Robert Z. Orlowski, MD
MD Anderson Cancer Center
Interview Date: January 5, 2018
Much is happening in the world of myeloma. Where are we headed in 2018? Dr. Robert Z. Orlowski of the MD Anderson Cancer Center joins us to share the latest. He reviews a variety of treatment options for smoldering myeloma, emphasizes the expanded use of daratumumab for all patient settings, reminds us that cyclophosphamide (an older drug) can still be used effectively and reviews the importance of maintenance therapy. He notes the progress of minimal residual disease MRD) testing. He shares the up-and-coming immunotherapies like isatuximab, the new Glaxo-Smith-Klein antibody and the use of venetoclax for patients with the 11;14 translocation.
Most importantly he shares the importance of being treated by a myeloma specialist. Newly diagnosed patients who see a myeloma specialist can have 40% better overall survival. And in general, those who are treated by myeloma specialists can live 22% longer than those who don’t. To find a myeloma specialist, click here.
To find the clinical trials discussed in this show, click the links below:Daratumumab for HR Smoldering Myeloma Dara for Low Risk Smoldering and MGUS KRd for HR Smoldering All Daratumumab Studies New GSK Antibody for Relapsed Myeloma Studies Using Venetoclax for 11;14 Myeloma Isatuxumab Studies (Anti-CD38 mAB) All T-Cell Studies (Including CAR T) Len/Elo Maintenance
Dr. Orlowski on Myeloma Crowd Radio
Jenny: Welcome to today’s episode of Myeloma Crowd Radio, a show that connects patients with myeloma researchers. I’m your host, Jenny Ahlstrom. I’d like to thank our episode sponsor, Takeda Oncology, for their support of Myeloma Crowd Radio and myeloma patients. It’s a new year and we have much to look forward to in 2018. For the Myeloma Crowd, it means eight Myeloma Crowd Round Table Meetings for those who want to understand more about their options for relapse and the latest in research. Our first meeting will be held on March 10th in St. Louis. And it also means a new program called Myeloma Meetups which we’ll share in the next few months that will provide an easier way for myeloma patients to get together to share information.
We are also launching a new Muscles for Myeloma program which lets you join any local run, walk, bike ride, or any other fitness event in your area and allows you to create a fundraising page so you can get fit while also helping advance a cure for yourself. We’re also working on a solution to help myeloma patients understand their treatment options in a product called HealthTree which will also provide new insights to myeloma researchers. So it’ll be a busy year for us.
But in the world of myeloma research, there is also an incredible amount of new and exciting things happening, and there’s no better way to kick off the new year in our 105th show than with our very first guest on Myeloma Crowd Radio, renown myeloma expert, Dr. Robert Orlowski. Not only is he an avid myeloma researcher and scientist, he’s also a caring doctor who sees how research affects patients every day. He truly excels at explaining research in simplified ways for patients and helps us understand how to apply what we’ve learned to our own care.
So thank you, Dr. Orlowski, for joining us today. We welcome you to the show.
Dr. Orlowski: Well, thanks very much for having me, Jenny. It’s always a pleasure to get out all of the great news about the exciting things happening in myeloma.
Jenny: Oh, there’s so much that we’ll cover. But let me give an introduction for you for those who aren’t familiar with you. Dr. Orlowski is Chairman and Director of the Myeloma Section in the Department of Lymphoma and Myeloma at MD Anderson Cancer Center. Dr. Orlowski serves as Chair of the Southwest Oncology Group which is called SWOG and is a member of the NCI Steering Committee, Multiple Myeloma Tissue Bank Steering Committee, the BMT Committee, and American Society for Biochemistry and Molecular Biology. He’s on the Editorial Board of Hematology and the Journal of Clinical Oncology.
Dr. Orlowski has received many awards over a number of years including the Leukemia and Lymphoma Society Scholar in Clinical Research, the Leukemia and Lymphoma Society Man of the Year Award, and Emil Frei III Award for Excellence in Translational Research from MD Anderson. He leads the MD Anderson Moon Shots Program for high-risk myeloma. He has a wonderful daily online newspaper that you should subscribe to. That’s a service you can google called Paperli, and it’s called The Myeloma Daily. You can also follow him on Twitter @Myeloma_Doc.
Now MD Anderson is unique in that it is one of the largest, if not the largest, center for myeloma clinical trials which is supported in part by a very prestigious SPORE grant that is a federally funded grant. Both Dr. Orlowski and MD Anderson are wonderful centers for treatment and especially for clinical trials. I know we’ll be talking a lot about those today.
So Dr. Orlowski, I’m going to let you guide the conversation because there’s so much content that came out of ASH and is exciting in 2018. If we can start with high-risk smoldering myeloma, or smoldering myeloma, and move forward or any other way you’d like to do it.
Dr. Orlowski: Well, that sounds great. And if you don’t mind, I actually wanted to cover one topic before we even get to what treatment is best for myeloma because over the past year – and there was another abstract at ASH – there’s some very, I think, important data about where you should be treated for your myeloma.
