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Using Antibiotics in Myeloma Combos To Kill Myeloma Cells by Reducing Inflammation with Dr. Tomer Mark, MD, Weill Cornell Medical Center
Using Antibiotics in Myeloma Combos To Kill Myeloma Cells by Reducing Inflammation with Dr. Tomer Mark, MD, Weill Cornell Medical Center image

Nov 09, 2016 / 11:00AM MST
HealthTree Podcast for Multiple Myeloma

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Episode Summary

Antibiotics can be used in combination with standard myeloma drugs to increase their myeloma-killing impact. A common antibiotic, clarithromycin (typically used for sinus infections) has been tested in myeloma and has found to help kill myeloma because it reduces inflammation, allowing the immune system to do its job to kill harmful cells. Dr. Tomer Mark, MD of the Weill Cornell Medical Center shares his use of Biaxin (clarithromycin) in a combination called "BIRD" - Biaxin, Revlimid and Dexamethasone. He notes that the use of the antibiotic with lenalidomide and dexamethasone can get equally good responses as VRD (Velcade-Rev-Dex) or CyborD (cyclophosphamide-bortezomib-dex). He likes the antibiotic combination option because it can spare patients some up-front chemo toxicity and allows doctors to reserve some active myeloma treatments for later, when patients relapse.  It is a common and inexpensive drug to add to the mix and Dr. Mark is now testing the BIRD combination with carfilzomib and in other combinations after seeing positive results from a previous study. Dr. Mark shares how this drug will continue to be tested with other new combinations and describes his upcoming clinical trials to further test this easy option. Clinical Trials Discussed in This Show Car-BIRD for Relapsed/Refractory Myeloma The Myeloma Crowd Radio Show With Dr. Tomer Mark


Full Transcript

Jenny: Welcome to today's episode of Myeloma Crowd Radio, a show that connects patients with myeloma researchers. I'm your host, Jenny Ahlstrom. We'd like to thank today's episode sponsor, Amgen, for their support of Myeloma Crowd Radio and all they do for multiple myeloma patients. And before we get started, I'd like to tell you about our Myeloma Crowd Research Initiative, or MCRI 12-Day Challenge that we are wrapping up this week. The MCRI is the first completely patient-driven initiative seeking for solutions for high-risk myeloma and ultimately, all myeloma. We believe that patients can and should help accelerate cure for themselves so with input from six leading myeloma doctors and five highly-educated myeloma patients and a very thorough review process, we've selected two critical projects that need our financial support. These projects are immunotherapies using T-cells or your own immune system cells to fight myeloma. We're now raising funds for these two projects. But in addition to donations that you can make, over the last two weeks we've gained the support of a corporate sponsor to help fund this research. We identified 12 challenges that patients could take to educate themselves and others about myeloma and to spread awareness. For each of the challenges taken and shared, $1 is donated by the sponsor. So today we will be posting all 12 challenges and if you haven't had a chance to complete them, please take a look later today and do them. They are simple actions you could take that could actually save lives. The 12-Day Challenge has been incredibly fun to see thousands of you getting involved to promote myeloma awareness that could help patients get diagnosed earlier and get better treatments. And our last challenge was probably the most fun of all: Devon Harris, the founding member of the Jamaican Bobsled Team, making a video to tell us how we can push for better outcomes for myeloma in the African-American and global black communities. So we will be announcing the winners of our prizes from our prize locker later this week which will include a free myeloma genetics test from Signals Genetics and two free case reviews by myeloma doctors as well as other prizes. Now the choices for myeloma patients are expanding greatly and Dr. Tomer Mark joins us today to discuss some new combinations and some immunotherapies as we head into the biggest hematology conference in the world next month. And I've had many patients comment about how much they love him as a doctor when they saw this upcoming show. So Dr. Mark, thank you so much for all you do for myeloma patients and welcome to the show.

Dr. Mark: Thank you for having me.

Jenny: So let me give a small introduction for you as we get started. Dr. Tomer Mark is Associate Professor of Medicine and Associate of Attending of Clinical Medicine as well as Associate Director of the Center for Multiple Myeloma at the Weill Cornell School of Medicine and New York Presbyterian Hospital in New York City. He won the ASH Clinical Research Training Institute Award and was honored as the Morton Coleman Assistant Professorship in Multiple Myeloma. He reviews for journals including Transplantation, Clinical Lymphoma and Myeloma, Expert Opinion on Biological Therapy, The British Journal of Hematology, and Leukemia and Lymphoma just to name a few. He developed the outpatient stem cell transplant program at Weill Cornell Medical Center and is also the Director of the Myeloma Autologous Stem Cell Transplant Service. So Dr. Mark, welcome.

Dr. Mark: Thank you.

Jenny: So questions for you. I guess we will start with kind of the newly-diagnosed setting. I know that in medical research, it's typical to start a brand-new therapy or treatment in the relapsed setting versus the newly-diagnosed setting. Maybe you can first describe the logic that goes behind that.

Dr. Mark: Sure. The reason why we start newer drugs in relapsed to refractory setting is because of our lack of experience. For one thing, the newer drugs are developed in a laboratory setting typically with cell lines or primary cells that are refractory to the older drugs. And so they're sort of designed to overcome resistance to older drugs. But the more practical reason, again, is lack of experience where you have a drug like bortezomib that's been used in more than 100,000 people, when you have a brand-new drug you're not exactly sure what the side effect profile is, whether it could be toxic or whether it could not work at all. And so when you're starting a newly-diagnosed patient with multiple myeloma you really don't want to make mistakes. There's not a lot of wiggle room and you want to start with something that you know will work. Whereas for relapsed/refractory patients, although it is still very important that that treatment you use works, very often there are limited options. And so your hand is sort of forced to try one of these newer drugs.

