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Dr. Philip McCarthy, MD
Roswell Park Cancer Institute
Interview date: February 21, 2014
Dr. Philip McCarthy shares his deep experience with transplantation in myeloma. He tells us that transplant eligibility depends on fitness, not age, and that older patients can successfully complete transplants. He notes that research is showing that the most effective induction therapies before transplants are triple combinations that include a proteasome inhibitor, an iMiD, and a steroid and tells us why this is better than either a two-combination or even four-combination approach. He shares a study recently closed with 750 patients that aims determine which approach is best for transplant – a single transplant, a tandem transplant, or a single transplant with maintenance therapy (we look forward to seeing this data). He describes a study that is looking at the timing for transplant, whether it’s better to have it up-front or later and tells us that the up-front transplant may be better in younger patients. He tells us that the right approach for the right patient is based on a full set of diagnostic tests including testing for minimal residual disease which is tested through both flow cytometry and a new test called PCR. He also describes a new test to study the heavy chain from a company called Binding Site. He describes efforts to make these test more standardized so that when research is done for myeloma patients, they are comparing apples to apples. He shares studies that show best approaches for patients with del 17, del 13 and renal failure. He describes his research efforts to help minimize side effects like mucositis and assist patients’ immune systems to recover at a faster pace after transplant. In the caller questions, he also answers an important question about lenalidomide and secondary cancers and how the benefits and risks are reviewed.
The live mPatient Myeloma Radio podcast with Dr. Philip McCarthy
Jenny: Welcome to today’s episode of mPatient Myeloma Radio, a show that connects patients with myeloma researchers. Patients can help accelerate the pace of research by joining clinical trials. If we doubled our participation from the very low less than 5% that we currently have to 10%, researchers like Dr. McCarthy who we’ll be talking with today, could do the work at a much accelerated pace.
If you like to receive a weekly email about past and upcoming interviews, you can subscribe to our mPatient Minute newsletter on the home page and you can follow us there on Facebook or Twitter.
We’d also like to tell you about a new site called myelomacrowd.org. That is the first comprehensive site for myeloma. It has, in a single place, everything you would want to know about myeloma, and it’s a place where you can find out about the diagnostic testing that you might need, myeloma clinical trials, find myeloma specialist, find and connect with other myeloma patients and support groups or the Facebook groups. And we even cover what you might want to consider during treatment.
Now, on to our show for today. We are very privileged to have Dr. Philip McCarthy of the Roswell Park Cancer Institute with us today. So, welcome, Dr. McCarthy and thank you so much for joining us.
Dr. McCarthy: Thank you for the invitation to speak.
Jenny: Well, I’d like to give an introduction for you, if possible.
Dr. McCarthy: Sure. Thanks.
Jenny: Dr. McCarthy is the Director of the Blood & Marrow Transplant Program at Roswell Park Cancer Institute, and a Professor of Oncology. Dr. McCarthy has been a BMT physician and hematologist and oncologist since finishing fellowship training in 1989. He’s been the BMT Director at the RPCI since 1997. He’s a member of the Cancer and Leukemia Group B, Cooperative Clinical Trials Group, the Center for Institutional Research on Blood and Marrow Transplantation (CIRBMT) , as well as a member of the editorial board of the two BMT Journals.
He has been a clinical investigator in oncology particularly in BMT for more than 20 years. He served as a chair or co-chair of many clinical trials and is a member of the protocol team for the ongoing BMT Clinical Trials Network study, and we will get into those studies as we go. Dr. McCarthy is a member of ASH and ASCO, and his research interests are devoted to developing new auto and allo treatments for hematological disorders including myeloma that will lead to improved patient outcomes and decreased toxicity.
So hopefully, that’s the most talking I will do during this show. Dr. McCarthy, thank you so much for joining us. And as one of the main presenters for the myeloma session at ASH, do you want to start by just telling us a little bit about what you are able to present there?
Dr. McCarthy: Oh, sure, thank you. I’m going to talk first about the education session. There were three of us, Doctors Mateos, Landgren and myself and we each took a different portion: Dr. Landgren focusing on smoldering, Dr. Mateo is on the transplant ineligible patients and I talked on the transplant eligible myeloma patient.
And I guess the first thing you could talk about in terms of transplant eligibility is what do we mean by that, and a lot of patients are quite fit even above the so-called older age group, say, 65, and that tranplant may be an option for somebody who is otherwise fit and it’s not really age criteria. In Europe, you have a tendency to go by age so that often the cutoff to 65 and there are plenty of 67-year-olds just as there are plenty of unfit 50-year-olds who may have other what we call co-morbidities there. They are ill from other illnesses.
And so what we talked about was the current standard for patients who would be considered transplant eligible as they receive some form of induction therapy. And now we’re moving more toward the triple drug inductions where you would use an IMID, an immunomodulatory drug, a proteasome inhibitor and steroids. There’s one other regimen that involves using proteasome inhibitor, cyclophosphamide and steroids which is similar and generates some of the results.
And the goal initially is to treat the best response and then collect stem cells. There’s currently a study that’s ongoing. I can talk about that a little later of transplant now versus transplant later, but assuming the patient goes on to stem cell transplant, the patients usually receive high dose of melphalan or some variation thereof, and then receive their stem cells back, not so much as a transplant but as a rescue. And then the patient recovers from that and that can be a fairly intensive procedure.
And then we are faced with what to do next. And a lot of what we do is based on what the cytogenetics, what were the risk stratifications as part of the upfront evaluation of the patient. And then we will consider the patient for consolidation, which is more common in Europe. We are studying that in the US as well as some form of maintenance therapy. We’ve had all kinds of controversies with that, but it appears that maintenance will allow the patient to stay in remission or have their disease in control for an extended period of time.
And so there are variety of different approaches to maintenance. One is using bortezomib. The Dutch reported on their results on that a couple of years ago and then also updated at ASH. The French updated their study. The Italians have two maintenance studies using lenalidomide versus placebo and the other one using lenalidomide and steroids. And there are some ongoing studies, one of which in the US is the BMTCTN which is a single versus tandem transplant versus a single followed by consolidation, all followed by lenalidomide maintenance. And in Europe there are two very large trials that are asking questions regarding both maintenance, consolidation, transplant now versus later, different types of induction.
There are lots of opportunities for patients to participate in trials and for both patients and physicians to better understand what’s the best approach to treating myeloma. I hope I didn’t talk too long.
Jenny: Oh, no, it’s great. And it’s a lot to think about because there are lots of new options available. So it just gives you more choices.
Dr. McCarthy: Yes. And that’s good and bad because we still, for example, don’t know what’s the best induction regimen because the only comparative study was something they called the EVOLUTION trial. Dr. Kumar was the lead author on that and that’s presented in Blood I think it’s about a year and a half ago. And that was a Phase II randomized trial. So it was really designed to see if you could get a hint of a signal as to which arm would be better.
What they showed in that was that a four-drug regimen was actually inferior, likely to be inferior to either of three drug regimens which is the len-bortezomib-dex or the cyclophosphamide-bortezomib-dex. And when they did four drugs with cyclophosphamide-len-bortezomib-dex, they had too much toxicity. So we need to do these studies to make sure that we’re doing the right thing for our patients and we’re not generating regimens that are going to generate too much toxicity and the patient won’t be able to get treated
The one theme that most docs are thinking about is how can you get therapy into the patient with them able to tolerate it, have good quality of life, and not have gaps in the therapy where they got so sick from their last regimen that it takes them two months to recover from that or three or four months or you have to change to a different regimen because of intolerability. And that those types of things are of concern because it appears that the more you can expose the cancer to treatment, the better off the patient is going to be.
Jenny: Maybe we should talk about what the experiences you’ve seen as with when you should consider transplant.
