Dr. James R. Berenson, MD
Institute for Myeloma and Bone Cancer Research
Interview Date: February 5, 2016
Dr. James Berenson, MD shares his work on a new test being developed to track myeloma. This test measures the amount of a specific protein called BCMA which is regularly found on myeloma cells. Today, myeloma is measured by levels of M-protein (also called the M-spike) found in both the blood and urine as well as imaging tests to measure lesions and bone marrow biopsies to test for levels of plasma cells. The advantage of using the BCMA test is that BCMA protein levels turn over in your blood every day, allowing a measurement with a quick blood test to determine if you are responding to treatment or not. A test like this would prevent patients from staying on treatment that is not working well. Measuring the standard immunoglobulin levels (like IgG, IgA, etc.) to adjust treatment takes more time because these turn over slowly. Additionally, the standard free light chain tests show a lot of variability and are hard to interpret for patients with kidney disease. The BCMA test runs independently of kidney issues. For patients who have “lost” the M-protein and are considered non-secretors or no longer make the light chain, this test can still track their disease without the need for bone marrow biopsies. Today, doctors use a variety of methods to assess disease staging, but current staging methods are not very accurate to predict prognosis. In early testing, Dr. Berenson has found that having normal BCMA levels shows good prognosis while having very high or extremely low BCMA levels show poor outcomes. The test is expected to be commercially available at the end of 2016 and gives patients and doctors significantly more information about their disease.
Dr. James Berenson, MD on Myeloma Crowd Radio
Jenny: Welcome to today’s episode of Myeloma Crowd Radio. I’m your host, Jenny Ahlstrom.
We’d like to thank our episode sponsor, Takeda Oncology for their support and all they do for myeloma patients.
We have two announcements today before we get the show started. The first is that we’re introducing Myeloma Crowd TV, a monthly episode that will air on the Myeloma YouTube Channel and on the Myeloma Crowd website. This is a program for patients, by patients on topics that matter to you. So you can check out our first episode that is a great review of the exciting announcements from last year. And you’ll find also that on the Myeloma Crowd website.
Our second announcement is a program we just barely opened up called Muscles for Myeloma. Now at ASH we heard a lot that myeloma specialists are segmenting patients into fit, unfit and frail categories and are tailoring treatment based on those categories rather than by age. So this is a fitness challenge to get us all up and moving while helping a good cause, Myeloma Research. A patient’s ability to handle a more difficult treatment or extended treatments also typically gives them longer overall survival. So even though you may not feel up to it, any exercise plan is better than no exercise plan for myeloma patients.
So here’s how it works. You can click on the link on Myeloma Crowd site in the top-right corner and create your own Muscles for Myeloma page where you can tell everyone how you plan to get fit between March and April of the year. Now add a photo and even a video if you like. You can invite your friends, family or coworkers to join you and create a team page. And then to add some accountability, you can ask your friends and family to sponsor you for each minute you exercise. I could be one cent per minute, ten cents a minute, a dollar a minute, anything. Let your supporters decide. It’s like the elementary school walkathon but for myeloma and all proceeds will be donated to the Myeloma Crowd Research Initiative, two important immunotherapy projects that are dramatically changing myeloma care.
I’m so excited about this because exercise is really what got me out of my myeloma funk after treatment. It’s truly what kickstarted me into being a patient advocate. So even we’re just coming out of transplant or other treatments, there is something we can do to work on better fitness. And of course you should consult with your doctor before starting any program.
Now on to today’s show we are delighted to have Dr. James Berenson with us to discuss very important work he’s doing on a way to track myeloma’s absence and growth. Welcome, Dr. Berenson.
Dr. Berenson: Thank you. It is my pleasure to be with you today.
Jenny: Well, we are thrilled to have you. So let me introduce you before we get started.
Dr. James R. Berenson is Medical and Scientific Director and President and Chief Executive Officer of the Institute for Myeloma and Bone Cancer Research in Hollywood, California. He’s also President and Chief Executive Officer of Oncotherapeutics. Dr. Berenson is a member of many committees and societies including ABMTR Multiple Myeloma Working Committee, the Scientific Board of the International Myeloma Foundation and the MMRF. He is on the Medical Advisory Board of the Lymphoma Research Foundation, the Myeloma Working Committee of the Autologous Blood and Marrow Transplant Registry, and many others.
Dr. Berenson has been on the Who’s Who list including the Sterling Who’s Who, the 2000 Outstanding Scientists of the 20th Century, the Madison and Emerald Who’s Who lists and Distinguished Professionals of Who’s Who list. He is also a member of the IBMTR Working Group Myeloma Committee as well as a member of the Leukemia Lymphoma Society Foundations Board of Directors. He’s editor for publications including the Annals of Hematology, Annals of Oncology, British Journal of Hematology, Clinical Advances in Hematology and Oncology, Targeted Oncology and many, many others.
So Dr. Berenson, thank you so much for joining us on the show today.
Dr. Berenson: Thank you.
Jenny: Now, when you were in Utah, we had an opportunity to get together and you had a chance to ski a little which hopefully you had a great time here.
Dr. Berenson: Yes, before I did my training over in Salt Lake, beautiful place.
Jenny: Well, perfect. We’re very grateful that you’re doing the work that you are. But we were talking about something that I thought would be very, very interesting for patients to understand. I guess we will start by understanding first how myeloma is currently measured and what tests are typically used on an ongoing basis to track the disease because this is what you’re working on.
Dr. Berenson: Yes. So in myeloma, we don’t actually have an ability to measure the tumor because it’s throughout the bone marrow. So unlike breast, lung, colon where you can get your hands, if you will, around the size of the tumor, since myeloma is throughout the bone marrow which is the inner part of your bones, we indirectly follow this by measuring blood levels and urine levels of a protein product which is the antibody. Since this is a cancer anti-body producing cell and normally one plasma cell, the antibody producing cell, the malignant culprit in myeloma but normally a plasma cell makes one antibody and then those without myeloma we make billions of different types of antibodies. But what happens in myeloma is too many of these plasma cells gather in the bone marrow and they spew out and secrete into the blood and sometimes into the urine the monoclonal protein.
