Robert Z. Orlowski, MD, PhD MD Anderson Cancer Center Interview Date: January 5, 2017 

The year 2017 promises to be another exciting one in multiple myeloma. Dr. Robert Orlowski shares key developments from last year and what we have to look forward to in the coming year. He describes several important advances last year: the further approvals of elotuzumab and daratumumab and the latest on bone strengtheners - that denosumab may be better than Zometa. He also shares the new approaches in smoldering myeloma to prevent progression, the latest on stem cell transplants and the use of minimal residual disease (MRD) as a useful measurement. He shares a new tool for patients with renal failure that can improve their function in order to avoid dialysis and where were are headed with the broad class of immunotherapy approaches. Dr. Orlowski provides an impressive, overarching view of what we can look forward to in the management and treatment of multiple myeloma in the coming year.

Thanks to our episode sponsor

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 would like to thank our episode sponsor, Takeda Oncology, for their support, and we’re so grateful of their continuing support for the Myeloma Crowd Radio Show. Now, before we get started with today’s show, I’d like to mention that because of your help in 2016, we are very close to reaching our goal of raising $500,000 for the Myeloma Crowd Research Initiative. Since this is our first time doing it, I’m just so pleased to tell you that we’ve raised over $425,000 to date and we have provided each researcher with an initial grant last year. Based on the progress report from the CAR T-cell project, we donated an additional $100,000 to the University of Würzburg. At the end of 2016, we are waiting for upcoming clinical trial results from the Johns Hopkins project in their progress report, and then we’ll continue our review process for additional funding. So, thank you so very much for participating for helping raise funds from friends and family for high-risk myeloma research. It’s just incredible, the success that we’re having. I’m so happy. Now, it’s the beginning of a new year and we can’t think of a better way to bring in 2017 and with an overview of where we’re headed with Dr. Robert Orlowski of the MD Anderson Cancer Center. He was always on the leading edge in myeloma research and is so proficient of presenting it in such an understandable way. Welcome, Dr. Orlowski.

Dr. Orlowski: Well, thanks very much for having me. I wanted to take a moment to wish everyone that they had a good start to the new year, and hopefully, we’ll have a happy and healthy rest of the year moving into the future.

Jenny: Yes, it’s going to be a great year, I think. Well, let me give a brief introduction for you before we get started. We have a lot to talk about. Dr. Orlowski is Professor of Medicine in the Department of Lymphoma/Myeloma with the Florence Maude Thomas Cancer Research Professorship in the same division. He is the Chair of the Myeloma Section or Director of the Myeloma Section. He has a dual appointment and is also Professor in the Department of Experimental Therapeutics. He is a member of the NCI Steering Committee, Multiple Myeloma Tissue Bank Steering Committee, Computerized Provider Order Entry Steering Committee, BMT CTN SOSS Myeloma Committee, and American Society for Biochemistry and Molecular Biology. He’s the Chair of SWOG, which is the Southwest Oncology Group that constructs clinical trials, and is on the Editorial Board of Hematology and the Journal of Clinical Oncology. He has received many awards over a number of years, including the LLS Scholar in clinical research, LLS Man of the Year, Emil Frei III Award for Excellence in Translational Research from MD Anderson. He has completed an innumerable number of clinical trials and studies and is the recipient of an NIH SPORE grant. I think I haven’t counted but I think last time I looked, MD Anderson have the largest number of myeloma studies at any facility in the country. So, you are doing really truly amazing work.

Dr. Orlowski: Well, thanks very much for that great introduction. Again, I’m happy to be here. Maybe we can start with some of the developments in myeloma that happened just before the ASH meeting so that people are up to date about those, if that’s okay?

Jenny: Perfect. I will let you drive the conversation.

Dr. Orlowski: Great. Well, a lot of things, of course, happened at ASH and we can cover quite a few of those, but I didn’t want to have people forget that there were a couple of important developments before then. Two of them were approvals of daratumumab, which is the anti-CD38 monoclonal antibody in combinations. In 2015 in November, dara was approved as a single agent, but then towards the end of 2016 just before ASH, it was approved in combination with lenalidomide and dexamethasone, and also in combination with bortezomib and dexamethasone. Those combinations look like they would be much more effective than dara as a single agent. When you look at the studies that led to those approvals, both of them had approximately a 60% improvement in outcomes. That’s one of the biggest improvements that we’ve seen with the addition of a single drug in any myeloma trial. I think the take home message from that is barring some very unusual circumstances, dara really should be used in combination with either bortezomib or with lenalidomide. Probably, in some cases, it would be fine to use it with carfilzomib or with pomalidomide, although we don’t have quite as much data about those combinations yet. What that means is that this drug is really great in the relapsed setting both alone and in combination.

Jenny: Now, they are moving it to earlier clinical trials, correct?

Dr. Orlowski: Yes, exactly. I’ll cover that as well. Briefly, the other thing to mention, which also happened just before ASH, is that denosumab, there was a study done of that drug which is also an antibody but if used for myeloma bone disease and it was compared to zoledronic acid which is the current standard for patients with myeloma and bone disease What was found is that the denosumab seem to actually be more effective than zoledronic acid at delaying bone complications, which still happen more frequently than we would like in patients with myeloma. It will take a little bit of time, probably, for the FDA to review these data and get this drug approved for myeloma. But if you have bone disease, this is definitely something you should keep an eye on because it may be that people should be switched over from one to the other, or especially in some cases like if there is a problem with kidney disease, kidney function, it may be better to even start on denosumab as opposed to zoledronic acid.

Jenny: When do you expect that that will be approved? Is it just in clinical trials right now?

Dr. Orlowski: Well, that was actually a report of a phase 3 study, and I would expect that the data will be filed with the FDA, if it hasn’t already been done so that it probably will happen this year. I would therefore think that the drug should be approved before the end of the year and maybe substantially sooner. But do keep an ear and an eye open for that.

Jenny: So, that would be a replacement instead of Zometa or Aredia. You would use that one instead.