Dr. McCarthy: A good question. There is actually a clinical trial in the US. It’s called the French-American study. So Dana-Farber is leading, Paul Richards as the US PI (principal investigator), Michele Atall is the French PI or Principal Investigator. And what that involves is an RVD or a len-bortezomib-dex induction. Patients have their stem cells collected, all of them do with the cyclophosphamide mobilization.
You could argue back and forth as to whether or not that’s the best way to go or if you should use something like plerixafor or Mozobil. Anyway, that’s how the study was designed. And then patients randomized for either continued RVD or onto a single autotransplant followed by RVD consolidation. All patients after completing this upfront therapy then go on to maintenance. Now, it gets complicated here because in France, they are giving maintenance for a year and the US is the maintenance will be until progression.
So this trial should hopefully tell us which patients should strongly consider a transplant up front, which patients could delay it because they’re doing a lot of cytogenetic testing and molecular analyses to try and risk-stratify patients for whom transplant may be better because right now we can’t say for sure. We do know in retrospective studies that the idea of you get treated, definitely get your stem cells collected, and then the idea of do you delay transplant or do you go to transplant right away, that question is not definitively answered. But both approaches are reasonable as long as the stem cells are collected early because if the patient gets a lot of therapy and since the marrow gets beaten up by the therapy, it’s harder to collect stem cells and it doesn’t lead to a successful transplant.
Plus with myeloma, there are some centers that are doing tandem transplants. We can talk about that in a bit. And since the majority of patients do have disease recurrence, if the disease recurrence is prolonged enough beyond, say, two years, a patient could be considered for a second transplant after re-induction therapy to knock the cancer back down again and control disease.
So that was a rather long-winded response to saying there are people who can do it early or late. I find that a younger patient who’s rather fit, it’s reasonable to consider an early transplant because they will tolerate it fairly well, and then with close observation and probably some form of maintenance to keep the disease from coming back
Jenny: Well, I know on some of the other interviews where we’re talking about trials that were possibly using a monoclonal antibody before and they said if that doesn’t work, then you could go to a transplant. So there are different approaches that you could take. What do you recommend to your patients when they come in and they say – let’s say, for example, I were to be high risk, how do you determine that for them?
Dr. McCarthy: Yeah, good question. There are actually two really different high-risk trials. I think you’ve interviewed both docs, but one is the RVD plus elotuzumab versus RVD for very high-risk patients. That’s coming out of SWOG as part of induction. And then there is the allogeneic protocol which is about to open out of the BMTCTN also for very high risk. I think if it’s somebody who’s 70 years old and has high risk features such as deletion 17 chromosome abnormality, that would be a patient who perhaps the RVD elotuzumab versus RVD study would be a better choice because there’s a lot of toxicity associated with allogeneic transplant.
There’s no right answer here, and what we’re doing is trying to figure out are these very high risk patients going to benefit from either approach? And so there are small phase two studies that if there’s a reasonable signal, it may be something we would consider then for trying to figure out how you do a comparative study later on.
The other problem with these types of treatments is real disparateness between getting RVD elotuzumab and getting an allogeneic transplant, and a lot of that is both driven by the center you go to because some centers are going to be more inclined to offer one and another. Again, neither is the better option. It’s often we don’t know and that’s where we’re trying to find out. And sometimes it’s personality driven by the patient in terms of how much risk that the patient is willing to take.
We have all different personality types since some patients are incredibly aggressive in their approach. So for example, a lot of patients will go to Arkansas and they get a very aggressive approach to treatment. It’s not allogeneic but it’s lots of transplants, at least two, and lots of consolidative therapy. And that’s one strategy for a highly dedicated, highly motivated patient. There are other transplant strategies or chemotherapy strategies that are a little bit less intensive and so far there doesn’t seem to be much difference but we need to do head-to-head comparisons.
That’s why, for example, the 0702 trial which looked at a single versus tandem versus single followed by RVD consolidation is a good study because it’s going to give us some clues as to – will patients be able to tolerate these things, the majority of them as opposed to a self selecting population and really which approach will generate the best results.
So another long-winded answer.
Jenny: Can you go in some more detail about that trial and what you’re looking at and the different approaches, the single versus tandem versus…
Dr. McCarthy: Oh, sure. This study just closed in the last quarter of 2013. And this was a BMTC 10 trial. It looked at patients who got some form of induction therapy. So the induction therapy wasn’t mandated and you had to do one thing or the other. And then patients registered after having a response. We did collect all the data regarding the cytogenetics and other features of the disease.
And then the patients got a single autotransplant. And then they would either go to one of three pathways. They would get a second transplant or they would get consolidation therapy for four cycles after the transplant or they would go straight to maintenance. All three arms are followed by maintenance.
Now, this study again just closed and it will take probably another year and a half to two years before the data will be mature enough to tell us which is the best approach. There are 250 patients on each arm, 750 patients total. The PIs of the study are Doctors Krishnan and Somlo and Stadtmauer and Dr. Pasquini. So they really did a great job of leading this trial, and we’re very grateful to all the patients who were willing to participate in this trial
The other thing we’re doing on this is we are measuring what is called MRD. And that’s the minimal residual disease, so I’m going to be using that term a bit. And MRD can be measured in different ways. The two most sensitive ways are by flow cytometry and that’s where you take antibodies which have a little fluorescent tag on them and they bind to different cell surface molecules, and you can have the antibodies that bind to different markers on the tumor or on normal cells. And then you run it through laser in these little markers fluoresce and light up, and our flow cytometrist then measure what’s normal and what’s abnormal.
The other one is to do molecular testing, usually preliminary chain reaction. That involves looking for small bits of the immunoglobulin gene that gets rearranged in the myeloma cell. It gets rearranged in normal cells, but it gets specifically rearranged in the cancer cell. The only problem with that is you have to have usually the diagnostic sample to generate markers that allow you to look from MRD by this molecular technique.
Anyways, we’re going to be looking at MRD along the way after completion of the upfront therapy and then at time points following the start the maintenance. The reason why we think this is important is the Spanish have shown that if a patient becomes minimal residual disease negative, in other words, you cannot detect any cancer early on in their treatment, that is a good prognostic sign, and we want to see if we can do that.
The one thing we’ve discovered and we’ve actually got some benefit out of this is that their flow cytometers all do things a little bit differently, that’s why it’s not been easily standardized. Cytogenesis is a little bit easier but flow is hard. So we actually had Bruno Paiva come visit us. He is the lead author from Salamanca. He’s actually moved to Pamplona now. But when he was at Salamanca, he did all this flow studies showing the importance of MRD testing
And so he came over and spoke with our flow cytometrist, Paul Wallace. And now they have gotten together and they’re actually setting up a conference to try and standardize all of this so it allows all physicians and their patients to understand what really is MRD negativity and is it the same in Salamanca, Spain, as in Buffalo, New York, as in Houston, Texas, so that we have a platform that we can really compare results. And that’s a really important part of this is that we are trying to get together and standardize everything that we do so we can compare results.
Jenny: Well, Dr. Landgren mentioned that too. He said even in the United States, there’s a hundred times variants in the level of flow cytometry that’s done. So you don’t know if the patient, even the questions to ask really
Dr. McCarthy: Yeah. And in fact, the woman he works with, the flow cytometrist at NCI, she’s been in touch with Paul and they’ve been working on trying to come up with a standard procedure. And the Europeans, I love the name of this. Their flow of cytometry standardization procedure is called Euroflow, and it sounds like a prostate drug
But anyways, it is a way that you can take your data, your flow cytometry data and plug it into – they have an online algorithm and it helps you determine if the type of disease your patient has and also whether or not they’re MRD positive or negative. It works really well for things like chronic lymphocytic leukemia and some lymphomas. They’re tweaking it to try and get it to work better for myeloma. In most countries, not all but most countries participate
So, Dr. Landgren is totally right. Until we can get a better handle on this and all people are using the same language with regards to how we analyze this. It’s not going to be very helpful for manuscripts because you can’t compare apples and oranges, and it’s not helpful for the patient. So our hope is that within the next two years, this will be standardized so that there will be a simple way of doing it. People will still want to do investigational work to see if they can find something better or a better way of doing it. But once it’s standardized, it will mean a lot more to us in terms of understanding if there’s still disease left or is it gone, and can we keep it away.