Jenny: That makes a lot of sense because there are a lot of options for the newly-diagnosed patient. So maybe you want to address how trials are constructed for newly-diagnosed patients then because you have a trial that we're going to talk about in a minute.

Dr. Mark: Sure. For newly-diagnosed patients, I would say about ten years ago, the focus was getting a response and a deep response. Now that we have a whole bunch of drugs that people respond to well off the bat, now the focus is two-fold, number 1 is tolerability. So having that same level of effectiveness yet increasing somebody's quality of life. And the second is how deep can you go? Can you get people into a minimal residual disease-negative state, wipe out every site of myeloma that they have without using a transplant? And we're getting there right now. Whereas ten years ago it was treat and then transplant, now it's treat, test for minimal residual disease, and question mark transplant.

Jenny: Okay, fascinating. It's hard because sometimes you see papers come out that say transplant is still the most effective but then you think compared to what? Because they're not doing a head-to-head comparison and sometimes the delay in time to study something is extended and then new things are coming out in the meantime. I know last year you had a study that was carfilzomib and then the BIRD combination. Maybe you can describe what that was and how you came to create that? But I'm curious to know how you determine which study that you'll choose at your facility, because you only have a limited amount of time and energy and resources, I would think. So how do you pick the very best options for your patients as part of that?

Dr. Mark: The way we try to set up trials for newly-diagnosed patients at our institution, it depends on the phase of the study. If it's a phase II trial like the Car-BIRD trial that we'll talk about in a little while, it's trying to get more active agents that are typically used in the relapsed refractory setting more towards frontline. And the rationale for Car-BIRD was based off on an earlier study by Andrzej Jakubowiak at University of Michigan, now at University of Chicago, where he combined carfilzomib, lenalidomide, and dexamethasone as upfront treatment for his patients and had absolutely fantastic response rates. We believe that the very good partial remission rate or better on his study was 100% and the complete remission rate was close to 70%. And so that was the primary reason we chose to try and bring Kyprolis in the upfront setting; it's only approved for relapsed or refractory myeloma at this time. So it’s trying to give our patients sort of that early access option. When it comes to phase III studies, it typically comparing standard of care to something that you think may be a little bit better. And so at Cornell we're sort of famous for using clarithromycin in our regimens and we can talk about that more a little later too. And clarithromycin's actually been adopted by many myeloma experts around the country, but there's been no head-to-head study. And so our next upfront trial is a randomized phase III of BIRD which is clarithromycin, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone to truly show that adding the clarithromycin enhances the len/dex activity.

Jenny: Okay, let's talk about that for a minute. Why did you choose that particular drug because I don't hear it very often and what does it do to kill myeloma and why are you using it in that combination?

Dr. Mark: That's probably the most common question I get. It happened sort of by providence. The first report of using clarithromycin in multiple myeloma comes from an ASH meeting long ago where Brian Durie talked about using Clarithromycin in patients with multiple myeloma that have a cyclin D1 translocation, that's the 11;14 translocation. And he started using clarithromycin because he had heard that clarithromycin had activity in mantle cell lymphoma which also has that cyclin D1 translocation. Now it turns out that that was based on a sort of a false assumption but he demonstrated some activity for clarithromycin. That led to another study done in New York City by Morton Coleman here of the BLT-D regimen which was Biaxin, that's the trade name for clarithromycin in combination with thalidomide and dexamethasone, and that had really good response rates, in the high 90s. So there was sort of something to it. But then other researchers used clarithromycin as a single agent in myeloma and showed no activity whatsoever and so this sort of fell by the wayside. It was resurrected again at Cornell in the BIRD study which was clarithromycin, lenalidomide and dexamethasone. And in that study there were around 70 patients or so and there is an overall response rate of 90%, a very good partial remission rate or higher of 70% and a complete remission rate of 40%. If you compare those numbers they are equivalent to the other popular regimens of VRD which is bortezomib len/dex, and CyBorD which is cyclophosphamide, bortezomib, dex. And given that they all seem equal on paper, that tells you that the Clarithromycin seems to be doing something. For one thing you're sparing people the extra chemotherapy of cyclophosphamide and you're sparing people using all the active agents upfront in myeloma. One of the problems that we've had before is if you start somebody on VRD chemotherapy and they relapse, what are you going to do? You're going to later give them carfilzomib or pomalidomide. But if you start somebody on BIRD, when they relapse you can give them Velcade and vice versa if you start somebody on CyBorD, when they relapse you can give them BIRD and then you have an entirely different active combination. Now even with that BIRD data and that publication in Blood, people still did not believe it. And so we sent our data to the Mayo Group and we had no hand in this. They took our data and they compared it to their experience with lenalidomide and dexamethasone. And in their review, our complete remission rate for BIRD was twice as high as far as len/dex and our time to progression was twice as high. Our time to progression was around 50 months for BIRD versus 25 months for len/dex. And again, that's just because you add a simple antibiotic treatment. I think the reason you don't hear more about this is that nobody makes money from clarithromycin. Generic, been around for years, right?