This is an antibody, a protein, and it can be found in the blood and it can be found in the urine. And the urine, when it’s found there, it’s usually part of the antibody. We measure that as a whole antibody which consists of two long chains called heavy chains which can be C-alpha most commonly or C-gamma, the two most common that’s for IGA or IGG. Uncommonly, you can see C-delta or C-mu that’s for IGD and IGM and very rarely see epsilon which is for IGE. So that’s a heavy chain component. Then you have two shorter chains and those are called light chains because they are lighter in weight. They’re about half the length and those can be either lambda or kappa in myeloma just like with normal people, there’s more kappa than lambda myeloma.
So it’s been said these are abnormal antibodies. That’s not actually true. They’re normal antibodies but they’re being put out by an abnormal malignant plasma cell. So what happens in myeloma, unlike normally when you have billions and billions of different antibody producing cells making trillions of antibodies, in myeloma, you have a clone that takes over and you only make one antibody and that’s the M protein, which in full force is an entire heavy and light chain so like an IGG kappa or maybe an IGA lambda. But in some folks, they don’t make the heavy chain; they only make the light chain component. So they are kappa or lambda light-chain myeloma. And then that slips into the urine.
So in a normal kidney, the whole antibody is too big to get through the membrane into your urine but the smaller one can fit through; and therefore, you find it in the urine. We call that Bence Jones protein. We measure that as 24-hour amounts of urine protein and then figure out what part of that urine protein is the abnormal component. Now, in the last few years, the group at Binding Site has developed a way to measure that same light chain in the blood, the so-called serum free light chain assay and that is done as well to monitor the disease. So changes and decreases in those levels suggest improvement in your myeloma and increases suggest things are going to poorly with the myeloma.
The other thing that’s done to monitor myeloma is to do bone marrows and radiologic tests and those sorts of things. Those are kind of difficult to follow in a typical myeloma patient. So moderating myeloma with bone marrow tests because myeloma is so, if you will, variably involved in the marrow; you can see spots where it’s 10% myeloma and other spots it’s 50%, other spots they’re 1%. You generally can’t really guide your treatment with percentage or proportion of myeloma cells in the bone marrow. So we don’t typically do that. We do that in patients to diagnose them when they’re required to have bone marrows for clinical trials or if their blood counts are very low and we’re not sure, is it the myeloma or is it the treatment that we overdid and wiped out their bone marrow function, then will do marrows. The marrows are not that great.
Now, radiologically, there’s been a great increase in the number of MRIs and PET-CT scans and I’ve seen a bunch of patients getting those today. We generally still perform bone survey, that’s a plain X -ray of the bones, and we do not routinely do that as followup because many times the radiologist will imagine new lesions that are not real. You have to be very careful. And MRIs we’ll do in-patients who have particular areas of symptoms but we don’t routinely do that in the same for PET-CT scans except for under specific circumstances.
So the tests that we generally use to follow myeloma traditionally are blood and urine levels of the protein over time. Now, it turns out the amounts of those at the time you’re diagnosed, don’t really prognosticate. They don’t really predict how well you’re going to do. So there have been attempts with other staging systems with other proteins to tell how long you’re going to live with your myeloma. I would tell you the good news now is people are living so long in our clinic, those particular staging systems are not useful anymore. So we’ve relied on first the Durie/Salmon in the last ten years on what we call the International Staging, which is simply based on the blood levels of your healthy serum albumin and, if you will, your unhealthy beta-2 microglobulin which is on the myeloma cell and once shed in the blood then you can measure it. So if you have more myeloma, you have higher levels of this beta-2 microglobulin level in the blood.
So those tests have been used, the two of them, to say you are Stage I, II or III. But I would tell you, we just analyzed about 300 patients in our own clinic. There is no use to that anymore. That has not been a useful staging system. So prognosticating myeloma with what we’ve had to date in the last few years, thanks to all the new drugs, is not very useful.
Jenny: Well, it is good to know. I mean it is helpful if you were a later stage that it might not be indicative how you will end up.
Dr. Berenson: Yes. And one of the reasons for that, Jenny, is that we have now thankfully so many good drugs to treat kidney myeloma; that you come in with myeloma that’s mucked up and your kidney function is poor, and we know that this beta-2 microglobulin protein is affected by kidney functions. So even if you have diabetes or high blood pressure causing kidney problems, you’re going to be a Stage III but it’s not for myeloma. But these days we have such good treatments for myeloma bone disease that we can, in most folks, reverse it. So those people who used to have Stage III and do poorly, now a Stage III can readily be reversed because of the effectiveness of the new drugs we have in 2016.
Jenny: And in your opinion, if the staging system, the Salmon/Durie and the ISS staging systems are kind of outdated I guess with the newer drugs? What do you think would be a good replacement?
Dr. Berenson: Well, I guess that will segue me into talking about our new marker which is not certainly been proven 100% to be there, but we’re on our way. So in the last several years we’ve discovered a new protein that is in the blood of myeloma, other leukemia patients, lymphoma, and now even immunodeficiency patients. So this is a protein which is being targeted by many companies now to treat myeloma because it’s present on late B-lymphocytes, the type of cell that‘s the malignant culprit in myeloma, again the plasma cell. And what we’ve shown is that it’s shed in the blood and it is in the more myeloma the higher the level. And we now know with certainty that the higher the level, the worse your outcomes are going to be not only in terms of how long it is going to take you to progress from your present treatment but actually how long you’re going to live. It really does predict outcome, that specific marker.
Jenny: Okay. I think patients may have heard about this marker before just because other companies are doing work targeting this. So do you want to go into what that protein is and then maybe what it does?
Dr. Berenson: Yes. So that protein is called B-cell maturation antigen (BCMA) and it was found and identified because in certain kinds of rare lymphomas, they had cloned out this protein 10- 15 years ago. And then it was shown that that protein was present and on late B-cells and also on malignant plasma cells, those normal plasma cells, so that when this protein was bound by certain factors — one is called BAFF, the other one is called APRIL — this would drive the growth of the myeloma in normal development of late B-cells and plasma cells to make antibody. So this is a normal component of late B-cells but happens to be present in large amounts on malignant plasma cells as well.
