Robert Z. Orlowski, MD, PhD
MD Anderson Cancer Center 
Interview Date: January 8, 2019

There is a tremendous amount of progress being made in multiple myeloma. It was stunning to see the significant work being done in the field of myeloma at the recent American Society of Hematology meeting in San Diego. We are very fortunate as myeloma patients to have the breadth and depth of new developments for our disease by a wide variety of companies. 

Myeloma expert Dr. Robert Orlowski of the MD Anderson Cancer Center shares his top 18 abstracts of 2018 and covers every stage of disease from early conditions like smoldering myeloma, treatments for newly diagnosed patients and options and clinical trials being run for relapsed patients. 

Learn why myeloma is being treated earlier and how researchers are working to prevent progression to active myeloma. Hear more about the status of immunotherapies - like BiTEs, CAR T treatment, antibody drug conjugates and others. Dr. Orlowski shares an incredible summary of topics to consider at each phase of disease in a clear and concise way. There is much to be learned in this valuable show. 

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. We'd like to thank our sponsor for this episode, Takeda Oncology and are very grateful for their dedicated support for the Myeloma Crowd Radio show.

Before we get started with this show (which is absolutely one of my favorites of the whole year), I'd like to just give you a brief update. Now, as many of you know, we've developed a tool called HealthTree and we went on a 50-city tour last summer and into the fall to share that tool with myeloma patients. We now have almost 2,500 patients using HealthTree, and the benefits of doing that is that you can understand treatment options that you can discuss with your doctor. You can find clinical trials that are personally relevant. You will be able to see reporting which we have started producing in there about patients who are participating in HealthTree.

In the future, you'll be able to find financial resources that you qualify for. You'll be able to also find and connect with patients who have similar features to you or maybe are treated at the same facility or in your same state or have your same genetic features and communicate with them. And then we have more features that we'll keep a surprise that we're building right now inside of HealthTree, but we're so excited about that project and are so grateful for your participation because it's only by patients really helping gather all the information about their situation and then sharing it with researchers that we can really help the researchers move their work forward.

We've also like to announce our second Myeloma Crowd Research Initiative funding three projects. We've now raised $104,000 out of our $500,000 goal, and we invite you to donate to those projects, and those will be complimentary to HealthTree and are also important projects in myeloma. We have three. Dr. Chung is studying the immune system status of patients and how that impacts their overall survival and progression of myeloma in addition to their myeloma genetics. Dr. Rodriguez is studying personalized 3D tumor modeling, so being able to take out your own sample of your myeloma with your bone marrow microenvironment and seeing which drugs are most affected against that. And Dr. Zhan who is studying the presence of CD24 on the surface of precursor stem cells that could be causing relapse. Each of these projects are completely unique and different and also add to the body of knowledge that we need in myeloma.

It is the beginning of a new year and we can't think of a better way to ring in 2019 with an overview of where we're headed with Dr. Robert Orlowski of the MD Anderson Cancer Center. He is always on the leading edge in myeloma research and is just so fabulous presenting it in such a nice way. This show has become our annual tradition and is, like I said earlier, completely one of my favorites. Dr. Orlowski, welcome to the program.

Dr. Orlowski: Well thanks, Jenny, very much for having me and I wanted to take the opportunity to wish everybody a Happy New Year and hope that this will be the best year yet in your journey through the process of myeloma.

Jenny: We hope so too. We're looking forward to what you're working on and we're so thrilled that people such dedicated and smart people like you are working on it for us. Let me give you just a brief introduction for you before we get started.

Dr. Orlowski is Professor of Medicine, the Department of Lymphoma/Myeloma section is the director of the myeloma section with the 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. He's a member of the NCI Steering Committee, Myeloma Tissue Bank Steering Committee, Computerized Provider Order Entry Steering Committee and BMT Myeloma Committee and American Society for Biochemistry. He is the Chair of SWOG which is a cooperative oncology group (the Southwest Oncology Group) that leads major clinical trials throughout the nation, not just in the Southwest but throughout the nation. He is also an editorial board of Hematology, the Journal of Clinical Oncology and many others. He has received many awards over a number of years including the LLS Scholar in Clinical Research award, the LSS Man of the Year award, the Emil Frei III award for Excellence in Translational Research from MD Anderson. They are one of the facilities that has probably the most clinical trials open in myeloma and has been the principal investigator on many of these and is the recipient of a coveted SPORE grant.

Dr. Orlowski, you had an idea of how would like to proceed with our theme for the year and I will let you do that and then fill in with other questions that I had, but this was a pretty good ASH that we just finished.