Dr. Orlowski: Potentially, because it does look like it could be at least equivalent and possibly better. This study compared it to zoledronic acid not to pamidronate, but we generally think that the zoledronic acid is better than pamidronate or at least equivalent. Yes, it is possible. I would say again, for people with renal problems and bone disease, this would be the preferred drug right from the beginning and it may be that slowly, this drug will replace the zoledronic acid as well.

Jenny: That would be great. Wonderful. Those are the two that happened before ASH and then there was so much that happened at ASH.

Dr. Orlowski: Sure. Well, I thought maybe it would be helpful to kind of divide up the discussion into some categories. The first one I thought I would cover is smoldering myeloma. There’s been a lot of interest in smoldering myeloma because the hope is that if we treat especially high-risk and intermediate-risk smoldering patients early, maybe we could prevent them from progressing to full blown myeloma. And if we learn enough about the myeloma biology, maybe we could even prevent the myeloma altogether and cure it at that point. There was one study that was presented, which I thought was interesting which looked at elotuzumab with lenalidomide and dexamethasone in high-risk smoldering patients. The elo/len/dex is now approved of course for patients with relapsed disease, but here, they were using it for high-risk smoldering. The study did show an overall response rate of about 70%, and at least among the small group of patients who were treated, none of them had progressed yet over the reported course of the trial. This is still an area where the standard of care is watchful waiting. But if you have intermediate or a high-risk smoldering myeloma, it’s definitely worth looking for clinical trials because it may be that early intervention will be the key here, and that’s something I would definitely recommend to patients.

Jenny: That sounds great.

Dr. Orlowski: Other data that I thought were interesting in the early patient population is there were data from one of the studies from the BMT CTN, which is one of the cooperative trial networks that look at doing studies among different institutions. They looked at patients with myeloma who had been recently diagnosed, who had undergone initial therapy and stem cell transplant, and the question that they asked was, what is the next therapy, the next consolidation that would be most important? This was a three-arm study and what happened is that in one of the arms, after transplant, patients got lenalidomide only. In the second arm, they got bortezomib, lenalidomide, and dexamethasone first, and then lenalidomide maintenance. In the third arm, the patients who’d gotten the first transplant actually got a second transplant, and then they went to lenalidomide maintenance. This was a very highly anticipated study and the results were quite interesting because the three arms were essentially equivalent. That means that with these data, if you’ve had a first transplant, especially if you’ve had a very good response overall, it didn’t look like there was a benefit to either additional chemotherapy or a second transplant, and that the best thing would be just to proceed right on to maintenance lenalidomide. This is one of those situations where more therapy was not necessarily better, and I think that’s exciting because we don’t want to overtreat patients because of course, that causes side effects, and you can also run into problems with financial toxicity, which is a hot topic lately.

Jenny: Plus, you might be able to save some things for later if you don’t exhaust them upfront. In that study, did they do a lot of separation and look at different patients with different kinds of myeloma to see if there were subgroups that did better on any additional arm or they just brought the overall numbers? And then, how many patients were in that study?

Dr. Orlowski: Yes, great question. It was just the first presentation of the data, and actually, it came out as what’s called the late-breaking abstract. I think we hope to see additional information coming out because you’re right, it may be that some subgroups within those different arms would do better. For example, I would suspect that if you’ve had a first transplant and you’re, for example in complete remission, and you’re MRD or minimal residual disease negative, you would benefit less from, let’s say, a second transplant than if after the first transplant, you still have quite a bit of myeloma leftover. I think those questions still need to be answered from that trial.

Jenny: Right, and as I remember, this was the late-breaking one Monday, I think, right? I guess my question is it looked like they had, I think it was 38 months or something that they had tracked. Do you think those outcomes will change as time goes on? Can they continue to take a look at that and study people further out than the three years?

Dr. Orlowski: There will be additional analysis, and you’re right, especially when you’re looking at transplant studies, sometimes it can take several years before there is a benefit obvious for the group that got the transplant. But at least as a first pass, it looked like the arms were the same, and they presented not just progression-free survival data but they also presented overall survival data, and the overall survival numbers were also not different between the three arms. We’ll definitely get additional updates, but at least for the first pass, as I mentioned, the good news here is that more therapy was not necessarily better.

Jenny: Right. I think finding that out for each individual patient is so key and critical because like you said, you don’t want to overtreat, but you also don’t want to undertreat, and finding that balance for you as an expert treating patients is challenging. It’s good that these studies are being done. I’m thrilled.

Dr. Orlowski: Yes, definitely. I mentioned MRD, that’s of course the hot topic in myeloma. So far, what we know is that whatever patient group you look at, whether it’s newly diagnosed patients, relapsed patients, refractory patients: if you’re MRD negative, you do better than if you’re MRD positive. That makes sense because less cancer is always going to be better than having more cancer. Many places now are doing these MRD assays, and one of the best ways to do it is by looking at a bone marrow and doing what’s called flow immunophenotyping where you’re essentially fingerprinting each cell that is in the bone marrow aspirate and the standard is to do two million cells and you’re looking for how many abnormal myeloma cells are in there. I would suggest that at least from a prognostic perspective, because you know you’re going to be doing better if you’re MRD negative, this is something that the patients in your audience should look to try to get. What we don’t yet know is the two main questions. Number one is if you’re MRD negative, can you maybe get less therapy or even stop therapy for some period? The second question is, if you’re MRD positive, does that mean that you should get more treatment to try to turn into MRD negative? I think those are questions that we’re still trying to answer but will be very key moving forward.

Jenny: I think that will give a lot of insight. I know there are some patients that can stay MRD positive but they can stay that way for a very long time. I mean, decades even. And there are some patients that are MRD negative and then it comes back.