There was a paper in the Journal of Clinical Oncology published late last year that looked at outcomes for myeloma patients based on where they were treated and how many myeloma patients those centers actually saw. It turned out of the survey, the average number of patients was around five to seven patients per year. And of course, if you look at the outcomes, you might predict that places that see more myeloma patients, that the outcomes would be better and that was in fact the case. But the magnitude, the amount of the difference was very dramatic. In this paper, they found that if you were treated in a place that was in the bottom 25% of how many patients they saw, you had a 22% increased risk of dying as opposed to if you were seen in a place that saw lots of myeloma patients.
Also, at ASH, there was an abstract, and for those of you that want to look it up this was abstract number 529, which was put together from data that some of my colleagues in the University of North Carolina were able to get. They looked at North Carolina Cancer Registry data and again compared outcomes of patients with myeloma based on whether they were seen at a comprehensive cancer center or whether they were seen in a community practice. And they actually found that if you were seen within one year of diagnosis of your myeloma at a comprehensive cancer center, you had a survival that was 40% better.
You know, sometimes what patients do is they say, “Gosh, let me go to an expert and they’ll get me their opinion, and then I’m going to go back to my home doctor and follow through on that.” And there’s lots of good reasons to do that, of course, because it’s more convenient and you can spend more time with friends and family. But when they looked at the outcomes, it turned out that in this kind of sharing of patient approach, if you will, there was still an increased risk of death compared to if you received all of your care at a comprehensive center.
So I think that’s important information to take away because many of the therapies that we now use don’t make a 20% to 40% impact on survival, and yet here, just by going to a place which has myeloma experts, you can improve your outcome really dramatically. I think the reasons for that are probably a couple. First of all, when you see only a handful of myeloma patients per year in the community practice, you don’t have as much experience. That’s number one. Number two, when you see more of myeloma patients you can have clinical trials available, and clinical trials usually do give patients new options that often are better. And number three, when you have more myeloma patients, you have better established treatment pathways and better supportive care.
So I know we often talk about what the best therapy is and what the best support of care is and about clinical trials, but you also may want to think about exactly where you’re getting your therapy. These, of course, were data only from North Carolina but I don’t think there’s a reason to suspect that it would be different in other states. So the message is if you can get to a center of excellence and get your treatment there, by all means really try to do that because it could make a bigger difference than even what kind of treatment you actually get.
Jenny: I think this point can’t be stressed enough before you move on because I think there was a study done by one of the pharmaceutical companies, and they found that 80% of patients were being seen in this local community setting. So if you want to dramatically increase the life expectancy collectively of myeloma patients, those patients should go to centers of excellence and find a myeloma expert to guide and direct their care at a minimum. It’s not too hard. Even if you have to travel to get a consult and if you have to go back and get your care locally, that can be done. And it’s not just too difficult to go once or twice a year to do that, but at a minimum. So I appreciate what you’re saying, and I completely agree with it. I think there’s no better way to really dramatically increase the life expectancy of myeloma patients than with this very simple step.
Dr. Orlowski: And just as a disclaimer, I had no involvement in those research studies. So obviously, I have a conflict of interest because I would love to take care of more myeloma patients but this is research done by other folks in the field. So I appreciate being able to share those data with folks. Maybe we can now move on to smoldering myeloma. Many of you listening may have smoldering myeloma. This is a condition where you have myeloma cells in the bone marrow and an abnormal protein, usually in the blood or urine, but you don’t have any symptoms. And right now, the standard of care in that setting is still a watch-and-wait approach.
Of course, that can be frustrating because the last thing people want to hear after they’re diagnosed with cancer is their cancer doctor saying, “Well, we’re not really going to do anything about it.” Part of the reason for that is that there are different groups of smoldering patients. We can identify some that are at high risk versus low risk. The low-risk patients have about a 1% or 2% per year risk of progression which means that it’s so low that they probably shouldn’t really not be getting treatment. But the high-risk patients, the risk can be up to 10% per year especially in the first five years.
So there are a couple of studies that were presented at ASH that are looking at different approaches to try to treat those patients. One of them was the so-called CENTAURUS study which used daratumumab as a single agent and, of course, dara is one of our best anti-myeloma drugs. In the study, they used a couple of different dosing schedules, but the response rate with this drug by itself in the more intensive-dosing areas was over 50%, around 54% to 56%. So that means that half of patients had a reduction in their disease burden, and about a quarter of those patients had what was called a very good partial remission, which means a 90% or greater reduction in the amount of myeloma. We think that that kind of reduction should translate into a longer time before patients progress to symptomatic disease although we really need randomized studies to try to show that. There will be a randomized trial looking at daratumumab versus observation.
So some of you, if you’re in that category, may want to look for it. I think the only concern that I would express is that if you use daratumumab up front, and you later progress to symptomatic myeloma, will the daratumumab be as effective then since you’ve already been exposed to it? And that’s a question that we don’t yet know the answer to, and it is something to consider.
