Dr. Jatin Shah, MD, MD Anderson

Interview date: January 10, 2014

Dr. Shah describes his focus at MD Anderson to overcome drug resistance and provide ways to use new therapies to further expand the capacity of existing drugs that work well today in myeloma treatment. He shares several options for patients who are resistant to Revlimid and entirely different approaches for patients who are resistant to Velcade. In several instances, new drugs are being used in open studies can "reactivate" the resistant drug so that it can be used once again in treatment. He shares a large number of approaches for both newly diagnosed patients that include new and more convenient oral-based options, a non-transplant approach using the monoclonal antibody elotuzumab with a common combination (RVD), and a pre-transplant approach using this same combination (RVD) with a new drug called panobinostat that has shown promise in refractory patients. For relapsed or refractory patients, he shares the good news that the carfilzomib and pomalidomide combination has the same benefit for high-risk patients as it does for low-risk patients and a new drug called filanesib (also called ARRY-520) shows effectiveness for patients with minimal options because of drug resistance. Also for relapsed patients, he describes a early approach using a new oral PIM inhibitor called LGH447 (without steroids!) He also shares a new approach to shut down the Wnt pathway to make existing drugs more powerful and reviews the most interesting findings of ASH. With so many options, how is a patient to choose? Dr. Shah gives recommendations about how to choose a clinical trial that is the right drug, that is right for you, at the right time. He dispels myths of participating in a clinical trial and suggests how patients can become more educated to maximize the use of time with the doctor for their very best care. 

The live mPatient Radio podcast with Dr. Jatin Shah

Jenny: Welcome to today's episode of mPatient Myeloma Radio, a show that connects patients with myeloma researchers. Happy New Year, everybody! We had a nice break and hope you did as well, and now we are on to 2014 with a full year of new therapies and clinical trials for multiple myeloma.

So just a few things to mention before we get started: If you'd like to hear about the very latest in the series in a weekly email, we invite you to subscribe to our mPatient Minute newsletter. Just go to the home page of www.mpatient.org to sign up, and you can find our links to our Twitter and Facebook pages there as well.

I'd also like to mention that we've created new Facebook groups that are subdivided by some genetics. As we have been talking with researchers and finding out that myeloma is not a single disease, we thought that we may be able to help share discoveries by subtype. So for example, if you have the 11;14 translocation or a gene 17 deletion or MGUS or smoldering myeloma, there is now a group for you. And I've gotten some requests for a light chain only group, a Waldenström macroglobulinemia group and a plasma cell leukemia group, so I've added those as well. But please feel free to join the groups that apply to you and post any research or information you find to help the whole group benefit, and you can find these on the home page of www.mpatient.org on the sidebar.

Now, there was a flood of information that came out of ASH in December, and we are very fortunate to have with us today Dr. Jatin Shah of MD Anderson who had many, many papers that we're presented at ASH, and he is extremely active in running clinical trials. In fact, we had to postpone this interview in order for him to have the time to prepare.

So, Dr. Shah, welcome. We are so pleased to have you with us.

Dr. Shah: Thank you so much. It's a pleasure to be here, and I appreciate the opportunity to come talk about what all the advances in myeloma have been over the last years.

Jenny: Well, they're significant. So let me give a little introduction for you before we get started. Dr. Shah is assistant professor in the Lymphoma/Myeloma Department, Division of Cancer Medicine at the University of Texas MD Anderson Cancer Center in Houston. He is also the Associate Program Director for the Malignant Hematology Fellowship, the Director of Myeloma Clinical and Translational Research, and is on the Multiple Myeloma Tissue Bank Steering Committee at MD Anderson. He received the Young Investigator Training Course Award from the South Western Oncology Group in 2012, has written numerous papers and is the principal investigator on many myeloma studies, many of which we will talk about today. He presented much of his research at ASH which we will discuss.

So Dr. Shah, maybe for those who aren't familiar with ASH and what it is, can you give us a brief overview of what that conference is all about?

Dr. Shah: Certainly. So ASH is the abbreviation for the American Society of Hematology. It's an international meeting that occurs every year in December and very well-attended with 20,000 to 30,000 folks that come from around the world to talk about all the advances and research that's ongoing in different hematologic malignancies including different leukemias, lymphomas and myelomas as well. It's an opportunity for us to both share the data that's done as well as understand and communicate with other oncologists and collaborators about the research that's ongoing.

Jenny: And this is the first year that I actually attended ASH, but the target is specialists or hematologists or oncologists, right?

Dr. Shah: That's right. So there are educational sessions that are there for various healthcare providers, but it's predominantly healthcare provider driven.

Jenny: And the information is presented in a few different ways. So sometimes I saw that people present their information in an oral presentation and sometimes they present their information by creating a poster and putting it in a hallway and standing next to their poster and are available to answer questions, which I thought was easier to understand than many of the biology sessions which were completely over my head.

Dr. Shah: Yes, there are multiple different types of sessions that are ongoing continuously with different meetings, talking about basic sciences and very basic science research, translational research and then clinical research as well. So I think it really targets a number of different researchers and investigators.

And you're right, there are different forums to present the data, and the way it works, there are thousands of abstracts or short synopses of research that are presented, and then they cull them down and what we think are the most important or relevant research items are presented in an oral session where we have 15 minutes to present in an oral session and in detail the research and then give opportunities for folks to ask a few questions at the end of that oral presentation. But as you can imagine, there's limited time and so really a few of the research items are presented in this setting.

The majority are presented again, as you mentioned, in these posters where the data and the research information is presented on this large poster, and everybody can have time to review it and ask questions and share information or discuss ideas. So there are a couple of different formats how this data is disseminated.

Jenny: Well, it was a very valuable and helpful conference, and it made me realize how little I actually know about myeloma. A lot of people have covered it. I know IMF has covered it, MMRF has covered it and other organizations like the Cure Panel had a post on it. From your perspective, what do you see as the most valuable information that came out of ASH because there was much to see there.

Dr. Shah: There is. As you mentioned because it was very difficult to process all the new information that comes out of ASH, as there are literally hundreds of different abstracts are research that's presented in myeloma alone, and so there are a number of different meetings that happen after ASH to share what we think are the most important things.