Dr. Orlowski: You’re right. You’re definitely right. You can be MRD negative and still relapse. What that says is that although the testing that we have now is more sensitive than it used to be, it still doesn’t detect one myeloma cell that may be present in a sample if you have, let’s say one cell in ten million and you only count two million. You may miss that one myeloma cell but that one cell may be enough to cause a relapse. The other thing is of course when you do the bone marrow, you’re looking at the area of the marrow near where the needle goes in. And three inches over or on the other side of the iliac crest, it could be that the situation is a little bit different, but it still provides us with more information than just doing the either serum or urine immunofixation, electrophoresis, and the serum free light chain studies.

Jenny: Well, absolutely, and that gives you so much more information that could change treatment and could maybe even change clinical trial construction, right?

Dr. Orlowski: Well, actually, great point because many of the trials now are looking to use MRD negativity as an early endpoint. The good news about patients doing so much better than they used to is that of course they’re living longer with a better quality of life. The challenge that that presents in terms of developing new drugs is if newly diagnosed patients are now living 10 to 15 years, which is probably where we are right now, it takes a lot longer to see if a new drug that you add to therapy results in a longer survival. But if we could show that MRD negativity does correspond to a longer survival, and there are some studies that suggest that’s the case, the great benefit of that is that we can do MRD testing much sooner, and that could help to accelerate the development of new drugs because even though patients are doing better, we’re still not curing the majority, so we can’t be too happy yet.

Jenny: Right. But you don’t want to have to wait ten years for study results to come in before you decide something is or isn’t working.

Dr. Orlowski: Exactly, and that’s where the MRD comes in because you can check that much sooner. Therefore, hopefully, that could be used in the future as an FDA drug approval endpoint.

Jenny: Right. Great. Well, good progress on MRD negativity and testing. It’s fantastic.

Dr. Orlowski: One category I’d like to also quickly mention, we talked earlier a little bit about patients with renal failure. The standard practice here in America has been of course to treat the myeloma with chemotherapy. In some cases, patients may need hemodialysis. The problem with the filters that are used in the dialysis machines here in America is that the pores which are kind of like little holes in the filter, it’s kind of like cheesecloth. The holes are very, very small in the filters here and really don’t take out free light chains very quickly. But for a number of years in Europe, there’s been a different kind of dialysis filter available that has larger pores, larger holes, if you will, and that allows better removal during dialysis of the light chains. The Europeans did present a study where they randomized patients with renal failure to get bortezomib and dexamethasone, and either standard dialysis or dialysis with this new filter. They showed that this new filter which takes off the light chains better resulted in a higher rate of recovery of renal functions. Hopefully, this will be something that will be reviewed also by the FDA. That will be great because of course nobody wants to be on dialysis if they don’t have to be, and it may be that if we have this available in the U.S., we’ll be able to save some patients from having to go on dialysis continuously.

Jenny: In your experience, when something is discovered in Europe and then we bring it to the states, does it take a long time to go through that process? I mean, the FDA has their own process, I know, but if it’s been proven and results come out of Europe, how fast does the U.S. adopt those types of things? Because this clearly sounds like it has great benefit.

Dr. Orlowski: I agree it does. It really depends on the quality of the data. The FDA doesn’t really care whether the data come from America, from Europe, or from a combination. Many of the actual recent studies, for example, the dara with bortezomib study, the dara with lenalidomide study, these were international trials but a minority of the patients were actually from the U.S. and the majority were in Europe. The FDA will accept European data without a problem as long as the study is well-designed, and I think this one was. Although this won’t help a large number of patients with myeloma, we still see renal failure in about one out of five patients with myeloma. And if we could recover more of them so that they don’t need dialysis, that would be a big benefit to their quality of life. And by the by, since dialysis is not exactly cheap, it would also save healthcare resources.

Jenny: I think to me, that’s a big number, one out of five.

Dr. Orlowski: Definitely.

Jenny: Yeah, that’s terrific. Great advance.

Dr. Orlowski: Other areas to talk about, I think briefly, we mentioned dara quite a few times and it really is an exciting drug. For those of you that have been on it, you know that it’s given as an IV. With the first infusion, there can be some reactions in about 40% to 50% of patients, and as a result, the infusion time can be quite long. In some places, it can take up to 6-8 hours or even more. One new thing that’s been looked at is whether the daratumumab can be given subcutaneously (as a shot under the skin). There was a small study reported where they took the current daratumumab, mixed it with another enzyme called hyaluronidase, and they gave it to patients subcutaneously. Now, this did require several sites of infusion because the volume that the daratumumab could be squeezed into was still too large for one injection site and it took up to four to five sites in some cases. But the exciting news from this early study, and so don’t do this at home yet because it is not yet FDA approved, but the exciting news is that it looked like the response rate was the same as with comparable IV dara. The time for the infusion was much shorter, and it even looked like the risk of infusion reactions was smaller. We do need larger studies, and as I mentioned, this isn’t yet FDA approved. We’re probably a few years away. But if we could give this drug with a shorter infusion time and with fewer side effects and the same efficacy, that’s another example of where that would be a big win for patients because if they can stay in the doctor’s office or the infusion clinic for a much shorter period of time, they get more time to enjoy their life outside of the clinic.

Jenny: Yeah, absolutely. But this is in clinical trials right now, so you could join a daratumumab sub-q study, right?

Dr. Orlowski: Yes. There are studies available and this isn’t something yet that you can do at your local hospital or clinic. Do watch for it though because I think it will be something that’s done more and more often in clinical trials.

Jenny: Well, with the use of daratumumab in so many clinical trials, I would think it would be a great invention to include it because so many other studies are using daratumumab now.

Dr. Orlowski: I agree with you, and daratumumab as you mentioned earlier, as well as elotuzumab, are beginning in trials to be used upfront for newly diagnosed patients. There are some studies that haven’t yet been reported but that we hope will come out soon where dara and elo were used for newly diagnosed patients. These were mostly patients who were not eligible for stem cell transplant but those trials have finished enrolling, and hopefully, the data will be available soon. If they’re positive as we expect that they will be, those antibodies will then be approved for newly diagnosed patients, and that will be helpful to further improve outcome in that setting.

Jenny: It just seems like this class of drug is really, really effective.

