Dr. Robert Orlowski, MD, PhD MD Anderson Cancer Center Interview Date: December 18, 2015 

This will be remembered as a banner year for multiple myeloma with the introduction of 5 new FDA-approved drugs. Dr. Orlowski gives us his take on the year with a "Top 12" from the December ASH conference in Orlando. His top picks include both clinical studies looking at combinations of different current drugs, the newly approved drugs, and beginnings of using immunotherapies in clinical practice. Learn more about the new announcements with an easy-to-understand but deep perspective from a multiple myeloma expert. 

 

Thanks to our episode sponsor, Amgen

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 today's episode sponsor, Amgen, for their support of Myeloma Crowd Radio and myeloma patients. Now, before we get started, as many of you know, last January we invited a prestigious scientific advisory board of myeloma experts to join us to help find exciting research being done for high-risk myeloma patients. We also invited a team of educated myeloma patients to participate. The goal was to serve an unmet need, essentially, for high-risk patients by raising funds for projects that would not otherwise get funded that were critical for patients who today are not having great outcomes. So we began that process last January. We submitted research proposal request to hundreds of myeloma researchers. We received back 36 very high quality proposals. Those were vetted down to a list of 10. We did a radio show in each of the 10 and then we selected two. So we have been fundraising since the fall for these specific projects including, as many of you know, our 12-day challenge. We have successfully now raised over $150,000 so far with a goal to hit $200,000 by year's end. We had a very generous anonymous donor who just donated $30,000. So as a shot out, I just want to say an incredible thank you to that donor and all who have participated in this process. It's becoming a reality. These doctors will be able to get started on the research they're doing beginning in January. So this is the first time that a united group of patients, including all of you, have joined together to help fund the road towards a cure. The field is looking so very hopeful. We're just thrilled with all of the new developments. Now, speaking of new developments, Dr. Robert Orlowski from MD Anderson Cancer Center is joining us today to talk about all these new advances and recent announcements especially coming out of ASH. Dr. Orlowski, welcome to the program.

Dr. Robert Orlowski: Jenny, thanks very much for having me. I wanted to take the opportunity to wish everyone out there happy holidays and best wishes as well for the New Year.

Jenny: Thank you so much. Now, let me introduce you first before we get started. We have quite a bit to talk about. Dr. Orlowski is Professor of Medicine in the Department of Lymphoma/Myeloma with a Florence Maude Thomas Cancer Research Professorship in the same division. He has a dual appointment and is also a Professor in the Department of Experimental Therapeutics. Dr. Orlowski is Director of the myeloma section in the Department of Lymphoma/Myeloma at MD Anderson. He's a member of the NCI Steering Committee, the Multiple Myeloma Tissue Bank Steering Committee, and the American Society for Biochemistry and Molecular Biology. He's the chair of SWOG. If you're not familiar with that, it is a Southwest Oncology Group which helps create and craft clinical trials for multiple myeloma. He is also in the Editorial Board of Hematology and the Journal of Clinical Oncology. He's received numerous awards over a number of years including the LLS Scholar in clinical research, LLS Man of the Year, the Emil Frei III Award for the Excellence in Translational Research from MD Anderson and he is the recipient of a very coveted SPORE grant from the NIH which is awarded to top researchers. It's quite a rare award. Dr. Orlowski, thank you so much for joining us. I think you had in mind maybe giving us a top 10 or a top 12 abstracts on ASH or topics from ASH that were covered just so -- if patients don't know what ASH is, do you want to just begin by telling them what that is first? Dr. Robert Orlowski: Sure. Well, ASH stands for the American Society of Hematology. Once a year, usually early in December, there's an annual meeting, and this is where researchers from all over the world get together to present their most exciting and most recent data. Myeloma, of course, is one of the hottest diseases out there in terms of new drug development. So it's often an exciting time when we get to see what people are doing all over the world to combat this disease. What I'll do is give you a quick overview of what I thought were some of the top abstracts. Of course there are many wonderful presentations. We don't have time to cover them all but I'll do my best to hit what I think are the highlights. First of all, you mentioned earlier about SWOG. I think one of the most important presentations was a SWOG-led study which was for newly diagnosed patients with myeloma. They were randomized to receive either lenalidomide and dexamethasone or len and dex but with the addition of bortezomib. The three drugs showed a better response rate, a longer time in remission and also a longer overall survival. This study is important because for many years we've been using this so called RVD regimen as sort of de facto standard of care but this is really the first study which shows that in fact this combination is a superior one to a two-drug combo. A second abstract that I thought was very important was a study from the French myeloma group predominantly. What they did is they compared bortezomib, cyclophosphamide and dexamethasone, which is also known as CyBorD, to bortezomib, thalidomide and dexamethasone as an initial therapy prior to stem cell transplant. For many years CyBorD has been talked about as being one of the best regimens. The same has been true for bortezomib and thalidomide and dexamethasone but it's always helpful to have a comparative study. This trial did exactly that. Interestingly what it showed is that bortezomib with thalidomide and dexamethasone looked better. So CyBorD is certainly still a good option but I would probably, if I had the choice just between these two, go with bortezomib and thalidomide and dex or as per the prior presentation, bortezomib with lenalidomide and dexamethasone. A third study to highlight was an exciting one that had been done by the French. We actually are also participating, we being many centers in the United States led by the Dana-Farber as well as with MD Anderson. Here in this study patients are getting bortezomib, lenalidomide and dexamethasone then they get randomized. All patients have their stem cells collected. Half of the patients get an early transplant. The other half get more chemotherapy and don't go on to transplant until there is evidence of progression of their myeloma. The results showed two interesting findings. One endpoint was what's called progression-free survival. That means time until the myeloma begins to progress. As you would maybe expect, the people who got the early transplant with a high dose melphalan had a longer PFS than the patients who got only chemotherapy. However when you look at the overall survival, because the patients who got only chemotherapy even if they progressed earlier were able to get a transplant at that time, the overall survival for the two groups was essentially identical. That suggests the possibility that at least for some patients it may be possible to delay stem cell transplant especially if they do very well with their initial chemotherapy. We'll probably have some questions about that a little bit later on that we can get to. The next abstract that I wanted to cover was a study that we actually did at MD Anderson. We know that lenalidomide, bortezomib and dex is a great regimen but it still doesn't achieve complete remission in all newly diagnosed patients. So what we did is we added panobinostat as a fourth drug. Probably many of you know that panobinostat is approved for relapsed myeloma. Typically if a drug works there and you give it to newly diagnosed patients it works even better. In this update of our study we found that the four drugs were tolerable and that there was an indication that maybe they worked better than just the three drugs, RVD combo. Actually about half of patients were able to achieve MRD negativity even before they went on to stem cell transplant. So that's exciting because if you're MRD negative before the transplant you certainly will probably be after the transplant and your outcome after the transplant should be better as well. One other thing to mention in the abstract category for recently diagnosed patients, and this has some application to the high-risk setting you mentioned, Jenny, because in addition to the great initiative that you've put together to tackle high-risk myeloma, we also, here at MD Anderson, have been interested in that. So we have what's called a “Moon Shot” for high-risk myeloma which was basically a donor-funded effort with a number of different approaches. The one that was presented at ASH as an oral presentation was the use of natural killer cells or NK cells. These are cells that are part of the immune system and that can have anti-myeloma activity. What we did in this trial is that patients with high-risk disease who were getting stem cell transplant, right after the high dose melphalan which is the main chemotherapy wit transplant, they were getting, in addition, cord blood-derived laboratory-expanded NK cells. The thought is by doing so you will have not just the benefit of the melphalan chemotherapy but you'll have an immune attack against the myeloma with the NK cells. What we found is that NK cells were very well tolerated. There were virtually no side effects. Although the follow up is still short there was an indication that the response quality looked very good. So this was something we were excited about at were the reviewers. We hope to be able to expand upon this further in the future and treat a larger group of patients.

