I couldn’t tell that person without a doubt that if something was to happen, we will detect it before it does.

Jenny: What about changes in your genetics?

Dr. Fonseca: The genetics is interesting. There’s two aspects of genetics. One of them is the core, and the other one are the secondary changes. The core genetics never change so the 4:14, 14:16, those will never change. The secondary ones can. A person can acquire a deletion of 17; a person can acquire monosomy of something or some rearrangement. What we say is the core genetics only need to be tested once, like the translocations. Sometimes we’ll repeat testings. You could repeat the p53, you might repeat also gene expression profiling, but to some degree, that’s almost like a self-fulfilling prophecy because if I’m seeing a patient and the person has been through a number of lines of therapy and then I’m seeing that patient again in consultation and it appears the disease is acting up and has some features of aggressiveness, I am not sure to what extent that’s going to get me in a better position to decide what we’re going to do for treatment because right from that moment I know I have to put the best next combination that’s available for that person.

To some degree, in the setting of patients who have been previously treated, the markers we use at the time of diagnosis start losing a little bit of their prognostic significance. It gets a little bit complicated as you go down into subsequent lines of therapy. Even to some degree you might say that it could be counterproductive. For instance, let’s say you have a patient who has one of these high-risk markers or at least a classic high-risk marker, so let’s say the 4:14, and that patient is now getting seventh line of therapy. Well, we know that most patients who have a 4:14 unfortunately will not get to the point that they can see seven lines of therapy. So that in and of itself tells us that that particular patient with that 4:14 probably has a more favorable prognosis as opposed to a more aggressive one.

Jenny: Interesting. Thank you for spending so much time on the testing because I know that if we’re going to get to more personalized care, then we need to find out what kind of myeloma we have, but it’s clearly complicated.

Dr. Fonseca: Yes, definitely.

Jenny: Thank you for spending time on that. Would you like to go ahead and talk about your clinical trials or what you’re working on now?

Dr. Fonseca: Sure. I’m part of a larger team. We’re all here in Mayo Clinic in Arizona but work in collaboration with the Mayo Clinic at large with our colleagues both in Rochester and in Florida. We have quite a range of clinical trials that are open for patients that go from the pre-symptomatic stage — the MGUS and the smoldering — to fully active myeloma. We have a number of trials. I think for the frontline therapy we have been engaged on multi-drug combinations including the CYCLONE clinical trial which uses carfilzomib in combination with dexamethasone, dyclophosphamide and thalidomide which has proven to be a very good approach. Similar approaches probably you’ve discussed in your program. The carfilzomib, lenalidomide and dexamethasone combination of Dr. Jakubowiak. That’s one of the interests we have.

We have also looked at multiple drug combinations in the setting of relapse and refractory, as well as novel agents. So we have ongoing clinical trials with a number of drugs such as oral proteasome inhibitors. We have clinical trials going on with monoclonal antibodies specifically one which we are very keen on is the C38 antibody which has been shown in other centers to be a promising avenue for patients with myeloma.

As a result of some of the research that has been going on here, we have inhibitor of this gene called CDK5. Dinaciclib is the drug and this was worked on by my colleague, Dr. Stewart, which is also showing some good promise. We have been engaged on the study of other drugs through some research both with animal models as well as some historic data. We’ve actually started to use some of the novel formulations for all the chemotherapy so we have drug that is called the NAB-Paclitaxel which is an analog of Taxol which is used in many other cancers with some ability to control the disease in fairly advanced patients.

So we have sort of a whole range of options that are available for patients. One of the challenges always is that one has to meet the criteria for being in the clinical trial; and two is almost always they have to actually pretty much live next to the treatment center because a lot of these trials will require either frequent visits or usually the administration can only be going at the site. I think one of the things we hope is that all our centers and many centers will have clinical trials so that they are available closer to where patients live. That’s one of the things we continue to work on.

I would say that’s the spectrum of what we have right now in clinical trials. We have been very fortunate. I think one of the things that keeps us going with clinical trials is that we have been very fortunate, for instance, in working with pomalidomide. I think that Mayo had the opportunity of treating hundreds of patients before it was approved and see firsthand that it’s a drug that is able to control the disease in many patients.

I personally had patients who had evidence of disease that was clearly refractory to lenalidomide and the revlimid. And then they were responsive to pomalidomide so those are very gratifying as well as, in this case, through the efforts of Dr. Stewart, we are able to have access to carfilzomib very early on in this development. Back then the company was called Proteolix and the first patient, as I understand, the very first patient ever to respond to carfilzomib was a patient of mine here in Arizona. That’s kind of the feel that keeps us going forward for participating in these clinical trials.