Dr. Orlowski: Yes, it is, and there is still room for other antibodies because even though dara and elo are great drugs, they don’t quite yet give 100% complete remission in all patients, so we need to still be able to look for new combinations. And also, other drug targets for antibodies because there are other proteins on the cell surface of myeloma cells that could be attacked by antibodies.

Jenny: Just a question about daratumumab or elotuzumab, I know if somebody becomes refractory to one of those, in the other drugs like let’s say lenalidomide or bortezomib, sometimes you can add something like an HDAC inhibitor or something else that will kind of bring it back to life. Have they found anything that is particular to these monoclonal antibodies that helps them become effective again?

Dr. Orlowski: Yes, great question. You mentioned that retreatment with some of the small molecules like bortezomib or lenalidomide has been shown to be effective. We don’t have any large retreatment studies available yet but there were some abstracts presented at ASH that showed that even if the patient had received the daratumumab, for example, before and the myeloma had grown that you could retreat them possibly in a new combination and still get a benefit. At least I can tell you that in my clinical practice, I have seen patients who have had progression on elo and then benefit from dara, and also vice versa. I’ve had people who have progressed on dara and their myeloma has stopped responding. And when I’ve switched them to elo, they’ve been able to respond. Probably in part, that’s because the two antibodies bind to different proteins on the myeloma cell. We know from other cancers that one of the ways that cancer cells can become resistant to antibodies is by making less of the protein that the antibody binds. And then if the antibody can’t bind to the cancer cell, the immune system doesn’t know where to go and they evade the effect of the immune system. It’s kind of like they turn into a stealth myeloma cell.

Jenny: They lose their signal so you can’t target it anymore.

Dr. Orlowski: Exactly.

Jenny: Have you ever used dara and elo together?

Dr. Orlowski: That’s something I have not done. There are some theoretical concerns about that because the elotuzumab works in part with NK cells. They’re natural killer cells. They’re a type of white blood cell that helps to fight off cancer. Whereas, the daratumumab seems to reduce the number of NK cells because they express CD38, which is the target. There is a concern that dara may reduce the NK cells which are needed for the activity of elo. I think we need to look at those combinations but very carefully in a controlled trial because there is this concern. You don’t want to use two very expensive drugs and wind up having them fight against each other.

Jenny: Right. No, that would not be good. Okay, just curious. Since you said they were hitting two different targets and two different proteinsm I was just curious.

Dr. Orlowski: Now, there are studies looking at checkpoint inhibitors. These are antibodies that help to take away some of the immunosuppression that cancer causes, and therefore, helps your own immune system to attack myeloma. There are studies showing that, for example, pembrolizumab, which is one of the checkpoint inhibitors, can be active in combination with either lenalidomide or with pomalidomide. There are studies ongoing to look at whether these checkpoint inhibitors can re-sensitize patients, for example, to daratumumab, because one mechanism by which a patient’s myeloma can become resistant to dara, we mentioned the possibility that the target protein expression may go down. But another possibility is that there can be something called T-cell or NK cell exhaustion where the cancer causes the patient’s immune cells to become tired, if you will, and they no longer attack the myeloma cells. These checkpoint inhibitors reinvigorate the immune cells. They make them stronger. That’s one example where combinations of antibodies are being tried. I think there’s a very good rationale for those combinations. It’s too early yet to tell whether they’re working or not, but probably, by next year’s ASH, we’ll have some data, and there are a couple of studies. So, your audience should really look for those.

Jenny: There were lot of studies open, it sounds like. I mean I think there are four or five different kinds of checkpoint inhibitors, right?

Dr. Orlowski: Yes, definitely.

Jenny: I’ve seen a lot of them. The number I saw was 18 or something like that.

Dr. Orlowski: I’m sure by now it’s probably even higher.

Jenny: With the checkpoint inhibitors, how you said it can help with the T-cell exhaustion. Is it something that smoldering myeloma patients should look into because you want your immune system to be able to knock down the myeloma at any point and kind of keep it in check? Are checkpoint inhibitors being used in any smoldering scenarios?

Dr. Orlowski: Well, it’s funny that you asked. For the audience, you can tell them that this was not a question that I prompted you to ask.

Jenny: No, it is totally unplanned.

Dr. Orlowski: We have a study at MD Anderson where we’re looking at pembrolizumab for patients with smoldering myeloma because the thought is exactly what you described that maybe at the early stage, the myeloma cells are suppressing the patient’s immune system. By reactivating the immune system, we could reduce the amount of myeloma and at least minimally delay the time until progression. We just started this study towards the end of 2016, so it’s still too early to say whether it’s working or not, but it’s definitely an area of interest. Beyond checkpoint inhibitors, we talked about antibodies in general and the fact that there are other targets that are interesting. Definitely, one of them to mention is something called BCMA, which stands for B-cell maturation antigen. The reason this was interesting is that it is highly expressed on myeloma cells but is expressed really very minimally on other cells. That’s an ideal target because you want to try to avoid hitting other types of cells. There are many different approaches that people are taking targeting BCMA. One is with traditional antibodies, kind of like dara or elo. Second is using what are called antibody drug conjugates or ADCs. These are antibodies which have attached to them a drug, and what happens is that when they bind to the myeloma cell, the myeloma cell gobbles up the antibody. It releases the drug inside the myeloma cell and then the drug kills it. There are early signs that these drugs are working, and then, two other types of approaches that are targeting BCMA: One is the chimeric antigen receptor or CAR T-cell, and there were both laboratory and clinical study results that were shown at ASH that did reveal that CAR T-cells against BCMA are beginning to show activity against myeloma. So far, the responses, for example, in lymphoma in leukemia, there were complete remissions that were very durable or long lasting. So far in myeloma, that hasn’t been seen. Most of the responses have been partial remissions or complete responses that did not last quite as long. But in fairness, these are still phase 1 studies, and I think the technology is very exciting and there are a number of these CAR T-cell studies around the country targeting BCMA, as well as other proteins. We have one of these coming to MD Anderson. The last, I think, kind of therapy towards BCMA that I wanted to briefly mention are what are called BiTEs. That’s an abbreviation that stands for Bi-specific T-cell engager. This is a drug that has kind of two ends to it, if you will. One end binds to the myeloma cell, and the other end binds to the patient’s own T-cell. It brings them together and it makes it easier for the T-cell to attack the myeloma cell. These are going to be entering clinical trials in myeloma in 2017. The advantage that this technology has over a CAR T-cell is that to make a CAR T-cell, you have to first collect T-cells from patients, then you have to take them to the laboratory, modify them to express the chimeric antigen receptor. You have to expand them so that there’s a whole bunch more of them. Then you have to send them back to the patient and infuse them. That process can take two to four weeks or more. Sometimes myeloma grows very slowly and two to four weeks without therapy is okay. But in other instances, that two to four weeks may be too long and the myeloma may be progressing too rapidly. The advantage of the BiTEs is that they’re what we call “off-the-shelf”. Meaning that it’s a drug which is already made and ready to go. It’s the same for each patient, and so there isn’t a two to four week or more delay in the manufacturing process of this drug. You don’t have to wait and worry that your myeloma is growing while they’re trying to make these magical T-cells for you off in some factory somewhere. I think it will be interesting over the next few years to see which of these work best. They may both, whether it’s the CAR T-cell or the BiTEs, they may both work best in combination, such as in combination with these BiTEs or the checkpoint inhibitors. Jenny: Have the BiTEs been used alone yet in clinical trials? You said they are coming in 2017 in clinical trials.