Jenny: Before we go on, do you want describe the Moon Shots Program at MD Anderson because I'm familiar with it but I don't think most people are.

Dr. Robert Orlowski: Sure. Thanks for asking and for the opportunity. One of the things that our president at MD Anderson, Dr. DePinho, did is he wanted to, of course as do we all, but he wanted to focus on making a big difference over the next five years in certain cancer areas. So through the generosity of many donors he was able to raise a war chest, if you will, of funds, and then he put together a group of cancer experts to review applications. He sought proposals from all over the cancer spectrum, not just myeloma. Those proposals which were felt to have the best chance of making a big impact were selected for funding. One of those which was selected was this high-risk myeloma effort. What we're trying to do now is expand further beyond the study that I just mentioned to you, and also develop chemotherapy drugs as well as immune therapies that hopefully will be specially targeted against high-risk myeloma. The exciting thing is that many of these will also be applicable to standard risk myeloma but we're testing them first in high-risk disease because, unfortunately, patients with high-risk myeloma relapse sooner. The only good thing about that is that if we try a new treatment and it works we will know more quickly if it works in that setting than in patients with standard risk disease.

Jenny: Makes sense.

Dr. Robert Orlowski: So previous abstracts that I reviewed for you briefly were ones that dealt with recently diagnosed myeloma. Now I'm going to move into some of the things in the relapsed setting. Abstract number six was the presentation of a study with an oral proteasome inhibitor. The generic name is ixazomib. This is a large phase three trial which compared lenalidomide and dexamethasone to ixazomib with lenalidomide and dexamethasone. The study showed about a six-month improvement with a longer time in remission. The tolerability of this combination was very good as well. You probably know that this drug was approved by the FDA in November because of these data. I think it's a big improvement from a convenience perspective because instead of having to be injected with either bortezomib or carfilzomib, in some cases you may now be able to take this medication orally. Another abstract for relapsed myeloma was an update of data from the elotuzumab study. Elo is a monoclonal antibody which binds to a protein on myeloma cells and makes them more visible to the patient's own immune system. As you probably know, this was also approved in November in combination with lenalidomide and dexamethasone. This abstract that I'm referring to gave longer follow up, now three-year safety and efficacy data, and it showed a continued benefit for the group of patients who got the elo/len/dex. I think that's exciting because in some studies we see an early benefit but may not always be maintained later. In this trial it actually continues to show a difference. Elo wasn't the only antibody around which there was excitement in myeloma at ASH. The next abstract looked at a drug called pembrolizumab in combination with lenalidomide and dexamethasone. Now, pembro is a drug that is already approved for some other cancers. Some of you may be aware of President Carter's melanoma which is being treated with a drug that has the same mechanism of action. We're now trying this in myeloma. This presentation showed that the drug looked active in the combination. There was some excitement as well because even patients whose myeloma had previously grown on lenalidomide and dexamethasone seemed to respond when this antibody was added. This will be another immune therapy that maybe could be combined with other antibodies in the future.