I think there are a number of things that come out of ASH this year, and we can talk about this a bit more but some new data in newly diagnosed myeloma, some trials and research in relapsed myeloma. There are some updates on the maintenance therapy options that we have as well as new drug options that are being developed as well, including monoclonal antibodies targeting CD38. That was very exciting. We didn't see any data at ASH but we also heard about the panobinostat PANORAMA trial which is also positive, and so that was exciting as well and so we look forward to getting more information about that and then other new drugs as well.

Jenny: Well, why don't we start in with the research that you're doing at MD Anderson. I'm not sure how you want to approach it, but maybe we should start by talking about patients in categories, like newly diagnosed patients and what MD Anderson is doing and what you're working on for them.

Dr. Shah: Certainly. So I mean I think when we talk about newly diagnosed myeloma, we can talk about two different things. I mean one, we can talk about what we -- again, it's not exhaustive, but we can talk about what happened in ASH as well as what's going on here.

Jenny: Sure.

Dr. Shah: So one of the things that we saw at ASH are some exciting new data in newly diagnosed myeloma and the first one was the FIRST trial. That was a very large trial, the largest trial that we've ever done in myeloma, and looked at patients getting Revlimid and dexamethasone for 18 months, (for again newly diagnosed) versus continuous Revlimid and dexamethasone where folks take it and they're tolerating it or responding well with stay on Revlimid and dexamethasone continuously. And that's the first time that we've seen that type of data.

We talked about continuous versus short-term or definite amount of time. It showed that continuous Revlimid and dexamethasone had an improvement in survival, progression-free survival for patients. And so I thought that was an important piece of information that was presented at ASH for the first time really showing that continuous Revlimid and dexamethasone was of benefit to patients.

The other important piece of information that came out I think is a very intriguing piece by the Spanish group that looked at sequential therapy versus concurrent or sequential therapy which basically patients normally would get VMP or Velcade-based therapy for one cycle then a Revlimid-based therapy and alternating back and forth. And usually what we normally otherwise do currently is use Velcade therapy until we have some side effects or it stops working, and then we'll switch over to Revlimid or some other therapy or either vice versa. This is the first time that we've done sequential therapy where they alternate every other cycle and they compare that to our standard approach and showed that to be a very reasonable approach as well. So I thought that was an interesting piece of information as well. Those are two examples.

Jenny: Does that minimize the side effects?

Dr. Shah: It did. I think that was interesting thing there that with the alternating therapy, there was I think rather similar toxicity between the two arms. But that was interesting because it gives us an option now as we're trying to basically make sure as you mentioned earlier that there's different subsets in myeloma. They all respond to different drugs. So here's a way of trying to make sure we get all of the good drugs into our patients without giving it all at the same time because if you give them all at the same time, it becomes too toxic or too tough on patients. So if we can alternate therapies, we're getting our best therapies into patients.

Jenny: And did that have an impact on whether you become refractory to that drug or not?

Dr. Shah: So we don't have that information quite yet.

Jenny: That would be the next step maybe.

Dr. Shah: Exactly what happens after our patients progress, and how they will respond to subsequent therapy is important.

So coming back to what we're doing at Anderson, one of the couple of trials that we're looking here at Anderson as well as nationwide: There's a trial looking at high-risk myeloma patients. There's a trial with SWOG as well as Intergroups at multiple sites around the country including here is looking at RVD or Revlimid-Velcade-dex with elotuzumab, and elotuzumab is a monoclonal antibody that looks and targets CS1 on the cell surface of these myelomas.

So that's I think a potentially important way of targeting high-risk myeloma. I think as we move forward, these monoclonal antibodies may be a very important way to target high-risk myeloma and this is the first step in that, and so that's an important trial in patients with high-risk myeloma.

Jenny: And this is independent of a transplant or before transplant or not including one?

Dr. Shah: That's a great question. That's not including a transplant. The role of a transplant is controversial in high-risk myeloma. I think there's still a role for it, but this trial does not include transplant as part of that. You can certainly collect stem cells for transplant in the future, but it's not intended as part of the primary therapy.

Jenny: I was reading some things about elotuzumab and compared to maybe daratumumab or another monoclonal antibody, and it looks like elotuzumab works better in combination rather than alone. Do you want to explain how that works?

Dr. Shah: Yes, certainly. I think all these monoclonals are very different. They have a different target and a different way of attacking myeloma. So I don't think one can compare one to another. I think they're all going to be important options for our patients and are going to be really change the paradigm in terms of how we think about and how we manage myeloma.

So you're right. I think elotuzumab by itself, we're not sure how active it really is. We're still trying to get a better idea in maybe some patients with smoldering myeloma if elotuzumab by itself may be active or not. But I think really, the important part with the elotuzumab is in combination with Revlimid, it appears to be highly active and also very durable. And so what we see is that patients in the phase II trial had a prolonged benefit controlling their disease with a combination of Revlimid, dexamethasone and the elotuzumab. I think that's the exciting part where oftentimes Revlimid and dexamethasone will keep the myeloma in remission on an average of 11 months or so; where with the addition of elotuzumab we are extending the remission out two and three years where patient's disease is controlled, I think it's a major improvement for patients.

Jenny: Before you go the next one, you said it targets CS1. Can you explain what that is?

Dr. Shah: Certainly. So when you look at myeloma cells, on the surface of the myeloma cells, there's a little protein called CS1. So what this elotuzumab does is it's also a protein and it basically binds or targets only CS1. So it will go to wherever CS1 is and we know it's on these myeloma cells. So it only binds to that and then will, in combination with Revlimid, kill those myeloma cells. It's very targeted. It doesn't go and attack every other cell in the body. It doesn't go affect any other cell other than those that affect CS1, and myeloma cells we know have a high concentration of CS1.

Jenny: And then for high risk, how are you defining high-risk patients? Just so people know if it would be appropriate for them or not.

Dr. Shah: Sure. So there are a number of different things that we look at to identify high risk. For example, plasma cell leukemia is one, and that's when you start seeing circulating plasma cells in the blood and not just the bone marrow; high LDH and that's a blood parameter or blood level that we look at; and there are a number of chromosome mutations or translocations that we look at. Those are pretty specific tests when you do your bone marrow biopsy and we do these chromosome analyses and FISH analyses looking for these mutations. There are certain ones that could be identified including deletion of 17 for example or translocation of 4;14. Those are rather technical but that's something that when you meet with your physician, you can discuss those, but those are commonly seen when the bone marrow biopsy is done.