Dr. Orlowski: Well, there have been BiTEs used and there’s one approved in leukemia. So far, there is not one yet approved in myeloma but there will be trials in 2017 with a couple of these. Do look for those if you’re looking for new options in the relapsed or refractory setting.

Jenny: Oh, absolutely. This sound really exciting. I know checkpoint inhibitors don’t necessarily work alone, so you’re always combining with something like lenalidomide or like you said pomalidomide. I’ve now heard some people talking about using the CAR T-cells in addition to the checkpoint inhibitors. So, it sounds like there might be lots of combinations.

Dr. Orlowski: Yes, there can. The rationale here is that even the activated CAR T-cells can sometimes become exhausted, and the same pathway is involved in causing that exhaustion. This is the PD-1, PD-L1 pathway, and if you use an antibody to block that pathway, then you can keep the T-cells strong for a longer period of time.

Jenny: Out of all these different immunotherapy type approaches, which look the most curative to you?

Dr. Orlowski: Well, we certainly hope that these all will contribute to the cure of myeloma, although it’s a little bit too soon to say whether that will be the case or not. To me, what look most exciting are these CAR T-cells and also the BiTEs. But sometimes, at Christmas, for example, you get a nice new toy and it breaks very quickly and you’re disappointed. Other times you get a nice new toy and it does even better than you think it will and it lasts for many years. So, we’re not yet sure which of those categories these drugs will fall into.

Jenny: Right, it’s just too early to tell.

Dr. Orlowski: Yes.

Jenny: Well, there were other new drugs and kind of different classes also at ASH, and probably, that will be used in the coming year. Do you want to describe some of those? Like the selinexor and venetoclax, some things like that.

Dr. Orlowski: Yes, those are two great examples. Even though we have lots of drugs, patients do still get to the point where their disease becomes refractory to IMiDs and proteasome inhibitors and antibodies and HDAC inhibitors. Selinexor, which you mentioned, is a very interesting and so far, looks like an exciting drug. This is a small molecule which acts by blocking the movement of proteins within the myeloma cell from the nucleus to the cytoplasm and back again. By itself, the drug has been shown to have some activity, but the really exciting activity is when you combine it with other drugs, for example, with dexamethasone. There was one study that showed that selinexor and dex had a response rate of 20%, even in patients whose myeloma was no longer responding to four or even five of the main drugs that we use out there. Also, in other combinations, selinexor with carfilzomib, selinexor with bortezomib, both of those with dexamethasone, the response rates are substantially higher. So, if I had to put money down on which will be the next new FDA drug approved for myeloma, I think that this would be probably the leading candidate in my mind.

Jenny: So far, it’s just been used for really late relapsed/refractory type patients. I guess once that goes to that process, it would move up the chain a little bit bot be earlier, you could tell if it would have preventative impact at an earlier stage.

Dr. Orlowski: Correct. The other drug that you mentioned is venetoclax. This is a drug which is already approved for CLL, which is a type of leukemia. It works by blocking one of the important survival mechanisms used by cancer cells, and there were a number of updated studies of this drug presented at ASH. The drug by itself seems to have most activity in patients that have a translocation that’s called t(11;14), which means that parts of chromosomes, 11 and 14, get exchanged. The response rate there was about 40%. The response rate with the single agent was lower in other subcategories of myeloma. But when there were combinations with venetoclax and bortezomib, for example, the response rates were higher, and other subtypes of myeloma were also sensitive. But I think in general, this is an important point to mention because one of the frustrating things I would say from a myeloma physician’s perspective is that so far, most of the drugs that we have, we seem to apply equally to all myeloma patients even though we know that not 100% of them, unfortunately, are going to respond. The reason that we’ve done that is that we haven’t had a biomarker where we could predict that patients with myeloma in category A will respond best to drug combination X, whereas, people with myeloma category B need Y combination. But here is an example of a drug where we know that the best response rate as a single agent is in people with t(11;14), and that can be evaluated on a bone marrow. So, that’s I think very exciting because one of the ways we can maximize patient outcomes is by being able to select the best drugs and combinations, not just for any myeloma but for their own particular type of myeloma. That way, they’re going to have a better likelihood of responding, and that means that other patients that maybe we would predict would not respond well, we would switch to a different combination. That’s great because first of all, we want to of course get to an effective therapy as quickly as possible. Why expose someone to a drug that isn’t going to work and yet can have side effects? Once again, it’s a nice way to save money because we may be able to avoid using certain combinations in some of the myeloma subtypes, get to something that works better, more quickly, and therefore, save money.