So in the last couple of years, several companies that we and others are working with are actually targeting the same protein for therapy thinking that if they can block it, that receptor will stop the growth of myeloma or in some cases, they’re using toxins that are hitched onto the back of an antibody which is delivered in high concentration of the myeloma because the myeloma has that tag marker BCMA on it. You bring the antibody and then you dump truck the toxin and you kill myeloma. So there is a big huge interest in BCMA as a target for treating myeloma in the last 12 to 24 months now.
Jenny: And a question, you mentioned that it is on late stage B-cell lymphocytes and in malignant cells. So would that mean it is on all myeloma cells including early stage and late stage? I know sometimes the doctors will talk about the stem cell basically or where the cell that is creating problems after even the late stage stuff is killed.
Dr. Berenson: Yes, I don’t think we can tell you with certainty yet that it’s present on a stem cell population. I think it probably is but I’m not going to make that leap of faith yet. But I think it probably is present across a spectrum of early, if you will, the Eveready battery cell that you can call the stem cell — I call it the Eveready battery cell — that just keeps giving you the myeloma that we need to eliminate. I think it’s there as well.
Jenny: You did this very well when we met in Utah. Do you want to explain how BCMA tracks with the M protein or what you found when you were framing this test?
Dr. Berenson: Yes. So that’s a really good question, Jenny. What is the advantage of this potentially new test we’ve developed? Well, the beauty of this is that BCMA turns over in your blood every day, whereas some of you may have heard of the new monoclonal antibodies interfering with your ability to detect complete remission. That’s because antibodies, whether the treatment antibodies like Darzalex, daratumumab, elotuzumab, Empliciti, these antibodies hang around a long time. Their half-life in the blood is three to four weeks. It’s kind of like if you’re looking at BCMA which is sitting outside my window, I’m looking at our sun and so I get a very quick read whereas with conventional markers, because the turnover of IGG is so slow, it’s like you’re looking at the light of the sun that’s about four galaxies away.
So we believe with our new marker, since the turnover is so fast, we can get a read (and we already have data on this) within a few days to tell you whether a drug is or is not working so you don’t have to remain on therapy for two months getting side effects and getting treatment that isn’t really working. You should be moving on. But we can’t tell you that because we have been able to get a marker that can turn over that fast. And we now have it with BCMA.
The other advantage that we have with this, there are a subset of patients and there are more and more evolving over time that become either non-secretory or, for example, one of my favorite patients in the Bay Area who started non-secretory but a lot of people become non-secretory over time and what that means is they do not make the conventional marker, the IGG or the light chain marker. They don’t make anything. We’ve had no way to follow them and with BCMA we have a really great test. We’ve shown that this test correlates with bone marrow that these people have to have every few months or PET-CT scan activity. We now have a blood test to follow them which is just great because they haven’t been able to be followed up until now.
Jenny: Yes. Now one wants to do bone marrow biopsies every few weeks to check on your disease status. Also when you were showing some of the charts that you had, it looked like the BCMA tracked almost identically to the M protein. So that’s what gave you the idea that you could use this as a supplement or even as replacement.
Dr. Berenson: Yes, that’s correct. It does track faithfully with conventional markers. But one of the things we have noted is that with the free light assay, there’s a lot of variability in the results and those results are very hard to interpret with anybody with kidney disease. And this test beautifully, unlike a lot of other tests, runs totally independently of renal function, of kidney function. So you can faithfully look at this whether your creatinine is 5 or whether it is 0.5. And that’s a huge advantage compared to some of the other tests we’re using to monitor myeloma right now.
And for example, 24-hour urine protein is only as reliable as the patient is to gather it up. A lot of patients don’t accurately collect it. By the way, we’ve shown this is also in the urine although we’re not using that currently to monitor patients. But 24-hour urine proteins are really a lot of times inaccurate and change also with kidney function, the results of the M protein.
Jenny: Okay. And then when we were meeting, you said something about BCMA at too high of levels and then BCMA at too low of levels, and that might give you an indication of how you might do this. So do you want to talk a little bit more about how you can use this as a prognostic tool?
Dr. Berenson: Yes. We’re just publishing the data now. It’s a really cool story. So what you probably all know as a myeloma patient, you generally don’t make normal antibody. And for many years, it’s been known or thought that there is a protein or soluble substance in the blood that suppresses your ability to make normal antibodies. So you make all this one antibody; you don’t make anything else. And we’ve now figured out what the culprit is; it’s BCMA.
So what happens is when BCMA is shed into the blood, it soaks up those factors I mentioned earlier, BAFF and APRIL, which are the fertilizers that drive your normal B-cells to make plasma cells to make antibody. So basically, we are sequestering the fertilizer that drives your immune system when you have BCMA at a high level. So therefore, you don’t make antibody. And then what we noticed is in people that were in complete remission, everybody has BCMA because everybody makes plasma cells. So the normal levels run about 35 to 40 nanograms per milliliter. And what we noted somewhat surprisingly that complete remitters half of them had very, very low BCMAs and half of them had levels that were 35 range. And then when we looked further, the ones with extremely low BCMA, they don’t make antibody because they don’t have plasma cells. And the ones that actually have normal BCMA levels make normal antibody.
So we’ve gone on now to show that this is a marker. In fact, they will call as soon as this is on. we’re writing a large grant now. We showed it’s a beautiful marker for patients with immune deficiencies without even cancer. Kids with the “bubble boy” type of disease — actually the thing that led to ibrutinib, they have this mutation which is called the Bruton’s tyrosine kinase. Those people have no BCMA and they don’t have any plasma cells. So we have a monitor now for cancer of the immune system and too little of an immune system and it’s the same darn marker.
The other thing that’s really cool about BCMA is it not only is a monitoring device; it’s again a predictor of outcome. And I’ve never seen one marker that really can do both of those and we can do that with BCMA. We can actually mark your myeloma prognosticating your outcome but we can also use it to monitor you.
Jenny: Okay. So people with normal BCMA are doing best to summarize your results?