Dr. Orlowski: It certainly was. I thought that since this was the ASH in 2018, I would highlight 18 abstracts that I thought were interesting and could make a big impact on patient outcomes. I have them organized to start with the myeloma precursors which are MGUS or monoclonal gammopathy of undetermined significance and smoldering myeloma, then we can talk about what to do for initial therapy of newly diagnosed disease, a little bit about transplant and maintenance and then finish up first with relapsed myeloma and then finally with refractory myeloma.

Jenny: Sounds wonderful.

Dr. Orlowski: Let's start with the MGUS and smoldering space. Many patients who develop clinically active myeloma have one or the other of these precursors and there is a lot of interest in treating these patients especially if they have high risk of progression because the hope is that we can first of all prevent some of the problems like bone disease, kidney disease that could happen. And also there is a possibility that if we treat earlier, it might be easier to cure patients. One of the abstracts that I thought was interesting looked at using elotuzumab with lenalidomide and dexamethasone. This was from Irene Ghobrial's group at Dana Farber and they focused on high risk smoldering myeloma with this combination. At 36 months, 95% of patients were without progression to myeloma.

Normally, we would think that if these were high risk patients, about half of them would have progressed within two years. Now, with this therapy, 95% did not progress within three years. So it's not the same as a randomized trial but it sounds really attractive. Folks should know that there are other studies looking at this patient population which include studies with daratumumab which is an anti-CD38 antibody, also combinations like daratumumab with lenalidomide and dexamethasone and there also is a plan for a study of isatuximab which is another CD38 antibody with lenalidomide and dexamethasone.

For those of you that want to get involved in therapeutic trials, if you have smoldering myeloma, there are going to be a lot of options. Just really briefly, I'll put in a shameless plug for something we're doing at MD Anderson, Elizabeth Manasanch who is one of our other faculty here is running a neoantigen vaccine study. This I think is interesting because all of these other therapies we have talked about are chemotherapies with maybe some immune therapy added. But in this trial, what we're doing is we're sequencing the DNA and RNA in the myeloma cells were identifying the mutations that these cells have and then vaccinating patients so that their immune system is able to better attack those mutations.

I think there is two really cool things about it. Number one, this is a personalized vaccine because each patient will have different mutations in their myeloma cells, and so they will get different vaccines. The second cool thing is that these mutations will only be present in the myeloma cells and not the normal cells. Unlike chemotherapy which can have an impact on some normal cells, you should not have any side effects from this vaccine except for maybe just a little bit of soreness in the arm when you get a flu shot.

Jenny: That's completely amazing. I wonder, you're talking about I know early conditions, MGUS and smoldering myeloma. But other patients are going to want to try this too maybe even in people who are in a remission status. Is that going to be something that's available for them too?

Dr. Orlowski: It's a great question. We're looking first at patients who have smoldering disease because it's going to be easier to identify if there is an immune response which we hope there will be. If we see activity which would mean not just that there's an immune response but that there is a reduction in the amount of myeloma, then we would absolutely want to take this for example maybe after stem cell transplant to vaccinate again whatever leftover myeloma could be there.

Jenny: That is an amazing idea. I love this idea for the early conditions because like what you were saying, no side effects and personalized. It's just completely amazing. What a great idea.

Dr. Orlowski: Let's move on to folks that have newly diagnosed myeloma and there were quite a few abstracts that I thought were interesting. Let's start with initial therapy which often is either VRD (or bortezomib/len/dex) or KRD (carfilzomib/len/dex). There is an ongoing randomized study comparing them, the results won't be known for a couple of years but Ola Landgren did a registry study from the Multiple Myeloma Research Foundation’s CoMMpass study and they compared patients that got either VRD or KRD. This isn't as good as a randomized trial but at least it gives us an early peek of what it could be and there was a suggestion that people who got KRD did better with a lower risk of progression than if they got VRD. Keep that in mind if you're looking for therapy for newly diagnosed disease that maybe KRD at least for some patients could be better.

Jenny: That's Kyprolis, right?

Dr. Orlowski: That's correct.

Jenny: I mean for patients who aren't aware of that.

Dr. Orlowski: Correct. Sorry. We're used to using the generic terms because we're not supposed to use the trade names when we do continuing medical education talks. A second study that was also interesting in this area was presented by Francesca Gay. This was the so- called FORTE trial which was a three-arm study where one arm patients got carfilzomib with cyclophosphamide, dex and then transplant. A second arm, they got carfilzomib, lenalidomide, dex and then transplant. And then the third arm had carfilzomib, len, dex stem cell collection but no transplant and then followed with more carfilzomib, len, dex. They looked at what was the response rate and also the MRD or minimal residual disease negative rate.