Jenny: Is that a monoclonal antibody or that's a checkpoint inhibitor or what is that?

Dr. Robert Orlowski: Good question. In this case it's both. This is an antibody which works by blocking some of the checkpoints. So checkpoints in immune function have to do with the fact that cancer cells often suppress the patient's own immune system. They do this to survive. We now understand some of the mechanisms which are used by the cancer cells. These checkpoint inhibitors take that inhibition away. So if you will, they boost the patient's immune system and therefore provide additional benefit by allowing it to attack cancer in general and in this case it was multiple myeloma.

Jenny: That's great.

Dr. Robert Orlowski: Now, a couple other abstracts to mention quickly. Number nine was a study that looked at a different oral proteasome inhibitor called oprozomib. I told you earlier about ixazomib but there's another oral drug in this class called oprozomib. It was combined with pomalidomide and dexamethasone. It showed a 50% to 70% response rate which is pretty high in the relapsed setting. I think we're looking forward to additional studies of that drug in the future. Getting to the finish line here. Abstract number 11 was a study of an anti-CD38 antibody called isatuximab. Many of you are probably familiar with daratumumab which is a drug that's been FDA approved and also binds CD38. But there's another antibody against the same target. An update of the data at ASH showed that it works quite well. Because it binds to a different portion of the target than daratumumab, it's possible that in fact the two could be used either together or sequentially. Abstract number 12 on my list was a late-breaking abstract which had to do with chimeric antigen receptor T-cells. Probably you've heard about these. There's a lot of excitement about them. This is a technology where you can take out the patient's own T-cells, modify them in the laboratory so that they can better recognize myeloma cells, and then infuse them back in so that they can kill the patient's cancer. This was a study from the National Cancer Institute which showed that even in very heavily pretreated patients, responses could be seen. This was still relatively early trial with only a handful of patients treated but really was exciting because of the fact that this technology, I think, is going to really be more broadly applicable to myeloma patients. Finally, I'll give you a Baker's dozen. So abstract number 13. We've mostly talked about myeloma right now but there's a related disorder called light chain amyloidosis. Some patients have this by itself. Other people have both myeloma and amyloid. Amyloid is a disease where the monoclonal protein made by myeloma cells can clump together and be deposited in various tissues and cause damage to those tissues. The same chemotherapies can be helpful as in myeloma against amyloid but what they tend to do is they kill the cells that make the protein but they don't get rid of clumps of garbage protein that have already been put down. There was a really exciting abstract for amyloid with a new antibody called 11-1F4, which actually looks like it's able to bind specifically to the amyloid fibers and make it easier for patients to get rid of that junk protein. So very exciting. It could really change the landscape for amyloidosis. So those are my top 12 plus a Baker's dozen of things that I found exciting from ASH.

Jenny: Well, that's perfect. There's so much content in what you just said. I'm not quite sure what we should talk about first. Maybe we can talk about the monoclonal antibodies, and then as we hit these topics we'll go back to these top 13 and ask some follow up questions.

Dr. Robert Orlowski: Sure.

Jenny: So daratumumab was approved. Elotuzumab was already approved earlier, right?

Dr. Robert Orlowski: Correct.

Jenny: So I went to a session where Dr. Jagannath was talking about how to use these and when to use them. Do you want to cover how does a doctor decide when to use these? When would you add them? It depends on how they've been approved in part I guess. As a myeloma specialist what was your perspective and take away after hearing about all of that?

Dr. Robert Orlowski: That's a great question. The exciting thing is that elotuzumab and daratumumab, although they're both antibodies, they bind to different targets on the myeloma cell, so that raises the possibility that they could both be used albeit at different times. As you pointed out, right now they've been approved in different settings. So elotuzumab was approved with lenalidomide and dexamethasone in patients with one to three prior therapies. So that's the setting where we would most often, at this point, use it. Daratumumab was approved right now by itself and for people with three or more prior therapies is one of the common ways that it's given. So probably, at least initially, we would tend to use the elo with len/dex earlier and the daratumumab later. Sometime next year we're going to get data of daratumumab with lenalidomide and dexamethasone versus len/dex in the same patient population for which the elo with len/dex has been approved. Although it's not always fair to compare two different studies we'll at least be able to get some idea of whether one looks better than another although the best way, really, would be to do a head to head comparison.

Jenny: I think that would be really helpful for patients. So when say three or more prior therapies, if you've gone through transplant, your induction therapy and then transplant, you're going to be at least to three, right? So let say somebody relapses after transplant, which do you choose at that point? Elo with len/dex or daratumumab with another combination or what do you do? I guess it just depends on the patient.