Dr. Berenson: That’s the leap of faith. We hope we’re going to have enough data to say that. We don’t quite have enough. We have a nice strong trend that way but we need more followup But it appears that if you’re in complete remission and your BCMA is really low, that is not such a good thing. I saw a physician patient from Fresno earlier and I was cheering him along. He’s with an RVD and complete remission and his BCMA was 23 in the normal range. I said that’s really good news and you probably make a normal antibody, whereas if your level is three or four, you probably have an impaired immune system and that may not be such good news. It also may mean that because you don’t have a good immune system you’re getting a lot of infections. We’re seeing that story with immune deficiency patients. So if they have really low levels, those are people that seem to be at higher risk to get a lot of infections.
Jenny: And then what happens to patients who have BCMA that are off the chart high or how much over the normal level does it have to be?
Dr. Berenson: Yes, that is a great question. What happens to people who have sky high BCMAs, not a good thing. So if your BCMAs are in the top quartile, the top 25%, when you walk in, that’s not a sign you’re going to do very well. High levels are bad. We also know that the level that you have predicts how deep your response is going to be. So if you come in with a level of 50 instead of 5,000, you’re much more likely to achieve a complete remission than a guy that walks in with 5,000. So unlike IG levels or M protein which does not predict the depth of response whether you have a five or a 0.5, this level does. The higher means less like you’re going to have a good response.
Jenny: Well, that would give you so much more information about your disease state, I would think, but just then rather than just testing your monoclonal protein in x amount which might tell you a little bit about your disease burden and maybe some about your bone damage. Have you seen any relationship with bone damage to BCMA?
Dr. Berenson: No, we have looked to that, Jenny. We show that was really independent of bone disease so I can’t tell you this is a bone marker per se at this point. We don’t have that data. It probably isn’t but that’s actually good in a way because it predicts your outcome irrespective of bone disease, kidney disease, hemoglobin, conventional staging, age, sex, all that. It’s independent of all.
Jenny: And so you made me curious, is there any way I can go back to my labs or other patients can go back to their labs and is BCMA tracked anywhere in the standard labs that we’ve already had done most likely?
Dr. Berenson: No. This is not yet commercially available. We are developing that as a commercial assay. I would expect that to be true by the end of the year although we are now wrapping it into multiple pharma and academic trials. So we’re collaborating with the Mayo, UC San Diego, the Farber, the Italian Group and trying to spread the love about BCMA. And now we’ve embedded it into trials with all of the new drugs that you could think about. Each company now seems to be coming on board and there are multiple companies, as Jenny mentioned, that are targeting BCMA to treat myeloma. So they’re especially interested to see whether this will predict responses to their anti-BCMA therapeutic approaches.
Jenny: Yes. I guess that’s my next question. So let’s say you have too high BCMA and you test for it and then you knock out the BCMA with one of these BCMA targeted treatments, then you said if you go too low, that’s not good either because you’re not developing plasma cells. So how does that work? Is there any concern about knocking out all BCMA?
Dr. Berenson: Well, I think you ask a really great question and the good news and it’s really preliminary but what we are seeing so far, the density of BCMA on myeloma cells appears to be much higher than a normal plasma cell. So we may be able to knock of the myeloma and not as much impact your normal cells. We don’t know that for sure, Jenny. I certainly admit that you at this point.
I would also tell you though interestingly that one of the approaches that we want to take is because BCMA is shed in the blood, there are two bad things that may happen if you’re going to use an anti-BCMA approach. One is there may be so much of it in the blood you’ll never get the antibody to the plasma cell, it is all going to be soaked up in the blood and therefore you’ll never be able to use it effectively to kill the myeloma. Two is, if we can keep it on the plasma cell, it will be a better target because there will be so much density there, it will be much better for the anti-BCMA to come in and bind and do its thing. And then I mentioned earlier that when this BCMA is rolling about in the blood, it’s grabbing up all the fertilizer that drives your immune system so we obviously don’t want that to happen. So we want to prevent the shedding.
Well, it turns out there’s an enzyme called gamma secretase which actually clips this guy and lets it go in the blood. So we’re now in the throes of using blockers of gamma secretase to see if we can keep BCMA on the myeloma cell and prevent it from going to the blood, make it a better target, prevent the immune deficiency and hopefully those anti-BCMA approaches will work better.
Jenny: Okay. So what you are saying is that sometimes it is in the blood and because you need to get it to the bone marrow as well, it gets used up basically when you treat the blood with high concentration levels in the blood that can never get to the bone marrow. Is that what you are saying?
Dr. Berenson: Yes.
Jenny: Some of the BCMA targeted treatments?
Dr. Berenson: That’s possible. Yes, that’s possible. I can’t tell you we have any data at all because we’re just beginning those trials now with anti-BCMA antibodies. We’re really early.
Jenny: Yes. I know there are some monoclonal antibodies to do that. There are also CAR T-cell targets targeting the BCMA. So do you have any insights on how it relates to that?
Dr. Berenson: Well, I tell you it could be the same problem if it is circulating. We’ll just have to see what happens. That was my first work in oncology back in the early ’70s which show that T cells kill tumors back in about 1973, a while back. But now we’re actually doing it therapeutically.
Jenny: Well, it’s exciting and tragic that it takes so long but exciting that it’s coming. So when you talk about development of a test like this, how long does it take to develop something like this?
Dr. Berenson: Well, we hope that this will be able to be obtained and from your doctors in a commercial assay within the next nine to twelve months, certainly much faster than drug development. As you know, this is not a drug. It’s an assay to measure and monitor the disease, so it’s quicker. But it will be probably by the end of this year I think we will be able to have a test that you can use routinely to monitor the disease.
Jenny: And like you said, it’s just a blood test.
Dr. Berenson: Well, it’s in the urine too but we haven’t developed that far enough along yet to tell you how to monitor that. That’s definitely in the urine.
Jenny: And for your patients in your clinic, are you using this test for everyone or just in a clinical trial environment or how are you using it?
Dr. Berenson: No, we are routinely using it but I must tell you obviously this is not an on label test and so therefore you can only use it as a research only test at this point. But it certainly is telling us a lot about what’s going on with our own patients.