Comparing the two transplant arms, people who got the KRD or carfilizomib/len/dex did better than people who got the carfilzomib/cyclophosphamide/dex. Definitely, len is probably a better drug in this setting than cyclophospamide. But the really interesting part is when they compared the people who got car/len/dex and transplant versus car/len/dex followed by more car/len/dex without transplant, the results were actually fairly comparable which suggests at least with the level of follow up that they had that it might be fine in some cases to collect stem cells and maybe use them later but not necessarily do upfront transplant right away. That may be something to think about for the future.

Jenny: Great.

Dr. Orlowski: The third abstract for transplant-eligible patients was the initial data presented by Pete Voorhees on the so-called Griffin study. The Griffin trial combined bortezomib/len/dex with daratumumab and this was just a small initial cohort. But if they included the patients who got VRD/dara, then transplant, then two cycles of consolidation VRD/dara and then maintenance, they had an overall response rate of 100% which is not unusual but 94% had complete response. Almost all the patients were able to achieve a complete remission which I think is really exciting because of course, if you achieve complete remission, then you probably have a longer time in remission and hopefully that will translate into a better overall survival.

Jenny: Yes, 94%. That's amazing. Just a reminder, this is for newly diagnosed patients. They're bringing daratumumab up front and using it at the beginning of treatment.

Dr. Orlowski: Exactly. Also, along those lines, there were two abstracts of daratumumab in transplant in eligible patients. One was an update from Thanos Dimopoulos on the so-called ALCYONE study. This was a trial where they did bortezomib, melphalan and prednisone with or without daratumumab. It's a combination (the VMP part) that is not that commonly used in the US, but they did show a more than doubling of the rate of responses. For example, in the progression free survival area, on the average, the people that just got VMP had 19.1 months in remission whereas even at 30 months with the VMP/dara, there were still 60% that had not progressed.

And so a big difference by adding daratumumab and similarly in the second that was presented by Thierry Facon which was the so-called MAIA trial. Here, they did lenalidomide and dexamethasone plus or minus daratumumab and they were able to show that the complete response rate which with len/dex alone was 24% went to 47%, essentially double the complete response rate if you added daratumumab. These will hopefully lead to more approvals of daratumumab in newly diagnosed patients. I think that this is clearly rapidly becoming one of our best drugs in the myeloma space.

Jenny: That was even without a proteasome inhibitor in that MAIA trial, right?

Dr. Orlowski: Correct.

Jenny: Lenalidomide and dex with or without dara, yes. Interesting.

Dr. Orlowski: There are studies on their way looking at VRD plus or minus dara and also VRD plus or minus isatuximab. I think we'll have those four drug combination data hopefully in the next couple of years also.

Jenny: Do you want to comment on four drug combinations because there is some concern. I know when they tried to add the fourth drug like cyclophosphamide or something like that, it didn't really provide a lot of benefit and provided more toxicity. But when you're giving something like daratumumab or some of these other monoclonal antibodies, that's not necessarily the case. You're not necessarily adding more toxicity, right?

Dr. Orlowski: You're exactly right. The cyclophosphamide, when it was added as a fourth drug, there was maybe a modest improvement in outcome. But because it's a cytotoxic drug, the amount of side effects and toxicity that it added really was not acceptable. With antibodies, and this includes daratumumab and isatuximab and elotuzumab, all of these mainly really only have the infusion reaction as a risk that can happen with sometimes the first infusion but usually not later, so the amount of added side effects that you're adding are modest whereas the benefit is really dramatic.

Jenny: It's wonderful to see that happening and bringing it closer to the front of treatment.

Dr. Orlowski: Now, there were a couple of abstracts about stem cell transplant and maintenance that I thought were interesting. One was an analysis from the Michele Cavo, one of the Italian myeloma specialists, that looked at several studies that had been done in Europe comparing a single to a double stem cell transplant. They combine the data again from several studies. They concluded that the double transplant was better than the single transplant overall, but it seemed that the major benefit was in patients with high risk disease who also had high stage according to the international staging system stage.

There is a suggestion from this analysis that if you are high risk, that maybe a tandem or double transplant is better. I think the main weakness of the data are that those studies that they put together did not include some of the regimens that we talked about earlier. For example, bortezomib/len/dex/carfilzomib or len/dex and daratumumab. None of these combinations were included in those trials, and so that suggests that maybe a second transplant was a benefit simply because the amount of myeloma reduction from the initial therapy and first transplant were not as good as could be achieved with better therapy.

Jenny: Is that just a factor of the availability of drug combinations in Europe versus the United States?

Dr. Orlowski: You're right about that. Many of the drugs become available first in the United States and it takes a little bit longer for them to be available in Europe and also there are some differences in patient populations who can get a transplant in Europe versus who cannot. Usually in Europe, if you're over 65, you're generally excluded from getting a transplant whereas in the United States, we still do transplants even in 70 and sometimes in 80-year old patients as long as they're otherwise pretty healthy.