Jenny: Well, thanks for explaining that because I don't want them to be as technical as they are. I want people to know about the deletions or translocations that they have because I really think that if they don't know they should go ask their doctor what they are because now that you are starting to look at things like this and subdivide people, I think it's going to be very helpful for people to know their disease biology.

Dr. Shah: Exactly. I think the challenge is that it's a constantly evolving field to understand what is high-risk side cytogenetics or what is high-risk disease. So I think the key is to have that conversation with your physician saying, "What are my chromosome mutations or what is my chromosome's karyotype or what do the cytogenetics show on my bone marrow biopsy? Do I have a high-risk disease?" And have that conversation with your physician. And if so, then how do we treat this differently or not differently? And so I think that's an important part of the conversation to have with your own physician.

Jenny: Thank you for sharing that. I totally agree.

Dr. Shah: Another option that we're looking at in newly diagnosed myeloma hereis RVD plus panobinostat. I think that's RVD or Revlimid, Velcade and dex is an important combination for newly diagnosed patients, and so we're trying to build upon that saying that's a good option for patients, but how can we do better? How can we improve or increase the chance of patients getting into a complete remission?

We know that majority of patients respond to RVD, but what we're trying to go after now is those patients in the complete response and trying to improve the complete response rate. And right now with RVD, that's after four cycles of therapy, that's going to be around the 20% to 30% range, and we want to try and do better than that.

And so we have a trial with RVD plus a drug called panobinostat, and we know that panobinostat is active especially when we combine it with Velcade in relapsed myeloma, and that was the exciting news that came out of ASH that the Phase III trial, where half the patients got Velcade and steroids and half the patients got Velcade and steroids plus panobinostat, show that panobinostat was improving survival and outcomes. So it was a positive trial. It was an active drug, and it was an important drug. So now we're looking at panobinostat in a newly diagnosed setting saying can we recapitulate that and trying to get better responses for our patients going into a bone marrow transplant. So that's one option that's I think unique to what we're doing here, trying to improve about what we think is an important standard of care with RVD.

Jenny: And so can you explain what panobinostat does and how it works?

Dr. Shah: Certainly. So panobinostat is a class of drugs called HDAC inhibitors, and basically what these do is modulate or affect the myeloma cells and how they work. What they do is in combination with the Velcade makes the myeloma cells more sensitive to the Velcade. Or if the myeloma cells are refractory to Velcade where Velcade no longer works, it resynthesizes the myeloma cells to Velcade. So it reintroduces that as an opportunity to use Velcade again and help patients if they have responded previously with it.

Jenny: I think that's remarkable because sometimes you hear about the drugs, well, if you've exhausted one drug, then you have to move on to others. But being able to go backwards and say let's go to a drug that was working and make it effective again is pretty critical.

Dr. Shah: It is. Really there are two main ways that we can move the myeloma field forward, and one is developing new drugs that work differently, things like the ARRY-520 that we'll talk about later or other drugs like the monoclonal antibodies and this panobinostat.

The second way is recognizing we have very good drugs as it is right now for example with Revlimid and Velcade, and they are effective but not for all patients. And so how do we make those drugs better? Or if patients become resistant to those drugs and those drugs no longer work, how do we understand why they become resistant and overcome that resistance? And that's an important area of research here at MD Anderson and both of those are in a targeted fashion saying, "How do we understand mechanisms of resistance and then overcome those?" And panobinostat is important I think with both of those. So that's the trial that we have right now from newly diagnosed patients.

The other trial that we have right now that just opened up that we're very excited about is an oral proteasome inhibitor. We have Velcade which is an injection in the stomach as well as an IV administration. There's also carfilzomib which is an IV administration. And now we're trying to develop an oral formulatation where patients can just take this pill version called oprozomib, and it's similar to one that is a Velcade oral formulation called ixazomib.

And so now those are oral proteasome inhibitors now that are being developed. And so at ASH, we saw some data with newly diagnosed myeloma patients getting an all oral combination of ixazomib, Revlimid and dexamethasone, and that was very exciting because I think it makes so much easier for patients now to receive therapies and take therapies as opposed to coming to the doctor's office very frequently. It becomes another important option. We're looking at one now with oprozomib, Revlimid and dexamethasone, and that trial just got launched in the last few weeks. So we're very excited about that option for patients as well.

Jenny: Well, that makes a huge difference for the quality of life for patients to not have to spend so much time in the clinic.

Dr. Shah: Exactly. I think we still need to better understand how well-tolerated it is and how active it is. But you are absolutely right. I think this could be a very important step forward for quality of life for patients.

Jenny: Well, it impacts you physically and emotionally too. I was just in the clinic most of this week, so I know. Is there anything else you would like to share for our newly diagnosed patients?

Dr. Shah: The other trial that's also ongoing right now is this large international trial as well called the IFM/Dana-Farber trial where we're looking at everybody getting RVD. The trial basically looks at patients getting a transplant right away as part of their initial therapy or collecting their stem cells and doing a transplant later when they have fallen out of remission. It's an early versus a delayed transplant approach. So that trial is also ongoing here at MD Anderson as well as multiple sites around the country. That's a very important trial, a high priority trial in the myeloma community to really answer that question of when is the right and optimal timing for a transplant, and so that trial is also ongoing as well and a high priority trial.

Jenny: Is that trial also looking for whom transplant is beneficial? Because if you have these different types but everybody in just “myeloma” and you're not dividing them in new subgroups at all, can you say, okay, we're going to use Revlimid, Velcade and dex and then trying the transplant. It would seem like it would be hard to get the data accumulated if everybody – maybe deletion of 17 has a different response to a transplant than gene addition of one or I don't know. How does that work when you look at that data?

Dr. Shah: Yes. So I think right now, you're right. That trial is really to answer the question of the optimal timing of a transplant. I think that right now we feel that transplant is an important part of how we treat myeloma patients. We have decades of experience with transplant really showing it's a very effective way of treating myeloma patients. But also, to me the benefit of a transplant is not only in controlling their disease initially but the durable responses. And so that means that what's my best chance of having control of my myeloma and staying alive for not just one, two, three, four years but for ten years and beyond, and that's where we have data with long-term durable responses with transplant that we don't have with other therapies at this point in time saying, "Can we get long-term survival?"