Jenny: Well, I have friends who are non-secretors and I think especially for them, I don’t know what percentage of patients have that or become that over time but this is —
Dr. Berenson: Well, several percent present with it and probably up to ten percent over time. And a lot of people become oligosecretory and they stop making antibody over time and people always say to me, “Well, my IGG is only 900. When I first came in it was 3,000.” But it’s because over time the cells become less productive of the marker. That happens over time.
Jenny: So when you hear IGG because most people know, “I’m IGG kappa,” or “I’m IGG lambda,” or whatever, but those have never really had very good prognostic indications like you don’t really know how you’re going to do if you have one or are the other of those. Generally, I think there might be some that are more higher risk I guess than others but does this BCMA or do you find it in like IGG more kappa or in the lambda?
Dr. Berenson: That is a good question. It doesn’t correlate nicely with any of that. So it doesn’t correlate with whether you’re IGG or IGA or IGM or whatever at all. What we do know however, as I mentioned earlier, that if you have an IGG myeloma and your BCMA is really high, your IGA and IGM are going to be on the floor. And that’s again because the BCMA is binding up the factors that drive your normal immune system. You can’t do that. It correlates with the level, as I said, but isn’t higher if you are an IGA than an IGG. None of that correlates.
Jenny: And let’s talk for a minute about the status of your immune system because now that all these immunotherapies are coming out, I have had doctors say we need to not only know your genetic features to treat your myeloma because there might be certain drug combinations that are better or certain treatments that are better for you with particular genetic features, but you also have to understand the condition of your immune system. So how does a patient go about understanding the condition of their immune systems? It sounds like BCMA might have an impact there.
Dr. Berenson: We think it might. We hope it does on both ends of the spectrum. We don’t know for sure. In terms of monitoring your immune system, we are pretty simplistic about it now. We measure lymphocyte counts. Sometimes you can measure what’s called certain types of lymphocytes, certain types of T cells in your blood or natural killer cells and we’re really in its early stages of figuring out how to monitor immune systems of patients in a clinically meaningful way.
We can do tests, but in a clinically meaningful ways, we don’t necessarily know how to do it. It’s clear that myeloma patients have a woefully inadequate immune system, and that’s why we tell you not to use live vaccines like the herpes zoster vaccine. And we are certainly even though you get flu shots in these types of things, in most cases they don’t do much because your immune system isn’t working very well.
Jenny: Well, yes, I am curious about that because if you look at some people they’ll use the monoclonal antibody like daratumumab or elotuzumab and it work for them and for other people, it will work for a while then it won’t work for them or the CAR T-cells, sometimes it works, sometimes it doesn’t. So I am just wondering how you can segment those people on how who’s it’s going to work for.
Dr. Berenson: Well, that what the companies are hoping that BCMA may at least make a stab at that so the companies making variety of monoclonals now are all over us to see if we can use the BCMA assay to predict responses to immune oncology approaches. We don’t know anything about it yet but that’s one of the hopes we have with this new test.
Jenny: Okay, great. Well, we look forward to seeing it. And I think it will be exceptionally interesting and wonderful to get this test in the clinic for patients.
Dr. Berenson: We do too. By the way, it’s very, very useful for CLL. We were working on lymphoma. It’s certainly very, very useful for Waldenstroms as well. We have a lot of data in Waldenstroms and CLL now. We are going to be publishing that soon.
Jenny: Okay, perfect. Well, I have some other questions for you just because of what came out of ASH and the presentation that you did so if you don’t mind, we’ll move on to a different topic.
Dr. Berenson: Sure.
Jenny: Your ASH presentation was on Kyprolis which is a proteasome inhibitor and you were studying how to dose Kyprolis. What did you learn from your study about the dosing?
Dr. Berenson: Well, it’s very interesting. So we’ve been involved with proteasome inhibitors since the early days of Velcade, and what we had demonstrated in our early work with Kyprolis that this was a drug that could overcome resistance of patients to Velcade. Velcade-resistant patients would respond. And the company had told us that the drug would have to be given two days in a row weekly. And that was based on a rat colon cancer model in which the drug worked better twice a week than once a week. And I told them, in the Berenson way, well the rats lie but the clinic doesn’t. Let’s do a trial.
So then we embarked on a trial to give the drug once a week and the drug was incredibly active, if anything, I think more active. And we have finished that trial. We’re just getting that I hope published for the final review on the revised manuscript in the Blood we presented at ASH that in patients who received the drug 70 milligrams per meter squared over 30 minutes rather than the conventional 27 for two days twice weekly, the response rates look to be higher.
Now we even went further. So we’re currently conducting a clinical trial. And I hope that we get some interest in some of the audience and friends and them that may have myeloma to believe it or not take people who were failing twice a week dosing and simply take the drug instead of twice a week once a week and, by God, it’s working. I’ve never seen that doing oncology in 40 years that you could actually just change the schedule like that and get activity and we are seeing it. So we are very hopeful that the future of Kyprolis will be a once a week administration which we believe will be more active. And so far we’re certainly not seeing more side effects with that more convenient schedule.
Jenny: It’s very exciting. And so why do you think that is that you can fail at twice a week and then you can get it at once a week and then it’s working for you?
Dr. Berenson: Well, in the lab with the higher dose, you get a higher concentration. It’s called Cmax, maximum concentration of the drug into the blood, and that has more profound blocking on the proteasome and longer so you get more sustained and deeper proteasome inhibition with once a week dosing rather twice you actually get better. That may be the reason why but it so striking to see someone who’s just completely failing on twice a week and then you go once a week, boom. I mean that’s pretty cool.
Jenny: Yes, that’s amazing. Totally amazing. So in some of the studies, I know they are testing now doing Velcade versus Kyprolis kind of head to head studies. The ENDEAVOR study, it looked like they were comparing Velcade, Revlimid and dex with Kyprolis, Revlimid and dex. But it looks like the Kyprolis was a higher dose so I’m just kind of wondering, is that an equal comparison? And can you take a similar to proteasome inhibitor and change up the dosing and do the same thing?