There also was a study that the Europeans did, which used a much more aggressive approach, and this was a study presented by María-Victoria Mateos. What they did is they actually did induction therapy with carfilzomib, lenalidomide, and dexamethasone. Then they did stem cell transplant, then they did some more consolidation with the same three drugs as at the beginning, and then they gave lenalidomide and dexamethasone as a maintenance. So this is an approach where basically you’re taking patients with smoldering myeloma and treating them as if they had active multiple myeloma. So it’s certainly not for the faint of heart because this is really full-dose therapy. The number of patients that they’ve treated through to the consolidation phase is still about in the 30 to 40, but about 70% of the patients who had gotten that far had a stringent complete remission which means complete disappearance of the myeloma protein from the blood and urine, normal free light chains and a normal looking bone marrow.
So I think it will be interesting to get longer followup and see whether some of these people could even potentially be cured. But because we don’t know that yet and again there’s this concern that maybe you might relapse later and then have a lesser benefit with the drugs that you’ve already been exposed to, that this is still something only to be done on research trials.
Jenny: So I think the point there is if you have smoldering myeloma, you want to be working with a doctor who has clinical trials open for smoldering myeloma so that at any point you feel like you’re at high risk smoldering and you want to start some sort of treatment, you’re prepared and ready.
Dr. Orlowski: Yes, I definitely agree with that.
Jenny: Also, I think we should point out that some people don’t know what ASH is. Maybe you want to explain what ASH is because we’re going to be referring to it this whole show.
Dr. Orlowski: Sorry about that. That’s a good point. That’s the American Society of Hematology, which is one of the major meetings where blood cancer doctors get together and all of the most recent and exciting data are presented and in myeloma, as well as other blood cancers. A lot of the new information comes out. It happened to be in the second week of December in Atlanta, and actually it snowed for two days in Atlanta so that was kind of exciting for those of us that live in the south and don’t see snow as much as we used to. But that was the ASH meeting that I was referring to.
Jenny: Right, so much research is presented there that it’s a deep dive into myeloma research. So it’s wonderful that you can help us sort through it and help prioritize.
Dr. Orlowski: My pleasure. Well, maybe we can move on to things that are new for patients that have symptomatic myeloma and that are newly diagnosed. There’s a couple of papers or abstracts that I thought were interesting. First of all, there was a poster looking at carfilzomib, lenalidomide, dexamethasone, and daratumumab as an upfront therapy. Many of you know that daratumumab is approved for relapsed or refractory disease in various combinations but hasn’t yet been approved as part of initial therapy. But there was an abstract looking at that four-drug combination which should, we would think, be very effective. It was still very early, but the overall response rate was 100% and 91% of patients had what’s called a very good partial remission, which means again at least a 90% reduction in the amount of myeloma and about a quarter of patients were MRD or minimal residual disease negative. I’ll get a little bit later into what MRD means, but it’s one of our most sensitive approaches to detect if there is myeloma left over in the patient’s body.
So we would hopefully see additional data with that combination in the future. It still isn’t available routinely, but it definitely is an interesting approach that we’re going to hear more about.
Jenny: This approach with this QUAD therapy, KRd, and daratumumab, this is irrespective of a later transplant or not. Correct?
Dr. Orlowski: Correct.
Jenny: This is just newly diagnosed and you would just use this first.
Dr. Orlowski: Exactly. Now you mentioned transplant, and I’m glad you brought that up of because there was a large European study that was presented that looked at the possibility of stem cell transplant versus standard-dose consolidation. In some of the centers that were involved, they did a double or so-called tandem stem cell transplant. The interesting results were that, first of all, as one would expect, if you did a stem cell transplant, you had a longer time in remission than if you did not do the stem cell transplant. But they also compared people who were getting two transplants versus one. Some of you may know that there have been a number of these studies done over the years. Some of them seem to favor two transplants. Some of them seem to not make a difference in this study. There actually was a small trend favoring the double transplant arm especially for patients with high-risk chromosome abnormalities, and the most common high-risk abnormalities would be things like deletion of 17p or a (4;14) translocation. Most of these you would get from FISH studies on your bone marrow to make sure that you know what your risk group is.
So I think the issue of tandem versus single transplant is still a little bit up in the air, and my one concern about this particular trial is that the initial therapy that patients got which was bortezomib, cyclophosphamide, and dexamethasone before they went to transplant is really not considered the optimal initial therapy here in the United States. We would think that bortezomib with lenalidomide and dexamethasone or maybe KRd or maybe adding daratumumab to those would be much better.
So I think we have to be cautious about recommending the tandem transplant because it may be that if you get a better induction and a greater reduction in the amount of disease, you don’t need the two transplants. But I thought I would bring that up because it was an interesting study.
Jenny: Yes, Europe just doesn’t have the access that the United States does to the newer drugs. I think a lot of times, people aren’t aware of that.