Jenny: That makes sense.

Dr. Orlowski: The other abstract in this space that I thought was interesting was presented again by Thanos Dimopoulos. This was the so-called TOURMALINE study where they took patients after transplant and randomized them to maintenance with ixazomib which is an oral proteasome inhibitor or they got a placebo. This study was mostly done in Europe and there was a five-month improvement in time to progression for patients who got the ixazomib as oppose to the placebo and more patients improved the quality of their response after transplant if they got the ixazomib versus if they only got the placebo.

[Ninlaro_mobile_ad]

This is, I think, a positive study. It does show we for example have people who cannot get lenalidomide-based maintenance. Sometimes it's because of rashes or other reactions. Sometimes it's because even with low dose lenalidomide, they have low blood counts and can have problems with infection. These data will hopefully allow us now to use ixazomib as a maintenance in those people. In some cases, for example with high risk disease, we would probably think about recommending the combination of lenalidomide and ixazomib. We actually did a study of that combo here at MD Anderson was presented at the 2017 ASH meeting and we're trying to write that up and submit it as a manuscript so that the data would be available to everybody. But that's a nice regimen because both of the drugs are oral, so it's very convenient for patients to take.

Jenny: Right. It sounded like there has been some study also about the use of a proteasome inhibitor specifically for high risk patients. Do you want to address that at all?

Dr. Orlowski: There was a study looking at bortezomib, len and dexamethasone from Sagar Lonial's group at Emory. This was a single agent trial, so it wasn't randomized but the data did look good and certainly using bortezomib with len would be a good option as well. Of course, the ixazomib is a little bit easier because you can take it as a pill instead of having to get it as an injection. Also you mentioned SWOG earlier. We have a trial that will be opening probably in the next couple of months through SWOG for maintenance which will randomize patients to either lenalidomide or to lenalidomide with daratumumab. And then the other nice thing on the study is that for patients who are MRD negative after two years, we're going to have some of those patients stop therapy because we think that maybe if you're MRD negative especially over two years that perhaps you might do so well that continuous maintenance would not be needed.

Jenny: That's such an interesting idea. First, using daratumumab as maintenance therapy because I haven't heard a lot of that. And then also being able to decide who can potentially stop maintenance therapy and who can because there is no drug I think that has zero side effects.

Dr. Orlowski: You're definitely right. People are always happier when they're off of chemotherapy even if it's a very well-tolerated drug or combination and of course there is always the benefit of not having to go back and forth to get the drugs and reduce the cost because you're not schlepping to the doctor as often.

Jenny: I know that maintenance therapy has proven to extend progression free survival and overall survival in a lot of instances. I just wonder, is there any issue in creating resistance by being on a therapy for a long period of time. Is that ever an issue? 

Dr. Orlowski: Well, so far, what we have seen is that patients who progress on maintenance can still have good responses to other therapies but we do have to typically change the drugs that are being used. It may be in fact as you say that there is some resistance which is occurring and fortunately we have enough other drugs to use that that doesn't become as much of a problem.

Jenny: Right. It might just be great if somebody is MRD negative and then they end up stopping the maintenance if that might help in the long term. But I guess you have to be really careful with knowing who will progress and who won't and that's tricky to figure out.

Dr. Orlowski: Indeed. Let's move to the relapsed myeloma setting. These are people who usually have had one to three prior lines of therapy and sometimes they have progression off of treatment. I think there were four abstracts that I thought were interesting. One was a presentation from Daniel Auclair from the Multiple Myeloma Research Foundation. They used a questionnaire to try to identify what factors were important to patients in their therapy. The main things they looked at were various side effects as well as what benefits could be achieved. When they crunch the data, they actually found that there were generally two groups of patients. One group really preferred that their therapy avoid the risk of side effects. The second group were people who wanted to get the maximum benefit in terms of time and remission and were willing to accept more side effects.

I think we could probably predict that ahead of time, but the really interesting thing is that there were no patient characteristics that predicted which patient would fall into each of those groups. For example, one might suspect that maybe older patients would be less willing to take the risk of side effects, but in fact age was not a factor in identifying these patients. Although we need more data in this area, what this really argues is that health care providers need to do a better job of talking to patients about what they want from their therapy rather than assuming that oh, Mrs. Smith wants X and Mr. Jones wants Y because we may not be able to predict that and it's important that everybody is involved in the decision-making process.

Jenny: Absolutely. Some of this might be personality. Some people are just more aggressive about the care that they get and they're more proactive and I have noticed that too that some of it is just personality and that's regardless of age.