We have the same type of thing with cytogenetics. A lot of laboratories did not select for the myeloma cells when the bone marrow aspirate is done, and what that means is taking usually an antibody to a marker that’s seen on the plasma cell. It’s called CD138. CD stands for cluster designation. It was how they set up all these different markers. And 138 is present on malignant plasma cells.
And so you take an antibody and it binds to it and you conjugate or you have the antibody attached to a bead or some other column and it pulls out all the plasma cells, and then the laboratory people will do analysis of the chromosomes in those plasma cells, and it’s a much better way of getting good information for risk stratification. Does the patient have a deletion of 13 or for (4;14) translocation and all these other things that are associated with outcome and also the type of therapy a patient should receive.
The French were way ahead of us on this. They’ve been doing CD138 selection for years. Hervé Avet-Loiseau is the PI or the principal investigator of the cytogenetic analysis. He’s just done a great job of getting a standardization approach for that, and it allows the doctors and their patients to be able to figure out what’s the best regimen for treatment.
Jenny: Now, the molecular testing that you’re talking about, which test is that? Is that the genetic expression or the gene expression profile test or is that a different test
Dr. McCarthy: It’s a different test. I can talk about GEP in a second, but this is PCR. So what happens is as plasma cells and all of us, like when we get a tetanus shot, our body starts making antibodies to tetanus. And there’s not just one but there are usually several, and so it’s this called a polyclonal response. And then what happens is the immunoglobulin chain, the heavy and the light chains at one end reconfigure their – it’s called the binding site — so that it will specifically say, for example, recognize tetanus.
And there’s a recombination event where these things get shuffled around in the developing plasma cell or developing B cell to allow for different antibodies to be formed. Well, in a myeloma cell, what’s happened is the plasma cell is only making one type of antibody usually or a light chain or heavy chain. And so it is clonal. So you can take little bits of the DNA and make little primers they’re called, little groups of nucleotides that are based on the recombination where the genes were reshuffled, and you can then do a DNA reaction to see if this is present or not in the bone marrow sample.
It sounds fairly complicated but I can remember doing this when I was a post-doctoral fellow and it was a little tedious, but it really gave you answers if you were looking for small amounts of the presence of any type of cell population. The problem is you need to measure that shuffling, you most often need a diagnostic sample where there are a lot of plasma cells there or a sample where you have a sufficient number of plasma cells that you can isolate them out and make these primers they’re called to that particular clonal abnormality, because if you have a contaminating population of all different types of cells, you won’t get a clean signal.
So that’s the way you can measure minimal residual disease by a molecular test called PCR. The Italians have done a lot of this as some of the other groups, Palumbo’s group in particular. But it hasn’t gone widespread because a lot of times you don’t have a sample of your patients being treated in the community. This isn’t a standard test right now. It may be in the future, but so far not yet.
Now, the GEP is something else. That’s gene expression profile, and that’s looking for RNA. So what happens is your plasma cell is full of DNA and then to make protein, you make RNA which is the intermediate molecule and then from the RNA you make protein. It’s translated into protein.
So the GEP which was developed at Arkansas, Shaughnessy, et. all with Dr. Barlogie, and what they show is that when they look at their patients who got Total Therapy and they’ve had a variety of different approaches over the years, I think there are up to total of therapy five and six, and they looked at all the patients’ RNA expression — and this is hard to do because RNA is not a stable molecule, so you need a fresh sample — and then they looked at the different genes that were turned on and off in the patients who did well and those who did not do well, and they found they have different panels. They found the 70 gene panel.
If particular genes were expressed, they did not do as well as the patients who didn’t have this profile. And it’s about 15% of the patients, 16%, 17%, somewhere in there. Now, there are others that have been developed. There’s one that was developed in France. There’s another one, I think the Mayo Clinic developed one through ECOG, Eastern Cooperative Oncology Group. And the Dutch have one called EMC92. The E stands for Erasmus Medical Center which is the center I believe in Amsterdam or Rotterdam.
Anyways, they have a 92-gene profile which also they think will allow them to protect the good and bad outcomes. So the problem with all of these things so far with the GEP is that it identifies a high risk population, but it doesn’t tell us what we need to do. It tells us that these are patients who should be strongly considered for clinical trials such as the RVD elotuzumab versus RVD, the SWOG trial, or the BMTCTN allo trial. Those would be both acceptable criteria for considering a patient for either of those trials because those are both high-risk features.
So you can see, molecular testing is used for a variety of things. One is used for risk stratification both on a cytogenic and a molecular level. It’s used for detecting minimal residual disease. So it allows us now with these really interesting tools to be able to help us decide what’s the best way to treat a patient. But the big thing to emphasize is everything needs to be standardized.
The GEP70 is standardized. There’s actually a commercial company that makes it. I think it’s Signal Genetics. The EMC92 is at the FDA. They’re trying to get approval for it. They need to validate it more in larger data sets. They’ve done it in Europe. It needs to be done here in the US.
There is one more thing as well for risk stratification is proteins, and there are two ways of doing that. One is serum free light chains, which looks at the amount of normal and abnormal light chains that are being made by the bad plasma cells. And what you want to see is normalization of that after therapy because usually the serum free light chains are abnormal because the plasma cell is either making too much of one or the other.
There are two types of light chains. There’s kappa and lambda. And either the cancer cells are making too much kappa or too much lambda, and so there’s an excess of one or the other, and we can follow that for determining response.
There’s a new test that was just FDA approved. The company’s name is The Binding Site. They make the serum free light chains, but they now have made something called heavy light, which is going to be able to tell you how much of the monoclonal protein that’s being made by the cancer cell, how much of it is polyclonal which is all the different ones that you expect in a normal situation and how much are monoclonal.
And right now it’s only available for IgA and IgG myelomas. But there are some data to show that this may allow for risk stratification in a different way instead of cytogenetics. It does it on the basis of how much abnormal protein is there. And when you combine it more traditional ways of risk stratification like the international staging system which involves measuring the amount of albumin in the blood as well as the beta-2 microglobulin, you can now incorporate this heavy light. And it’s a quick and easy way of determining risk.
That’s another thing. You want to have these tests, but you also want to make sure that they are practical to do, and these are very practical tests that you can do right away.
Jenny: So when you have a patient come into your clinic and you want to be gathering data for research, and once you start treatment, some of those markers are lost. What tests do you standardly have your patients perform?
Dr. McCarthy: To monitor response?
Jenny: Well, just for diagnostics and to determine treatment.
Dr. McCarthy: Got it. If they’re newly diagnosed patients, then everybody gets blood, urine testing. We usually will do a 24-hour urine to measure the amount of protein in the urine. Is there albumin in there because the kidneys are leaky? Are there monoclonal proteins? And the blood we’re looking for, monoclonal proteins, both whole immunoglobulin as well as the serum free light chain, we’ll measure a chemistry panel, kidney function, albumin label, beta-2 microglobulin. These are basic things that we’ll be looking for on a routine chemistry screening.
We’ll also measure if the patient is anemic. We’ll get a CBC. And then usually there’s something that tells us this patient has too high a protein where we’re pretty strongly suspicious that the patient either has a myeloma or may have monoclonal gammopathy of undetermined significance
And so then they will get a bone marrow test and their bone marrow test is sent for routine histopathology which means we’ll take a look at it under the microscope. Usually, the pathologist does that or we may go over to the lab to look at it as well. And that’s done via taking some liquid out, the bone marrow aspirate, as well as taking a small piece of bone which gives us an idea of what the architecture of the bone looks like. The aspirate is going to give us a better look at the cells that the biopsy gives us, the architecture and then also a better percentage of the marrow in terms of how much of it is involved by bad plasma cells.