Dr. Orlowski: Yes, we’re definitely lucky here in the United States from that perspective. And then one more study that I’ll mention for newly diagnosed patients because it was one that I think a lot of excitement was focused on, and this was for patients who were not eligible for stem cell transplant. The study compared bortezomib, melphalan, and prednisolone or VMP to VMP with daratumumab. So these are the first Phase 3 data looking at dara as an initial therapy, and the group that got the daratumumab had a 50% reduction in the risk of progression or death.
So that’s really a huge benefit. It probably will lead to an FDA approval of daratumumab for this particular patient population who’s not transplant eligible, but it may also allow some of us to use daratumumab up front with other combinations, although that’s still a little bit more murky because we don’t have data in the randomized study yet with those kinds of combinations.
Jenny: This sounds like daratumumab seems to be this great additional drug that is extending what they call progression-free survival and potentially overall survival for patients and, what I’ve heard, with fewer side effects than some of the other drug combinations may be or patients may experience. So in your opinion, it sounds like the great add-on?
Dr. Orlowski: I agree, the added side effects are really very mild. The typical reaction is with the first infusion, people sometimes can get what’s called an infusion reaction, which can be sometimes just a bit of a runny nose or a cough or a little bit of shortness of breath. It’s rare to have a severe reaction, and usually that reaction does not recur with the second infusion. As we may touch on later, right now there are studies looking at giving daratumumab, not IV, but subcutaneously under the skin, and those look to be at least equally efficacious if not maybe a little bit more so. And because it goes in much more quickly, you don’t spend as much time in the chair, and the infusion reactions are actually less than they are with the IV form.
Jenny: Now that will be fantastic. That will be wonderful.
Dr. Orlowski: So let’s move on to relapsed patients because even with all of the new therapies that we have and the better upfront outcomes, people do still develop relapsed disease. There were updates of daratumumab in various combinations including with bortezomib and with lenalidomide. Thanos Dimopoulos from Greece presented these. You probably know that there was about a 60% improvement in outcomes from the randomized studies for patients who got daratumumab and the updated analysis really continued to show a huge benefit. I would definitely say that for the vast majority of patients, if you haven’t gotten daratumumab as part of your first line therapy, you should definitely get it as part of your second or third line treatment because as with other drugs, if you save it for later, it will still work but the benefit is usually not as great if you give it later than if you give it earlier. So the earlier you get on the daratumumab, the bigger will be probably your benefit.
Jenny: That was a theme that I heard frequently at the conference is don’t save your best therapies for later on. I didn’t know if you wanted to elaborate on that.
Dr. Orlowski: I agree with that. I think in the past, the concern was that we had so few therapies, relatively speaking, that you didn’t want to, if you will, shoot all your bullets out at once. But now we have so many exciting new drugs that are coming and, of course, will touch on CAR T cells that I think you are better off using your best treatments early. And even if you do relapse, by the time you relapse, which will be much later than if you don’t use the best therapy, if you don’t use the best therapy, you’ll relapse sooner. But by the time you do relapse, if you do relapse, we’re going to have much better things available for you. So there’s no need to worry that you won’t have anything to fall back on.
Jenny: I agree.
Dr. Orlowski: There also were some studies looking at cyclophosphamide, and there were a couple of different combinations that this was looked at which included, for example, pomalidomide with cyclophosphamide and dexamethasone and also carfilzomib with cyclophosphamide and bortezomib with cyclophosphamide. It’s really, I think, fair to say that all of the data did support that cyclophosphamide, which is an old drug and maybe not as exciting anymore, but it still shows excellent activity, it’s very well tolerated. I wouldn’t use it in place of daratumumab, for example. But if you’ve had daratumumab and unfortunately eventually progressed, then going with a cyclophosphamide-based combination or maybe bendamustine, which is a drug that we’ve had a lot of experience with and it works quite well, those are all very reasonable things to do.
Jenny: Now I was curious about so many studies using cyclophosphamide, and I didn’t know if it was because it was a global conference and there were a lot of European studies or if it was being used still regularly in the United States.
Dr. Orlowski: I still use it quite a bit in my patients because as I mentioned earlier, I find it to be well tolerated and it has very good efficacy, so I would not put aside cyclophosphamide. There is a risk or a concern, I should say, because cyclophosphamide is in the category of drugs called alkylating agents which sometimes can damage chromosomes and cause second cancers. It’s gotten, I think, a little bit of a bad rap because of that. But it actually generally causes fewer cancers than other drugs in that category like melphalan which is the drug that’s used at the time of stem cell transplant. So I still find cyclophosphamide to be very useful.
Jenny: Okay, great.
Dr. Orlowski: There also were some studies about maintenance therapy and maintenance can be done either after stem cell transplant or in some cases, if people haven’t had transplant or can’t get transplant, maintenance can be done after just plain chemotherapy. And the goal of maintenance is to use a lower dose of an active drug over a longer period of time to keep the myeloma down while hopefully not causing too many side effects and giving patients a good quality of life.