Dr. Robert Orlowski: Well, it's very much dependent on the patient. There's no one-size-fits-all. But the way that we define what's called a line of therapy is that it's a planned treatment which sometimes can include many different chemotherapies as long as the myeloma does not progress. For example, if you are newly diagnosed and then you get bortezomib, lenalidomide and dexamethasone as initial therapy and then you get transplant, and then, let's say, you do bortezomib as a maintenance therapy, as long as the myeloma hasn't progressed at any time during that period, that's considered one line of treatment. So when the myeloma does progress you're actually only in your second line even though you may have gotten four, five or even six drugs.

Jenny: I didn't know that. I thought it was just treatments. That's very interesting. Okay. Well, that makes sense. Let me go back to my notes here. Isatuximab, is this the SAR drug by Sanofi?

Dr. Robert Orlowski: It is. Correct.

Jenny: It's usually SAR and then a lot of numbers. I really ever remember what that is but now I have the name. So you're saying you could potentially use that with daratumumab. So that's very fascinating because they're hitting the same target.

Dr. Robert Orlowski: Well, that's a theoretical possibility. So far they have not been used together. The first thing that we really need to do is to try to get isatuximab approved both alone and in combination with lenalidomide and dexamethasone. But yes, because they attach to a different portion of CD38, which is the target, theoretically one might be able to use them together although that doesn't necessarily mean that the combination would be better than either drug by itself.

Jenny: I know we're getting addicted to having drugs be approved pretty quickly as myeloma patients. So it's very exciting to see what happened this year especially. So when do you think that drug will be FDA approved? Because it seems to be behind the others but is up and coming too.

Dr. Robert Orlowski: Sure. Well, there were five approvals in 2015 and three in November alone. So 2015 is going to be a tough year to beat. I think the isatuximab probably would be either late 2016 or more likely sometime in 2017, and then other drugs that look exciting that could get an approval sometime in the next couple of years would include drugs like selinexor which is a drug that blocks proteins moving from one part of the myeloma cell to another. I do think in the next couple of years there's a possibility that we will have even one of the CAR T-cell therapies approved for myeloma. There are some other drugs that look quite exciting as well. So I think it's a very exciting time in terms of getting new therapies available. With every new treatment which prolongs the ability to keep people in remission I think we come closer to a cure.

Jenny: I believe so too. It's just really exciting what's happening. Secondly, you mentioned ixazomib. Sometimes people want to know is this just an oral version of Velcade. Can I call my doctor tomorrow and say, "Could you swap me off Velcade and put me on ixazomib?" As a myeloma specialist what would you say? Because I'm sure you're going to get those types of questions.

Dr. Robert Orlowski: Sure. That's certainly an exciting option. The data that we have so far with ixazomib, for example, from the trial that I described earlier, the ixazomib was taken right from the beginning. People did not start on bortezomib and switchover. We don't really have a lot of data about that approach yet. So what I would tell patients is that if they're on bortezomib and they're doing well in terms of side effects and the myeloma is responding well, I would probably stick with that. If they're on bortezomib and having lots of problems like neuropathy, then I think it's reasonable to look at switching to ixazomib because the drug does have a much, much lower risk of neuropathy than does bortezomib. So for right now that's the one setting where I would consider switching.

Jenny: It seems to be that they were having pretty good results with ixazomib even for high-risk myeloma. I know bortezomib has good impact like in deletion 17p patients. Did you have any indication for high-risk about what that drug might do?

Dr. Robert Orlowski: Well, one of the groups that was followed very closely on that trial were patients with deletion 17p which is one of the high-risk features. The study did show that addition of ixazomib made a significant difference with an improvement in their outcome. So I do think that patients with high-risk should definitely be considered for a proteasome inhibitor of one kind or another which could be bortezomib or carfilzomib or ixazomib. But even with those drugs high-risk patients still don't do quite as well as the standard risk patients. So we're going to need to get additional drugs approved to make that difference be hopefully smaller.

Jenny: Okay. Perfect. The other was a study or a paper on a study that was done on Kyprolis or carfilzomib versus bortezomib or Velcade. Do you want to comment on that at all? I didn't attend that session but I would have liked to.

Dr. Robert Orlowski: Sure. You're right, that was a very exciting presentation. What was done in that study is that bortezomib and dexamethasone was compared to high dose carfilzomib and dexamethasone for one to three prior therapies. Now, the difference between standard dose carfilzomib and high dose is that at the currently approved dose patients get 20 mg/m² and then it goes up to 27 mg/m² but no higher. In this study it was first 20 and then 56 mg/m². It did look like the time in remission for the carfilzomib with the high dose and then also dexamethasone was about twice as long as it was for bortezomib and dexamethasone. So probably although this won't be necessarily a new drug approval but the current approval for carfilzomib will probably be modified to indicate that a higher dose may have an increased benefit. I say may just because in the trial that we're talking about there wasn't a head to head comparison of the standard carfilzomib dose versus the high dose. We're actually doing that as part of a SWOG trial. So we hope to have some of those results presented at next year's ASH meeting which will be in San Diego.

Jenny: That will be a very nice one to attend. That's my question I guess. You kind of made that point. Is it fair to compare a higher dose of one to a lower dose of another or does that mean you might want to increase the dose with all the proteasome inhibitors? I mean you might not want to if you have neuropathy issues, but if you have all the versions that don't have as much neuropathy maybe you can bump it up. I don't know.