Jenny: And what is it? Is it an antibiotic?

Dr. Mark: Yes, it's an antibiotic. It's typically used to treat sinus infections. You may ask, how could that possibly work in multiple myeloma? There are actually several reasons. Number 1 is antibiotics, especially the macrolide antibiotics like clarithromycin are anti-inflammatory. And so it's been shown that if you give kids with frequent asthma attacks clarithromycin, the severity and frequency of their attacks go down. If somebody is admitted to the hospital with a COPD exacerbation which is purely inflammatory in nature and you give them antibiotics, they get over their COPD exacerbation quicker. And when I did my internal medicine residency in Boston, the head of our department was an infectious disease doctor. He would tell us that people would come in to your clinic with clearly a viral upper respiratory tract infection and they would beg you for a Z-Pak -- azithromycin. He said the reason they beg you for a Z-Pak is it works. Even if you have a viral infection, it activates your T-cells and helps them to fight that infection and inflammation. And if you think about the way lenalidomide works, it works in a very similar way -- it turns on T-cells and NK cells to fight myeloma. And so now that there is some more data about that there are other groups that have looked into the molecular mechanisms of clarithromycin in multiple myeloma and there is now laboratory data supporting clarithromycin turning off inflammation in people. In addition to that mechanism of action, clarithromycin also competes with dexamethasone for metabolism in the liver. So dexamethasone has a relatively short half-life, it's all out of you in about 24 hours and that's why we used to give pulse dex in the olden days, 40mg a day for four days, and that is a very tough thing for people to take because they don't sleep for four days. And what we've shown with clarithromycin is you get a very similar effect of having a prolonged sort of dexamethasone effect in your body because of decreased clearance in the liver but you don't get the side effects; people don't get the insomnia. And the side effects are very close to what you would have with taking dexamethasone only once a week.

Jenny: So you're saying you're using it alone or using it with dex?

Dr. Mark: Using it with dex together. So the BIRD is Biaxin, lenalidomide and dex.

Jenny: Oh, I see.

Dr. Mark: And so essentially what you're getting is instead of a quick on-and-off for your dexamethasone, you're getting a smooth plateau that lasts for several days and it's probably more active against the multiple myeloma. The third sort of mechanism is that research has shown that in the presence of clarithromycin, lymphocytes are more sensitive to killing. So essentially it decreases the lymphocyte defense from cytotoxic events -- so plasma cells are technically lymphocytes -- and so that may be another mechanism of action for that. So circling back to our Car-BIRD study, given the Jakubowiak data showing that CRD is highly active and probably more active than VRD, CyBorD, we decided to try it with BIRD since we know that that works just as well as VRD and better than RD and separate them out in time so that we could potentially avoid toxicities. So we give the carfilzomib and the dexamethasone until maximum response at which point we switch over to BIRD which is an entirely oral regimen. We use that to max response at which point the patient then goes directly to lenalidomide maintenance. At some point along the way we do collect stem cells and store them but these patients don't go up for upfront transplant. And so the hope is getting it just as good as CRD without the toxicity. And Morton Coleman is still involved in this project and he calls it the one-two punch. You knock out the carfilzomib-sensitive cells right in the beginning and then you mop up with the BIRD for anybody that was resistant to the carfilzomib.

Jenny: That's a great approach. I have a question because you're a director of the stem cell transplant unit. So how do you look at the comparisons between starting somebody out with early transplant versus something like this? Because transplant is not an easy process but patients are willing to do it if it's going to be the ultimate in effectivity.

Dr. Mark: Sure. My view is that transplant is a tool, it's not a destination. And if you look at academic centers versus private hospitals, you'll find that the private hospitals are the ones that are promoting transplanting everybody -- if not one then two transplants. And so you got to figure that there's a little bit of dollar bias going on over here because transplants are highly-profitable for hospitals. If you look at academic centers like us, Dana-Farber, Mayo, transplant is usually reserved for patients in relapse or patients that otherwise don't tolerate chemotherapy. So although I am director of the transplant for myeloma program over here, I have to say that we do not transplant the majority of our patients -- at least, not upfront. And the reason for that is that all myelomas are different and I think it's wrong to treat every single patient with myeloma exactly the same. I think that the treatment has to be tailored and customized to the patient. And the right way to use transplant is either to treat an early relapse so you get somebody right back into complete remission, or to treat that patient who cannot achieve a complete remission with induction chemotherapy. And our agents are so good right now; I have to say that here at Cornell almost 70% of our patients get into complete response with just chemotherapy alone. And so if your patient's in complete response, if they're taking chemotherapy and the plan is to give continuous chemotherapy for the long term, I can't tell if they're going to need a transplant a month after they finish the primary induction or 5, 6 years afterwards. And so I do sort of leave it up to the patient a little bit, we talk about the pros and cons of transplant, and at the end of the day, I do believe that people who get a transplant tend to live longer than people who do not. The timing doesn't matter at all. I think that your transplant benefit in terms of years added to life would be the same whether you do it right away or you wait a little while. And I say the exact same thing to patients. There has been a study in the past looking at early versus delayed transplant that showed no difference in overall survival. If there is a benefit to doing early transplant, I would say it would be for quality of life. If somebody's having a really tough time with chemotherapy, a transplant gives them an opportunity for getting a deep response and then going on to maintenance which is usually much more tolerable than primary chemotherapy. You get to drop the steroid which is usually the most evil thing of the bunch.