So there was one study from the British that looked at lenalidomide as a maintenance therapy, and the interesting thing there is that they found very good outcomes even in patients with high risk disease and lenalidomide was able to improve the progression-free survival. They actually found an 18-month or so improvement in the group as a whole. So that’s a year and a half longer in remission which is pretty good. And although in the high-risk patients the outcome wasn’t quite as good, there was still an improvement. With the high-risk patients, I think most of us in the field would recommend some kind of combination. There were also two abstracts that we presented from MD Anderson that looked at lenalidomide with ixazomib, which is an oral proteasome inhibitor, and a separate study that looked that lenalidomide with elotuzumab, which is one of the other monoclonal antibodies approved for myeloma. Both of those looked like they were really well tolerated and although they’re not randomized studies, so we have to be a little bit cautious, but the early data did look like there was going to be a longer time in remission than what you would expect with lenalidomide alone.
So I think if you’re a good risk myeloma and you’re in complete remission or close to it, probably lenalidomide by itself is perfectly fine. But if you have high-risk disease, you should get lenalidomide with a proteasome inhibitor or with an antibody. And maybe even if you’re a good risk but you still have a fair amount of myeloma left, you should also get a more aggressive maintenance, although we don’t really yet have data about that.
Jenny: And the patients’ question is always for how long should I do this, right?
Dr. Orlowski: Yes. A great question and there are studies that are ongoing that are comparing different durations of maintenance, and we don’t have the answer yet. For right now, I still recommend that as long as people are tolerating their therapy well, that they continue on maintenance until there is some sign of progression. But hopefully, in the future, especially, for example, with MRD testing, we may be able to hopefully find patients who have such a low level of myeloma that we can either stop maintenance altogether or maybe do the maintenance more intermittently so that you don’t have to take it every month, for example. But that’s still a hope and not something that we would yet routinely recommend.
Jenny: But then I think about the ixazomib and lenalidomide maintenance, even if you have to do two is that they’re both oral so it makes it easier.
Dr. Orlowski: Definitely, but remember even with the antibodies, the elotuzumab in the study that we did, although it was weekly IV for eight weeks at the beginning, after that it was once a month and once a month is not horrible and daratumumab, which is also being looked at as a maintenance, eventually also goes to monthly, and as I mentioned earlier, the subcutaneous dosing is going to be a lot more convenient. So something to keep in mind.
Jenny: Right, absolutely. So interesting.
Dr. Orlowski: Now I’ve mentioned a couple of times this notion of minimal residual disease, and there’s a couple of ways that this can be measured. The most common right now is that the bone marrow is done, and what is then performed on the sample is something called flow immunophenotyping. For me, that’s a fancy way of essentially fingerprinting all of the cells that are in there. The advantage of that is that if you just have a regular aspirate, the pathology people will look at a couple hundred cells but the flow can look at up to two million, which is the number that we do at MD Anderson. So two million, of course, gives you much greater sensitivity to detect the myeloma compared with 200, so that’s one benefit.
The second benefit is that sometimes a pathologist can look at a cell under the microscope. They can’t tell if it’s a normal plasma cell or a myeloma plasma cells because they look pretty similar sometimes, but the fingerprinting can tell the difference between them. So for example, if you have 2% plasma cells on your bone marrow after transplant, you have a better outcome if those are normal plasma cells than if those are 2% myeloma plasma cells. And that’s what the MRD testing allows us to do.
The other technique is one that is also so far using bone marrow samples, and it’s called next generation sequencing where there’s actually sequencing of some of the genes which is done to try to tell how much myeloma is left. The general finding in the MRD studies is that if you’re MRD negative, you have a better outcome than if you’re MRD positive. Now that’s not shocking because less cancer is always going to be better than more cancer. And right now, we don’t yet know, for example, if you’re MRD positive, does that mean you should get more treatment to try to push it down to MRD negative? But if I were a patient, I would want to have that testing just to know what my prognosis is if nothing else because you need to make plans and that information can be very helpful.
Jenny: In my opinion, this is one more reason to go to experts like at your facility because MRD testing is really not done everywhere right now. So if you go to your local oncologist, they may not be doing this MRD testing. It’s done quite often in clinical trials and at some select centers. But until it gets spread out through the community, this is a very compelling reason, in my opinion, to go to experts.
Dr. Orlowski: And in fairness, there are many centers that do the MRD testing, but you want to make sure that you’re getting your bone marrow evaluated at one of those because again, at least it gives you a better idea of your prognosis.
Jenny: Right. And I heard a lot also about MRD testing that it may be more important for high-risk patients to be MRD negative than normal-risk patients? Is that what you found also?
Dr. Orlowski: Well, the data do say, of course, that MRD negativity is a great end point for everybody. One thing to mention though, people should not angst if they are not quite at MRD negative status, if they’re MRD positive, and there’s a few myeloma cells that isn’t necessarily a bad thing. It turns out that there were data presented at ASH that showed that the people who have the worst prognosis, unfortunately, are those who get to MRD negativity and then very rapidly lose it, and those do actually worse than people who are MRD positive and then convert to negative or even if you’re positive and stay positive.