Dr. Robert Orlowski: Well, it's a very good question. One thing that we know about new drugs when they get approved is that we learn more with each year about what the best dose and schedule of these drugs could be. So the chances are two or three years from now we'll probably be using some of these drugs in a different way than we do now. For example, with carfilzomib, right now the most common way to do it is to do two days in a row, IV, for three weeks on and one week off but there are several studies that are looking at the possibility of doing the carfilzomib at an even higher dose than the 56 but just one day per week for three weeks on and one week off. That would be exciting because if you can get the same benefit or, who knows, maybe even more but not have to come in for three infusions because instead of six you're only doing three, that would be a win-win for everybody.

Jenny: Yes. Less time in the clinic is better for everyone. The other proteasome inhibitor, the other oral one that you mentioned, is that taking carfilzomib, that proteasome inhibitor, and kind of turning it into an oral version as well?

Dr. Robert Orlowski: It's not exactly the same as carfilzomib but the chemistry is similar, you're right. We think that sometime in 2016 there will be larger studies with that drug available if people are looking for new treatments. We hope that maybe a couple of years down the road from that, if the trials are positive, there would be an approval, and then we would have two oral proteasome inhibitor to pick from.

Jenny: That's a challenge. I mean it's a blessing, a great blessing but it's also a challenge. We were talking about this before the show started. It's one of our write-in questions that I probably should save for the end, but I'm going to ask it now. It seems to be pretty complicated for the myeloma specialists to pick and choose and know what to use and when. How do you help the local oncologists who are treating patients and they don't attend ASH and they don't know all the details behind it? What do they do?

Dr. Robert Orlowski: It's important, of course, to try to stay current with all of these drugs. I'm always impressed at the knowledge of the local oncologists quite frankly because me being at MD Anderson, I get to focus just on myeloma, and yet they have to keep up with every drug in every type of cancer, and yet when I talk with them at meetings they seem very up to date about what's going on. I do think however, especially given the number of new drugs approved, one thing to always suggest is that it's never a bad idea to consult with a myeloma expert so that you have an opinion from somebody who specializes in that cancer. In terms of giving advice on which of these treatments should be used, that's a little bit tough in a kind of generic fashion because I think that what we need to try to do is understand better whether certain therapies work best for some patients whereas others work better for a different group. We're not quite there yet. But as of right now I think in the relapsed setting the most exciting combinations really look like carfilzomib with lenalidomide and dexamethasone and also potentially elotuzumab with lenalidomide and dexamethasone. So those three drugs regimens look really great. And then also from a study that we led at MD Anderson, carfilzomib with pomalidomide and dexamethasone looks really exciting. So if I were relapsing after my initial therapy, those would be the three things that I think would be most likely to result in a great benefit.

Jenny: As you said at the beginning of the show that it's becoming clearer that these triplets are better than these two doublet drugs. I'm just looking at that list, carfilzomib, len/dex and elo/ len/dex and car/pom/dex. I'm wondering if someday you could take that dex out of that combo. Maybe that's just wishful thinking.

Dr. Robert Orlowski: Well, it's a great question that lots of people ask because the dex is nobody's favorite drug, that's for sure. Part of the problem is that it really does seem to add to the benefit of almost all of the chemotherapies that we give but where things may change is with these immune treatments like the antibodies that we mentioned. Many people are concerned that steroids, which of course suppress the immune system, may actually be holding back the efficacy of some of the drugs we've talked about like the elo, like the dara, like the pembro, and maybe the same thing will be true for the CAR T-cells. So I think there's a lot of interest not just on the patient's side but also on the doctor's side to look at ways that we could at least reduce the steroid dosing. I do think eventually we'll probably be able to get rid of them but we're not quite there yet.

Jenny: Okay. Well, I want to cover two topics and we already have caller questions, so I will get to those. We will probably go over so don't be nervous that I'm not going to get the caller questions. Let's talk about transplant a little bit. I attended a session by Dr. Giralt of Memorial Sloan-Kettering. He was saying people ask him all the time with these new combination drugs that are coming: Can we ultimately get rid of transplant because everybody would love to. But he said melphalan is probably still the most effective single agent. For people who just don't like transplant and don't do it just because they don't like it, he just says the data just doesn't support that approach. So what is your opinion on transplant as a whole? I thought that's interesting what you said about the IFM study about transplant, about early versus late. You're saying it might not matter when you get that.

Dr. Robert Orlowski: Well, I think that it's not so much early versus late because the transplant that was done in the group that got a delayed transplant, that was part of the second line of treatment. So I do have stem patients who come and say, "Listen, I want to leave transplant for the absolute last thing that I do against myeloma." I tell them that I think that's a mistake because if you have myeloma that has relapsed after five, six, 10 prior lines of therapy the transplant is going to be much, much less effective. But I do think that the data showing that transplant as part of the second therapy is roughly equal to transplant given as first therapy are becoming more and more robust. So what that says is that it's possible. Now, remember, this is a hypothesis. We haven't proven this but it is possible that if you're newly diagnosed and you get into a complete remission with just chemo alone and especially if you have MRD negativity, it may be okay in that setting to collect stem cells and store them away and then just do a little bit of maintenance therapy and not do a transplant upfront. We really need to do a study like that. If you don't achieve a complete remission and if you're not MRD negative, then doing a transplant to get to that point I think makes a lot of sense.