Jenny: Well, I think that’s a dream of myeloma patients. What you’re saying is really exciting, that we can individualize therapy or tailor treatment to a particular myeloma. Because myeloma changes over time, this just makes me think that it’s so true that we need experts on our side when we go in for myeloma treatment. I can’t stress that enough for patients that they have a myeloma specialist like you in their corner because even if you get treated with a local oncologist, you need somebody that has this type of depth. As you can hear, there are so many different options that are coming and available. I just think it’s critical for people to have a myeloma expert on their team who has the flexibility and the knowledge to know what to apply and when.

Dr. Orlowski: And because of all of the approvals that we’ve had. In 2015, there were five new drugs or new combinations approved. In 2016, there were three new combinations approved. There probably will be other drugs approved in 2017 as we discussed. These are just the chemotherapies. Never mind the fact that as we talked about denosumab may be approved and other things. Frankly, I harken back to an abstract at the 2015 ASH that looked at how many myeloma patients the average oncology doctor in a community practice saw. On average, they see between one and two new myeloma patients per year and they managed a total of five to six myeloma patients at any one time. Given that there are at least nine or ten subtypes of myeloma, that means that they can sometimes go two, three, four years without seeing a single patient of one of the subtypes. Frankly, I take my hats off to them because I think the community docs are great. They really do their best to keep up with what’s going on in cancer, in general. But I do think that it’s difficult when you treat patients with a relatively rare cancer where the field has essentially exploded with new opportunities. I think it’s difficult to keep up with what to do for each individual. I think it’s great to get your therapy with the local doctor. But I would definitely recommend for your own peace of mind to get a second opinion at a major center with a myeloma expert because if you were out looking for a new car, you would shop to get the best deal. Here, what you’re doing is you’re looking around to make sure you’ve got the best advice and then you can go ahead and get that treatment locally.

Jenny: Right. I do want to stress that because you can do that. I do that and many other myeloma patients that I know do that. They’ll travel to an academic center. They’ll get a consult with an expert like yourself. They will ask their local oncologist to implement that plan. And then if things change or shift or that you need to make modifications, you can go back and recreate the plan. But I think our lives are at stake. I’ve gone to both a local oncologist and to myeloma experts and there’s just no question of the difference. The Mayo Clinic even had data showing that you’ll live longer if you are seen by a center that has over 50 myeloma patients. I’m guessing and I don’t know what you would say about the number but I would guess anywhere between 200 and 600 to 800 patients per year. That’s a big difference than two or five.

Dr. Orlowski: Yeah, definitely. Of course, ultimately, it depends on how many myeloma physicians they have because if they see 50 myeloma patients a year, which is definitely better than one or two, but they have ten doctors that do it, then you’re still seeing somebody who only sees five new myeloma patients per year. But for example, MD Anderson, we usually see 550 to 600 new patients per year in addition to, of course, all the follow-up patients. As you mentioned, there are many other places that see comparable or even more numbers. I would definitely recommend going to one of those if only for a second opinion.

Jenny: Well, I agree. I think it’s an important point to stress. I know at ASH, I know a lot of people will listen to this show and think to themselves, “Gosh, there are so many new drugs out there. Do I still need a stem cell transplant?” Do you want to share your perspective on the role of stem cell transplant in the age of all these new therapies?

Dr. Orlowski: Yes, it’s a great question. One of the best studies that has addressed that is a French trial, which actually, there’s also an American arm which is being done and the American data are not yet available. But in this French study, what they did is they looked at bortezomib, lenalidomide, and dexamethasone as initial therapy. After three cycles, every patient had stem cells collected. Half of those patients had an early transplant and then additional chemotherapy and maintenance. Whereas the other half had their stem cell stored away but not used and got chemotherapy and maintenance. And they only did a transplant if their myeloma relapsed in the future. So far, what the data have shown is that the group that got the early transplant had a longer time in remission, but the difference was only about nine months. So, it wasn’t a huge difference. And then in terms of overall survival, the overall survival at four years was equivalent. The data are still not completely convincing because if you’re a transplant devotee, what you would say is, “Well, you stayed in remission nine months longer because of the early transplant, and maybe some 10% or 15% of those patients maybe even stay in complete remission indefinitely.” If you’re someone who is not a devotee of transplant, you’re going to point out that the overall survival was the same, and so it’s safe, therefore, to minimally delay the transplant until the time of first relapse. And you would say maybe some of those people would never relapse, and therefore, never need a transplant. I think this is why it’s important to try to have each patient be seen by an expert and individualize their care because other factors come into this. For example, if you have good-risk myeloma versus high-risk myeloma, it may be that the high-risk myeloma patients would benefit more from a transplant, although some data argue that it could be less. The other question that comes up is whether MRD negativity, going back to the beginning of what we talked about, whether MRD negativity is important because maybe if you’re MRD negative and in complete remission especially with good risk disease, it may be very reasonable to collect the stem cells, store them away, and just do a little bit of maintenance therapy. But these are questions that we don’t yet have all of the trial data that we need to answer. That’s why I think you really need an expert to discuss your case and think about things individually. Also, the patient’s own situation and their preferences and their family’s preferences need to be taken into account.

Jenny: Well, I so appreciate the approach that you and others are taking to individualize care for people. The question I have, because you’ve run so many clinical trials is, how does that influence your clinical trial construction? Could you create smaller clinical trials for different subgroups? I know some of these trials have thousands of patients, some have hundreds at the phase 3 level, anyway. I know they have to be validated in that way but I’m just wondering if that would be a possibility to change the way that these clinical trials are constructed so you can get through all these different and exciting options faster and more individualized. That’s a challenge.