Dr. Orlowski: Definitely. Patients have the right to decide what issues are most important to them and what therapies they want.  Years ago, we would only have one or two things to pick from. There wasn't much of a point to have that discussion. But now, we've got so many different options that I think patient opinions are always important but now are even important than ever because of the number of options.

Jenny: I think it really stresses the importance of patients to become well-educated about their disease because it's really tough to have intelligent conversations with you in the clinic if you haven't done a little bit of homework because your expertise level is so deep that you can help patients identify things based on some of these preferences. But unless they understand what the options are, that might be available to them. It's very difficult for them to ask the right questions of you, so you can help them get to the right answers. I think there is some weight on us as patients and it doesn't seem fair that we need to learn more about our disease, but I think it helps.

Dr. Orlowski: Well, just as with anything, if you go out and buy a car, most people will do some research to try to figure out which car fits exactly their needs and look at the price and what features the car has and is it likely to breakdown or not, and the same thing needs to be done when you're picking between different cancer therapies. Hopefully, one of these days, what will happen is we'll have something that will cure everybody and then it'll be an easy decision but we're not quite there yet. In the meantime, we have to pick between different options.

Jenny: Some are decisions between good, better, best. There are a lots of good options.

Dr. Orlowski: Going back to relapsed myeloma in terms of treatment options, just three more abstract to cover. One was from Hartmut Goldschmidt in Germany. They looked at using either a second transplant or lenalidomide and dexamethasone continuously if people have relapsed after one to three prior therapies. The interesting conclusion from their study is that actually there was no significant difference in the progression free and overall survival between those two options. I think that shows how effective the chemotherapies now can be in the relapsed setting that oftentimes they can be as good or better than a second stem cell transplant. There are other studies that are looking at this question, so we may see different answers in the future.

Two others very quickly both had carfilzomib in them, one was from Pieter Sonneveld and they looked at carfilzomib with pomalidomide and dexamethasone which had an 87% response rate. And then from Dr. Costa who is over at University at Alabama Birmingham, they looked at venetoclax with carfilzomib and dexamethasone. The overall response rate there was in the 70% to 80% range. But if you had the 11;14 translocation, venetoclax is an especially good drug for those patients and that combination had a 100% response rate. This is one of the first drugs where it's really important for patients to know what molecular abnormalities they have because venetoclax really works incredibly well in people with this 11;14 translocation but it isn't clear if it makes a huge difference in people without that abnormality. There are additional studies that are being done to look at that, but keep in mind, you should know for example what your FISH results are because those are the tests that look for the various chromosome changes that you can see with myeloma.

[Pomalyst_mobile_ad]

Jenny: Well, I couldn't agree more. I think patients needs to know what kind of myeloma they have and add that to HealthTree in great detail. You can add your FISH test results and you can add a Gene Expression Profile test if you have that done or even very rarely a Next Generation Sequencing test done because those things change over time, don't they?

Dr. Orlowski: Definitely. I'm glad you brought that up. The FISH results that you have for example at the time of diagnosis can sometimes be different if you repeat that test at the time of relapse or later on. You shouldn't assume that the myeloma that you have now is the same that you had a couple of years ago or that it will be the same as you will have a couple of years from now.

Jenny: Right. It's so important. A lot of people are confused by it. I think probably 80% of patients don't really understand their myeloma genetics very well. And so we put together a questionnaire that you can download that's on the homepage of HealthTree and take it to your doctor and say, "Help me understand my FISH test results," or "Can I get a copy of my FISH test results, so I can see what these are?" I think something that came out at ASH that I noticed too was that somebody was talking about -- let's say you have a deletion 17 and you have done an incredible amount of research on deletion 17 as well and that the percentage of a genetic mutation may indicate higher risk versus a lower risk. Let's say you have a lower percentage. It's not just the genetic feature that you have, but potentially how much of it you have.

Dr. Orlowski: You're right because for deletion 17p as you mentioned, there are studies that show that if only 5% of your myeloma cells have deletion 17p, that's a better situation than for example if you have 60% of your cells with deletion 17p. I wasn't going to mention this, but since you brought it up, what the heck. I'll do a shameless plug.

Jenny: Go for it.

Dr. Orlowski: We did have a laboratory abstract that we presented. This isn't a clinical trial yet, but it looked at a drug which is called an antibody drug conjugate which seemed to have increased activity against deletion 17p models of myeloma in the lab compared to the normal 17p myeloma model. We're going to try to move that to the clinic probably in the second half of this year. But if we could see similar results in the clinic, that would be great because deletion 17p is one of the bad prognostic signs. If we could kill those myeloma cells more easily than the normal cells, that would be really a huge advance for myeloma patients.

Jenny: Right. Which antibody drug conjugate is this?

Dr. Orlowski: Well, this doesn't have a name yet. It's called HDP101. Hopefully we'll see some activity, we can come up with a cool sounding name for it.