Jenny: Well, that makes a lot of sense. That provides a lot of clarity around that because I do have friends that have tried to do just different combination therapies that weren't really working, and then the transplant, when try to do it, it doesn't work.

Dr. Robert Orlowski: Unfortunately myeloma still has a tendency each time it relapses to be more resistant to treatment. So you want to try to do the transplant early rather than as your last line of treatment.

Jenny: It's kind of confusing for patients because they don't really know what early means sometimes. They don't know if that means "Oh, gosh. Within a month of being diagnosed I need to be getting a transplant." So that's very informative. Thank you for helping clear that up. The last thing I'd like to talk about before we go to some questions, and we can talk about this for a while, is the whole field of immunotherapy. Maybe we can talk about it first as it relates to transplant because what I see people trying is let's go to transplant first, kind of empty the cup, as some people talk about it, of the tumor burden, unload the bulk of the tumor burden through transplant, and then try these immunotherapies both as your immune system is ramping back up in a normal way after transplant. So maybe you want to talk about how transplant would be used with immunotherapies and then maybe how it would be used without immunotherapies.

Dr. Robert Orlowski: Sure. Well, that could be probably a topic for a whole one hour show just by itself. There are of course different immune therapies. Some of them seem to work better if there is less disease, for example, vaccines. Probably at least with the technology that we have right now vaccines are probably going to be challenging to get to work if you have lots and lots of any cancer. If you have only a small amount, then vaccines might be a good way to build up immunity and get rid of what could be left over. If you have more cancer, then I think some of the therapies we've talked about like the antibodies, the checkpoint inhibitors and the CAR T-cells are fairly reasonable ways to go. The advantage of the transplant is that with the high-dose melphalan you're able to kill off quite a few of any leftover myeloma cells, and because you're putting the patient's stem cells back in, you're able to hopefully restore their immune system to a point where it may be better able to attack the myeloma. Now, of course if you do an allogeneic transplant where you have stem cells from a different donor, you don't donate to yourself, an allo transplant has always been said to potentially be curative. The problem there is that the toxicity of that approach is much greater. So I think that what we're hoping to do in the future is to either find some combination where we do a transplant and immunotherapy or what we're actually going to be doing some time next year at MD Anderson is we're going to have a trial where newly diagnosed patients are actually going to be started first on immunotherapy for a period of time. If their myeloma responds they're going to continue on that. If it doesn't, then we'll put them on standard chemotherapy. We're going to actually try to find a way to get rid of chemotherapy and replace it with immunotherapy completely.

Jenny: Which immunotherapy would you be looking at to be the most powerful one to start in a newly diagnosed setting like that? The CAR T-cell stuff?

Dr. Robert Orlowski: We have a number of combinations that we're going to look at. Each of the patients will be studied closely to look at the effects on the immune system that these treatments have because right now we have a couple of antibodies that are going to be part of this but we don't know for sure if these are the best ones. We're hoping, therefore, to be able to build on that as a platform for the future.

Jenny: I know some facilities are starting to run -- like the NIH, the one that you mentioned, they were targeting BCMA. I heard someone that attended that session say that the next time they do it they're going to have patients who have a lower tumor burden like they have to have 50% or less tumor burden so they don't get cytokine release syndrome. It sounds like they're learning as they go how to make it, number one, more effective and then more safe. I guess my question is because these CAR T-cell therapies are therapies and not necessarily a drug, how long does that process take to get that through the clinical trials and into the clinic because sometimes with a drug it can take a very long time. Is it faster to do these immunotherapies or because it's not necessarily a drug? It's more like manufacturing process.

Dr. Robert Orlowski: Well, it depends a little bit on the type of immunotherapy. If you're talking about just an antibody even though that's sort of technically an immunotherapy, it's still similar to a drug. So those tend to be a little bit faster. The CAR T-cells, because they involve, most often, taking out some cells from the patient, manipulating them in the lab and then putting them back in the patient, those often take a little bit longer to get going because the process is more complicated to develop the treatment. Therefore to make sure that the safety factor is maintained it takes more time to prove that you can do it safely. What we also are working on here at MD Anderson, and we're not the only place but I think we're one of the major places this is happening, is we're working on using these chimeric antigen receptor T-cells not from a patient but from a different donor. The advantage of that is that you don't have to wait a long time to generate each cell individually from each patient. So the problem with the auto CAR T-cells is that we have to take cells from each individual patient, we have to then modify them in a lab, we have to grow them up so that there's a certain number, and then infuse them, and that takes time. If you can take the cells from a donor, then you can save time because you can use the same cells for several different patients and also it makes a little bit cheaper although that's not the major motivation, I would say. If you do this allogeneic donor, then it should be much faster to get to each patient individually.

Jenny: Well, I guess you could pre-manufacture them at that point and have them be ready to go. So companies are starting to look at manufacturing process and trying to figure out how they jump in the game on this or facilities are doing this?

Dr. Robert Orlowski: Well, that's actually a combination of both because often times what happens is that we work with companies to generate the cells, and then when they're shipped they go through what's called the GMP lab here or the Good Manufacturing Practice laboratory to make sure that the cells are safe and they're not contaminated. Sometimes the same laboratory as is used for stem cell transplant.