But in general, if you’re MRD negative, you’re going to do a little bit better. And you’re right, Jenny, there are data that suggest that if you have high-risk disease, it’s even more important to get to MRD negativity. We do try to push harder for our high-risk patients. You mentioned earlier that we have an interest in high-risk disease and recently the Leukemia and Lymphoma Society also awarded us a large grant to study high-risk myeloma here at MD Anderson. High-risk myeloma, by the way, in newly diagnosed patients is only in about 20%. So if you think back to the beginning of the broadcast when we mentioned that the average practice in the community sees maybe five to seven new myeloma patients per year, now you’re talking maybe one or two of them being high risk. So there again that points out the need for you to go to some place that has a myeloma specialist.
Jenny: Yes, I totally agree.
Dr. Orlowski: Now beyond MRD, a couple of other general points on improvements in care, hopefully all of you have gotten your flu shots already. Of course, some years the flu shots work better than others. But part of the problem in myeloma patients can be because with a combination of the disease and also some of the therapies that you’ve had, some patients don’t have as good an immune response to the vaccine as if you didn’t have myeloma. And there were data presented at ASH and some of these have already been published that suggested that maybe a second sort of booster shot, if you will, of the flu vaccine could improve the level of immunity. So this was not a large randomized study, which would be the best way to look at this, but it really did suggest that maybe we need to consider making that kind of change or at least doing the study considering that the risk of the flu shot is quite low, and yet the biggest cause of death for patients with myeloma are infections. So if we could reduce those, that would be a huge benefit.
And also along those lines, there was one study that suggested that an oral antibiotic called levofloxacin could make a difference in outcomes, so that may be something to consider. And other things that we do in some patients include gamma globulin infusions especially if you have a low IGG level and multiple infections. So all of these are supportive care measures that can also make a huge difference in your outcome.
Jenny: Yes, I believe it.
Dr. Orlowski: And then I think the last area that we should probably cover are new therapies for refractory myeloma. Refractory myeloma means myeloma that is progressing on treatment or that is progressing shortly after finishing the most recent treatment. I think there’s a few really exciting drugs in this area and then, of course, we’ll end up with CAR T cells which everybody is really excited about.
I’m going to briefly mention a few of the drugs. There is a BCMA antibody drug conjugate. Now what this is, BCMA is B-cell maturation antigen, which is a protein on the surface of myeloma cells, and what this drug, which is a GSK drug is an antibody that binds to that protein and the antibody has a drug linked to it which is then internalized and kills the myeloma cell. They were able to show a 60% response rate. This is a once-every-three-week IV. The only side effect that is notable or different than other antibodies is you can have some blurry vision and corneal changes which need to be followed closely. But really you may have known that this drug now has breakthrough designation status by the FDA, and so we hope that it soon will be FDA approved, although the trial that needs to be done still hasn’t been completed but it’s really a great drug.
And then isatuximab is another drug. This is an antibody against CD38, so it has some similarities but also differences from daratumumab. It definitely shows activity both alone and in combination. Outside of the antibody area, there’s a couple of small molecules or drugs. One is a drug called Selinexor. This drug is oral. It interferes with the movement of proteins from the nucleus to the cytoplasm in myeloma cells. There were data presented with a number of combinations including with dexamethasone and bortezomib with dexamethasone that show it really is a very effective combination. There are trials ongoing with those combos. So definitely, look for those if you are in need of new therapies.
The other main small molecule to keep in mind is a drug called venetoclax. This is a BCL-2 inhibitor, and it works especially well for people that have a translocation between chromosomes 11 and 14. Again, you would know this from your FISH results on the bone marrow, and that drug by itself has a 40% response rate in (11;14) patients. And if you combine it with other drugs, it can go up to as high as 80%. So really a great drug and probably the first targeted drug for a particular sub-population of myeloma the patients because all the drugs we’ve talked about up to now are pretty much given to every myeloma patient, whereas this one works especially well in the (11;14) people. We hope to have more of these targeted therapies for specific subgroups as we move forward.
Jenny: And this is why it’s important that you know what type of myeloma you have.
Dr. Orlowski: Exactly. And then, of course, the most exciting thing, which I’ll end up with, are the CAR T cells. I’m sure many of you already know what these are all about, but the way this works, for those of you who may not, is that T cells are taken out from the patient’s own blood. These are different cells, by the way, than your stem cells. So if you’ve had the stem cells collected and frozen away, unfortunately, at least as of right now, those can’t be used in this process and you need to do a repeat collection. But the T cells are then modified in the laboratory to express what’s called the chimeric antigen receptor or CAR, and what that does is it allows the T cells to recognize myeloma cells better. They are grown up in the laboratory. They’re infused back in IV. And when they find a myeloma cell, they are stimulated to grow and to also become activated or, if you will, angry and they attack the myeloma cells. It’s a really great form of personalized immunotherapy.
Earlier this year or I guess now in early 2017 at a different meeting, there were a couple of studies presented that showed very encouraging data. What we’ve seen now at the ASH meeting is that there were additional updates. So probably, the one, because there are a couple of companies that are developing these approaches, but the one that is furthest along is from Bluebird. It’s called bb2121. They’re also working with Celgene. What they showed in their updated data is that the response rate in these patients, and these are very heavily pre-treated patients, relapsed and refractory disease, and the overall response rate were about 95% – you heard that right, 95 – and half of patients are in complete remission including many who are MRD negative.