Jenny: Do you mind if I back up and just ask you a little more specifics about some —

Dr. Fonseca: No, no problem.

Jenny: So the NAB-Paclitaxel, is that correct?

Dr. Fonseca: Yes.

Jenny: Oh, okay. As I understand that’s used in pancreatic cancers, and can you explain how that works or what that does?

Dr. Fonseca: This belongs to the class of drugs that are called tubulin inhibitors so what they do is they disrupt the cable systems inside cells that make them transport proteins that make them divide. It’s a major, major disruptor for the cells. It’s like cutting the hydraulic system on a plane pretty much.

There’s a number of drugs that do that. NAB-Paclitaxel is this taxane that is bound to albumin in such a way that it seems to be more directed towards tumors safer. We had an interest in it for a number of reasons. Many years ago there were some publications including one from Dr. Dimopoulus in Greece that has found that patients who had MGUS and were treated for other cancers — again, breast and lung, et cetera — they looked at the MGUS level and they tried to say, okay, since this patient had MGUS and they were measured again, can we tell which drugs actually brought down their proteins? So they were not being treated for myeloma; they’re treated for other cancers but indirectly told them about the effect. One of the drugs that came out of this was Taxol.

We came out with the idea of testing this in a pre-clinical model here with my other two colleagues, Drs. Bergsagel and Casey. And it turns out that it showed promising activities in the model. Their model has been quite able to predict which drugs will work and which ones will not in the clinic. So we are very gratified to see that was the case.

So we opened up a clinical trial here that is currently ongoing. It’s a clinical trial that is being aimed towards very advanced disease. So the majority of the patients that are going into this trial have seen all of the standard drugs in combinations, and even then we have seen some responses. For us at least it’s exciting. We want to learn how we can, one, optimize its use whether we can use it in combination which seems to be the winning strategy, in general, in myeloma; and whether we could, at some point, move it more into an earlier phase of the disease because we have used it in cases which are fairly advanced at this point.

Jenny: It seems like there are so many new inhibitors or cell regulation inhibitors that are in a Phase 1, maybe early Phase 2 type of clinical trial. How does a patient pick one that might work the best for them?

Dr. Fonseca: It is a challenge and a little bit of this or a lot of this is subjective. As much as we want to bring drugs that are showing some promise in pre-clinical work, it’s really not until we get to the clinical stage that you know for sure. There were some strong with clinical work, for instance, with bortezomib. But on the other hand, some of the other drugs maybe wouldn’t have shown a lot of promise so the IMIDs, in general, now we know how they work and we can show in the laboratory some of their effects. But it wasn’t necessarily straightforward, so how do you decide on not to move thalidomide or lenalidomide into the clinic because of some sort of confusing results in pre-clinical medicine? Maybe we wouldn’t have those drugs here.

It’s quite a bit of a trial and error, and I think that’s true for some of the drugs. HDACs, for instance, HDACs probably have some of the most elegant science behind the drugs that should work in myeloma, but we still need to do better in the clinical trials. The clinical trials so far reported are not as impressive as we thought they should be. Now, it doesn’t mean they won’t work. In fact, I think everyone thinks that they will ultimately work. But the bar is pretty high right now because we have good drugs for myeloma so we really have to show some clear value of new drugs as they’re being proposed in the clinic. And again, in medicine and biology, in general, there’s a lot of complexity of how one goes about planning and executing to success.

Jenny: I agree. I think the first stop is to talk to your myeloma doctor.

Dr. Fonseca: Of course.

Jenny: And then do your homework.

Dr. Fonseca: Yes. I think talking to your doctor — fortunately, there is usually some good communication of early signals because of the reports that occur at, say, the national meetings and the scientific meetings. So I’ll use an example. If there is something that looks very promising, very quickly those trials expand from being a small trial into something that is much larger. Again, thinking about pomalidomide, a few patients shows activity, before we know it, large groups of patients are treated. The same was true back in the day when lenalidomide and revlimid were first approved. We had this tremendous access program that was made so that patients could have access to the drug way before it was approved. It was still a “clinical trial,” but the real intent was just to be able to have patients have access to the drugs so they could go ahead and get treated once we knew that it was effective.

Jenny: That happened with carfilzomib too, right? It got fast tracked?

Dr. Fonseca: As well too, yes.

Jenny: Can you also explain the CDK5 and what that is and how it works?