Jenny: Would they be as effective or would they be more effective coming from a different donor?

Dr. Robert Orlowski: I don't think we know yet for sure. The technology is similar so there should be equal efficacy. I think the only concern about an allogeneic or a donor cell is the possibility of the graft versus host reaction as there is with an allogeneic transplant but we now have some tools to try to modify the donor cells so that hopefully that reaction will not occur.

Jenny: All right. Well, we look forward to seeing what everyone, including you, are going to do on that. That's very, very exciting. That's actually one of the studies that the MCRI is funding is a CAR T-cell project for BCMA and CS1. So it's very exciting to see what's happening. You touched on this a little bit. This is my last question then I'll open it up for questions. If we have time I'll ask a few more. You touched on the checkpoint inhibitors. I read the paper on it. The results were looking good. You mentioned another one that had like 50% to 70% overall response rate. It didn't seem like they were that high. I saw a lot of activity around that or a lot of excitement around that. What am I missing about that that makes these checkpoint inhibitors so exciting as kind of one of the next big thing to watch or is it?

Dr. Robert Orlowski: Well, I think excitement about that presentation was not so much the overall response rate but the fact that there were patients on that study whose myeloma had grown through lenalidomide and dexamethasone and then responded just with the addition of this checkpoint inhibitor. So that makes it exciting to think about the response rate if you gave the three drugs right up front for someone who hadn’t been exposed to any treatment at all.

Jenny: That makes sense. So you don't have to worry about them relapsing and you just use it right up front.

Dr. Robert Orlowski: Correct.

Jenny: Okay. That's fascinating. There's so much to talk about. Well, let me open it up for caller questions. 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. Hello.

Caller: Yes. Hello.

Jenny: Go ahead with your question.

Caller: Dr. Orlowski, how are you?

Dr. Robert Orlowski: Good. How are you?

Caller: Good. I really enjoyed your presentation. I have two questions about Revlimid in the salvage studies, particularly the one with elo. Are these patients naïve to Revlimid? Where do you find them or where did Dr. Lonial find them? The second question is there are a lot of people who have been maintained on very low dose Revlimid. Let's say 5 mg and have progressed. This sort of ties in with the first question. Would you then give them elo-rd at the higher dose of Revlimid or would you just assume that that's a waste of time considering they progressed on a smaller dose of Revlimid?

Dr. Robert Orlowski: Thanks very much. It's a very good question. The studies that led to the approval of elo and indeed many of these phase three trials that lead to approval are done not just within the United States but are done internationally. Practice patterns are different in different countries. So in some areas it is easier to find patients who have not been exposed to lenalidomide before or who were exposed but were sensitive and then had myeloma relapse off of treatment. So for the elotuzumab study you could not have lenalidomide refractory disease. What that means is that you could not have myeloma progressing on lenalidomide even a low dose to be able to get on that study. So the answer to your question is that we don't know how well elo/len/dex would work in somebody who's myeloma is progressing on lenalidomide at, say, 5 or 10 mg. I would think it's still worth trying. My prediction would be that the combination would work but probably not as well as in people whose disease is not progressing on lenalidomide.

Caller: Thank you very much.

Dr. Robert Orlowski: My pleasure.

Jenny: Great. Thanks for your question. We have another caller. Go ahead with your question.

Caller: Happy holidays, Dr. Orlowski and Jenny. This is Dana Holmes. Thanks so much for taking my call. Dr. Orlowski, I realized that the smoldering abstract didn't make the top 11 but I have a two-part question and follow up related to smoldering myeloma, so if you would just bear with me. My first question is if you could select one and only one of the available or soon to be available early treatment intervention clinical trials for high-risk to progress smoldering patient with a standard risk disease profile, for instance, 1114 translocation, what would it be and why? The follow up question is if you could design a dream high-risk smoldering trial, if you may, using either the available drugs or those still being tested, what would it be and why?

Dr. Robert Orlowski: Well, thanks very much Dana. I know we're followers of each other on Twitter. So keep up the good work.

Caller: Yes. We are. I always love your posts.

Dr. Robert Orlowski: You're right. The smoldering space, although there were some abstracts at ASH, I don't think any of them yet are what I would call practice changing which is why I didn't highlight any of them. Just to be a little bit on the advertising side, there is a national trial for smoldering myeloma which is comparing lenalidomide to observation. So that's one option to consider. In terms of what drug classes I think are also exciting, probably the antibodies are ones that I would really think of. There was a study with elotuzumab which finished enrollment. There is a study with daratumumab and then early next year here at MD Anderson we're going to open a study with isatuximab. So I think these are exciting because --

Caller: Isatuximab in smoldering myeloma?

Dr. Robert Orlowski: Correct.

Caller: Oh, okay.

Dr. Robert Orlowski: So the reason these are exciting is that, first of all, although the antibodies are not that convenient because it is IV and it takes a few hours to infuse, the side effect profile is relatively benign compared to some of the other chemotherapies because these are very targeted agents. If you take something like daratumumab or isatuximab, both of which have about 30% response rate in very, very heavily pretreated patients, you would think that if you give it to previously untreated folk, the response rate should be at least double, if not, higher. The other hope is that if patients do respond but then eventually progress because the antibodies are different classes of drugs, the myeloma would hopefully still respond to things like bortezomib and carfilzomib and lenalidomide and pomalidomide so there would not be any cross resistance. So those would probably be where we would like to go and where we are going. I think after the isatuximab study we also would like to learn from those patients, see how the drug affects the myeloma and the immune system, and build on that to develop some kind of antibody cocktail which would hopefully do even better than a single agent.