We’ll also send it off for, as I mentioned, cytogenetic analysis earlier. We will send it for flow cytometry which helps us determine the markers on the cancer cells. And we will also then do some type of radiographic workup. Traditionally, we have done skeleton surveys. We still do them. But if a patient presents with any degree of pain, they’re usually getting a spine MRI because we want to make sure that there’s nothing immediately pressing that needs to be dealt with such as a compression fracture or potentially the plasma cytome, the aggregation of plasma cells is pushing on the spinal cord.
And that means that we have to do something right away off – it could be radiation therapy or usually it’s steroid treatment with or without radiation therapy. And then sometimes we’ll be doing PET scans if we are concerned that we’re not finding a lot of radiographic evidence of disease and sometimes that can be picked up with PET scan.
So those are the sort of basic things that we do and they are important to do to make sure that we have fully staged the patient. We are doing now molecular testing or we’ve been saving up to do it – it’s a long and painful story but in New York state we cannot do a GEP70 because the company is in the middle of negotiating with the regulatory people in Albany to get that done. So we did a few of them but then we had to stop, so I’ve been anxious to get that restarted again.
But we find it with cytogenetics, we have a pretty good idea on risk, again, if they’re done properly with the CDI38 selection and also something called FISH, which is florescence in situ hybridization, which is a specific way of marking the chromosomes in the plasma cell to look for both deletions and translocations where the chromosomes get shuffled.
Jenny: And we were told that the FISH, they have certain probes and you get what you test for, but it may not show everything. Is that correct?
Dr. McCarthy: Yes. You have to know what you’re looking for. That’s correct. So we know that there are certain chromosomes that are commonly associated with myeloma 13, 14, 17, 16, 21, also 5, 9, sometimes 11, especially if you’re looking for a hyperdiploidy. And so, yes, these are big pieces of chromosome and they’re lit up with – they have a fluorescent tag on them and then they bind to different areas of the chromosome and then they will light up. And if there’s a translocation, you’ll have movement of the color where you have two colors together where they don’t belong next to each other if everything were normal.
But you’re right. We need to know what we’re looking for. And I also forgot, chromosome one. And right now, these are the most common, but there are probably more that we don’t understand enough about because not all deletion 17s do have very aggressive disease. There are some that don’t behave aggressively.
I was taught as a medical student that IgG myeloma presents in renal failure, and they don’t do as well because the disease is very aggressive. I just had a patient who’s 15 years out from his original presentation of IgG myeloma has just had progression of his disease. He wasn’t on any maintenance therapy because he was treated back in 1999.
There’s something different about him, and we don’t know yet. And so that’s why we’re trying to collect all of this. We have a large procurement bank here where we store samples as do many other centers. And we’re going to try to go back and look at why did this patient do well? What features of his disease cause it to behave in this way? And then there are others who have very aggressive disease that comes back.
We have done some research. We presented a small paper at ASH, a poster looking at immune reconstitution. At the time of transplant and also after – day 100, after stem cell transplant, and we found that patients who did better had different types of T cells. They had an increasing of a type of T cell called gamma delta, and another type called CDA, the effector cells.
So we’re trying to figure out how we can correlate this with what type of therapy they received. We’re not sure if we’re going to be able to do that because we only had 70 patients. We’re going to look at more. But are there ways that we can get patients’ immune systems to be in a way, to be in a state that allows the disease not to come back?
The Mayo Group has shown and they have shown this in a variety of disorders that lymphocyte count seems to correlate well with outcome, that if by day 15, after stem cell transplant, if your lymphocytes are at a certain level, high enough, you do better than if they stay low for an extended period of time.
So why that is? We’re not sure. So we need to understand this better because it appears that the immunotherapy we’re thinking about using may be dependent on having a good immune system to allow these drugs such as elotuzumab and daratumumab to work better. We do know that based on preclinical as well as recent clinical trials that antibodies seem to work better when they are combined with lenalinomide.
And we’re not sure of the mechanism of how it works. Lenalinomide up-regulates natural killer cells, that it up-regulates what is called the immune synapse, so when the antigen presenting cell is presenting to the T cell, lenalinomide will up-regulate that interaction, cause the T cells to get activated. Now, if we can get them activated and then in concert with antibodies, we could potentially kill off myeloma cells because these antibodies are specifically designed to attack the myeloma cells and spare the good cells.
So these are all new things that are potentially on the horizon. And if we can understand our immune systems better and figure out ways to make the immune system work better, it may allow us to help keep the disease in check or the Holy Grail would be to cure patients.
Jenny: That would be the best outcome ever. So let’s turn back a little bit and talk about once your molecular profile has been determined or you know the genetics of your subtype of myeloma for your patients, how are you determining then the next step of treatment or what do you recommend for them based on those markers, those biomarkers?
Dr. McCarthy: Sure, sure. We do know that patients with deletion 13 and 4;14 should likely get a proteasome inhibitor and right now the upfront treatment would be a bortezomib containing regimen and so that helps right there. And these are for transplant eligible, and we can talk a bit about the RD date of the first trial that was presented at ASH, but I’ll say that for a sec. And then either combined with cyclophosphamide and dexamethasone or combined with lenalinomide and dex, you treat the patient to best respond.
So right away, that’s why we’ve been thinking about using a proteasome inhibitor as part of the upfront treatment. We do know with lenalinomide, it’s a much better drug than thalidomide, for example. And you again generate deeper responses without all the toxicity. Thalidomide has a lot more toxicity in terms of neurotoxicity. So you’re thinking about that as well because the schedule is also important.
Right now the schedule for bortezomib is two doses the first two weeks for a total of four weeks every cycle. But if you have somebody who has significant diabetic neuropathy, you may want to be more — you are going to have to be a little more cautious because you don’t want to have the patient have disabling neuropathy from your treatment. So we’re in the middle of trying to – so then you may go to once a week and which allows you to get more drug in and more tumor cell killing.
So those are usually the types of induction regimens I’m recommending. In the old days, we used more doublets for transplant eligible patients either RD or len-dex or bortezomib-dex. But I think a lot of us are moving away towards using the triple therapy because it generates deeper responses, and deeper responses correlate much better with better outcome. You can collect stem cells earlier because you’ve had a better response. You can put them in the freezer. You can then continue the treatment once you put the stem cells in the freezer and then take the patient on to transplant.
So I think that what we’re looking at, now there are some studies, there is an ECOG trial that’s going to be looking at in standard risk myeloma patients, they’re going to do a carfilzomib-len-dex versus bortezomib-len-dex as part of upfront induction therapy. And then patients either stay on that treatment, they can go on to autotransplant, and then there’s a maintenance of two years I believe versus a maintenance until progression question that’s also being asked as well in that study.
So that’s another interesting study for a standard risk patient population, those who don’t have, say, deletion of 17 and have more favorable cytogenetic features. And we think that carfilzomib maybe a better drug in terms of neuropathy. There have been some cardiac issues that we don’t understand completely just yet, but that maybe incorporated into upfront therapy in the near future.
There’s also the other drug, ixazomib or MLN9708 which is an oral proteasome inhibitor which is in clinical trial. It will probably be first released for relapse refractory diseases, but our hope is that after it’s approved that we’ll start doing some trials with it as part of an upfront regimen, and we may then have an all oral induction regimen of ixazomib, lenalinomide and dex.
Jenny: That would be pretty amazing.