That's what we're trying to do is say in my mind, when I'm talking to patients, there's lots of ways we can control disease initially. What I'm more worried about is what's my best chance, five and ten years down the road of still being alive, still doing well, and benefiting from additional therapies? That's what I think the role of transplant plays for us right now.

And so it still becomes an important part of how we approach myeloma, but I think your question is right in terms of which patients benefit the most from transplant and which patients may not benefit and do not need a transplant, and I think that's where high-risk and that plays more of a conversation in high-risk myeloma where I think it's debatable with the role of transplantation in that setting.

And there are no trials right now that are ongoing that look at risk stratifying patients and then saying transplant or no transplant. We haven't gotten to that point yet. But I think it's a very important question that needs to be answered.

Jenny: It's probably a completely different study, but we love that you're looking at this, about how long to extend our disease-free experience.

Dr. Shah: Exactly.

Jenny: That's a great thing to look at. So thank you.

Dr. Shah: So that's it I think right now for newly diagnosed myeloma, and I think that will continue to evolve over the next year, but that's our current approach and clinical trials that are ongoing.

Jenny: Do you want to move into the next category?

Dr. Shah: Sure. So I think this is, again, where we talked about earlier, and I think there are a couple of different approaches to relapsed and refractory myeloma. One is again new drugs with new targets and then overcoming resistance and saying how do we overcome resistance, and then continue to use our therapies that are already available that could be very effective. And so I think we're excited in relapsed myeloma because right now, just in the past year, a year and a half, carfilzomib has been approved for relapsed myeloma as well as pomalidomide as well. Last year as well it's been approved for use in relapsed and refractory myeloma.

There's a trial that was presented at ASH and that's also ongoing at Anderson and several sites and that's a trial of carfilzomib, pomalidomide and dexamethasone. We are combining those two drugs for the very first time, and that's showing very, very exciting activity in patients with very heavily pretreated myeloma and it's going to be a very active combination.

And importantly, when we looked at patients with high-risk cytogenetics or high-risk disease, we have a very similar response rate or activity in those patients as well. So oftentimes, patients with high-risk disease may not get the same benefit from some of these therapies, but with a combination of carfilzomib and pomalidomide, those patients have the same benefit as everybody else, both in how well they respond and how long they respond. So I think that was very exciting.

IFM or the French Group also presented data with pomalidomide in high-risk disease and also found that pomalidomide can be active as well just with pomalidomide and dexamethasone. So think there are some very exciting data with both of those drugs in relapsed myeloma. So that trial and preliminary data was presented at ASH and that trial is ongoing in Anderson as well as a few other centers around the country.

The other area now as we move forward is developing a new class of drugs. One such example, previously called ARRY-520, is now called filanesib. So that's a completely new class of drugs. It's independent from our Velcade and carfilzomib class of drugs and our IMiDs like our thalidomide, Revlimid, pomalidomide, and it works in a very different way.

And so there's updated data that was presented at ASH where filanesib by itself or in combination with dexamethasone was active and really I think for the first time showed activity with a different class of drugs outside of what we've talked about. So that was very exciting to see that in patients who no longer responded to the Revlimid, Velcade, carfilzomib, and pomalidomide, and really have very few options that this became an important option for about 20-25% or a quarter of the patients. So I thought that was exciting.

And then we presented some data in a poster format as well at ASH looking at the combination of carfilzomib plus filanesib, and there's also data presented with Velcade plus filanesib as well. I think both of those are very exciting combinations that we can safely combine those two drugs and that they're very active. And so that trial is ongoing right now at MD Anderson where we're combining carfilzomib plus filanesib without any steroids, which makes it very attractive for patients.

Jenny: Yes, it does.

Dr. Shah: And so that has been very well-tolerated. Patients have done very well on that. There are some side effects that we see with that combination with some low blood counts that can be managed. But for the most part, folks are doing very well with it and tolerating very well and showing it to be an active combination. And so in fact, that's supporting a large phase III trial that's going to be opening up internationally with carfilzomib with or without filanesib, and that's going to be opening sometime in 2014. There's also another trial of filanesib that's going to be opening as well by itself this year as well.

I think those are very exciting data that was presented at ASH with a new class of drugs that's active and the ongoing trials now and that are planned in the future, which will hopefully provide benefit to more patients.

Jenny: Can you give an explanation of how filanesib works, what it does and so on?

Dr. Shah: Certainly. So again, this works very differently from our current class of drugs. It basically works by stopping the myeloma cells from dividing. So as these myeloma cells grow and then divide, as they begin to divide, it stops them in that process so they no longer divide. And once they stop or are frozen in that process, then those cells will die. So basically it just stops the myeloma cells from growing and dividing.

Jenny: I saw on their website that they have a video that explains how that product works. So I think I might include that. (Watch the video about filanisib to better understand this KSP inhibitor)

Dr. Shah: Exactly. There's a very nice video about that.

Jenny: And then are there other studies you want to talk about?

Dr. Shah: Oh, certainly. I think having that positive data from the PANORAMA trial I think was very exciting. It really rejuvenated interest in HDAC inhibition in myeloma, saying this is a very important target. So I think as we move forward from here, there's a trial ongoing here of carfilzomib plus panobinostat, again saying can panobinostat make carfilzomib work better as well.

And so there was data presented at ASH of that combination. Would that similar combination with a slightly different schedule, how the panobinostat was administered but that was done by the Sarah Cannon group, and that looks very promising. Similar combination trials were done with Emory and we have one as well here with a slightly different schedule with panobinostat that's given for the first two weeks and then off for two weeks.

I think an exciting advance and data, confirming this is an important target, targeting HDAC inhibition, and this is an important drug that's active and now we're looking at it in different combinations both in newly diagnosed, as I mentioned, as well as now with relapsed myeloma.

Those are I think a couple of important combination trials where data was presented at ASH and trials are ongoing here was well. Another important in the relapsed and refractory setting with the trial at MD Anderson is called LGH447. This is a PIM inhibitor. It's again a different class of drugs entirely where it's a different way of targeting myeloma and targeting myeloma cells. And again, that's very early on in the Phase I trial, so it's not as advanced as the panobinostat or the filanesib but I think it shows some very interesting data. We're seeing some signals of activity where it may be active in myeloma as well. So that becomes again another important option as well for patients. Again, that's an oral pill that you take every day without steroids. I think it's an important option at least from a clinical trial perspective for our patients as well.