Jenny: Yes, everyone hates that.

Dr. Mark: Right. If somebody is taking BIRD chemotherapy and they're in complete response and they feel good, they're going to work, then I'll harvest and store and then we'll transplant when it's convenient for the patient.

Jenny: And you're saying that using the Car-BIRD is also giving people lower side effects using the dex anyway, right? Is that what you're saying?

Dr. Mark: So there's Car-dex and then BIRD and then len-maintenance. And so I would have to say there is a lower rate of side effects because the combination is less intense and people like it because it's entirely oral. Once people are on the BIRD and the len-maintenance they come here once a month. So thinking about going to see your myeloma physician once a month is great, you know?

Jenny: Yes, right.

Dr. Mark: And working in the upper east side of Manhattan, these people generally are very busy, active, going to work, don't want to see the doctor, and not really preoccupied with their medical conditions. And so having a long-term chemotherapy plan that people tolerate and can live with is ideal. I would think that in other areas of the country where people may not be as "busy" or as sort of work-focused, where they can afford to go to the doctor a little bit more often, other regimens would be just as good.

Jenny: Well, but still no one likes sitting in the infusion room for hours, no one enjoys that really.

Dr. Mark: Sure.

Jenny: So yeah, that's terrific. Okay. So you presented this paper last year at ASH. Can you go over all the results -- maybe you just did that, but if there's anything you like to say about that? And then if that study is complete then where are you going next with this combination?

Dr. Mark: Sure. So at last year's ASH, we presented the Car-BIRD data in total and the Car-BIRD data looked generally pretty strong. So in terms of the results over here, for just the Car-dex sort of induction portion of it, the VGPR and better rate was around 84%. And then when you add the BIRD consolidation to it, an additional 11% of patients respond VGPR or better. So at the end of the day we have a 95% VGPR and better rate which is --

Jenny: And so this is very good partial response (VGPR), right?

Dr. Mark: That's correct. So that's pretty much the same as the CRD combination altogether that Jakubowiak had but again, we separated this in time. In general, it was very well tolerated and the doses of carfilzomib that we used went all the way up to 56mg/m². It's been shown that carfilzomib, there is a dose response relationship and that the more you use the deeper the response you get. People are worried about cardiac toxicity and renal failure with carfilzomib but we treated more than 70 patients and I have to say there is probably only one or two cardiac events in people who had pre-existing heart disease and advanced age. The renal failures that we saw were also not that many, five or less, and all of them but one were reversible. The one where it wasn't reversible, we weren't sure whether that renal failure was actually due to progressive myeloma or not. Now on our Car-BIRD phase, people have been on lenalidomide maintenance for two years plus. We have somebody going into the third year of lenalidomide maintenance. And people are doing really well at just taking one lenalidomide at 10mg a day.

Jenny: Okay. And do you have an open study now?

Dr.  Mark: So Car-BIRD just wrapped up. We're about to open our phase III BIRD versus RD study and that is actually an international study. We're the primary site in the United States but Dr. Mateos is opening it up with PETHAMA in Spain and they're a very active group as well. And we hope to get some sub-sites in the United States as well since this is going to be a large study. In addition to that, we're about to open up one of the industry-sponsored trials of daratumumab in combination with lenalidomide and dexamethasone as upfront therapy. We're working on another sort of investigator-initiated protocol of using the next Takeda drug which is ixazomib and adding that to BIRD as upfront therapy. That would be another entirely oral regimen combining a proteasome inhibitor, IMiD, and clarithromycin, our favorite drug.

Jenny: Yes, so that will be the first oral proteasome inhibitor, right?

Dr. Mark: Yes, that's right.

Jenny: Yes. And these three studies -- the phase III, the daratumumab, and the ixazomib with the BIRD -- those are all for newly-diagnosed patients as upfront therapy, right?

Dr. Mark: Those are all newly-diagnosed, yes.

Jenny: Okay. Well, it's sort of hard to find studies for newly-diagnosed patients that I've found so these are great options.

Dr. Mark: Yes. And it's also tough to get patients for newly-diagnosed studies because VRD is so easy to prescribe; you just get it with your local oncologist. At a myeloma center, we generally see people when they're in trouble, when the local oncologist can't take care of them anymore.

Jenny: Well, I think that's very common. I think it's tough to find those patients because they are going to their local oncologist or even to their local doctor and they say okay, let's start you on treatment right away which is…(the “standard”) My story is many people that I know, many patients that I know, their same story, you really have to say, "Well, wait a second, before I start this, I want to make sure it's my optimal outcome." So I have a lot of questions for you about the clarithromycin and that, but maybe we want to insert some of what we talked about earlier. Earlier I was sort of asking you how you picked. I mean with all these different options, so you just named three, for newly-diagnosed patients and there are a lot more for the relapsed/refractory patients, how does a myeloma patient make those decisions with their doctor to find the best ultimate outcome especially as we move to personalized medicine and treating patients more individually, this is not an easy thing.

Dr. Mark: No, not at all. I find it that the patients are very confused, that it’s a really difficult decision. The patient actually place a lot of burden on themselves to sort of come up with the answer and given that there are so many options out there, that actually makes it more confusing. I find that we really need to guide the patients because there are so many options and there are so many things that you can read about online and everybody has an opinion. But without this experience, picking an option is really hard. And some patients they want to direct their own care from the get-go but I find that equivalent to me knocking on the cockpit of an airplane saying "Okay, I want to take over."