Dr. Fonseca: CDK5, well, yes. My colleague, Dr. Stewart — I don’t know if he’s been on the program or not — but he would tell you that he participated in this high-throughput program where they tested a very large number of genes with the sole intention of finding: if we down regulate a gene you can do that through a technique that is called RNA interference, but if you down regulate a gene, how would that help or perhaps even — not help, perhaps antagonize the effect of the drugs? So he did what is called high-throughput RNA interference screens where you can actually test thousands of genes and then you can use standard concentrations of a drug using a myeloma cell line. Through those experiments, some of the first hits that they got were related to this particular gene, the CDK5.

They hypothesized that CDK5 in combination with the bortezomib may be a reasonable thing to test in the clinic. This is an ongoing clinical trial. The clinical trial has shown some activity. It’s very early so right now what we’re looking at is the combination. I think one of the things that happen when you do combinations is that you want to know that you do better than the standard alone. But I think the signals are that this is if not with this compound, with this molecule that inhibits the gene perhaps with others, there’s sort of promising signal that’s a great pathway to follow. I’m not sure probably over the next year or so we’ll have more results on that, but that seems to be a very promising pathway.

Jenny: Great. Now, I understand also — I want to save time for caller questions so I apologize for rushing some of the questions. Would you like to discuss the patent that you’re developing? As I understood, you were developing a patent for testing.

Dr. Fonseca: There’s a number of patents that through the Mayo Clinic we have been able to either apply or obtain for various aspects of myeloma care. I think there’s from both the diagnostic and the therapeutic. Examples are from the diagnostic one, actually Mayo holds a patent on the FISH probes for the testing of myeloma. It was quite an eye opener. It’s very long and arduous process, but it’s part of the protection of intellectual property that the institution has.

Another example, one we’re working on right now is for things such as biomarkers for responsiveness to IMID. This helps us because one of the things we want is to have this be made in such a way that it actually changes how people are diagnosed and how their disease is prognosticated. For instance, some of the biomarkers for IMIDs, we might have the idea but someone needs to actually go and implement. So we need to have a laboratory or a company go out and implement it such that they can offer it as a clinical test, because if we just publish and we just present it as an idea, there’s really no traction. What really matters at the end of the day is that this becomes actually of use for patients. So those are some of the initiatives that we have been participating on.

Jenny: When you say IMID these are immunomodulatory drugs like thalidomide and pomalidomide, right?

Dr. Fonseca: Correct. That’s the work of Cereblon. There’s other groups that have worked on similar approaches. There are approaches for biomarkers, for instance, for the use of bortezomib. We actually have another initiative, but I don’t know if this is the one you referred to as well, looking at some of the biomarkers for bone metabolism which we’re very excited about that. We’re hoping to convert that also into a clinical test. It’s an uphill, a very, very long road to make one of these actually become a reality.

Jenny: These are follow-up question. What can patients help you do to advance your research?

Dr. Fonseca: When I see a patient I tell them, first and foremost, our primary interest and our primary role is to look after your well-being. As much as we appreciate your willingness and your altruism in participating in some of these things, the first reason for us to decide anything should be your best outcomes and your well-being.

A lot of patients we ask them, for instance, would you be willing to donate a sample at the times that we collect your bone marrow so we can test for this genetics, so we can test for genetics or new drugs? I would say it’s rare the situation where we don’t have patients who say, “Well, of course, I’m happy to do that.” I always stress to patients that should be not necessarily only because I want to do that but also because the regulations say we should do that, that we will care for them equally well whether they participate or not in research. We’ll treat them equally well, so this is just an option for them to participate in research.

There are times where we might present clinical trials because of the various stages of the disease. It can be a clinical trial right for frontline treatment of which we will tell patients, you can be treated in this way; you can be treated in this other way which is in the context of a clinical trial, so we’ll go through the details. I think just having an openness and building on the rapport and the relationship that no doubt we always establish as both a patient and a physician. That’s what ultimately drives our research.

The research has endurance, the research results have longevity. Sometimes we treat the patients the same way, but we just collect the data in a clinical trial so that in the future, five or ten years later, we can say, this is what we know and this is objective data for this. Just your willingness to ask us questions is what makes a difference and allows the agenda to move forward.

Jenny: Great. I want to open it up for caller questions, if that’s all right with you.

Dr. Fonseca: Sure. Of course.

Jenny: If you have a question, you can call 347-637-2631. And if you have a question, you can press 1 on your keypad.

Caller: Hi. Can you hear me?

Dr. Fonseca: I can hear you well, yes. Thank you.

Caller: Very good. I have a question about — so for those myeloma patients who are able to get into remission, is there any kind of clinical trial that’s being done to study how those patients can extend their remission length, maybe through diet, exercise? Is there anything that those who stay in remission for a period of time are doing that is perhaps consistent with long-term remission?