Now the updated data that they presented showed that some patients who previously had been just in a partial remission over time, because these T cells can persist in your body, were able to upgrade their response to a complete remission. However, there were a couple of patients who had been in complete remission who also progressed. So this is definitely an exciting therapy. It will probably not cure every patient with myeloma, but these are definitely the most exciting data that we’ve seen in the relapsed/refractory setting in the history of myeloma therapy. And although slots for the studies are not as frequent as anybody would like for them to be, the good news is that, in addition to Bluebird, there are many other companies that are working on similar technologies and some of those that I think I would mention, the folks at Juno have this. The folks at Kite have it. Then, of course, the Novartis people are working in this area in addition to the Bluebird folks. And there are some smaller companies as well, for example, Poseida Therapeutics and others. The technology is pretty similar across one platform to another. There are some small differences in the way the receptors are generated and also in the treatment but probably, at least as far as we know right now, those differences shouldn’t have an impact on their outcome.
So I really would try to encourage everyone that if you’re in the relapsed and refractory setting and you’ve had bortezomib and carfilzomib and lenalidomide and pomalidomide and daratumumab, those are the kinds of patients right now that really are best for these CAR T cells, and probably pretty soon you’re going to start seeing CAR T cell trials for earlier patients with myeloma, possibly even patients who are newly diagnosed. But right now, the relapsed and refractory setting is the place to go.
Jenny: And to me this is just stunning and wonderful and incredible. And right now, most of them are targeting that BCMA protein, correct?
Dr. Orlowski: Correct. The only I think complicating factor is that these cells have to be made individually. What that means is that the cells have to be collected from the patient, and it can then take two to four weeks for the cells to be manufactured and sent back ready to be infused. So some people, during that period, may need additional therapy to control their myeloma. There also are some interesting studies, by the way, because one of the abstracts that was presented was a combination of two different CARs. The notion here is that if you — it’s kind of like chemotherapy. We use combinations of drugs because it’s more difficult for the myeloma cell to become resistant to two or three drugs than one drug. And the same concept here. If you combine CAR T cells that react against two different targets, maybe the outcome will be better. We don’t know if that’s the case yet because these are still very early, but there are certainly some interesting data.
And then the other thing that people are working on are allogeneic CAR T cells. The concept here is that you can take a donor T cell, manufacture it with this receptor, and infuse it into patients. And the advantage there is that because the cell manufacturing is done ahead of time, you don’t have that two to four-week wait period. It’s basically ready to go, and you can get treatment with less delay.
Jenny: That’s fascinating. What was so interesting to me when I went to the conference is that I went to a session, it was actually an MD Anderson session that talked about the preparation that your facility has gone through to prepare for these CAR T products because it’s a little bit similar to transplant but very different than transplant. And your whole facility has to be aware of the potential reactions or how to treat and if you catch it early, it can be a minimal issue. And if you don’t catch it early, it can be a major issue. So I was very impressed.
Dr. Orlowski: You’re definitely right. The major side effect that I should have mentioned is called cytokine release syndrome because when these T cells become activated, they release various proteins called cytokines that can cause fever and inflammation. There are people who can get lung inflammation, even brain inflammation. There have been some deaths in studies of patients with CAR T cells, so this definitely needs to be done at places that have experience.
I do think over the longer term, we’re going to be able to do some of this on an outpatient basis, kind of like outpatient stem cell transplant. But right now, many of the studies are still doing in-patient therapy. It is right now still a risky approach although the cytokine relief syndrome in general from myeloma patients appears to be less of a concern than in the B-cell lymphoma experience.
Jenny: It’s so interesting. I think it’s so interesting to think about if you do induction therapy and a stem cell transplant and consolidation and maintenance, that can be considered one line of therapy. So to have this response with patients who have had 9, 10, 11 lines of therapy, this is a stunning.
Dr. Orlowski: Yes, it definitely is. And of course, we hope that if we give it to earlier patients, that who knows? Let’s be optimistic. Maybe we’ll get 100% complete remission, and maybe this could be the cure although folks like me are always a little bit hesitant to use the cure word until we can say for sure, because sometimes people can relapse even years afterwards.
Jenny, I know there are probably lots of questions.
Jenny: Yes, we do have questions.
Dr. Orlowski: Unfortunately, because I’ve droned on for a long time, we may not be able to get to many of them. So I did want to let people know that please if you have questions that we can’t get to, my email address is email@example.com. And if you send me your question, I’ll try to get back to you at least probably before the end of the weekend.
Jenny: You’re so good about that. Well, let’s go to questions if you don’t mind. I know we have other things to talk about, but there’s so much that you just can’t cover in a single hour. Caller, go ahead with your question.