Jenny: Yes, the experience isn't there to be sure.

Dr. Mark: And a lot of the reports out there are biased. So if you for instance take a look at the mSMART criteria for Mayo Group where they risk-stratify patients based on cytogenetics and other features into high or low risk and then say high-risk patients get VRD, medium-risk patients get CyBorD -- that's based on zero data. That's completely an opinion and people don't realize that. When you compare VRD to CyBorD to BIRD, they are all exactly equivalent in terms of efficacy but they all carry different side effects. And so if I were to take care of somebody who plays violin for the Philharmonic, I may want to choose an agent that does not have any peripheral neuropathy. If I had somebody who had a lot of vascular disease, a history of stroke for instance, then I would shy away from using a lenalidomide-containing regimen. But at the end of the day and we say this amongst each other, all patients get all agents anyway and so people wind up going through a succession of different things. So the one sort of thing coming out that may be better is of course the Kyprolis®-lenalidomide-dexamethasone combinations that have shown deeper responses, have shown elimination of minimal residual disease as upfront therapy. And as we are getting more into MRD testing, we now know that the deeper you go, the better you do. A group in the United Kingdom just showed that for every log reduction in amount of plasma cells remaining in the marrow, an extra year of life is gained. And so certainly in our practice, getting to that minimal residual disease negative state for every patient is the goal.

Jenny: And you're testing for MRD status when you test? Is that becoming more regular in everyone's practice, would you say?

Dr. Mark: I think among academic practices it's certainly caught on. It's yet to achieve sort of prime-time status for several reasons. Number 1, myeloma traditionally has not been very good on flow cytometry studies because as hard as it is to kill plasma cells in patients, it's harder to keep them alive outside of patients. And so as soon as you take that aspirate out of the patient, the cells start dying. And so unless you have a flow cytometry machine in your institution or can get it processed very quickly, the test becomes meaningless. And so at academic centers, we have a flow cytometry machine across the street and we run the samples over as soon as we get it out of the patient and so our data and data of other institutions comes from that. So it's not commercially available to the standard local community oncologist. So that's one issue. The other ways that we measure minimal residual disease by PCR or DNA sequencing, you have to have it done a priori, meaning prior to the patients starting treatment. Once you start treatment you may lose the clone and never be able to recapture it or measure it in a minimal way in a patient. And so when I see somebody who's had three prior relapses in myeloma I'm not going to be able to run that sort of test but I can always do the flow cytometry. And so as our treatments get better and we're achieving this benchmark, what we're doing is we're getting the myeloma so low in the person that it never has a chance to catch up. And so the patient is "functionally cured". And I imagine that we're functionally curing a slice of our patients nowadays but of course we won't know that for years.

Jenny: Okay, that's great; it's so much to think about. And it's one of the reasons why we really advocate being seen by myeloma specialists because the nuances of this disease are so complicated. I mean for you to be able to know that you need to adjust your treatment for a specific patient based on the patient individually takes a lot of sophistication.

Dr. Mark: I completely agree.

Jenny: So just a question about that, when you compare data you just look at the numbers like the progression-free survival (PFS) and overall survival (OS) and the complete response and very good partial response (VGPR) and those types of things and you're comparing those numbers head-to-head as a researcher or is there another tool that you use to compare… When you see studies come out from other institutions, how do you compare those?

Dr. Mark: Good question. So you're actually not supposed to compare two studies head-to-head for several reasons. Number 1 is that patients are different in different places. For instance you may have a phase II study from an area of the country that sees primarily African-Americans, or you may have a European study where primarily the patients are Caucasian. But when you're looking at… you can sort of sense broad trends. For instance we know that three drugs are generally better than two drugs in the younger fitter patients. However, in the older patient population there is a recent study called the upfront study that looked at three drugs versus two drugs in older patients and it turns out that there was no difference in efficacy, just more toxicity for three drugs. And what I liked about that phase III study is that it was done in a community setting so more sort of a real life setting. The other sort of difficulty is you can't really compare overall survival, progression-free survival for upfront regimens because the data is dirty. What happens is patients relapse, then they get onto a highly-active regimen and that regimen may be different for all of the patients that relapse from that same primary induction therapy. So that sort of muddies the water a bit and that patients aren't being treated uniformly and that it makes it impossible to compare. I think that again the typical three-drug regimens used in this country, they are pretty much all exactly equivalent. And when you are picking or at least when I am picking, I pick basically on patient factors. Meaning do I trust the patient to be able to fill a pillbox correctly and take their pills every day? Is this the sort of patient that I need to keep a closer eye on so I would like them to come into clinic more often to receive their treatment here -- those are generally the more fragile patients. How old is the patient, what is their goal of care? In general, younger patients, their goal is to live long as possible and so we absolutely will be aggressive and try to achieve that goal. However the 85-year old patient, their goal is generally not to go into the hospital and to be independent. And so you can get a nice response in these patients but if you destroy them with chemotherapy I think that's against what you meant to do.

Jenny: Right, yes. Well, again, it's a sophisticated use of these different therapies. In my opinion -- it's just my opinion -- I don't think the local oncologist really has the “know how” to do all that. I mean they usually have a standard regimen that looks like “the standard” and so they give it to you and it's … I don't know.