Dr. McCarthy: Yes. And then there’s also pomalidomide which was just approved last year, and that is another IMID similar to thalidomide and lenalidomide but a little more potent. And that is used right now for again relapsed/refractory. It appears to rescue patients who are refractory about the bortizomib and/or lenalidomide. And so that’s another drug. It’s been looked at up-front by some groups, but there’s not been a lot of trials yet. And I have a feeling that may take a little bit longer, but we’ll see.
The thing that’s amazing about the iMiDs is that they are very small molecules and just by tweaking them chemically, you get very different effects. So thalidomide has a tendency to be more neuropathic. It also interferes with angiogenesis, blood formation, whereas lenalidomide and pomalidomide don’t. And there are other IMIDs in the pipeline that potentially will be released in the future which we hope will have different effects and be used differently.
The one great thing is that there are so many new drugs that are being developed and looking at different pathways that it is going to allow us to be able to attack the cancer at different points and different pathways in development, in division of the cell or interactions with its microenvironment it’s called, attacking it with antibodies that will grab it.
One of my colleagues, Sarah Holstein, has been doing some work on – it’s called geranylgeranyltransferase or GGTAs. And what that does is it’s involved with protein synthesis, and by blocking this pathway, you can actually cause the protein to back up in the myeloma cell so the myeloma cell gets stuffed with protein and blows up. So it’s a nice thing to have happen. And she’s doing some pre-clinical work on this which we’re very excited about and that we hope it will lead to drug development; again, a totally different pathway.
As you know, there’s a variety. There are AKT inhibitors, kinase spindle protein inhibitors. There’s a variety of different things that hit different pathways. We may be borrowing from our CLL doctors who use ibrutinib which is a Bruton’s tyrosine-kinase inhibitor. There’s pre-clinical evidence that this also may be another molecule that may be useful. It was just FDA approved for CLL, and my guess is that we’re going to find some myeloma patients, probably in combination with other drugs where the BTK inhibitor may have some efficacy in myeloma treatment.
Jenny: Well, I think a whole new world of different approaches has been opened up. So can we go back a little bit now? You mentioned an approach that you might be taking for deletion 13 or 4;14 patients. Is there any specific approach you take for deletion 17 patients or gene — I guess I’m saying it wrong. I think it’s chromosome deletions or additions but for the deletion 17 or the addition of the 1?
Dr. McCarthy: Yes. One is a little bit harder now. We’re not certain. If you go back and look at the HOVAN-65/GMMG study — Pieter Sonneveld is the principal investigator on that — it’s a little bit older study so we have to take it with a bit of a grain of salt. Those patients who were transplant eligible either got VAD which is vincristine, adriamycin and dexamethasone. And I am old enough to have remembered when that first came out and we don’t use anymore. So that’s one caveat on this.
And then compare them to bortezomib, adriamycin and dexamethasone, and they call that PAD. I think they didn’t want to call it BAD. So they called it PAD because it stands for PS341 which is the pre-clinical name for bortezomib.
So they got that as an induction. They had their stem cells collected, and then they got a transplant. If they’re in Germany, they got two transplants and then elsewhere they got a single. And then they got either maintenance. The VAD arm got maintenance with thalidomide low dose, or bortezomib where they would get two doses a month. And both arms got those maintenance treatments for two years. And the patients who benefit the most from the bortezomib arm were those who had deletion 17, whereas the patients who got the VAD followed by thalidomide maintenance did not see that benefit and those deletion 17s did not do very well.
What was interesting though is that deletion 13s and 4;14s, there was a trend but the thalidomide seem to give some benefit. So you didn’t see a statistically significant difference between those with deletion 13s or 4;14s but you did with deletion 17. So I’m recommending bortezomib containing approaches for both induction and that’s the other problem with the study. The bortezomib was part of the induction and the maintenance but at least it told us that that patient population should get the proteasome inhibitor.
The other thing they showed in that study was that patients who presented in renal failure did really well with bortezomib containing induction. So that’s also a very important lesson is that the standard right now is patients with renal failure, should get a bortezomib containing regimen with dexamethasone. There are some studies looking to see if you can add a lenalidomide in low dose because it’s partially renally excreted to see if that will generate a better response.
Now, the ones we’re not certain. The Emery Group had a nice paper. I think it’s in press, but I know they presented it at ASH where they used low dose RVD, len-bortezomib-dex, as maintenance therapy forever until progression, and it was fairly well tolerated. They had reasonable results. It was a Phase II. It was a small number of patients, but I think right now that that would be another approach.
So if you didn’t go on the, say, the RVD elotuzumab versus RVD trial, I would first recommend, of course, a clinical trial, and I think the RVD elotuzumab would be – that’s right now the best trial in an intergroup setting. All the different cooperative groups are having it open up. And that would be the best for a high risk patient population or if you had a very young patient, somebody who’s in their 20s or 30s and had high risk features, you could consider an allo transplant for that patient population because we know right now with current strategies, especially stopping treatment that deletion 17s and the 1ps don’t do as well. But we don’t know for sure.
Jenny: Is there a specific transplant approach that you recommend for higk-risk patients whether you consider the single or the allo or the auto?
Dr. McCarthy: Yeah. That’s the big question. Let’s do allo/auto first. We have some young patients and we don’t have very many of them, but occasionally we’ll get a 27, a 28-year-old who has multiple myeloma and they often have bad risk disease. I can remember one young man had plasma cell leukemia, another serious presentation, another high-risk feature, along with high LDH, that’s the high-risk feature, as well as the GEP 70. And those are the patients who I would consider for an allo transplant.
Now, in the old days, by that I mean five to ten years ago, the standard sort of was a high dose melphalan, autotransplant followed by a reduced intensity allo. And that was based on the fact that the SWOG intergroup trial looking at chemo versus transplant versus autotransplant versus allotransplant, they found that the allotransplant arm which was myeloablative or full intensity, they had a very high toxicity. So that fell out of favor.
Now, we’re looking at can we increase the intensity of the regimen so you don’t have to do two in a row? You can do a single allo with a melphalan containing regimen. Some people are saying you should add bortezomib in, but that’s not been compared in a head-to-head manner. I think the most important thing is to get as intense as possible without having the patient suffer extreme toxicity or die of complications of the transplant because we’re not doing the patient any good in that situation. So we’re trying to figure out how can we be the most intensive without having untoward problems
So right now, the jury is still out on reduced intensity allo versus a more intense single allo for very high-risk patients. For the standard still for tandem transplant is you’ll do – if you don’t have a very good response after the first auto, you can consider the patient for a second transplant to generate a deeper response.
And I mentioned earlier, that 0702 trial is hopefully going to give us some better information as to do we always have to do that second transplant if there’s still a fair amount of disease, say, less than 98% reduction in the disease, less than a VGPR (very good partial response), or if we can consolidate the patient, say, with VRD and still get good results? Or if we put them on maintenance, will that be enough to clean up the disease and knock it down so it takes a long time for it to come back or not at all? And those are questions that we just don’t know until we see more mature data.
Jenny: Now, I know a lot of your work has been to do that, to alleviate toxicity and to improve outcomes. So maybe you want to talk about that and your open trials, and then we’d better open it up for caller questions.
Dr. McCarthy: Yikes! Boy, the time went fast.
Jenny: I know it does. But that’s okay. We can go over. It’s not a problem for me.
Dr. McCarthy: Okay. No, I’m good too. What we’ve got in terms of alleviating toxicity, we’re working with one of our local biotech companies. I’m trying to develop a strategy to decrease the amount of mucositis that is generated by melphalan. I found that the three things that – well, there are several things but one, mucositis. Some patients have very little but some patients have a lot, and we aren’t always able to predict what that is.
Some people have been looking for genetic markers in the metabolism pathways to see if they can predict who’s going to be high risk for developing mucositis and who won’t be. So that’s one. The other is another common problem with melphalan is fatigue. A lot of our patients really feel wiped out even after their counts come back up and that could persist for a few weeks. Are there some things that we can do to alleviate that sense of fatigue and allow people to feel better faster? And then also can we get the counts to come back faster?