Dr. Fonseca: That’s an interesting question. I think when you look at people going through remission there’s going to be a whole range. There’s remission that is achieved because the biology of the disease was favorable so we could get into that remission. But the studies that have been done so far have mainly focused on the idea of maintenance after transplant. Now most of the studies have not stated that, for instance, this is a clinical trial for patients in remission, which is specifically what your question is which is actually very good. I can tell you that there’s very few of any studies that I know that have looked at aspects such as diet or exercise or other interventions of well-being that potentially could extend this remission. I think it’s a worthwhile question and endeavor.

Perhaps the reason why we don’t have those trials is just a reflection of the immaturity or the impossibility we had before in being able to talk about a group of patients being in this remission which we now know is more common than not. I wouldn’t be surprised if other trials come along asking some of these questions specifically as you say as in diet. Outside of a trial, we just do either monitoring or have that long discussion about maintenance when the patient is in remission.

Caller: Can I ask one more question? Can you still hear me?

Jenny: Sure.

Dr. Fonseca: I can hear you, yes.

Caller: Okay. I didn’t know if I was muted. How about for those patients who the disease  is being controlled really well through whatever plan they’re on. Does that make sense for those patients to look towards a clinical trial or is that more of the approach of “Hey, things are going well for you, let’s just stay on the path that we’re on?”

Dr. Fonseca: There’s an old adage in medicine that says, “If what you are doing is working, just keep doing it.” In general, if I have a patient who is doing very well — I’ll use a specific example. If I have a person who is on maintenance and is doing very well post-transplant and it has been three years and I know the disease is not moving, I’d be very reluctant to recommend any change. I would probably wait until the time of such a change to decide on a new treatment.

Caller: Okay. Thank you very much.

Dr. Fonseca: Thank you.

Jenny: Thank you. Very good question. Thank you for the answer.

Caller: Hi. This is Rogelio calling from Mexico.

Dr. Fonseca: Hello, Rogelio.

Caller: What do you suggest for those who live outside of the US in terms of testing? How do they know how complete their tests are?

Dr. Fonseca: I would suggest that most patients should do some of the basic testing on the bone marrow through at least genetics and FISH. I know it’s not widely available. So if that would not be available, I would probably ask pathologists about some of the other markers. People have looked at the morphology of the cells so the cells might look more aggressive because they’re immature. They have some cell features that we would think of them as indicating aggressiveness. The technical term would be “nucleoli.”

There’s a number of things that can be done in addition to what’s just the standard testing. Certainly, I would advocate for some of this testing to become available. I think the prices for some of these things have dropped considerably so hopefully as time goes by, more and more people have access to this.

Jenny: Okay, great. Thank you so much. One more question, please go ahead.

Caller: Hi. Thanks for picking the call. My question is how long are most clinical trials if I participate? Do I have to move to your area for a period of time or can I travel back and forth? Do I just travel to the trial or is that it? Or do I have to go back and forth — what length of period are these trials?

Dr. Fonseca: Some of the clinical trials do require more intensive monitoring while you’re on the active phase of the treatment. As that treatment is completed, patients may go into what we call monitoring. That monitoring may require, say, visits every two to three months or something like that where a person can more easily be going back and forth. We have a whole spectrum. Some clinical trials may require a treatment once a month so patients from farther distances can come and be treated. Some trials require treatments twice per week and then it becomes very impractical for someone who is not actually physically in the same city to participate.

What I do and I think a lot of people do, I tell my patients about available clinical trials based alone on what’s available. I don’t want to make a determination for them whether it’s appropriate for them or not for them to be coming because the levels of possibilities and motivations are quite variable. Some patients might say, “That’s interesting enough for me that I want to be coming back and forth. Maybe I want to spend more time here.”

I tell my patients, “I’m going to tell you about the options just to see if you lived here and then you can decide with me.”

Caller: All right. Awesome.

Jenny: Okay. Thank you for the answer.

Dr. Fonseca: Thank you.

Jenny: Dr. Fonseca, thank you so much for joining us today.

Dr. Fonseca: I appreciate the opportunity. I hope this was informative. I’m happy to report that if we did this a year from now, the answers and the results probably would be quite different which just reflect the dynamism that currently exists in this field.

Jenny: That’s great. We’ll just have to have you on again.

Dr. Fonseca: Thank you. I appreciate it.

Jenny: We look forward to hearing more about your discoveries, and we offer you our support. We thank you for taking your valuable time. We wish you the best in your practice and in your research.

Dr. Fonseca: Thank you very much. I look forward to see you in the future.

Jenny: Thank you so much for listening to another episode of Innovation in Myeloma. Join us next week for our next mPatient Radio interview as we learn more about how we as patients can help accelerate a cure for multiple myeloma.

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