Dr. Mark: Well, there are some other nuances to that as well. We know from gene expression profiling that there are at least eight different kinds of multiple myeloma. And to treat everybody the same way I don't think is right but we don't really have data -- at least not a lot of data -- about risk-adapted therapy. What we have is just a few bits of data about this drug for sort of cytogenetic translocation and so on and so forth. But there's another sort of wrinkle to the difficulties of going to a local oncologist, I'll give you one example. I have a patient that went to their community doctor with multiple myeloma for upfront therapy and received lenalidomide and dexamethasone and developed a rash. And the patient's doctor said "Okay you have an allergy to lenalidomide, we can't use this agent anymore." And then proceeded to relapse and go through a number of different lines of chemotherapy, became really sick. Then finally was referred over here where we promptly restarted lenalidomide, actually we restarted BIRD, and the patient's now in his third year of complete remission. And so there's an experience component knowing that a lenalidomide-induced rash is actually pretty common and it's not an allergic reaction, knowing that we treat patients to progression. If you were a doctor who graduated medical school in the '80s you were taught you give a few cycles and you stop and you watch and wait because myeloma's not curable. But now we know the longer you take medicine, the better you do.

Jenny: Right. Well, let me ask you some questions around the antibiotic that you're using, the Biaxin. So it reduces inflammation and you're finding it to be very effective in this combination. I've also heard a lot about PD-1 and PD-L1 type of immunotherapies and when you talk about immunotherapies I know you have one coming up as well. But that sometimes at the front end like a CAR T cell or something might accelerate - I've heard it described from one of the doctors as you could step on the gas with your immune system and then some of the PD-1 or PD-L1 kind of takes the brakes off the immune system and lets it do its job. So it seems like the inflammation blocks some of the drugs from working. Then you're using all types of therapies and maybe immunotherapies in myeloma, do you see this antibiotic as doing the same types of things as PD-1 or PD-L1 or could they be used together to be even more effective to let these drugs do their job? Or is it entirely unrelated and I don't know what I'm talking about?

Dr. Mark: These things all sort of work in different ways but we're all sort of getting into the same thing which is basically activating T-cells and NK cells and having them clean up the immune system and to do immune surveillance. And so clarithromycin we know activates T-cells; the PD-L1 certainly activates T-cells, that's how it works. It turns out that elotuzumab actually activates NK cells and CAR T-cells are activated T-cells. And so yeah, we're all sort of getting towards the same end which is getting these cytotoxic T-cells and NK cells to go in and recognize those myeloma cells as foreigners, and to kill them. What's interesting is again, myeloma is a disease that lives off of inflammation. In the olden days we used to measure IL-6 which is Interleukin 6 and that's an inflammatory protein made by the liver and it is food for myeloma. If you want to grow myeloma in a lab you have to feed them IL-6 which is pure inflammation every day. And we frequently find that when somebody gets admitted to the hospital with a severe infection and they have myeloma and they go through ICU, sepsis, heavy antibiotics. What happens is their myeloma often goes to sleep for a little while and that's because of the intense anti-inflammatory cytokine release that happens during the course of the hospitalization. And so if we can find other ways to harness the immune system and control the inflammatory process, that's another key to controlling myeloma. We are interested in all those mechanisms here at Cornell, we're about to open up a PD-1 trial and we're looking into CAR T-cells as well. And you can trust that we probably will be adding or playing with Biaxin in those mixes as well.

Jenny: Well, I think it's a really exciting agent and are other people picking this up as well, seeing that you're getting good results with this?

Dr. Mark: Oh, sure, absolutely. The PETHEMA in Spain is committed to a trial with clarithromycin, that's a very large network. Johns Hopkins just had a poster at ASH last year about using clarithromycin in their patients. Funny enough, the Chinese have gone all over this and I have been reviewing a lot of papers about using clarithromycin in Chinese patients with multiple myeloma. And my good friend, Jim Berenson, in Los Angeles, he uses clarithromycin. I imagine that you ask multiple myeloma doctors about it, they are familiar with the data and they will use it from time to time to break plateaus in their patients or even a sort of upfront therapy. I think it's more the community oncologist or physician that doubts it. They think, how can an antibiotic possibly be active in a cancer? And my response to that is a doctor had to drink a bottle of H. pylori bacteria to prove that it caused ulcers.

Jenny: Right. So in what other combinations could you use this antibiotic and what other combinations would you like to try?

Dr. Mark: Well, we would like to try the clarithromycin-ixazomib-lenalidomide combination. I know that Dr. Asher Chanan-Khan who's at the Mayo Clinic in Florida right now used it in combination with bortezomib. And we didn't talk about any of our relapsed refractory trials but we had it in combination with pomalidomide and that's our CLaPD Study -- Clarithromycin, Pomalidomide, Dex -- and that also had very exciting results. Now if you take a look at Martha Lacy's data where she used pomalidomide and dexamethasone for myeloma patients that are relapsed after a median ofprior lines of therapy, the overall response rate was around 30% and the progression-free survival was a little shy of four months. If you add clarithromycin to the exact same population and we've done this study in 120 patients, the overall response rate is doubled at 60% and the progression free survival is doubled as well as more than eight months -- and again, simply by taking an antibiotic twice a day.

Jenny: Yeah, that's great. That's so impressive that an antibiotic can just have so much impact to the inflammation and give you such better responses.

Dr. Mark: And it's cheap, too.

Jenny: Right. I would say why isn't everyone adding this. I could see why you're so excited about it.

Dr. Mark: Right. Well, you know, you have to convince people.