Jenny: And that's also been used in lymphoma, right?

Dr. Shah: That's right. I think it's looked at in multiple different blood cancers including lymphomas and leukemias, and that trial is available here as well as other centers around the country.

I think the other data then that becomes interesting now, there's an AKT inhibitor. So there are multiple different targets and different drugs being developed. There's an AKT inhibitor that's also being developed as well, not at MD Anderson, but I think it's an important option for patients.

Other ones include the monoclonal antibodies which we have not touched upon yet. I think that's probably one of the more exciting areas as well in myeloma as we move forward.

So we talked about elotuzumab a little bit.

Jenny: Yes, talk about that.

Dr. Shah: Yes. We talked about elotuzumab in combination with Revlimid and dexamethasone. So that looks very exciting. I think additional data that was presented at ASH is daratumumab and this target, the CD38. And again, this is a same type of concept with the elotuzumab where if you look on the surface of those myeloma cells, you'll see a protein called CD38 and these monoclonal antibodies are basically smart drugs that target only CD38 so they don't affect any other organs and just target CD38 and bind to CD38 and then kill those myeloma cells. So what you then do is minimize some of the other side effects that we see with most of the other chemotherapies like the nausea or the vomiting and the hair loss or the diarrhea or whatever else can happen. So this really avoids some of those other toxicities and really by being targeted for CD38.

And so daratumumab, I think, is an exciting monoclonal that's being developed. There are others as well that are being developed that also target CD38. So there's a drug by Sanofi called SAR. That's also a very exciting monoclonal antibody targeting CD38, and also showing clinical activity as well. It's an important option hopefully in the future. And there's another drug called MorphoSys 202, again targeting CD38 as well. So I think there are three different monoclonals now that are being developed, targeting the same CD38, and very exciting as we move forward.

Jenny: Well, can I ask you a question about CD38 first? So I know in other cancers, I think it was CLL where they had one protein that was expressed, so they developed one monoclonal antibody for it and then it works really well for that. But with myeloma, it sounded like there were more targets. So is CD38 always presented in myeloma or not always presented? Or can you explain that a little bit?

Dr. Shah: Sure. So there are many, many different proteins on these surface cells. So for example in CLL and lymphoma, there is a protein called CD20 that's on there. Rituxan is a monoclonal antibody that targets CD20, and that's been now in use for many years now and been very active both by itself as well as in combination with chemotherapy. And that really had probably the biggest impact in lymphoma patients that we've had in the last 20 years. That drug alone had a significant improvement in curing lymphoma patients and prolonging survival for CLL and lymphoma patients. So I think there's a long track record of these monoclonals being very effective and important options.

And so when we come back to myeloma, CD38 is expressed on all myeloma cells. Both in newly diagnosed and relapsed myeloma patients, and seen commonly on all myeloma cells. So that I think is an important target.

There are other proteins as well that are expressed on myeloma cells, and some monoclonal antibodies are being developed for those other targets as well. So I think there are multiple different monoclonals. These two are probably the farthest along at this point of time.

Jenny: Well, I think all patients are excited about monoclonal antibodies because they're used as your own immune system essentially with the help of this drug to specify the target and, like you were saying, not get as so many side effects as you're going through treatment.

Dr. Shah: That's right.

Jenny: So they have long-term data on that?

Dr. Shah: I think that's what we're missing right now. I think what we know right now is that's active, patients respond to it. We're getting some complete responses with it and some very nice responses with it. So we know it's an active drug. What we don't know is how durable these responses are, and so that's yet to be seen. I think over the next few years we'll understand how durable these responses are. We'll get more information about combination therapy as well as they start combining these CD38 monoclonal antibodies. They're all going to be very important options for us. The daratumumab is the farthest along but the other ones are very quickly catching up. So I think all three of them are going to be all important options for our patients.

The bottom line is that over the next few years we'll get a better understanding of how durable these responses are as well as in combination. We have more and more experience of that. We already have some experience with it, but I think we'll get more experience.

So I think that's going to be very exciting data when it comes out over the next few years. There's going to be lots of clinical trial options that are going to be open to patients here at MD Anderson and elsewhere, looking at both all three of those. So I think patients should keep an eye out for those.

Jenny: Well, it sounds very exciting and it's wonderful that the progress is being made in the way it is.

Dr. Shah: The final thing, I'll quickly mention about that, again talking about overcoming resistance, there's something unique. I think one of our biggest areas of focus at MD Anderson has been understanding the mechanism of resistance and overcoming resistance. And so one of the things that we found is that this pathway called the Wnt/beta-catenin gets upregulated or overexpressed in myeloma cells; and when that happens, those myeloma cells become refractory or resistant to Revlimid.

And so we're looking at ways of targeting this Wnt pathway and suppressing it, and one way of doing that is potentially thalidomide. Thalidomide can suppress Wnt. We did a trial that's already been completed and presented at ASH last year, not in 2013 but in 2012, looking at the combination of Revlimid, thalidomide and dexamethasone. So interestingly combining for the first time two IMiDs in this relapsed setting of giving them at the same time, and what we found is that it's active and does show activity in relapsed myeloma, and that's including the patients who are refractory to prior Revlimid, so where Revlimid stopped working, by introducing the combination of Revlimid plus thalidomide, some patients were able to benefit from the combination.

So I think we can't definitively say that it was the thalidomide suppressing Wnt because it was not a large randomized Phase III trial, but that was I think very interesting data where we combine the data, combine the two IMiDs, and we're seeing some interesting activity there. I think that's an important option for patients.

Building upon that, another important drug that also suppresses Wnt or downregulates Wnt is called ATRA. ATRA is an old drug. It's been around for many years now and used in different leukemias and very active in APL and it's actually a very potent suppressor of Wnt. We now have a clinical trial here at MD Anderson, and unique to MD Anderson studying this combination of Revlimid, dexamethasone and ATRA. And right now it's for patients that are resistant or refractory to Revlimid, but we will open it up soon, if it's active, to patients who may or may not have had Revlimid before. But that's an important way of targeting mechanism of resistance, and this is just one way that we're approaching resistance. So we look forward to learning more about that combination.