Dr. Berenson: Great question. So it’s interesting that Velcade did what we call MTD dosing and never backed off so they did their 1.3 milligrams per meter squared and then they never got off their high horse with a lot of their neuropathy. On the other hand, the carfilzomib Kyprolis folks, they did what we call the MED dosing, minimally effective dosing. They quit development at 2027. But clearly, this drug has a lot higher dosing they can go do. We’re doing 70 once a week. This trial did 56 twice a week. So I would tell you that you can push the drug hard. The problem with Velcade, you can’t push it hard. So you can say it’s an unfair comparison but if you can’t give more the drug, in this case because of neurotoxicity, then you can give more the drugs. So I don’t think it is an unfair comparison. If the dose of the drug that you were administrating in the experimental arm of Kyprolis is well tolerated, who cares if it’s higher than the label dose. The label does frankly was too low.
Jenny: Well, that makes sense. And I know there are other trials coming out to compare them. Sure, there will be others that will compare the other new proteasome inhibitors like ixazomib and others that don’t have the same neuropathy issues.
Dr. Berenson: Right. I think I should chime in there though that the neuropathy with Velcade can be greatly reduced by using lower doses. We do not use 1.3. We use one. And we give four doses a month not weekly. Some people do it that way. We give it 1,4,8 and 11 and obviously the SubQ. So I think if you give less drug, less doses per month and SubQ, you really greatly reduce the risk of neuropathy with this drug, Velcade. And you bring it in really Kyprolis range.
Jenny: Interesting. So do you want to talk a little bit about that? Because I know that’s one of the things that you focus on the most is the dosing and administration of these different drugs. Maybe you can talk about first the existing drugs that we have or have had and how you do that, how you manipulate that. And then with the new drugs coming in, now what do you do?
Dr. Berenson: Yes, those are great questions. So let’s talk about the tried and true. First I mentioned Velcade, we give less drug, 30% less. We give four days a month rather four days three weeks. For example, with the chemo agents, with the alkylating agents, the Cytoxan and the melphalan, we give about a third to a quarter of the dose of cyclophosphamide and CyBorD. We give a lot less drug. We only give it the first four days of the month at bedtime. We combine it with vitamin C because vitamin C actually makes the alkylating agents work better although you’ve heard that vitamin C which is true, if you mix it with Velcade, it will undo Velcade’s activity. So we have to take the Velcade in the morning, the vitamin C one gram at dinner and the alkylator at bedtime. It’s a very well-tolerated regimen. It’s about 30% of the dose of cyclophosphamide and CyBorD.
Doxil, we did lot of work on Doxil. We’ve shown that low dose metronomic Doxil so the opposite of what we’ve done with Kyprolis giving instead of one dose every three to four weeks like it’s done conventionally, we give Doxil at low doses on Velcade days and it is great. And you don’t get mucositis or sores in your mouth. You don’t get hand/ foot which means you get sores on the bottom of your feet and the palms of your hands. You don’t get any of that with low frequent dose because in our animal models we’ve shown that low dose frequently both works better and you can actually get a lot more drug in than you do conventionally.
Moving on to the IMiDs, we don’t like the doses that are FDA approved. We think they’re toxic. We will use the Revlimid at ten. We’ll adjust the dose down with renal failure. We don’t start with 25. Pom at four is not well tolerated in my view. We use two or three. And a lot of the effects that are observed, the effects on counts especially neutrophils with Pomp are effects on memory, on mental function. I had several patients in this morning who volunteered to me their inability to keep their memory, to mentally function as well on the drugs at these higher doses which had been required to be given by the clinical trials these people are on. So I’m a firm believer that less is more. We know these drugs work and dance well together. They synergize. So why not use less of them not more of them. We’re all about that in our clinic.
Jenny: And your goal is to help patients control their disease with the best quality of life as long as possible.
Dr. Berenson: Yes. I mean I think the ultimate goal here is to do what my good friend, Gio, says. My wife is an actress and she was in a lot of theater he did in L.A. He used to say to her and the other actors on stage, it’s not about more; it’s about being more specific. And our whole thing here is to kill the myeloma and let you live your life. So we like to say it’s not about complete response; it’s about complete life.
We do have data though like other sites that complete response is associated with a longer survival. But in our clinic, it doesn’t matter whether you achieve it the first, second, third, fourth, fifth time you get a treatment. So we don’t necessarily throw everything at you with the first regimen. We don’t think that’s the right approach. We do believe that is the right approach if you have high risk features such as kidney failure where you don’t want to stay on dialysis so you really got a quick response. Or you come in with plasma cells in the blood, plasma cell leukemia or the myeloma has already spewed out of the bone marrow and is say in the liver or the lungs, that’s really bad. Or if you don’t have any blood counts and the bone marrow is totally myeloma, you’ve got to go after it. That’s only about 15% to 20% of myeloma.
So a lot of myeloma is a take your time kind of process. I think we have to be very careful about overtreating. I can’t tell you the number of patients I’ve seen in the last month who were beginning therapy who didn’t even need treatment for myeloma.
Jenny: Interesting. So with all the talk about minimal residual disease (MRD) status, let’s go back for a minute. Does the BCMA indication have anything at all to do with minimal residual disease? Do you test for that in your clinic or what do you think of minimal residual disease?
Dr. Berenson: Well, I think that, number one, BCMA will never be in and of itself a marker for that. It may be associated with it if you’re in the normal range. But as I said BCMA is present on normal plasma cells. So we don’t have a marker that will only target the malignant population which you have if you actually sequence the gene which is what my work was at Cal Tech when I started my expedition in myeloma in the early ’80s. If you sequence the immunoglobulin gene, the genetic material that gives rise to the antibody, you have a tumor-specific marker. Then you can measure minimal residual disease.
The problem with MRD assays, they are only as good as the sensitivity and the specificity of the assay. And having worked with my twin brother on his first company, my twin brother, as some of you know, it is a biotech E who invented a device that would select healthy stem cells of the bone marrow. And we did a lot of work on that. In order for the FDA to buy off, it was something that worked. We had to show that for every single patient we could measure one tumor cell in a million normal cells. So we had on every single patient develop specific conditions that would allow us to do that. Nobody does that to measure MRD today.
