Sergio Giralt, MD Memorial Sloan Kettering Cancer Center Interview Date: November 11, 2016
Stem cell transplant is still the single most effective treatment for multiple myeloma. But only 40% of whites have one while only 25% of blacks do. What? Dr. Giralt says that it is an issue of access to care, patient preferences and untrained local oncologists. Dr. Giralt shares his goals to make stem cell transplant even better and to make them easier by “flattening the symptom burden curve.” He stresses the importance of "giving your best drug up front." Today's pre-transplant options are typically three drug combinations which he tells us are far better than two drugs together. He notes that research is now being done to see if other combination therapies could be added for certain patients. For example, patients with the 11;14 translocations seem to do better on venetoclax so it could be added to the induction treatment for these patients. He says that the data supports maintenance therapy post-transplant because it extends progression free survival. He mentions the inclusions of checkpoint blockades, vaccines and other immunotherapies in the treatment mix. His two main goals are to increase access and improve outcomes.
Thanks to our episode sponsor
Jenny: Thank you for joining us on today's show on Myeloma Crowd Radio. I'm your host Jenny Ahlstrom. We'd like to thank our episode sponsor, Takeda Oncology, for their support. Now most myeloma patients will have a stem cell transplant in the course of their care. Even with the newer drugs available in the clinic, it's still an incredibly effective treatment in multiple myeloma. Many researchers are looking at what they can do to make transplant even more effective. I've already had tandem transplants back to back but knowing what I know now, I don’t think I would ever do another one at relapse without something else added to it knowing what's happening in the field. With us today is myeloma and transplant expert, Dr. Sergio Giralt, from Memorial Sloan Kettering Cancer Center. Welcome, Dr. Giralt.
Dr. Giralt: Thank you, Jenny, for having me and I want to say hello to all the Myeloma Crowd on the radio today.
Jenny: Oh, thank you so much for joining us. We're thrilled. We've had you on the show before but that was quite some time ago, so let me give a brief introduction for you before we get started with our questions. Dr. Sergio Giralt is Chief Attending Physician in the Adult Bone Marrow Transplant Service at Memorial Sloan Kettering Cancer Center. He is both a myeloma expert and a stem cell transplant expert. He is an IBMTR Executive Committee Member, a BMT CTN Steering Committee Member and President of ASBMT. Dr. Giralt is on the HemeMalignancy Watch Editorial Board and NMDP Board of Directors. He is on the Managing Myeloma Board, which is a video series for oncologists, and is a member of the International Myeloma Society, a member of ASCO Scientific Program Committee on the Leukemia, Myelodysplasia, & Transplantation track and a member of the Bone Marrow Foundation’s Medical Advisory Board. He is also the Program Chair for Clinical Advances in Optimizing Outcomes for Patients with Multiple Myeloma, The Center for Biomedical Continuing Education. Dr. Giralt was awarded one of the Best Doctors in America for many years and is a well-loved myeloma specialist. So thank you so much for joining us. Maybe we want to start with something from last year. I saw you present at one of the sessions at the American Society of Hematology Meeting or the ASH Meeting, and you gave a presentation about stem cell transplant. You were stressing the fact that it is still the single most effective therapy but sometimes patients aren’t even getting this therapy. Do you want to go ahead and address that?