Jenny: The names are always a little bit confusing. Going back to Dr. Costa's study about venetoclax, I overheard someone say that he was saying the venetoclax might actually boost carfilzomib. Is that true or what do you think about that? 

Dr. Orlowski: Well, there is certainly a possibility. What the venetoclax does is it blocks a protein that helps the myeloma cells to survive. And so it should make other chemotherapies work better, but we really need to randomize study to show that. So far although there are those kinds of studies on their way, we have not seen the data yet.

Jenny: It's interesting.

Dr. Orlowski: The last area to cover is relapsed and refractory myeloma. These are usually people who've had more prior lines of therapy and often their myeloma is growing on treatment. There were two abstracts looking at selinexor which is one of the newer drugs or small molecules. Actually, we hope that it will be approved by the FDA sometime in the spring. One of the studies that was presented was by Ajai Chari looking at the STORM II trial which was selinexor and dexamethasone. It had a 26% response rate although 3/4 of patients had at least stable disease or better and people stayed in remission on average for about four months. Even better was adding selinexor to daratumumab and dexamethasone which had an almost 80% response rate and a much longer durability and that was presented by Cristina Gasparetto. I think that definitely selinexor is a drug that can help a lot of people although it does have some GI effects which include nausea, decreased appetite and fatigue as well as decreased platelets. It's not the easiest of drugs to give, but it can be managed in the right setting.

Jenny: Just a question about selinexor. Do you have an anticipated timeframe where selinexor -- I know they're still going through clinical trials and then it's hard to tell, but just curious if it's coming to the clinic sooner or later or when that might happen.

Dr. Orlowski: Well, we're hopeful that it will approved in the spring by the FDA. If that's the case, then usually the drug can be available within a few days or a few weeks of the FDA approval. I guess the big question and I don't know the answer to this is whether the current partial government shutdown may not impact the FDA timeline. Hopefully, it won't.

Jenny: Let's hope not.

Dr. Orlowski: Two other categories of drugs that I thought were interesting in the refractory setting, of course, we've heard a lot about CAR T-cells. Most of the studies are targeting BCMA or B-cell maturation antigen which is a protein on the surface of the myeloma cells. There were updated data presented by Dr. Zhao from the Nanjing Legend study in China where they showed an overall response rate of 88% and patients stayed in remission an average of two years if they got into complete remission and were MRD negative. Of course the Nanjing Legend folks are now working with Janssen and that study will be available in the United States.

There also were data about a different BCMA CAR T-cell presented by Krina Patel from our center. This was working with a company called Poseida. The I think really attractive thing about their product is that it had a very low risk of cytokine release syndrome which is the main side effect of CAR T-cells, and this was present in less than 10% of patients. Their response rate at the highest cell dose was also essentially 100%. Then finally, there was a presentation from Dr. Jang of a CAR T-cell pharma company called CARsgen which had a 100% response rate.

The nice thing about their technology is that the chimeric antigen receptor was made from a fully human antibody. The nice thing about that is that we think that you really want these CAR T-cells to be present in the patient as long as possible to keep the myeloma away. Because they used a human protein, it's probably less likely that the cells will be eliminated by the patient's immune system than some of the other CAR T-cells which are using mouse-based proteins to which people will probably react more.

Jenny: Can I ask some follow up questions about the CAR T?

Dr. Orlowski: Sure.

Jenny: It seems like there are so many companies jumping into this space. A lot are going after the BCMA target. It's becoming obvious that not all CARs are the same in the way their production like what you just said that the human antibody with this CARsgen company. How long do you think it will be until we can identify which CAR might be the best? I know everyone seems like they're duking it out right now. That's one question. Then the second question would be have you seen a lot of CAR T studies starting to add a second CAR, would be an appropriate strategy to say we'll go after BCMA but then we'll go after something else in addition?

Dr. Orlowski: Yes. Both great questions. In terms of the first one, I think it's probably going to be a few years before we know which CAR T-cell is best. You're right in saying that there are many differences between them. For example, we talked about using a human antibody versus a mouse antibody, but there are also parts of the CAR gene that are different inside the cell, inside the T-cell and there are also differences in how that gene gotten into the T-cells and all of these studies right now are just looking at the efficacy of that one construct and not comparing it with other CAR T-cells. I think unless there is an obvious difference where hopefully one of these will cure everybody. Although right now, unfortunately, that doesn't look like it's the case. I think it's going to be a few years before we know which ones are the best.