Jenny: And its primary function is to suppress Wnt?

Dr. Shah: That's right. And so when we look at ATRA by itself in myeloma before, it really wasn't active by itself. So again, we're not looking at using ATRA to kill the myeloma cells directly. What we're looking at is suppressing Wnt and, therefore, making those myeloma cells more sensitive to the Revlimid. We have a very good drug with Revlimid. Let's see if we can reuse it or make it work better. And so that's the rationale behind the combination there.

Jenny: Good. Okay, that sounds like a good one. I know you have other studies, but is there anything else you would like to talk about in the relapsed and refractory group?

Dr. Shah: I think that's a pretty good flavor for what's ongoing right now. The other trial that will be coming up in the near future is that same oral proteasome inhibitor that we've talked about, oprozomib, where we're looking at it with Revlimid and dexamethasone in a newly diagnosed setting. We're also having a trial with that oprozomib plus pomalidomide and dexamethasone in the relapsed setting as well. So that's going to be another oral combination with oprozomib and pomalidomide and steroids in relapsed myeloma.

That trial is not open quite yet but should be open in the next month or two, and so we're excited about that option as well for patients. Again, building upon the carfilzomib and pomalidomide experience and trying to improve the quality of life for patients and we're trying to get it to an all oral combination.

Jenny: You have a lot going on. I see why you're so busy. So I have a question because I have a friend who actually traveled today to your facility because he is relapsed/refractory and some of his drugs are not working. I know he will get a very nice review and some recommendations while he is there. But with all these targets, how do you choose as a patient between all these different approaches?

Dr. Shah: Yes, that's a great question. I think that what's helpful to understand is first of all what drugs have we already tried before, how active were those drugs or not active were they, and then what side effects did you have on those. Those are the two important things in terms of if you had a very long response to Velcade for a long time but then Velcade stopped working, well then, that's important to know as opposed to if you only got Velcade for one or two cycles and then quickly progressing, you never responded to Velcade versus I responded for a long time to Velcade, then it stopped working. The second important piece of information is to know what side effects that you have from that therapy, or other complications from that that makes it prohibitive to go back to that. So those are all important I think when we just talk about prior therapies.

And then we start looking at clinical trial options and what are options that we look forward. Those become important to understand what are your refractory to what worked but then you may still be sensitive too if we try and do it again or if we do different combinations. Those become important options.

Each trial is designed differently. If you have Revlimid refractory disease, then options include Revlimid plus ATRA or we can move on to pomalidomide-based therapy or the carfilzomib-pomalidomide-dexamethasone combination for Revlimid refractory patients. If you're Velcade refractory and we didn't mention these two trials earlier and I apologize about that, but there are ways that we're targeting Velcade-refractory disease and that includes two trials. One is Velcade plus ACY-1215, which is another HDAC inhibitor.

As we talked about panobinostat and we looked at carfilzomib plus panobinostat, there's a trial of Velcade plus ACY, and that's an important option. Maybe we can overcome Velcade resistance with this combination. So that's an important option for patients. There's another class of drugs which target CDK inhibitors and there's a drug called dinaciclib that we're looking at in combination with Velcade and some very interesting data there as well. So potentially, if we want to try Velcade-based therapies, then we can try Velcade plus dinaciclib with the goal to try and do better than Velcade alone with these combination therapies.

I think it's really helpful to understand what prior therapies have been there, what are the side effects, what are the important options and then how do we build upon what we think is what we want to go from. You're right. It's very challenging because there are multiple different trials and combinations, and I think that's important to have that conversation with the physician.

I think the biggest thing that I can emphasize is when you are trying to make some treatment decision plans is to be as educated as possible and ask that question when you're in the room and when you are talking to your physician, specifically what are all my treatment options, what are my clinical trial options, and it's an important to ask that specific question because that starts that conversation and gets everybody thinking about not just standard of care options but also clinical trial options as well.

Ask that question, and if you've done some research saying, "Hey, I read about this combination. Can we talk about that? Is that an option for me? If not, what are other options for me? And go through all of the options with me." I think the more engaged you are, the better.

And I think of this side note when we talk about patient care and trying to get the best out of your visit to MD Anderson or anywhere else when you see a physician, I think it is something to bring a caregiver with you and write down all your questions before you come, and then write down the answers as you go through it because I think oftentimes we'll talk about a lot of information, but it becomes overwhelming when we're talking about so much information with a patient because they have lots of questions and thoughts and concerns and they forget questions, they forget answers that they may have already had. And so we see that commonly where I know I had a couple more questions where I forgot what they were.

Write all of your questions down when you come in. Bring a caregiver with an extra set of ears that can listen and remember and recall what we've talked about, and then write down some of those answers that we talked about or have the physician write down some of those answers. So that way you can really maximize your time and really feel comfortable leaving and thinking about it over the next few days as you mull over your options.

Jenny: Okay. Well, that's a great suggestion. As a patient, I felt the exact same way. I will get to my appointment and their time is limited, and you know that and you want to respect it. And so if you start talking about something and then you feel like your appointment time is gone, it's very easy to forget the questions that you have.

So as a patient, I decided that we needed to come up with a solution for this. So I built a phone app that is now in the app store, the Google Play store and the App Store called – there are two. One is called Chemo Brain Doc Notes and the other is called My Doc Notes, and it allows you to when you're thinking of that question that you want to find out about, you type in your notes and it can be in a variety of categories. And then when you get your appointment, if you want to go through your notes, you can. You can record it in voice memos and text memos. And then if you want to, you can also record your visit to go back to it later because I know most of the time sometimes I go to the visit and I can't remember what was said and the terms are so foreign that it's just too confusing.

So anyway, that has been built now for patients if they would like to use it. I'll be sending more information about it, but I think this suggestion is a great one because you really have to use that time very, very wisely with your doctor.

Dr. Shah: So this is just a way of being as efficient as possible and then maximizing that time.

Jenny: So I have one final question. This whole series has been based on the importance of participating in clinical trials. So my last question before we open it up to caller questions is how do you feel about patient participation in clinical trials?

Dr. Shah: That's a great question. I am very passionate about improving outcomes in lives of myeloma patients. And so there are many ways of doing that from providing great patient care to answering questions for patients to being supportive of patients.