Dr. Giralt: Oh, sure, Jenny, and thank you very much for asking that very important question. Actually, this year in American Society of Hematology, another randomized trial of early versus late transplant will be presenting, again supporting the notion that early stem cell transplantation with high-dose melphalan and autologous stem cell support will provide patients with the best chance of long-term disease control although whether there is a survival benefit or not is still uncertain. Now, having said that, I think what's to us dramatic is when we go across the country, if you're Caucasian, your chance of getting the transplant is 40%, and it actually decreases if you're over the age of 65. If you're African American and you've got myeloma, your chance of getting the transplant is only 25% and again it decreases if you're over 65. We really don’t know what is the problem. We know that there is a significant access issue, but we also know that there's a significant referral bias issue. We would like the Myeloma Crowd to actually advise every new patient to come in that they should request from their oncologist to be referred to a myeloma transplant center to be assessed (1) for stem cell collection; and (2) so that they can hear what has happened in transplant over the last couple of years. What we've noticed is particularly many of the community oncologists who might have undergone their training 10 or 15 years ago may not be totally up to date with the dramatic changes that have been made in supportive care in autologous transplant. Many patients are now out of the hospital in 10 days. Many programs do out-patient transplants. At Memorial, we have a robust research agenda and are trying to do what we call “flatten the symptom burden curve” so that transplants become a lot easier than what they used to be. We also know that patients have a significant bias. When patients are asked, they're concerned about the side effects and many of these patients confuse autologous transplants where they are the donors to an allogeneic transplant which is a much more complicated and difficult procedure. We do think that we have to find ways that we can actually provide patients with accurate information from people who are informed with up-to-date information for a treatment that now has three randomized trials supporting that it should be done early in the course of the disease.
Jenny: What really stood out to me at that ASH presentation was that you just said even with all the new therapies that have been introduced and approved even last year by the FDA, there were four new drugs approved, that melphalan that's used in transplant is still the single most effective drug we have in myeloma.
Dr. Giralt: Yes. When used as a single agent, there's no other single agent that has the same activity than high-dose melphalan. I do not know of any cancer that we treat where you would not give your best drug up front.
Jenny: Yes, right, it doesn’t make sense to say let's reserve it for later. That's great to know about transplant. We should be thinking about it early. It's fascinating that the statistics are so low. It's completely incredible.
Dr. Giralt: It is incredible and it should be a call to action. Why is this happening? We don't have enough transplant centers. Access to transplant centers is sometimes made difficult. What's going to happen with the Affordable Care Act where we make things harder? I think there is a lot of referral bias and a huge knowledge gap from the type of patients that we can try to close with instruments such as the Myeloma Crowd and trying to get to all the myeloma patient advocacy groups. The transplant centers are now very willing and want to work with the community to try to get a much more accurate information to people. And it's not only myeloma. It's all blood cancers. The Be The Match organization, the American Society of Blood and Marrow Transplant really have a huge initiative to get patients timely referred to the transplant center.
Jenny: Now, a question about what you said, because I'm a huge advocate for having myeloma patients go see a myeloma specialist as part of their care even if they have to travel to go get a consult and then go back to their local hometown to get their infusions or whatnot, but what, in your opinion, is the difference between a myeloma transplant specialist and a general transplant specialist? What's the biggest difference?
Dr. Giralt: Many of us, particularly in small and medium-sized programs, the transplantor does both myeloma and all the other indications and they understand myeloma and they understand transplant. For example, myself is not only am I a transplant expert but I focus a lot of my research efforts on myeloma. I'm trying to reduce the symptom burden of high-dose melphalan, and I also have a very robust research portfolio in allogeneic transplant for myeloid leukemias. I work in a program that does 460 transplants a year so I can focus on those two areas because I have enough patients to be able to look at what the issues are. But I mean for many smaller programs, if they're only doing 60 to 80 transplants a year, myeloma is going to be their main indication. In essence, every transplantor across the country has experienced doing myeloma transplants. They may not have research protocols for myeloma patients undergoing transplants although now we multiple national studies looking at a variety of questions from optimal induction, how do you best do the transplant? And then probably soon to come in a clinical trial near you is randomized trials with different maintenance strategies. I think most transplant programs will have access to clinical trials which you and I know are probably the best way to be treated for myeloma patient is to try to participate in a clinical trial.
Jenny: I completely agree and it's the whole reason that I started this show is to encourage patients to participate, not only because they're going to get excellent care in doing it and early access to drugs but that together if patients are joining in greater numbers, we'd be able to dramatically accelerate the pace of research in this field and help you do your job much faster.
Dr. Giralt: That would be great.
Jenny: I'm a big advocate for that. Well, let's talk about this transplant plus idea. Before the show started, we were talking about different categories of things that this falls under, and there are a lot of different variations of this or flavors of this. Do you want to just start in with one and then we'll get to them as we go along?