Jenny: Right, true. Well, maybe we want to talk for a minute about some of your relapsed/refractory studies and then I don't know if you want to mention the CAR T-cell study or anything else you have planned?

Dr. Mark: The CLaPD trial is sort of our premier trial for relapsed/refractory patients and again it was sort of a homerun for us. The manuscripts are being prepared right now but it was an entirely oral regimen for relapsed/refractory patients that people did really well on. It's been going on now for about six years and one of our first patients who was referred from Sloan Kettering for pomalidomide, we started this. And after five prior lines of therapy, this patient is now still in his fifth year of complete remission and he's not the only one. We have people who've been in remission for years and on just an oral regimen. So that's been great. We have other sort of homegrown trials. One is using palbociclib for relapsed/refractory myeloma. Palbociclib is novel in that it's a self-cycle inhibitor. It's an inhibitor of CD4 and 6 and that's very important for myeloma. Many myeloma patients have the cyclinD1 or cyclinD3 translocation which is basically a translocation that takes the brakes off the cell's cycle so the cell can keep on proliferating. What this agent does is it puts the brakes back in there. And we have a trial of that in combination with lenalidomide for relapsed/refractory myeloma and again that's an entirely oral regimen. And what we do is the patients come in, we will actually test their myeloma cells for this marker of CD4 and 6 activity. So we'll test them for the target, if the target's there then we will put them on this trial. We've got about four patients taking this trial so far and so far so good. We also have transplant trials for relapsed/refractory myeloma. One of our more interesting trials is a high-dose Revlimid. So it turns out that in the phase I studies for Revlimid, 50mg is actually more effective than 25mg but nobody could take 50 because of bone marrow suppression. So given that we're doing a stem cell transplant and we're destroying the bone marrow anyway, this is a great opportunity to give extra high doses of lenalidomide to see if we can overcome resistance. And so we are giving 350mg of lenalidomide daily which is way more than the regular dose and we're overlapping that with the high-dose melphalan for a transplant. And what we're seeing is just the high dose lenalidomide alone starts to produce apoptosis before the transplant.

Jenny: Or you're killing myeloma cells (aptosis), right?

Dr. Mark: Yeah, we're killing myeloma cells right before transplant. And so we're soon to be overcoming some sort of threshold. High-dose lenalidomide is being explored in other malignancies as well such as acute leukemia. It's sort of a shock and awe sort of thing for the myeloma.

Jenny: Interesting. Well, I have some follow up questions but I also want to open it up if anyone has a question and I have a write-in question. So let me do that first and then we'll go back to my other question. So if you have a question for Dr. Mark, you can call 347-637-2631 and press 1 on your keypad. Go ahead with your question.

Caller: Hi! So first of all, I want to just congratulate you on the Myeloma Crowd Radio for putting together week after week on treatments of this disease that it's very helpful and today's program was a great example bringing really new perspectives to us that haven't been brought out before. So thank you.

Jenny: Oh, thank you.

Caller: My first question is when is your phase III study in BIRD going to be open?

Dr. Mark: Any day. It's already been IRB-approved and FDA-approved. I'm just waiting for a final contract to go through and I've been told any day.

Jenny: That's also for newly-diagnosed patients, right, the phase III study?

Dr. Mark: Yes, that's upfront.

Jenny: Okay.

Caller: So if you've already been in treatment you wouldn't qualify for it?

Dr. Mark: No. That's for treatment-naïve patients.

Caller: Got it. And maybe I missed it but who is the first person to come up with this idea of adding antibiotics in the combos? What was the spark of the idea for that?

Dr. Mark: It was Brian Durie of IMF fame in the Salmon/Durie criteria or the Durie/Salmon criteria, depending who you ask, who read about it being used in mantle cell lymphoma and decided to try it out in myeloma. It comes basically from him.

Caller: All right, thank you for taking my call.

Jenny: Okay, thank you so much. Well, we are heading in to ASH and before we stop, I want to ask you about ASH. Can you maybe explain for patients what ASH is and why it's so important?

Dr. Mark: So ASH is the American Society of Hematology. And it has an annual meeting in December where about 50,000 hematologists from all over the world come and meet and exchange ideas and also listen to the latest and greatest data - trials that we're all very interested in for multiple myeloma. An example for that is the IFM/Dana-Farber trial of upfront transplant versus delayed. Those kinds of huge trials are presented there and they are often practice changing. New agents are often presented there as well, early stage data for drugs that may be active in multiple myeloma. And behind the scenes, so this is where researchers often meet amongst each other or with pharmaceutical companies to develop concepts for new clinical trials.

Jenny: And what are you watching for at this year's ASH?

Dr. Mark: Well, certainly that Dana-Farber study. That study is VRD transplant followed by len-maintenance versus VRD len-maintenance. So it really answers the question of should a transplant be part of upfront therapy for multiple myeloma. Well, I'm interested in a bunch of trials but the other trial I'm interested in is the results of a phase III trial using ixazomib in combination with lenalidomide and dexamethasone, that's a randomized trial of ixazomib-len/dex versus len/dex for myeloma that's relapsed after primary therapy. And so again that would be an entirely oral combination for relapsed patients. That is pretty attractive. And then we all want to see updates on daratumumab and other monoclonal antibodies in combination or single agent in multiple myeloma.

Jenny: And I know daratumumab and elotuzumab are looking forward to approval. Do you have any feelings for when these will be approved?