Dr. Orlowski: You’re right. I do think more and more, what people are doing in the field is to develop trials that are trying to use biomarkers, as we mentioned earlier, so that we hopefully are picking the patients who have the best likelihood of responding to the particular therapy that we’re using. We’re not quite there yet for every drug because sometimes, what we do is we see a drug is working. And of course, because patients still need new therapies, we rush forward showing the clinical trials that really validate its activity, but we don’t always understand as much about why those drugs worked and whether they work better in some people versus others. This is why in addition to doing clinical trials, I think it’s important to be an advocate for, and if you can, to support the laboratory based research that goes into developing new drugs, and also understanding why our current drugs worked and in what cases they don’t, because research funding from the National Cancer Institute is certainly very important and robust but not as much funding is available as we would like. Every dollar can make a difference. Keep that in mind as well.

Jenny: I do want people to know they can donate directly to a facility or a lab. That is possible. You don’t always have to donate to an advocacy group. You can donate directly to a particular doctor in some instances.

Dr. Orlowski: Yes, you can. Of course, there’s the Myeloma Crowd Research Initiative that you’ve put together. There’s the MMRF, there’s the IMF, and the Leukemia/Lymphoma Society. Those are the major advocacy groups that you can think of if you don’t want to donate directly to an institution or to a particular researcher.

Jenny: Right. Well, I wanted to ask you my last question, but we got through a lot, so I gave you a very long list. You were very adept getting through this list. We didn’t get through everything but we got through most everything. I heard about an MD Anderson collaboration and initiative, and I just wanted to learn more about that before we open it up just to a couple of caller questions before we end.

Dr. Orlowski: Well, we’ve got a couple of things going on. Among other things, there is what’s called a Moonshot in high-risk myeloma. The Moonshot concept, which actually was later adopted by the government and by President Obama and Vice President Biden, was a mechanism originally developed by Dr. DePinho here at MD Anderson. In this Moonshot, as I mentioned, we’re targeting high-risk myeloma. The two areas that we’re focusing on is the smoldering high-risk population, and we talked a little bit about that earlier. Also, we have trials for patients who are undergoing transplant who have high-risk disease where we’re adding a cellular immunotherapy. We’re actually using cord blood natural killer cells to try to augment the activity of just chemotherapy alone. So far, the data look actually quite promising, and we’re developing that further. That’s one of the initiatives here and then we have a number of targeted alliances with industry partners who have what we think are very attractive drugs, including CAR T-cells where we’re going to have entire trials with CAR T-cells located only at MD Anderson. Meaning that we’re going to have lots of positions available for patients rather than just one a month or something along those lines.

Jenny: Well, that’s good to know because I know there are only two open CAR T-cell clinical trials and it’s very hard to get in. So, opening that up through your facility and others will be a blessing for patients. Well, we’ve covered a lot. I’m just so very grateful for the work that you’re doing. You’re fabulous as usual. I’m so thankful to hear about this individualized care, about all the amazing progress. I’m sure we will see additional FDA approvals this year from what you were saying and what we’ve covered in all aspects of myeloma care and the supportive care and the treatment. I’m just so grateful for all you do for myeloma patients.

Dr. Orlowski: Well, I think the good news is that the myeloma field has many great scientists and clinicians and it’s really a hot area for research. I think that makes me optimistic that over the next five to ten years, we’re going to be not just doing complete remissions or CRs but that we’ll actually get to C-U-R-E for myeloma.

Jenny: Yeah! That would be terrific. Well, let me open it up for a couple of caller questions if you have time for that.

Dr. Orlowski: Sure.

Jenny: If you have a question for Dr. Orlowski, you can call 347-637-2631 and press 1 on your keypad. Go ahead with your question.

Caller: Hi, Dr. Orlowski. Thanks so much for sharing all the information. Also, I wanted to ask you, when should minimal residual testing be done and how often it’s recommended?

Dr. Orlowski: Great question. There’s no standard recommendation yet for how often the MRD testing should be done. Right now, it’s mostly being done on bone marrow aspirates, although there are some tests being developed that will only require a tube or a couple of tubes of blood. I think when to do it depends on whether a decision can be rationally made. Right now, as I mentioned earlier, we just don’t yet have the data. But I would still argue that if you’re getting a bone marrow, you may as well ask, and hopefully, get the MRD testing done because if you could be in complete remission, you will feel better knowing that you’re MRD negative than MRD positive because you know that the MRD negative people have a longer time in remission. It still doesn’t tell you exactly how long the remission would be but it certainly, I think, will be a positive aspect. And if you’re MRD positive, that still doesn’t mean that you’re in a bad situation. It could actually still be a very good one, but that may be a point at which to discuss whether you should get additional therapy or not.

Caller: Okay. Thank you. Thanks for answering.

Dr. Orlowski: Thank you.

Jenny: Great. Even if you’re MRD positive, it might be interesting to track it over time. That would be something, if you’re already getting a bone marrow biopsy, to watch.

Dr. Orlowski: Exactly.

Jenny: Is that something that’s indicative of growth in disease? Does it track with the, let’s say your M spike or your light chains going up?

Dr. Orlowski: Well, in general, there should be a relationship between them, although because the MRD can be more sensitive, sometimes you can be MRD positive even though your M protein in the blood and urine is negative and your free light chains are completely normal. But there are studies that show that if you convert from MRD negative to MRD positive, that does predict that you will have a clinical relapse in the future with myeloma protein in the blood and urine.

Jenny: It’s so interesting. Okay. Well, it’s so exciting to see the progress that’s being made. Our next caller, go ahead with your question.

Caller: Hi, Jenny and Dr. Orlowski, it’s Dana Holmes. Happy New Year to you both.

Dr. Orlowski: You too, Dana.

Caller: I always call in for questions with Dr. Orlowski. Thank you so much for doing yet another show with Jenny. Just terrific. Dr. Orlowski, the last time I spoke to you, I asked you to describe what your dream clinical trial for smoldering patients would be. Since it’s a new year, I’m going to pose that question to you yet again.