So you have slews of patients out there who are MRD negative and still have a monoclonal protein which to me tells you how bad the assay is. So I think a lot of these assays are pretty suspect and not very good. It’s tough, it’s expensive, and I don’t necessarily think that’s going to tell you that much right now. I think ultimately it might but I don’t think right now. And the other thing is a lot of people use bone marrow as the source of material to measure and I already told you earlier on how heterogeneous the bone marrow is. I’m looking across the wall at the wallpaper and it’s all the same color. But I also have a lot of pictures on that wall. And those pictures, if you will, are like having variable amounts of myeloma. So you can put your needle in one part of the bone marrow, it’s 10% and next toward zero. So I think that’s problematic. I really think that’s a problem with the assay in a myeloma patient to use bone marrow as your source to measure MRD.
Jenny: In a bone marrow, you are talking about quantities. You could get 10% or 50%, but also is there a difference in the type of myeloma cell or is that pretty consistent no matter where you get the bone marrow biopsy drawn from?
Dr. Berenson: It’s a great question. I don’t think we have a clue. I really don’t think we know if there are hotspots of myeloma in terms of what you talked about earlier, stem cell populations and other parts of the marrow that aren’t so plentiful with them. We don’t really know anything. We don’t know the answer.
Dr. Berenson: There was a little hint from one study that that was the case. It was different in different parts of the bone marrow. There was one study.
Jenny: Well, I know that other doctors have said that an average patient might have up to five different kinds of myeloma cells in their bone marrow. So I am just wonderingif there are different spots with different genetic features.
Dr. Berenson: I think it probably does vary. I think probably all the clones are probably present but maybe in one spot it’s 80, another spot it’s 20, but I think we’re really not at the point to do a very good job of looking at because it’s hard to get patients to give you five bone marrows, as you know.
Jenny: Yes and give me conscious sedation, ok? That is what I am excited about. Well, I want to open it up for caller questions. So if you have a question for Dr. Berenson, please call 347-637-2631 and press 1 on your keypad. And we’ll start with our first caller question. Go ahead with your question.
Caller: Good afternoon, Dr. Berenson. Thanks for taking my call. I’m a smoldering myeloma patient and I had a question about your BCMA assay. Is this is actually detected in smoldering myeloma patients and if it is, could it be used or will it be used as a progression risk biomarker?
Dr. Berenson: Yes. In fact, that is a really great question. And we know, number one, it definitely is a marker for smolderers. So normal average is 35, MGUS is 54, smolderers 85, and untreated myeloma is 520. So you guys are a little higher than MGUSers. The big 64 million dollar question is if you’re an MGUSer with, say, 500, are you more likely to need therapy more quickly? We have data suggesting that but we just don’t have enough patients to answer clearly yet.
Caller: Are you incorporating this assay while monitoring your particular smoldering patients?
Dr. Berenson: Yes, we are. But we’re only using it as a research tool at this present moment. I think it well proved to be just as robust as in the actives where if your level is higher, you’re not going to live as long. So I think it will predict. And certainly, the other telling thing and it’s really great data, in chronic lymphocytic leukemia which is a lot like smoldering myeloma, the time to require treatment is profoundly different. If your BCMA is above versus below the median, it is incredibly different. It’s like eight months versus 60 months. So if you had a high BCMA, you’re really going to move quickly on. And by the way, with the MGUS patients, we don’t have enough data yet to say the same thing unfortunately. But I can tell you that anecdotally, the patients who have gone on to develop myeloma were ones at the highest levels of BCMA with MGUS.
Caller: That’s interesting. Do you have any trials for high risk smoldering patients in your practice?
Dr. Berenson: No, we currently do not and I saw several this morning. I’m certainly very opposed to treating these patients with lots of toxic treatment when I follow them like a hawk. I don’t think that you’re benefiting them by intervening earlier, and I’m opposed to this relative risk being such that, hey, I am going to go give this patient toxic therapy when I had even some this morning there are 10 and 12 years out and never been treated and probably never will need therapy. So I think it’s a percentage game. But if I were a myeloma patient, I’d be willing to sit on the sideline and let all the other patients fight it out because I think this thing is going to be cured in not too distant future. Why do I want things like Pomalyst and Revlimid. They are going to mess with my mind when I’m going to hopefully live to 92.
Caller: What about some of the antibody trials that are out there for the high risk smoldering myeloma patients? Are they as toxic as the drugs that you just mentioned?
Dr. Berenson: Well, elo is certainly a completely nontoxic homerun for that. But unfortunately, elo has no single agent activity.
Caller: I think the trials for smoldering incorporate Revlimid with that.
Dr. Berenson: Yes. Well, there you go. And the data on Darzalex although 29% single agent activity, lot of infusion reactions, you know.
Caller: Dr. Berenson, you mentioned that you follow your smoldering patients very, very closely and that’s your preference. How do you follow a smoldering myeloma patient? What tests do you include or are there routine tests you do annual imaging, things of that nature?
Dr. Berenson: No. I certainly don’t anything like that but I do 100% want to be doing tests in which the patients will be getting, if they’re coming in for Zometa every month we’re going to be looking at the tests we do routinely and add BCMA into the test although we only do that quarterly but we certainly do follow the serum protein electrophoresis, quantitative immunoglobulins, serum free light chain. They don’t have a lot of urine protein. We do a spot urine and if they do, we will make them do a 24-hour urine. And they bring them in when they come in for their Zometa.
Caller: And what about, Dr. Berenson, if you’re putting a patient on Zometa, how do you establish the need for it? What testing are you using? Do you do DEXA scans at least or any sort of regular conventional X-rays to determine the level of bone decline, if there is any?
Dr. Berenson: Yes, that is excellent question and we routinely do bone density on anybody who shows no lytic lesions. We’ll also do it with people who supposedly have lytic bone disease in skull because a lot of that’s a figment of imagination of the radiologist. A lot of my colleagues treat anybody who has a hole in their head with a bunch of toxic treatment. We don’t do that. So if you have skull only disease, we’re not going to nestle through in all this garbage, the whole garbage dump into you. We’re going to try to take it slow, slow and slow. We don’t treat those people.