Caller: Dr. Orlowski, these antibodies, do they have more or less like a half-life? In other words once you give it, obviously, it's working in your body. But once you stop it does it typically then stop working? So would you need to continue the therapy if a patient, let's say in a smoldering stage, did respond?

Dr. Robert Orlowski: Well, the half-life of most of these antibodies tends to be on the order of 10 days to about two weeks. For those of you that don't know what half-life means, that means the time that it takes for half of the drug to leave the patient's body. It probably will be needed at least in the short run for patients to continue on dosing albeit with probably some reduced frequency. Let's be really dreamy here because you said fantasize about what the best studies and outcomes could be. It's certainly possible that if a patient achieves a complete remission and is MRD negative, that one could consider stopping the antibody and then just monitoring MRD and restarting if the MRD turns from negative to positive.

Caller: Okay. Lots of hope. I know Gary Petersen made you part of his dream team. So this is why I presented it to you as a dream trial. Thank you. Thank you for your response and thank you for what you do for the myeloma community, particularly for being so willing and available on the social media sites for patients. You're always so very responsive. Have a wonderful holiday, both of you.

Dr. Robert Orlowski: You too. Take care.

Jenny: Thank you so much, Dana. Thanks for your questions. Always great questions.

Caller: Hi, Dr. Orlowski. Thank you very much for a very informative session. Going back to the early versus delayed transplant, if a patient currently on car/pom/dex is in VGPR (very good partial remission), so the protein is detected but almost too low to quantify and close to a complete remission. Do you advise doing the stem cell transplant sort of earlier rather than waiting for relapse? A related question, the US part of that French trial is a little bit different. I understand the Revlimid is not stopped after one year. Do you expect a different outcome in the trial on the early versus delayed question?

Dr. Robert Orlowski: Well, thanks very much. Let me tackle the second question first. You're right. The French had a limited duration of maintenance whereas on the American side there is maintenance until progression. It's tough to know whether the outcome will be similar. That's part of why the trial is being done. By the way, we still need I think a couple hundred patients to finish enrollment on to that trial here in the US. So if any of you are newly diagnosed do think about that. In terms of the first question whether you should do a transplant if you're in VGPR after CAR and pom and dex, it's a little tough to sort of give a blanket recommendation without knowing more detail but in general the higher the response quality, the longer the time in remission. So if the VGPR can't be turned into a CR with more chemotherapy I think there's a strong rationale to think about adding the transplant at that point but I would need to know a little bit more about case to be sure.

Caller: Thank you.

Dr. Robert Orlowski: Thank you.

Jenny: Great. Thank you for your question. Dr. Orlowski, I had a question for you, just two quick questions. I saw in one of your articles that you posted in your paper -- and maybe I should mention this right now because you have a paper called Paperli which are online newspapers, and you have one where you poll different articles that are of interest to myeloma patients. Following that kind of gives you an idea of what's happening in myeloma. In one of those articles they mentioned that there was a specific gene that might indicate whether somebody responds or not. So are we getting closer to understanding which drugs may be better for which individual based on the genetics that they have?

Dr. Robert Orlowski: We are. We're not quite yet at the point where we can do these genetic tests and determine exactly what drug or combination is best. Actually if we go back to ASH, one of the interesting abstracts was about a panel of 14 genes whose expression could predict sensitivity or resistance to lenalidomide and were developing similar panels for bortezomib. I think that hopefully in the future what will happen is that we'll be able to use these biomarkers to better predict what combination is best for each individual. The advantage of that is that nothing right now gives 100% complete remission in everybody. To some extent even with standard therapies it's a trial and error. Let's try what we think is the best combination and see how it does. If we could predict ahead of time what combination is best we would be able to get more people into complete remission and we would do it more quickly because we wouldn't have to try something that wasn't going to work. Of course that would save money as well because why give somebody a chemotherapy if their likelihood of a complete remission to that treatment is low. We're not quite there yet. Give us a couple of more years and I think we'll be there.

Jenny: It sounds really exciting. I guess that follows into my last question. What do you see as a pathway to a cure for myeloma? People are starting to say that really publicly for the first time.

Dr. Robert Orlowski: Well, I think the immunotherapies, the antibodies and these CAR T-cells are probably going to be the things that hopefully get us there. So those with the chemotherapies and the stem cell transplant put together is going to be probably the package that we are able to get to make myeloma be a curable disease in the majority. I think we're already curing some but certainly not as many as we would like.

Jenny: Right. Well, we are so grateful that you took the time to explain everything for us today. It was an outstanding overview. As usual, you have a knack for really explaining things in a very easy to understand way for patients. So we thank you for that.

Dr. Robert Orlowski: My pleasure. Thanks again for having me. Once again, happy holidays to everyone.

Jenny: Thank you. Thank you so much, Dr. Orlowski, for joining us today.

Dr. Robert Orlowski: All right. Bye-bye.

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