Dr. Orlowski: Well, I think we mentioned earlier some of the ongoing studies with, for example, elotuzumab, lenalidomide, and dex, or with pembrolizumab. I think that what I would love to see, and I’m not sure what the right combination is, but what we’re trying to do here at MD Anderson is develop an immunotherapy platform which would hopefully rely only on monoclonal antibodies. The reason for that is that first of all, I do think that manipulating i.e. stimulating the immune system would be a great way to get rid of myeloma. Secondly, the problem when you start using drugs like lenalidomide and dexamethasone in smoldering patients, usually, these drugs are used for a long period of time. What that means is that if you’re on len for an extended period, you can have later problems with collecting stem cells, which is of course not a good thing because you do want to be able to do that if you progress to myeloma. That means that you may have to collect stem cells earlier in the smoldering patients. Some of whom may not have ever been likely to progress, to begin with. Now, you’re adding cost, but the bigger concern to me is that if you use, let’s say elo/len/dex as a smoldering patient or dara/len/dex as a smoldering patient and you have an initial response, but eventually, the myeloma progresses, have you now lost the ability to use those drugs, which are some of our best drugs. Therefore, even if you get a short-term benefit, is there a long-term loss of benefit? Those are some of my concerns, and why I think that immunotherapy, whether it be with antibodies or maybe these BiTEs, those are the kinds of combinations we’re looking at right now.

Caller: Terrific. Dr. Orlowski, I want to ask you this. If a treatment naïve standard risk newly diagnosed myeloma patient came to you as a brand-new patient, what would you, at this point, recommend to such a patient as initial treatment? Would you recommend an aggressive upfront treatment approach, sort of akin to the kitchen sink throw it all up front, or would you select the more measured sequential approach? And if the latter, what treatment would you start out with? Would you choose KRD over VRD? Would you add maybe elo or daratumumab to that?

Dr. Orlowski: Yes. Another great set of questions. Of course, some people’s kitchen sinks are bigger than others, so that’s a consideration.

Caller: Absolutely.

Dr. Orlowski: You know, there’s no “one size fits all” because it depends on what other medical problems, for example, the patient may have. Let’s say, for the sake of argument, that they have a lot of neuropathy and diabetes, then you may want to avoid drugs like bortezomib, in particular, and maybe reduce the dose of dexamethasone. It also depends on whether people can reasonably travel back and forth to get therapy. I think right now, the standard of care that everybody would agree on based on the recent SWOG study that just got published in The Lancet, would be the combination of bortezomib with lenalidomide and dexamethasone. Many people do feel that carfilzomib with lenalidomide and dexamethasone may be a little bit better, and there is a randomized study that ECOG is doing comparing those two. I don’t think that KRD, as it’s called, is going to be inferior. So, the question is whether it will be better while requiring more treatment, because at least for right now, the current K schedule involves six doses over four weeks. Whereas, the current V schedule usually allows you to get four doses over three weeks. So, it’s a little bit less treatment. I think whether you add an antibody or not, we don’t know yet, although SWOG finished a study comparing VRD to elo with VRD in high-risk patients. And we hope to be able to report those data when they’re mature. But I do think if you’re asking me to extrapolate from the data that we have, that adding an antibody like dara or elo to either VRD or KRD will be very reasonable. I think we should not forget about other combinations like the ixazomib/len/dex, which is an all oral combination, which I think would be especially good for patients who don’t want to travel back and forth too much, or older patients, and adding an antibody onto that one if that is to be approved in the frontline setting, which we don’t yet know because the data from that study haven’t become yet available. But those are some of my thoughts right now.

Caller: Well, thank you so much for that as always. Lastly, I came across an ASH abstract regarding panobinostat. It was from, let’s see, Dr. Hermann Einsele, I’m probably not pronouncing their names correctly, and Michael Huedecek from the University of Würzburg. Yeah. Jenny, you’re supporting one of their studies. The abstract related to panobinostat induces up regulation of CD38 and augments the anti-myeloma efficacy of daratumumab in pre-clinical models. From what I read, they have experiments ongoing to evaluate the synergy of panobinostat and daratumumab therapy in a mouse model. They’re ongoing. They basically stated that pano has a known ability to (I’m just reading this verbatim), “to modulate the transcriptional profile of myeloma cells and our data demonstrate for the first time that this ability can be utilized to augment the therapeutic index of antibody-based immunotherapy in multiple myeloma”. Can you foresee a clinical trial bringing both of these drugs together?

Dr. Orlowski: Well, there actually was also a previous publication, I think maybe a year or two ago now, that showed that ATRA or All-trans Retinoic Acid, which is approved in promyelocytic leukemia, has a similar ability to increase CD38 and improve dara efficacy pre-clinically. I think that it’s certainly an exciting possibility especially in patients maybe whose myeloma is initially responding to dara, but then maybe starting to progress. If that progression is due to low CD38 expression on the myeloma cells, which may very well be the case, I could definitely see a scenario where you would then continue them on dara and add in ATRA or panobinostat or maybe both to recapture the sensitivity. But if the progression is because of T-cell exhaustion and not decreased CD38 -- so we don’t yet understand enough about why resistance occurs to safe or sure that that’s going to be a successful approach. But it certainly sounds exciting, I agree.

Caller: Well, thank you so much. Always an education, and I appreciate you supporting the patient community in trying to educate us. And Jenny, you as well, thank you. You guys rock. Thanks so much and have a great week.

Dr. Orlowski: You too, thank you.

Jenny: Well, great questions. She asked some of the questions I had on my list, so we got even further down our list today. Dr. Orlowski, it’s a pleasure as usual. Thank you so much for participating again and giving us a view of what we can look forward to in 2017. We’re really excited about what’s happening in myeloma, and I know that patients can get involved. They can join clinical trials to help accelerate all this research and help to find a cure, essentially for ourselves. We’re highly motivated to do that. That is something we can definitely do. We just are so grateful for all the work that you’re doing.

Dr. Orlowski: Well, my pleasure, and again, Happy New Year to everyone, and hopefully, a very healthy new year as well.

Jenny: All right, thank you so much for joining us today. And thanks for listening to Myeloma Crowd Radio. Join us next time to learn more about what’s happening in myeloma research and what it means for you.