Right now, even with use of peripheral blood stem cells, growth factor shots such as GCSF or GMCSF, patients still are neutropenic for up to several days. And it’s during that time period that the patient can get an infection. So the shorter the time period where the blood counts are low, the less the patient will be at risk for problems.
The other thing melphalan does is it really beats up the GI tract, not just the mouth but also causes a fair amount of diarrhea and irritations to the GI tract. So if we can also come up with some molecules that will allow us to mitigate or decrease the severity of that, what we would call colitis or inflammation of the colon, that would also make it a lot easier.
We wouldn’t have to use as much intravenous feeding, something called total parental nutrition. If we can get around that, it makes it a lot easier for the patient to get through this because the biggest issue is still toxicity. It’s usually gone within the first 30 days in terms of severe toxicity, but the fatigue will last and a lot of patients, it takes a good couple of months before they’re feeling fairly well. They’re able to go back and do their regular job after their stem cell transplant.
So we’re working on that. We’re hopeful that we may have a trial within the next six months. I can’t say a lot about it yet because we’re trying to decide what’s the best approach and which molecule to use.
Some of the other trials we have open, we have the French-American trial which is the transplant now versus delayed transplant. And so that we think is an important study and that is open – is actually now called ALLIANCE. It used to be called CLGB, but we merged a bunch of our corporate groups, so we’re called the ALLIANCE for clinical trials in oncology or just the ALLIANCE.
We have an ALLIANCE trial which we are about to open which involves using pomalidomide, ixazomib, the MLN9708, the oral proteasome inhibitor with dexamethasone versus pom-dex. We’re very excited about that trial because both arms are very reasonable treatment for relapsed/refractory disease, and we think that this may allow us to better understand will the addition of ixazomib generate better responses. Peter Voorhees from the University of North Carolina is the PI of that study. Again, through The ALLIANCE which is open at ALLIANCE centers.
We are also going to be participating with the ARRY Biopharma trial. That’s the KSP inhibitor, kinesin spindle protein. And that inhibits the microtubials which allow the cell to divide polychromosomes apart and make a second cell or make two cells. And if you can interfere with this, you could potentially prevent the myeloma cell from dividing. A lot of what we’re interested is its activity as a single agent, and then, of course, it will likely be combined with other agents in the future. That’s a pharma sponsored trial.
We have finally a last, and this is very interesting. This is sort of an immunotherapy trial. It’s a Phase I. We’re opening it up. It’s for hematologic malignancies, people who have relapsed after a transplant, both an allo and an auto, but it’s designed for refractory myeloma in particular. It’s a fusion protein of IO15, and it appears that this molecule will induce CT18 memory cells increase something called interferon gamma, which is an inflammatory cytokine, which then may allow immune systems to get up-regulated and have an anti-myeloma effect.
Because it’s a Phase I, we’re looking now for toxicity. And our hope is that once we have the dose, we’ll be able to combine it with some active agents and maybe even overcome resistance because we’ve up-regulated the immune system. So Dr. Holstein is the PI of those trials in the relapsed/refractory and my colleague, Dr. Churchman, is the PI of the upfront versus the late transplant studies.
So those are our major research focus now and, of course, we’re still looking in our patients who get standard autotransplant and immune reconstitution. We’re hopefully going to have a strategy within a year as to how we might modulate that.
And lastly, my colleague, Dr. Kelvin Lee, is doing an interesting study. It turns out that if you give a patient lenalidomide and then vaccinate them with, say, the pneumococcal vaccine, they make better responses. And that’s pretty exciting. So it’s a potential platform for dendretic cell or tumor cell vaccines with lenalinomide to up-regulate the body’s own immune response to that.
Now, what he’s doing is he’s looking to see how much bortezomib wipes that all out. In fact, some people are talking about using bortezomib for – you know how children have severe peanut allergies? If you give bortezomib, you will completely wipe out their B cell production and you will wipe out their antibody production.
So what’s he’s going to try and do is reset the clock with this by giving the bortezomib, giving vaccines, seeing how well or not likely, how not they will respond. And then are there certain vaccines that still despite the bortezomib, you get antibody response so that will allow them to continue to use the bortezomib during treatments? So that’s another small trial that we’re doing here to help us better understand the immune system.
Jenny: And that sounds like an early trial or is it pretty far along?
Dr. McCarthy: That’s an early trial. He just opened that up. So he’s going to do about 10 patients and then measure antibody responses while they’re receiving bortezomib and then antibody responses to vaccines
Jenny: Wow. Well, there’s so much going on. It’s really exciting.
Now, I’d like to open it up for caller questions. So if you have a question for Dr. McCarthy, please call 347-637-2631 and press 1 on your keypad. Okay. Go ahead.
Caller: Hi. Hello, Doctor. My name is Rashmi, and I have actually a couple of questions, if you don’t mind. One is general. One is personal. So my first question is does it matter where you get the transplant for better survival and remission rates or does all transplant facilities provide standard care and treatment?
Dr. McCarthy: That’s good question. Well, I think all transplanters like to say they have the best center. But it’s hard to compare.
Now, let’s break them out, auto and the allo. For allo, it’s easier to compare, but a lot of patients with myeloma don’t go to allo up front. But there is a place that you can look up the results of the allo treatment, the allotransplants. It’s called bethematch.org, The National Marrow Program, and The Center for International Blood and Marrow Transplant Research (CIBMTR) are the ones who manage this website. And you can go and look at any transplant center reports the allogenetic data throughout the United States. I thinks it’s like 147, 148 centers, and look up how well they do for allotransplant. That’s one.
For auto, it’s a little bit different. Some places post their results and some places – you may want to look at – it’s much harder because there’s no public clearinghouse for that. However, you want to find out, number one, do they have a dedicated unit? Do they have dedicated personnel doing this? What kind of high dose regimen are they giving? Do they participate in clinical trials? Are they a member of a cooperative group? Are they associated with an academic center? And you get a better feel for how they do.
And then I’d also want to say, look, talk to some patients who’ve gone through this and see how well they do. To be quite frank, a myeloma patient should not – the death rate, the toxicity death rate should be the same as an induction chemotherapy rate. So it should be about 1% to 2% max. And to me, it’s a catastrophe when we lose a patient due to toxicity. So that’s the most important thing is that you find out – you have to ask a lot of questions and find out volume and things like that. It’s a lot harder though for an autotransplant than it is for allo. Allo, the data is a little bit more readily available.
Caller: Oh, okay. Thank you so much. That was really helpful. And my other question you just touched base on some part of it where you said there isn’t a good answer, but my husband is detected. They say that he barely crossed the line to myeloma. So at that point, is it beneficial to get the transplant and aggressive treatment or is the therapy and other things be better?
Dr. McCarthy: Yeah. So in others words, did he have smoldering myeloma?
Caller: Yeah, only for a couple of months. He got detected, they said, with smoldering in November, but January they did a PET scan and PET scan was inconclusive. And then they did a dye MRI and they could see like some lesions, like maybe a couple barely – they see it barely is what they say. So they wanted to do steroids and some radiation and then – I don’t know. They’re considering stem cell transplant, but that’s what I wanted to get your opinion on, like at early stage, would that be good or what?
Dr. McCarthy: Well, you’ve raised a lot of important questions. So nothing substitutes for seeing a patient and going through all the records. So I don’t want to specifically say your husband must do or not do something without looking at everything. But the classic way of deciding whether or not a patient needs therapy is do they fulfill CRAB criteria, and CRAB stands for high calcium, C; R is renal or renal failure, patients who have renal sufficiency; A is anemia; and B is bone disease.