Dr. Giralt: Yes. I'm going to say this is an extension of again one of the practice-changing clinical trials that was performed in the United States where we show through the CALGB and the BMT CTN trial about randomized maintenance with lenalidomide or not, that continued therapy with lenalidomide in patients who had undergone an autologous transplant had significant improvement in progression-free survival and even overall survival. Up to that time, the standard had been no maintenance. Maintenance was interferon which was toxic or maintenance with thalidomide which was very difficult to deliver. This demonstrated that high-dose melphalan by itself would not be enough for long-term disease control for many patients but that the addition of lenalidomide, so that would be your first “transplant plus”, not only deepened the response but actually doubled the progression-free survival and in now recent meta analysis presented by Dr. McCarthy and Dr. Palumbo at ASCO showed that there was a survival benefit when they put all the trials together. I guess the best question is, if I failed the transplant is there a benefit for a second transplant? There is now one randomized trial that was performed showing that if you had a remission that lasted more than 18 months, you could benefit from the second course of high-dose melphalan. There's a lot of retrospective data that suggest particularly that if you've had a remission that lasted more than 18 months, you could benefit from a second cycle of high-dose melphalan intensification. But I agree with you. I think as people think about “what's my next approach if I failed treatment”, and I'm getting, let's say, a salvage with carfilzomib, lenalidomide, dex or a salvage with daratumumab, lenalidomide, dex, should I be considering the second transplant? There are no clear-cut guidelines. I mean we would tell patients, look, the goal is to achieve the deepest response possible because achieving a deep response means it will take a longer time for the disease to come back and start damaging your end organs; your kidneys, your bones, or weakening your immune system. We also know that by reducing the tumor burden, we reduce the number of clones that can potentially go genetic alteration and become the aggressive clones that we feel like become plasma cell leukemia. Again, when people ask me, Dr. Giralt, should I get a second transplant? I usually say, yes, I think you should consider it. Should I get a standard of care is with high-dose melphalan and no maintenance. As you have said, I would encourage patients; I think if you're going to get a second transplant, it makes all the sense in the world to go to a clinical trial that offers you a second transplant plus something else. Remember, one of the problems that we have in the salvage transplant setting or that second transplant setting is that many of the drugs we would like to give have not been approved for that indication. There is a limitation to what we can give as therapy to patients undergoing salvage transplant outside of clinical trials. We probably can give pomalidomide. We can give lenalidomide obviously. We can probably give bortezomib. We can probably give ixazomib. But when we want to think about giving the monoclonal antibodies daratumumab and elotuzumab that require that they've been approved in patients who have failed to respond to either an IMiD or a proteasome inhibitor, those get to be a little bit more delicate, although now we're hoping that with the expanded indications for many of these drugs, we can then use them on label as continued therapy after a transplant.
Jenny: What you're saying is that there are those standard drugs that people typically have in the clinic, the proteasome inhibitors and the IMiDs and things. But when it comes to even adding a combination like, let's say, you're going to do pom, dara and bortezomib or something like that, you're saying that you would really have to look to a clinical trial to do a transplant and then that as followup?
Dr. Giralt: Correct. For many patients, if we say we want to do transplant and follow this pom, dara, dex as consolidation, many patients will not be able to get it because insurance wouldn't cover it.
Jenny: Oh, I see.
Dr. Giralt: And I think it's interesting. We're in the process of planning a salvage transplant trial. We call it the second chance protocol in which patients will get a very intense reinduction with four cycles of carfilzomib, lenalidomide, dexamethasone and daratumumab where we expect will be the myeloma chop. They will then get an autologous transplant with high-dose melphalan followed by four more cycles of carfilzomib, lenalidomide, dexamethasone and daratumumab. And then the idea is to see how low we can make them go in regards to the depth of response. The read out there is MRD-negative CR (complete response). After a year of treatment, the physicians will decide what form of post-treatment maintenance. It will be left at their discretion but we're expecting or hoping to get a significant proportion of patients who have relapse. They're patients who have had at least one to three treatments - to get a significant proportion of those patients in an MRD-negative state. We're hoping that trial will be open towards the end of next year.