Dr. Mark: I'm suspecting that we could hear the announcement as soon as ASH comes. And so if not approved at ASH time then I imagine right after the New Year.

Jenny: Okay. Well, we're excited to hear about those as well. And did you want to talk about your upcoming CAR study or is there any other thing you'd like to talk about?

Dr. Mark: Well, CAR T certainly is coming in multiple myeloma and it's very attractive. It makes a lot of sense using your body's own immune system training it to fight multiple myeloma. And it's been used with some success in other malignancies like CLL. And there's a New England Journal of Medicine paper not too long ago about using CAR T in myeloma with very nice results. This is a very personalized therapy for the patient, in that you are using their own cells. Again, you don't expect all the side effects or long-term effects that you would from an allogeneic stem cell transplant such as graft-versus-host disease but you get all the benefit and you have a continued immune surveillance against your cancer. So it may represent a functional cure. This is the first generation of CAR T in myeloma however and so we have to learn about things like controlling cytokines for instance after infusion of those T-cells. A cytokine storm can make somebody very sick with low blood pressure, for instance. And we don't exactly know what the target should be either. In that New England Journal of Medicine paper, the target was CD19, which is seen in a very small percentage in multiple myeloma but it worked. In our CAR T study, we're going to be using CD38 which of course is found in all the myeloma cells. But CD38 is also found in smooth muscle, it's also found in red blood cells and so we don't know what the off-target effects of that will be. And it's also the first generation of CAR T and so there may be refinements that need to be made in the future with the technology. I remember in college when I was doing DNA cloning and sequencing, we could sequence only about 100 base pairs at the time and it was an all-day process. Now you can put a drop of blood in a machine the size of a desktop computer and get somebody's whole genome in a couple of hours. So I imagine even as close as five years from now, CAR T is going to be very much more specific and an easier process but we've got to start somewhere.

Jenny: Right. And with the recent leukemia thing that we heard about last week, they're using a totally different T-cell approach where they did some sort of gene splicing or something for the baby with leukemia. It sounds like usually in CAR T-cells with your own T-cells that are being engineered and you're getting them back but this was like a donor-type T-cell, right?

Dr. Mark: Right, exactly, I think that gene therapy is coming. It was at ASH several years ago that they were using gene therapy to treat hemophilia and actually curing hemophilia in patients in the UK. So yes, it's here. The issue with multiple myeloma is it's in adults and gene therapy in adults is hard. You generally need to work with only one kind of cell at a time.

Jenny: So one more question from a write-in question and then my own question to finish up because we're getting close to time. It's surprising how fast the time goes. Well, let me ask my question first and then I'll go back to it. What is the value to you of patients participating in your clinical trials because it seems that you have an extensive number of clinical trials open for myeloma and are doing quite a bit of research in the space.

Dr. Mark: Without patients willing to do clinical trials, we can't move the field forward. There would be no innovation, there would be no new drugs, and there would be no optimization of therapy. And we are thankful for all of our patients that are willing to participate in clinical trials and I have to tell you that the people who are doing clinical trials, the researchers out there are doing it for altruistic reasons. Patients may think that they're being experimented on for profit, for gain but that is absolutely not the case. We are here to learn about multiple myeloma and to have patients live longer. And so without people doing clinical trials, it's not going to happen.

Jenny: Well, that's why we started this show. It's because there are less than 3% to 5% maybe of patients participating in clinical trials and I just can't imagine what we could accomplish together if we join the clinical trials, even doubled the number. It would be just so stunning; you could do your work so much faster and come to conclusions so much faster.

Dr. Mark: I completely agree with you. In Europe where a lot of patients go into clinical trials for the reason is that they don't have the drug available outside of the clinical trial, they accrue much quicker and generally get the information out there much faster than the United States. It's embarrassing actually. Because I think that first of all, patients in Europe don't have access to drugs like they do in the United States. And I think there might be more of a socialistic or collective spirit there. In America it's all about the individual.

Jenny: Well I know that in Europe it's more common too because they have smaller patient groups so it just makes sense to combine and collaborate and a lot of it is maybe because of that -- maybe not.

Dr. Mark: Well, the European data is great but if you take a look at the demographics, it is universally 80% to 90% white men in their 60s and we know that that is not the myeloma population. Myeloma is generally black men in their 70s. And so it's hard to sort of extrapolate that and use it in real life.

Jenny: Yes, or white women in their 40s. You never know what you're going to get. So the last question that I found was from Anna and she said there was a mention about the BIRD study from the recent Rome International Working Group meeting - what was that announcement?

Dr. Mark: Well, our Car-BIRD study was presented at plenary session over there in Rome. One of the fellows that we mentored for Car-BIRD actually won an investigator award over there. And so it's simply an opportunity to present that to a large audience.

Jenny: Oh, that's great. Well, we hope to see more about it, Dr. Mark. We're so grateful that you're working on myeloma and are looking for better and easier and more effective therapies for patients. We really owe you and the whole community an intense amount of gratitude for the work that you're doing.

Dr. Mark: Well, my thanks to the patients that participate in clinical trials and are invested in eliminating myeloma.

Jenny: Yes, we're so thankful for all you're doing. So have a great time at ASH and please keep going with your fantastic research.

Dr. Mark: Thank you, Jenny.

Jenny: Thanks. Thank you for listening to Myeloma Crowd Radio. We know that patients can help support the discovery of a cure and we encourage you to listen to the show and become involved.

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