Now, sometimes people will have a single lesion or a plasmacytoma and that is it. They may have a small amount of monoclonal protein in their blood stream. That’s not enough that you would consider high enough to treat. And if it’s just one plasmacytoma, sometimes just treating that with radiation and stopping is adequate and that you don’t have to do anything more.
So I think it’s very important to see, is this on the MRI? Is this a big lesion? Is it causing problems? And all these kinds of things. And then the percentage of plasma cells is also very helpful for understanding the bulk of disease. If you’re 5% or 10%, that’s very different than 20%, 30%, 40%, 50% plasma cells.
Caller: He only had 10% to 12% plasma cells in his last bone marrow biopsy, and right now the lesion is like they said is really small, but he has multiple fractures in his spine.
Dr. McCarthy: Ah. So he does. Then that would lead me much more towards thinking that he may need therapy, especially we think – has he had a DEXA scan? The bone density scan?
Dr. McCarthy: It might be worth getting a bone density.
Caller: The bone density was normal. His first MRI without a contrast was okay. They couldn’t see anything. The PET scan was inconclusive. And the one with the dye shows like a little bit shadows or whenever
Dr. McCarthy: Yes. So if you have multiple fractures, that would lead me more to think that there’s more tumor burden there, and that’s something you would discuss with his doctors. Are you absolutely certain that these fractures are related to the myeloma? It sounds like it would be if he’s a relatively young man. And that would lead me more towards the use of a bisphosphonate to help strengthen the bones, prevent more skeletal-related events they’re called, or SREs, as well as embarking in some form of therapy. And so that, it sounds like the B criteria and the CRAB criteria is being fulfilled, and thus the doctors are considering treatment.
Caller: Also, the treatment like the stem cell transplant —
Dr. McCarthy: Well, you would first start with induction therapy, and then after getting that induction therapy to generate a response, knock down the protein in the bloodstream, et cetera, then collect stem cells and then the decision is do you do the transplant now or later? And I think that’s something, depending on his age, how well he’s doing and a variety of other factors, would be a reasonable consideration.
Caller: He does feel fine though and he’s about 58 years old.
Dr. McCarthy: Yes. So he’s fairly young. So I think a lot will be – the number of fractures there are, discussing that with the doctor, making sure that you – are you certain that these are related to his plasma cell disorder because you’re right, 10% plasma cells is not a lot and you want to be absolutely sure that it’s cause and effect, that these are what’s causing all these compression fractures or these fractures.
Caller: Okay. All right. Thank you so much. Your whole description is very helpful and so you gain more knowledge. So thank you so much for answering my questions.
Dr. McCarthy: Oh, you’re welcome. Good luck to your husband.
Caller: Thank you. Bye.
Dr. McCarthy: Bye.
Jenny: Okay. We’ll take another caller.
Caller: Doctor. My question is about the binding site test that you said works on IgA and IgG that quantifies the number of polyclonal versus abnormal monoclonal cells. My question to you is will it give you a quantification if there’s multiple perhaps subclones that have resurfaced in a relapse to Velcade, for example?
Dr. McCarthy: No, yeah, yeah. Now, that’s going to be a little more problematic. I was talking mostly up front. It’s useful for that because as you probably know, most myeloma presents one, sometimes two clones at presentation. And so it’s going to be dependent on if you’ve got multiple clones, because usually even with relapse, you can get multiple clonal heterogeneity is what we call it. If you sample like multiple, say, aggregates of plasma cells, they can often have different cytogenetic abnormalities.
And there are two really interesting papers, one from the MMRF, the Multiple Myeloma Research Foundation, was the sponsor studies to them, and they looked at a bunch of — a large group of investigators, looked at a bunch of different sites and different types of myeloma and they found that there’s a lot of heterogeneity even within the same patient. And also the Dana-Farber group at about the same time in another journal published a paper also showing a tremendous amount of this clonal heterogeneity where even in the same patient and different lesions you had different chromosome or different molecular abnormalities.
So it does bring up the point that you will often have more than one thing going on. Most relapses are with – depending, will often have maybe a single clone at least in the blood but sometimes two or three. After a stem cell transplant, you can get something called oligoclonal banding. That’s where you get about four or five or six, maybe three different spikes or proteins in the blood, and then they sort of go away. And then once the patient relapses, it’s usually with one or two.
I’m not sure if it were more than two, I think it would be more of an issue, but I do know that this takes into account the different heavy chains, and it looks at the different light chains. So it’s looking at both in the same essay. So it may be able to help quantitate perhaps a couple of clones. I think if it were three or four, it might be more problematic. But that’s something that would be worth asking once the test is more readily available. At our own institution, we’re hoping to have it up and running by March. But again, it was just FDA approved – I think about a month ago.
I’m sorry, I couldn’t be specific but I will go look that up now. Now, I’m going to ask the Binding Site people.
Caller: One follow-up question on that. For that specific binding site test is the input for testing. Is it blood serum or urine?
Dr. McCarthy: It’s serum, yeah, or blood. It’s a blood sample, and then they run an assay. I thinks it’s serum. It might be plasma. They’re very similar but slightly different, but it is a blood test.
Jenny: Okay. Thank you for your question. Okay. We have another call, please go ahead with your question.
Caller: Hello, Dr. McCarthy. Thank you very much. You’ve done a wonderful job on a very complex disease. I guess it’s just a little bit more than rest in bed, drink liquids and take aspirin.
Dr. McCarthy: Oh, yeah.
Caller: And in any event, Jenny had put on her site an article with regard to the use of lenalidomide and secondary cancers. You are also listed on that with Dr. Palumbo and a number of other people as co-authors. And in that short review I found that a melphalan-based therapy with lenalidomide, and I’m not sure it was that way, but it has 4.8% chance of a hematological cancer versus less than 1% without it, without melphalan. Is that how I read that?
Dr. McCarthy: That’s correct.
Caller: And then if so, does the use of melphalan in a stem cell transplant create the same issue? Because we often use lenalidomide in maintenance induction and consolidation. So I’ve had stem cell transplants and not use lenalidomide but a lot of people have, and I’m sure that would be a concern.
Dr. McCarthy: Sure, yeah. That’s complicated. So let’s start with the non-transplant. It appears that the prolonged exposure to low dose melphalan probably is – it appears to be bad especially when it’s combined with lenalidomide, and it’s interesting. When I first started out in fellowship, the original treatment for myeloma — well, the first treatment that really worked fairly well was melphalan and prednisone. And the patients would take it for four to five days every six weeks along with steroids with the prednisone and then repeat. And then what would happen is you would often end up with a damaged marrow after, say, 12 months of this treatment and just because the melphalan is toxic over time to the bone marrow.
So it’s not that when you add lenalidomide to that, you increase that risk either sequentially or using it at the same time. So based on that article, we’re recommending that it’s probably not a good idea for prolonged melphalan exposure.
Now, with regards to stem cell transplant, and then it gets really complicated. The one weakness, in fact, if you read the editorial on the Lancet Oncology, one of the weaknesses of the paper was that the IFM0502 data was not included. There’s a variety of reasons why that was. So that’s the French study.
But if you compare the two studies, we both saw an increase incidence of second cancers, there’s about 3% versus 1% in the CLGB study and there is about 2.5%, 2.7%, 3% incidence – about the same thing on the French study. The thing that was different is in the French study, they saw about the equivalent amount of myeloid malignancies, so AML, acute myeloid leukemia or myeloid dysplastic syndrome.
In the French study, they found increased incidence of Hodgkin lymphoma and acute lymphoblastic leukemia, which we’re all very surprised at because that’s not what you would have expected with alkylater melphalan exposure. Usually, you get these myeloid malignancies. And if you look at the treatments in the two arms, the induction regimens are very different. The IFM study had a lot more VAD which again, we don’t use, half their patients got that. The other half got bortezomib-dex. And then 100, 104, about 74% of patients either got thalidomide or lenalidomide-based regimens. And then a lot of the French more alkylating therapy with something they called the D-septin, about 20% of their patients got two transplants. So just keeping all that in mind, there are enough differences.