Jenny: Okay. You're really throwing everything at it. That's incredible and wonderful.
Dr. Giralt: As we tell people, look, the myeloma is not going to be nice to you. Why should we be nice to your myeloma?
Jenny: That's a great way to think about it. I wonder how long do you think it would take to bring that to the upfront transplant for newly diagnosed -- I know you always start with relapsed/refractory.
Dr. Giralt: My guesstimate is that we will be seeing this in the upfront setting very close but I don’t remember. The thing there is that those randomized trials in the upfront setting now are becoming more challenging because patients do very well with the current treatment that we have. The other thing I think that the field is recognizing is cost issues are important. Cost-effectiveness analysis will need to be done and that we really need to think about what is the most cost-effective treatment for the myeloma patient or strategy. There it might be that putting everything in the kitchen sink, unless you get a huge difference may not be the most cost-effective way of treating patients and that in itself will require a lot of study.
Jenny: Don't you think that's more challenging in myeloma where you have a drug that's not the same for every patient?
Dr. Giralt: Oh, I think it's challenging in all patients but it's particularly challenging in myeloma because we have so many drugs. Now the combinations are really different. I think it behooves us as a myeloma research community to see if there are certain patients that will respond to certain combinations better than others. I think one of the things we've all been interested in is the response of the venetoclax in patients who have (11;14) translocations. Whether these patients should have a venetoclax containing regimen versus those that don’t have and (11;14) translocation. Venetoclax is a BCL-2 inhibitor and it's been approved for treatment of CLL, but there is a very strong signal for patients with (11;14) translocation myeloma.
Jenny: And that's fabulous that you can get it to that specific, more personalized medicine approach.
Dr. Giralt: Correct.
Jenny: You're just trying to find the right drug for the right type of patients and especially before their myeloma morphs.
Dr. Giralt: Correct. I think we're learning from the acute leukemia experience that myeloma is not one disease. It's a spectrum of disorders. The same way that acute leukemia, you treat acute promyelocytic leukemia with arsenic and all-trans-retinoic acid. You treat patients with complex cytogenetics with high-dose ara-c induction and you try to send them to transplant. We treat Philadelphia positive disease with the TKIs and imatinib, dasatinib or nilotinib. I think as we learn more about the different spectrum of myeloma diseases, we may be able to get some targeted therapies. Nothing is going to be like imatinib for chronic myelogenous leukemia but many of these targeted therapies will be able to help improve the responses of patients with myeloma.
Jenny: Okay. Well, let's talk about different options that you could add before transplant, or an induction, to make things different.
Dr. Giralt: I think it's good to start here: what's the standard today in North America? The standard today in North America for patients who are transplant eligible and the whole definition of transplant eligibility in North America is different from Europe, because here really age is no longer consideration. It's more functional performance status. The standard is either combination of lenalidomide, bortezomib, dex or cyclophosphamide, bortezomib, dex. A lot of controversy about whether there is a benefit of giving the cyclophosphamide, bortezomib, dex versus the lenalidomide, dexamethasone and lenalidomide, bortezomib. They've never been compared head to head. These two regimens are what your crowd will know as the RVD regimen and the CyBorD regimen. The Europeans compared bortezomib, thalidomide, dex, that's VTD to CyBorD, and they suggested that VTD had a benefit. Does that mean that RVD which is the American version of that regimen should be the standard? No, by no stretch of the imagination. I mean it's true that the response rate was higher but it may be that after the transplant, everything looks the same and they really did not prove that one was better than another in regards to disease control. They just showed that the response rates were higher. What we do know based on the SWOG study is that three drugs is better than two. When RVD was compared to RD, there was not only an event-free survival benefit, meaning people lived longer without myeloma, but a survival benefit. People lived longer, period. I think for that transplant eligible population, triple drugs, particularly probably containing the IMiD and the proteasome inhibitor should be the standard of care. Is there a role for carfilzomib up front? It is being explored. There's a randomized trial. We don’t know the results yet. What about four drug combinations? We know we add toxicities. Once cyclophosphamide