Research is the other way that we improve the outcomes and lives of myeloma patients to improve how well patients respond to therapy, and increase survival. Clinical research allows us to push that envelope so that we have more and more options for patients. The best example I can give is really for many years, from 1940s, '50s, '60s, '70s, '80s, '90s, we really had no new drugs for myeloma, and we only had the drugs that we still use now for example, melphalan and Cytoxan and dexamethasone, and people lived on average one to two years. And then with a transplant, people lived three and four and five years. It really was in the last decade, the last 10 to 15 years that we've had all these new drugs.

And so that has what's improved outcome now where patients are living five, six, seven years. We're having more and more 10-year and 15-year survivors. That's all based on these new drugs. That progress has been made because of patients participating on clinical trials.

And so these are patients that have participated on clinical trials and led to these new drugs being improved and they are helping current and future patients. And so I think that's very important to understand and appreciate how we got to this point. But also it's important to understand what clinical trials are, and I think we can all appreciate the value of clinical trials and lead to where we got today. But I think there are a number of things that we need to educate our patients about what clinical trials are, and there are lots of myths, and I think the biggest barrier to participating on trials is understanding what the myths about the clinical trials are.

So for example, patients may state, "I don't want to be a guinea pig" or "I don't want to take a placebo or a sugar pill" or "Any clinical trials are only when I run out of all options." "Why would I do a trial? Am I running out of options or there's nothing else for me to do?" And that's really an unfortunate myth. Another myth is "Phase I clinical trials are for brand new drugs and I don't want to do Phase I trials because they don't know anything about those drugs."

And so for example, the RVD plus panobinostat is a Phase I clinical trial. So that really takes into account a couple of things. One, we have a clinical trial for a newly diagnosed patient, so it demonstrates that trials are not for when you run out of options. This is the Phase I trial in newly diagnosed patients. So again, with drugs that we know are active, everybody gets RVD which we know is active. We're trying to build upon that, thinking can we do one step better with a drug that we know it's already active in other settings, and so we fully expect it to be an active combination and the question what is the right and safe dose with this combination.

So that gives an example of here's a Phase I clinical trial for newly diagnosed patients and breaks down some of those potential myths of clinical trials that are only for the end or Phase I's are experimental completely and I don't want to do those. Well, here's an important Phase I option for newly diagnosed patients. And so I think it's important to if you have hesitancies or concerns or questions about trials to ask them and say, "I have a concern about clinical trials because of this," or "I heard about this," and try to have that conversation so that way we can be much more informed because oftentimes your best option may be on a clinical trial and you don't want to miss that opportunity.  That’s the same thing with a transplant.

Many patients are concerned about doing a transplant, and that's perfectly reasonable because that's a big fear of the unknown or starting chemotherapy, and what we do is educate our patients and empower them and say, "This is the information," and that way they can make a more informed and educated decision. When we do that about transplant, patients are much more comfortable going through a transplant or chemotherapy, and the same concept has to apply the clinical trials because there is a fear of the unknown. Not only chemotherapy and the diagnosis but now we're going to do a clinical trial and it just adds another degree of uncertainty. So we have to try and do a better job educating our patients, and patients need to ask those questions and try and learn more. If we do those, I think we can certainly move the field forward together.

Jenny: Well, sure. I mean it's less than 5% of patients. It's more like 3% of patients are participating now, and if we doubled or tripled that number. I think that could dramatically impact what you're trying to do is help us find a cure.

Dr. Shah: Exactly, and we'd move the field even faster forward.

Jenny: I agree. Well, that's the whole reason we're doing this. So thank you.

And I would like to open it up for caller questions. So if you have a question about Dr. Shah's research, you can call 347-637-2631. And once you are on the call, you can press 1 on your keypad.

Jenny: Please go ahead.

Caller: Hi, Dr. Shah and Jenny. Thanks for having me on. By the way, a very articulate conversation so far and it's been a pleasure to listen to the dialogue.

Earlier in the interview, Dr. Shah, you talked about a therapy that had a complete response but I didn't get the name of that. What therapy was that that had a complete response? You brushed over it quickly, so I didn't write it down.

Dr. Shah: That's a great question. Thank you. I think in fact, when we look at newly diagnosed model, there are many combinations. So I don't want to give the false impression that this one combination or this one drug led to complete remission while others have not. I think what we're trying to say is that there are multiple combinations if you look in the newly diagnosed setting with RVD leading to complete remissions, and we're trying to improve upon the complete remission rate or the chance of getting into a complete remission by adding in panobinostat or other drugs.

And so I think when we look in the relapsed setting, clearly, Velcade has led to complete remissions so has Revlimid. And when we combine the drugs together, we can increase a chance of complete remission. When we look at Velcade plus panobinostat, there are patients that go into complete remission with that as well. So I think any one of these combinations, some lower, some higher, but can lead to complete remissions.

The monoclonal antibodies have also led to very nice remissions as well. So we'll get some very nice deep responses as well. So I don't want to give the impression that one is better than the other. I think all potentially can and the goal of all the other therapies is to improve that chance.

Caller: Okay. That's helpful clarification. When I look at the numbers on the papers and it talks about overall survival and progression-free survival, so a complete response doesn't mean the percentage of respondents. It's just somebody is getting a complete response. So what percentage of activity gets you excited as a researcher? Does 75% of patients that have a response rate, is that meaningful? What's the percentage? Is it 10% or is it anybody in terms of what moves the bar?

Dr. Shah: That's a great question. You're right. As you look at these hundreds of abstracts and hundreds of different clinical trials and data, and they present these numbers and say this is exciting data, what really is exciting and what's not exciting? And I think the challenge is there's no one answer for that, and it varies for every disease state and patient population that you're looking at.

So for example, in newly diagnosed patients, I think with the three-drug combinations of carfilzomib, Revlimid and dexamethasone or Revlimid, Velcade and dexamethasone, or any of these kinds of three-drug combinations, the overall response rate we expect to be very high in that 90% range. And so then we get interested in the complete response rate because now we're trying to push the envelope there and say we're not happy with the 20% or 30% complete response rate. And with carfilzomib-rev-dex, we're getting 60% and 70% complete response and near complete response rates, and that becomes exciting. And so that becomes a more important endpoint in newly diagnosed patients.