Now in terms of your second question, combining CAR T-cells, certainly just like one chemotherapy drug can be enough to kill lots of myeloma cells but probably not cure people and combinations are the way to go. I agree that combinations of CAR T-cells against different targets will probably be the best way to go. Right now, we don't know for sure what the next best target is other than BCMA because you want to pick a target which is on the myeloma cell and hopefully not on too many normal cells because the T-cells can't tell the difference between a normal cell and a cancer cell. If you pick a protein target which is also a normal cell, then you're at risk that there will be normal tissue damage by the CAR T-cell. It's a little bit tricky and I think it's going to be a little while before we have combinations.

But the last abstract I wanted to definitely mention is there was an abstract by Dr. Topp looking at a BCMA BiTE. The bite is spelled B-I-T-E and it stands for bispecific T-cell engager. This is like an antibody except that normal antibodies have two binding sites that are identical. But this one has one binding site that binds BCMA, and the second arm, if you will, binds to a T-cell and it brings the myeloma cell and the patient's own T-cell together. The T-cell becomes activated and then kills the myeloma. They did show at the dose that they recommended for further testing that there was a 70% response rate (seven out of ten patients) and many of those patients had complete remission and were MRD negative.

There are a few advantages of the BiTE over a CAR T-cell. The main one is that right now, it takes two to four weeks or more to manufacture the CAR T-cell. In the meantime, the myeloma can be growing which of course is not a good thing, whereas the BiTE is off the shelf. You don't have to wait. You can get it tomorrow if it's available once its FDA approved. And so the fact that the response rate and durability look quite good I think is exciting.

Jenny: I have questions about that because lots of patients call and say, "I'm trying to get into a CAR T trial." We have been telling him also that, "Yes, go ahead and apply and get your name on these different waiting list," because there are more CAR T trials opening but these BiTES are looking really interesting. From what I'm reading, it looks like they might give CAR Ts a run for their money. As a physician and an expert, how do you help patients pick if they're going to join a clinical trial, they're highly relapsed and they're looking to get into one of these studies. Do you say, "Go for the BiTE," as a strategy to bridge to a CAR T? Is it equally effective? I just don't know how to answer those questions.

Dr. Orlowski: Those are all great questions and we unfortunately don't yet have great answers. The problem with using a BiTE as a bridge is that right now, most of the CAR T-cell studies exclude patients who have had prior BCMA directed therapy. The rationale is that if you had a BiTE or an antibody drug conjugate against BCMA that may be the mechanism of resistance will be that your myeloma cells don't make BCMA anymore in which case the CAR T-cells are not going to be able to recognize the cancer. The rationale is good, but it seems that most patients who relapse so far still have BCMA on the surface of their myeloma cells.

Hopefully in the future, what will happen is that there will be a little bit more flexibility in those criteria. I would say for right now, if you're lucky enough to have a choice between a BCMA BiTE and a BCMA CAR T-cell trial, the main thing to look at is whether this is still in the phase one portion where they're still trying to identify the dose or whether the dose being used of either the BiTE or the CAR T-cell is already one at which activity has been seen. If it's in the point where activity is being seen, then as far as I'm concerned, it's basically a coin toss. I would do either one or the other because they really both look great at this point and it's going to be a while before we know which one is better.

Jenny: Compare the CAR T and the antibody drug conjugates. Do you have a preference, one over the other or the same comment?

Dr. Orlowski: Pretty much the same. There is a BCMA antibody drug conjugate from GlaxoSmithKline that people are really excited about and hopefully will be approved soon, had a 60% response rate in previous studies and showed good durability. Really, I tell patients it depends a little bit of course on what your disease is like because if you've got progressive myeloma that's growing slowly, then a  CAR T-cell is okay because even if it takes two to four weeks to manufacture the cells, if your myeloma is growing slowly, that won't be a problem. But if your myeloma is growing rapidly, it could be that you don't have the two to four weeks to wait and that maybe then doing a BiTE which is off the shelf or an antibody drug conjugate which is off the shelf would be a better idea. That's one factor to consider.

Jenny: BCMA seems to be the target. In your opinion, are there any other targets that should be -- or companies or facilities should be going after in addition?

Dr. Orlowski: Well, there are some other targets that look attractive, but the drugs that are going after them are not as far along. But for example, SLAM F7 which is the target for elotuzumab is relatively preferentially expressed on myeloma cells and rarely on other cells. That would be a good target. There are probably some others but not enough data yet to know for sure which one is the best other than BCMA.

Jenny: That's remarkable, it's happening, I think. It's really amazing. Did you finish 18? That's a lot.

Dr. Orlowski: I did actually. Thank you.

Jenny: It's amazing. You did it so beautifully and so easy to understand. It's amazing, that's why I love this show. We'll be including some extra editions in terms of explaining some terminology that we might have gone over, but you had an incredible amount of information to go over. Is there anything else that you want to highlight at MD Anderson before we open it up to caller questions?