Caller: Hi, Dr. Orlowski. Happy New Year! I actually have two questions. First one, what is your experience with maintenance in the post-transplant setting with daratumumab, pomalidomide, dex? And the second question is for those myeloma patients who exhibit the BRAF mutation, what’s your experience with using some of the MEK and RAF inhibitors that are so effective in melanoma?
Dr. Orlowski: Great questions, and Happy New Year to you too. In terms of maintenance, most patients probably if they have good risk disease and a very low level of myeloma after transplant, probably lenalidomide by itself is enough as a maintenance. But I do think if you have high-risk disease, or if you have a fair amount of myeloma left after transplant, a combination maintenance would be very reasonable to do and dara-pom-dex is definitely an active combination in the relapsed setting. So it should be very good as a maintenance therapy as well, although I personally have not used that particular combination. And then your second question was about BRAF and for those of you that may not know about this, one of the mutations that can be seen, it’s usually around 3% to 4% of myeloma patients is a mutation of a kinase called BRAF, which is much more commonly mutated, as you mentioned, in melanoma and other solid tumors. There are drugs that inhibit either RAF or MEK, which is another protein downstream of RAF, and there are data showing — most of these are from Arkansas — showing that these drugs can be very effective. To my way of thinking, when you have a RAF mutation though, you should use either a MEK or a RAF inhibitor in combination with other chemotherapies because the durability of the responses with single-agent therapy have so far not been quite what I would have wanted.
Caller: Got it. Thank you.
Dr. Orlowski: Thank you.
Jenny: Okay, thank you so much for your question and your answer, Dr. Orlowski. Okay, caller, go ahead with your question.
Caller: Hi, Dr. Orlowski. First off, thank you so much for all the content you’ve shared. It’s been very informative. My question is the checkpoint inhibitors were being used in myeloma clinical trials, and it looks like they were stopped but they are back open? Where do you think they are headed, the checkpoint inhibitors?
Dr. Orlowski: Well, it’s important information and question. We didn’t get to that although it was on the list. So the checkpoint inhibitors, these are antibodies which are meant to, if you will, take the brakes off the patient’s immune system, and the reason that they can be effective and again we mentioned melanoma earlier, but they’ve really revolutionized the care of melanoma as well as other solid tumors, and the reason the same drugs can be active in blood-related cancers is that cancers use certain mechanisms to suppress the patient’s immune system, and it’s the same mechanisms in different cancers. The reason there was concern, in particular, about pembrolizumab was that there were randomized studies that were done. This was a newly diagnosed patients who got lenalidomide and dex with pembro or without and in the relapse setting pomalidomide and dex with pembro or without. Unfortunately, patients in the pembro arm of those two large randomized studies had an increased risk of death without an increased benefit in terms of response rate or depth. So the FDA put all of those studies on hold and took patients off of the pembro studies.
Right now, what is being done is selective trials of checkpoint inhibitors are being allowed to reopen, and those are predominantly in patients where the combination is not with an immunomodulatory drug. I do think that they’re exciting drugs because we were part of the early studies in those agents. I can tell you, I had a number of patients, for example, who were progressing on lenalidomide and dexamethasone. And by just going on to the study and having pembro added, they were able to respond. I even have one patient who’s still in complete remission.
So there is definitely activity of these drugs. I think the question is can we figure out whether there are some patients who would most benefit, for example, if you have high-risk disease or maybe if you expressed high levels of the target for the checkpoint inhibitor, and that’s where I think we need to do more science.
Caller: Okay, great. Thank you so much.
Jenny: Okay, thanks for your question. I just had a follow-up question because I had heard someone talking about using the checkpoint inhibitors with the CAR T, and that might even take some of the side effects away from some of the checkpoint inhibitor side effects. I don’t know if you had heard those two being used together.
Dr. Orlowski: So there is interest, you’re right, in combining checkpoint inhibitors with CAR T cells. Most of the interest has been because when the T cells become activated, they really go gangbusters against the myeloma. But as you can imagine, they get eventually a little bit tired or what’s called T cell exhaustion. What these checkpoint inhibitors can do is they can reverse that exhaustion. So the major interest has been in trying to give those, for example, if you get a CAR T cell and you only get a partial remission and you don’t get a complete remission, maybe adding a checkpoint inhibitor would help to get that last bit of the way there. I don’t know of any data to suggest the side effects would be better with a checkpoint inhibitor than without one, though.
Jenny: Okay, wow, that is so fascinating. I think it’s clear why you need an expert in your corner because there’s so much happening, as you just described, in myeloma and it’s just truly, truly incredible.
So Dr. Orlowski, we’ll let you go and we’ll let other questions be emailed to you. We are so grateful that you took your time to be with us today. We know how busy you are both treating patients and doing research. We are so grateful that you took the time to spend with us, explaining things in a way that we can really understand.
Dr. Orlowski: Well, thank you again very much for the opportunity and please do email me with questions. Have a great rest of your year!
Jenny: Oh, thank you so much. And thank you for listening to Myeloma Crowd Radio. Tune in next time to learn more about the latest in myeloma research and what it means for you.