When we look at the relapsed setting, when we look at trials with patients who have one to three lines of therapy and that's the patient population they looked at, I expect a higher response rate. But when I start looking in patients who are refractory to everything, so for example filanesib, within that specific trial, those patients were refractory to everything; and in that setting, I'm willing to accept a lower benchmark because I know that's a much more difficult disease to treat.

And if 20% of patients are responding, that becomes exciting because I know that as I move that forward in one to three lines or newly diagnosed, those response rates will go up just like they did with carfilzomib. So I think it just depends which patient population we're looking at. If I'm looking at Velcade refractory patients, and I give you Velcade plus panobinostat and 37% of patients respond or 30% of patients respond, that becomes exciting.

So I think it becomes tricky to say here's the benchmark that you need to look at. I think it depends on which patient setting and which you're refractory to. So I know it's not the answer you're looking for but just trying a little bit to give more insight about why it's so complicated.

Caller: Do you look at biology of the disease in combination with response rates or do you just say it's myeloma? Or do you think if you look at an 11;14 genetic mutation and say it's 70% with that, but whatever, another one, 11;14, but another one, but that one is 10%, do you ever look at it horizontally and look at it across the genetic biology of the disease? Or is it just I have myeloma and I got 20% response rate and 30% here?

Dr. Shah: So we do that with the larger trials. As we look at some of these mutations, only 10%, 15%, 20%, 30% of patients may have a specific mutation. And so if I look at a smaller trial, there may only be five or six, seven patients with a translocation 11;14 in the trial. So it becomes difficult to interpret that data saying unless 100% of the patients with 11;14 responded and did fantastically well and is distinctly different and none of the patients responded with the others, unless you have a pretty wide or significant difference.

But for the most part, you can have smaller numbers of patients in each subset and it becomes difficult in the smaller trials, I think it becomes helpful when you look at the larger Phase III trials with several hundred patients and then you're going to get more substantial numbers to look at to make some more conclusions.

Again, it's difficult in that setting because these are not designed to look at specifically 11;14 so you can only look at that retrospectively, but there are no specific trials if you're looking. What I would think would be the next best step is for patients with specific mutations, this is the trial design just for you. We have not gotten there just because of the difficulty with the small number of patients to accrue and try to answer that question. But you're right. That should be the next step as we move forward is how do we target our therapies for a specific mutation, and I think that's what I think where we need to go next.

Caller: I've been looking at the new Facebook groups for mPatient for the different translocations. So it seems like what you're saying is nobody has ever done a trial for it yet or nobody has designed a trial yet for a specific translocation.

Dr. Shah: We have. We've looked at for example FGFR mutations. So there's a drug in a trial that was designed to look at patients with just an FGFR mutation. Unfortunately, I think there were some challenges in that trial in terms of accruing to it. So that was I think discontinued. So there have been attempts in the past made about that, and I think that we'll have to redouble our efforts to look at those types of approaches.

Caller: I think the patients and caregivers would – I think education is going to be an important part of it. If I had an FGFR, I would raise my hands and say for sure. But the sad reality is most patients don't know what their biology is of the disease, so they're not capable of actually raising their hands for the trial.

Dr. Shah: Exactly. So we're able to educate all patients saying when you go into your physician, know what your stage is, know what your cytogenetics are, know what your drugs are, know what your M protein is and know what your options are and then you can start having much more. We ideally like our patients to be more educated and more empowered.

Caller: Very, very well said. Thank you for taking my call.

Dr. Shah: Thank you. If I may make one last question before we run out of time. There's also an email address that I will share. It's called myelomatrial@mdanderson.org. So if you have any questions about trials at MD Anderson you can reach out. That's an email that we're happy to share with and people can access directly those to try and facilitate that conversation about potential trial options.

Jenny: Okay, that's great. And we will include that in the transcript so people can have that.

We have one more caller and I know we're running out of time, but it's 557-6827. Go ahead.

Caller: Hi, Dr. Shah. First of all, thanks for sharing your research. I want to know what the difference is between the clinical trials offered at a bigger facility like MD Anderson compared to a smaller facility or one that does not necessarily specialize in myeloma.

Dr. Shah: That's a good question. At the end of the day, I think what's important to understand is "Is this the right clinical trial for you at this point in time?" And I think those are the two things that I talk about with patients. So to me it doesn't matter if a center has five trials or 15 trials or how big the center is.

Here at MD Anderson we have a lot of trial options and that certainly is helpful and important to offer as many options to as many patients. When we get down to the bottom line, the quetion is"Is this trial the right trial for me at this time?"  I think if you answer those three questions, is this the right trial for me in particular given my disease at this point in time, and if that trial is available for you, then that's great. I think the difference between a small center and a large center in that situation doesn't matter. At a large center like MD Anderson we may have more of those options and may be able to answer that question yes more frequently, but at the end of the day, if that trial is available to you anywhere, then that's an important option to go forward with.

Caller: Okay, thank you. Thanks.

Jenny: Thank you so much. That is very well said.

Dr. Shah: The other thing about that clinical trial, even at the smaller centers, at the end of the day, when you're on that trial, there's going to be one research nurse assigned to you as well as the clinical research nurse. So the type of care that you will get on that clinical trial I think will be unparalleled because you'll have two dedicated myeloma research nurses who know about myeloma, the disease process, that trial and you, and really be an advocate for you through that experience. And so I think that should be really a uniform experience for patients anywhere participating in that clinical trial and is that extra degree of oversight and attention.

Jenny: Well, I think there are advantages that patients maybe have not considered before, but there are distinct advantages of participating in a clinical trial.

Dr. Shah: Absolutely.

Jenny: Well, Dr. Shah, we have taken a lot of your time. We are so very grateful for having you come on the show and sharing with us your important work. If there's anything we can do to help you in your work, we are happy to do it and would like to continue supporting you in what you're doing. So we wish you the very best and hope that we can help you in some way.

Dr. Shah: Thank you. And I think that goes vice versa. Anything we can do to help the myeloma community and the patients in general, that's our goal.

Jenny: Well, thank you and best wishes for continued success in all you do.

Dr. Shah: Thank you and take care.

Jenny: Thanks for joining us on today's show on "Innovation in Myeloma". Join us next week for our next mPatient Radio interview as we learn more about how we can help try and seek cure for myeloma.

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