So skull only myeloma is usually not real. A lot of that is a figment of imagination of the radiologist who sees on the form that says myeloma rule out and they always find a lytic lesion. And a lot of times, they’re not real. I cannot tell you the number of patients I have who come in to see me and have been on toxic therapy and even have MGUS and are told they have myeloma because of imagined skull lytic lesion or other lytic lesions. I have a really good radiologist read them that I deal with all the time. I’ve been reading myeloma X-rays for 25 years and they’re like, “There’s nothing here.” It’s just really frustrating.
Caller: Yes. It is really unsettling to hear that as a patient, really is. So you don’t use routine imaging but you do use imaging initially to evaluate, I would presume.
Dr. Berenson: Yes. And then like I just saw one of my smolders today and every few years to keep me honest, I’ll get a bone density on him to see if they move to require. So they have a bone density that’s worse than minus one, then I’m going to go ahead and shove into these people Zometa every month.
Caller: You obviously do bone marrow biopsies on smoldering patients.
Dr. Berenson: We only do it initially. Yes, I just do it initially but I don’t do it unless there is a change in clinical status.
Caller: What imaging to do though up front? The skeletal surveys or do you use —
Dr. Berenson: Yes. I don’t CATs and MRIs and all this stuff. I mean if you have a solitary plasma cell tumor, I want to know if it’s systemic so I am going to do PET-CT on those people. If you have a patient who has symptomatic disease in the back and most people do have back pain from being just older, I’ll do an MRI to look and see whether it’s generative disease, spinal stenosis or myeloma.
Caller: It’s a very personalized approach.
Dr. Berenson: Yes. We don’t assembly line myeloma here.
Caller: Yes, that is nice to hear. Well, Dr. Berenson, thank you so very much for your time. I very much appreciate it. Thanks, Jenny.
Jenny: Okay, thanks so much, Dana. Go ahead with your question.
Caller: Hey, Dr. Berenson. I’m just trying to nail down this alternative Velcade administration. You use one per meter squared, 1,4,7 and 11 a month?
Dr. Berenson: Yes, 1,4,8 and 11 every four weeks.
Caller: Got it.
Dr. Berenson: And then when you’re done with the treatment, usually six to eight cycles of that, we go to every other week maintenance and we give 1.3.
Caller: Okay. So when do you determine that that’s the time to make the change?
Dr. Berenson: Well, once you plateau your response but we usually go between six and eight. So your IGG goes from four to two to one to 500 and then sits at 500. We usually don’t give less than six cycles, usually not more than 8. We like Dick Van Patten so we say eight is enough.
Caller: Okay. So then you would go ahead and plateau and then go to 1.3 square meter per week?
Dr. Berenson: No, no, the initial therapy is 1,4,8 and 11 at one whether it’s with dex or Doxil or whatever, that’s what we do, or Revlimid. And then once you plateaued out, we we usually do that treatment plus one or two more when you plateau and then we go to every other week at 1.3.
Caller: Okay, have you published on any of this?
Dr. Berenson: Oh, yes. We’ve published a million articles on alternative Velcade dosing.
Caller: I know you have but in this particular —
Dr. Berenson: There is good data on maintenance at all. I mean there’s just nothing that maintenance does anything with Velcade.
Caller: Got it. Thank you so much. Bye.
Jenny: Okay, thank you so much for your question. Go ahead with your question.
Caller: Dr. Berenson, what is your view on transplant for patients that have achieved VGPR through chemo 20 cycles of car/pom/dex? And what is also your view on the timing of the transplant and its effect on overall survival?
Dr. Berenson: I don’t transplant anybody anymore. I am a guy who trained another guy who won the Nobel Prize for developing them in Seattle at the Hutch. But I don’t think that’s a modality you need to use anymore. We have so many options today. I would say that maybe one out of 30 patients benefit. I’d say one out of 30 that actually makes disease worse. I can’t tell who are the 3%, who are the winners, so I am not going to do it to not benefit 97%. So my timing of transplant is don’t do it. Occasionally at end stage I may have a patient goes for transplant but I think it’s fairly toxic ineffective program although somebody who is listening to this I know has done well by it (Jenny), and she may be one of those few percent. And I do have some of those people who are actually part of my brother’s CD34 selection trial in the late ’90s who are still doing well. But I have patients who were on Velcade trials back in the early 2000’s with beautiful complete remission. So it’s the long game here not the short game. But I think there may be a small percentage of people benefit but we don’t do it. We don’t recommend it.
Caller: And it is there an a priori way to determine either through genomic studies or something?
Dr. Berenson: if there is, nobody knows it. If there is, nobody knows the answer to that.
Caller: Understood. And even in a relapse setting?
Dr. Berenson: Yes. I don’t do it ever.
Caller: Understood. Thank you.
Dr. Berenson: Yes.
Jenny: Okay. Thank you so much. And I think it would be ideal to just have patient reported outcomes with a lot of data so we can see who does what with the best and then we know what to do.
Dr. Berenson: Well, you know what, Jenny, music to our ears because we are just about to publish our data on our own 300 patients in two separate articles, one on specific drugs. It’s beautiful data on everything that has ever happened with these folks, and also looking at our survival curves which are much to the delight of my patients. So I think groups should have to do that and we are doing that. And the really interesting provocative thing, I’ll tell you before closing, is that the response rates to these drugs keep on trucking. They don’t just one and you’re done. So don’t believe for a minute because you’ve put Velcade say with Cytoxan, it won’t work with Revlimid or that because you failed with Velcade, it won’t necessarily work with Kyprolis, the same drug. There are so many combinations now. It is amazing.
Jenny: Great to hear. Dr. Berenson, we are so glad you joined us today and are learning more about your tests. We look forward to seeing that come out. We’re just so grateful for your incredible research and your efforts on behalf of all myeloma patients. We’re just so thankful for all you’re doing.
Dr. Berenson: Well, thank you, Jenny and hope you enjoy the snow up there. Hopefully, I will get up there in March to ski with you, or you and Anna.
Jenny: Okay. Sounds great. Thanks you so much.
Dr. Berenson: Thanks a lot. Have a great weekend.
Jenny: Thank you for joining us on Myeloma Crowd Radio. We encourage you to get fit with us and join the Muscles for Myeloma Fitness Challenge.