Dr. Orlowski: I mentioned some of the things we were doing in smoldering myeloma. We also have CAR T-cells for relapsed refractory disease as well as now we're moving them earlier in the disease process and we also will have studies with these BiTES and lots of other immune therapy. Our commitment is always to hopefully have the most exciting therapies on clinical trials available to patients so that both people here locally in Houston and Texas and folks who are able to come from further away and stay for some period to get clinical trials would have the best options available. Of course this time of a year, it's relatively warm here.

Jenny: That's always a bonus, a good reason to come. I want to point out that what you talked about in the last several studies are all relapsed refractory myeloma. These are not in the clinic yet. Some of these drugs like selinexor and the BiTEs and the CAR T, they haven't been approved yet. Really, if you want these therapies and you're in that situation, you really need to look at clinical trials.

Dr. Orlowski: Very good, I agree.

Jenny: Well, let me open it up for caller questions. If you have a caller question for Dr. Orlowski, you can call 347-637-2631.  Go ahead with your question.

Caller: Hi, Dr. Orlowski. Thank you for your really comprehensive overview of the research at ASH. I really appreciate it. One question I had was what's the best strategy of a patient to get into a CAR T trial? It seems to be one of the more promising clinical trials out there. I have a family member with myeloma and I'm just wondering how I could help them with that.

Dr. Orlowski: Well, thanks very much for advocating on behalf of your family member. I think you heard from Jenny earlier that oftentimes the best strategy is to contact several centers and get on waiting lists at several sites because different centers will have different trials. Even when they have the same trials, there may be slots available at one site and not in another. That's really the best way to try to get on the list for the CAR T-cells is to make sure that you've got as many shots on goal if you will as possible.

Caller: Thank you.

Jenny: Thanks for your question. I had a follow-up question about that. There seems to be a lot of CAR T trials that are facility initiated. Some of the bigger facilities like yours and some others seemed to be working on your own CAR T trials. What's the progress of those and then how do you choose as a patient compared to the drug companies CAR T trials for example? That's a little confusing.

Dr. Orlowski: Great question. There are some centers including, as you mentioned, ours that are working on making CAR T-cells on site. Part of the benefit of that would be hopefully a more rapid turnaround so that the cells would be available more quickly and that would be helpful to people whose disease is growing more rapidly because you don't want it to go unchecked for too long a period. Most of those studies are still fairly early because this is a therapy which is not inexpensive to make as you can imagine.

And so most of the trials that are out there are company sponsored studies but I would definitely recommend that patients ask if they're talking about a clinical trial of a CAR T-cell at one of the sites. They should of course find out who the sponsor is and get information if it's a CAR T-cell being made at that site, get information on how much experience they have, how many patients have been treated, what the side effects have been and what the response rates have been so far because not every BCMA CAR T-cell trial is showing similar activity. There can be differences.

Jenny: We had a write in question actually before the show from Benjamin. He asked “I’ve read that the time to manufacture the CAR T could have an impact on a response. Do you want to address that at all? Like a window of a four week or a two week or less than that manufacturing process and then how do you see that changing over time?

Dr. Orlowski: That's actually a very interesting question. We don't know the answer yet, but one could maybe think about is what happens is the T-cells of the patient are taken out and the manufacturing which was done in the laboratory either on site or of the industry partner. The T-cells have to be expanded so that you have enough T-cells to infuse back in. If the T-cells expand very, very slowly, that could be a concern because when they're infused back in, they have to again be able to be stimulated and to expand when they find the myeloma cells. Theoretically, it could be possible that if the cells grow very slowly in the laboratory, they could also grow very slowly when they're put back into the patient and then the benefit against the myeloma might be less. But we don't know that yet for sure and that's certainly something we need to follow up on.

Jenny: Well, I think all that will come out over time and it's so exciting to see what is happening. Just the ability for you to cover 18 amazing abstracts and what we have to look forward to in the coming year is in my opinion really remarkable.

Dr. Orlowski: I also wanted briefly to say that if folks have other questions, feel free to email me directly. I give out my address. It's rorlowski@mdanderson.org.

Jenny: Perfect. Thank you so much for being so available and thank you so much for participating on this show today. You do a tremendous job at distilling really complicated information into such a simple way for us, and we really appreciate the overview and what we have to look forward to in 2019. Truly amazing.

Dr. Orlowski: It's my pleasure. Thanks very much for having me and thanks for putting all of this together as well as everything else that you do to support patients and research in myeloma.

Jenny: Well, we're just so impressed with people like you who are just driving the research  forward and can't thank you enough for your work. Thank you.

Thank you to our listeners for listening to Myeloma Crowd Radio. We invite you to join us next time to learn more about what's happening in myeloma research and what it means for you.