The other thing is the French patients only got two years of maintenance, and they stopped because they were worried about the SPMs, the second primary malignancies. We did not do that in the states, and we saw this sort of increase and then it went away. So my feeling is that if you get out to two or three years and you haven’t had an SPM, you likely are not going to get one, and that you assume all the risk and potentially none of the long-term benefit by stopping lenalidomide maintenance too soon.
The one thing also in the Palumbo paper sort of buried in there is that the risk of getting a second cancer is definitely higher with lenalidomide especially with low dose melphalan. But the risk of having progressive disease and dying from the myeloma was higher if you didn’t get it. So it’s sort of a risk-benefit thing. When you look at it, that’s still the risk of the cancer coming back as much higher without some form of maintenance therapy. Now, it should be bortezomib or lenalinomide, we don’t know, or should it be ixazomib, this new oral proteasome inhibitor. And we’re going to have to see based on just future trials.
So that’s why I tell patients — one last point. It turns out that this entity called monoclonal gammopathy of undertermined significance, and those patients have an increased incidence of developing also acute myeloid leukemia or myeloid dysplastic syndrome, bone marrow problems, and they don’t get treated, and that was based on an Ola Landgren study, looking at a Swedish tumor registry. So we know that people who have this sort of disease, either smoldering myeloma, MGUS, that they’re not requiring therapy, they’re being monitored, they still have a higher risk of developing bone marrow disorder.
So lenalinomide contributes to it, melphalan does, but there are other factors that we don’t understand enough to be able to tell us, “Oh, this is a bad risk patient, so we really shouldn’t expose him to this particular combination of drugs because they’re going to get leukemia.” We haven’t been able to figure that out yet, and that’s ongoing research we’re trying to sort that all out.
Caller: Thank you, Doctor. I appreciate your response. I have one question. It kind of goes back to what the lady had asked earlier and you had said about, this registry for allotransplants. My question to you is how do you determine what is the most effective treatment protocol for each patient? And what I mean by that is that do you consolidate your own survival statistics at your facility so you can tell which combination is more effective, or do you use clinical trial data as a surrogate for actual clinical results?
Dr. McCarthy: We do both because you may have a biased population, and you may have something different. How you do things may be a little different than somebody else. So you use both. We have a large database here in our transplants and we do about 140-150 transplants a year. Half are autologous and half are allogeneic. We’re always trying to figure out what can we do make things better because until the day that – we have to have it so that no one dies of toxicity and nobody relapses and everybody does well. We’re not there yet by a long stretch, but we are better than we were, say 10, 15, 20 years ago.
So we look at our own internal data. We’re always making sure we’re doing things right. And then we also look at the published literature. We look at – that report card, well, it’s not – I’m being a little facetious by saying report card. It’s an outcomes report. The outcomes report has a risk-stratification so that if you do very high risk patients, you get a higher score and they take that into account when calculating one-year survival. Whereas if your center does only low risk patients, they get a lower risk score and the scores go from one to five.
So you also have to take that into account because if your patient population is very high risk, destined not to do well, you’re going to have a one-year survival that’s going to be lower than a transplant center that has very low risk patients. You would expect them to do better.
So you have all these other factors that come in. How old are your patients? What are their co-morbidities? Is the patient in a good remission or not in remission at the time of their transplant? What other factors are involved? And it gets complicated so that you have to balance all of these out when you are trying to generate reports of outcome. And that’s why they’re talking about trying to do this with autos. But right now that’s been very hard because auto is actually — it’s a good problem. Autos, usually, by and large, do very well. And so that for a myeloma patient, the one-year treatment related mortality should probably be around 5% max.
As an example, the lenalidomide-dexamethasone ECOG trial that was published several years ago, the overall mortality was about 2% to 3% I believe. And so if you’re in that ballpark with chemotherapy, which is all out-patient as opposed to a more intensive approach with transplant, you feel good about it. So in a long-winded way, we sort of look at all factors because we want to make sure our results are not inferior to benchmarks within the published literature because if we do have inferior results, then we’re doing something wrong.
Caller: Well, I think that’s an excellent point on your part is that you actually are looking at those. I personally don’t quite understand why that doesn’t exist because there is what the CIMBCR or whatever that thing is, they’ve got all this data in there. They just don’t publish it by site.
Dr. McCarthy: They will be. I can tell you that. I’m actually on a committee to do that and we’re starting with – yes. It is right now it’s there. If you go to bethematch.org, you can get it for each individual center, but you would have to spend about four hours pulling out each individual center’s stuff and putting it into a spreadsheet. You can figure it out. And you can figure out because they have – and they look at the results based on are your actual results within the 95% confidence interval, in other words, there’s a 5% chance it’s a fluke and it’s a 95% chance that it’s a real event. So in other words, the majority of centers are within the 95% confidence intervals for expected outcomes. So in other words, their actual outcome is close to what their expected outcome should be.
There’s this small number of centers about 10 or so or 13 whose results are above what is expected, and there are some centers whose results are below what is expected. You don’t want to be in that latter group. And so why that is, there’s a bunch of reasons why that is. And when I say you don’t want to be in that group, they need to look at what they’re doing. And then there are some centers that they go down below what’s expected for a year and then they come back up.
Caller: My question, you said the average – this is my last point. I could go on and on and on and I apologize.
Dr. McCarthy: No, it’s all right.
Caller: Okay, is that you mentioned 2% is the death rate for people going through like initial therapy in the first year. Unfortunately, if I look at the SEER data, which represents one-third of all disease for multiple myeloma and all patients, about one-third in the country, they say the first year is 20% and last year was almost 30%.
Dr. McCarthy: Right. Now, it depends. It depends if that’s overall mortality versus – do you want me to stop or do you want me to keep going?
Jenny: Well, we have a two-minute hard stop. So go ahead.
Dr. McCarthy: Well, I’ll make it real quick. There’s overall mortality, there’s treatment related mortality, there’s disease related mortality. So you have to be aware of what patients are dying of. Are they dying of their disease or are they dying of toxicity of the treatment? And those are all types of things. So when I say 2%, I meant 2% treatment-related mortality as opposed to disease related mortality. That’s different.
Caller: Oh, okay. So this was actually relative mortality that’s based on the SEER, so that’s of all patients. But then, all patients, 20% to 25% die in the first year whereas a place – like at your facility, I would imagine. I don’t know because I don’t have the numbers, but I know a lot of facilities that it’s only 2% to 3%.
Dr. McCarthy: Yeah, but it depends because some patients are so sick they may not even be treated or they’re treated with palliative treatment. So you have to look – the average age of a myeloma patient is about 70 at presentation. But you’re going to have people up into their late 80s and you can have people who are in their 30s.
So you really have to look at what are their co-morbidities? What other things are they sick from? Do they have renal failure? Do they have bad lung disease? So you have to take all those factors into account when you’re looking at overall mortality and SEER is aggregate. This is all commers who are – those who are able to be treated aggressively, those who can’t be treated aggressively, et cetera.
And that’s why you have a higher mortality because you have a much more heterogeneous population. Patients who go on clinical trials usually have to fit criteria to do that, and that some of them – patients who are bad risk may not even be on a clinical trial just because they don’t fit specific criteria as opposed to all patients who require a therapy.
Caller: Okay. Well, thank you so much, Doctor. I appreciate your answers. And you obviously do a remarkable job keeping up with everything.
Jenny: I better say thank you because we just have 10 seconds left. So thank you, Dr. McCarthy, for joining us. We are so grateful that you have such deep dedication to myeloma, and keep going. If we can support you, we would love to. Thank you.
Dr. McCarthy: Thank you. Bye.