was added to RVD, it was more toxic. The combination of the four drugs was more toxic than three drugs and it didn’t show a lot more benefit. But it may be different with carfilzomib. It may be different with daratumumab and the studies need to be done, they have not yet been read out. Afterwards again we try to get people to transplant with high-dose melphalan. High-dose melphalan remains the standard of care for conditioning. There is a randomized trial combining melphalan to bortezomib and melphalan to busulfan. We don’t have those results yet. We know adding agents to melphalan generally does add toxicity. At Memorial, we just started a program looking at what we call targeted melphalan in the same way that busulfan has a sweet spot that this is that when you want the area under the curve or the amount of busulfan that you're getting to be within a certain range. We think the same thing has to happen with melphalan. You can now have strategies that you can actually target a melphalan dose or target a melphalan, you know, how much melphalan goes into the body that myeloma cells are exposed to because unfortunately when I give everybody 200mg per meter squared, not everybody handles it the same way. Some people metabolize it very quickly so the exposure of the myeloma cell is very little. Some people metabolize it very slowly so the exposure of the myeloma cell is high, but you also get more toxicity. We're trying to see if I give you a test dose of melphalan, can I predict how you're going to handle it so we can give you the dose that will give us that area under the curve that we think is a sweet spot?
Jenny: Can I ask you a question about that?
Dr. Giralt: Sure.
Jenny: One of the doctors said, depending on how you respond to transplant might be an indicator of how well you might do after all because you said I have some patients who are really hit hard by the melphalan, and they actually do better than the patients who just sail through transplant. Have you seen that to be true as well?
Dr. Giralt: I have seen patients who failed transplant who have done very well too. It's a question of actually doing the perspective observation. Some of this comes from the Australian data that looked at when I give the same dose of melphalan to everybody, some people get rid of it very quickly. Some people get rid of it very slowly. The people who get rid of it very quickly have little toxicity but they have a higher risk of relapse. The people who get rid of it very slowly have more toxicities but they may have better disease control. What we're trying to show is look, maybe there's a sweet spot and it's not a question of giving everybody the same dose, but trying to make sure that everybody has the same drug exposure. We just started these studies and we hope that in a couple of years we'll be able to show.
Jenny: Okay, we'll wait for those results and see what you come up with. Sorry, then you were going on to consolidation.
Dr. Giralt: Then I was going to consolidation and maintenance. Again, what we do today in North America is very much limited from what insurance will allows us or what things are covered. So lenalidomide and bortezomib are probably the drugs that are covered for long-term treatment after a high-dose autologous transplant. But as your listeners are probably making a list of all the drugs that they think would be available, we think the same way. We haven’t even talked about checkpoint blockade. We haven’t talked about vaccines. We haven’t talked about the other immunotherapies. The reality is that there's more combinations than trials that we can do, and that's why I think as we move forward we have to be very, I would say, astute in how we design our trials in the future. Our guiding principle is we want to give the patients the longest life, with the best quality of life, with the minimum treatment necessary. I think we've learned from the frontline setting that the longer that first remission lasts, the better it is for patients. When the patient's first line treatment fails, that second line treatment, unless the patient has been extremely deteriorated, should go with the same goals we want with the first line. The deepest response possible because we know the depth of response makes a difference. Patients who are relapsing on lenalidomide maintenance and they've been on lenalidomide maintenance for more than a year, you can even go back to the strategy that worked the first time, RVD and transplant. But as you and I discussed in the beginning of the program, we think look, this is right for clinical trials that these patients, even if they've had a two-year remission, the next remission is unlikely to last longer unless they do something different. And there are a lot of different things available there that should be explored preferably in the context of a clinical trial.
Jenny: Right. And it's such an involved process to do a transplant. I did mine outpatient so it was better than doing it inpatient, in my opinion, but it's still not an easy process.
Dr. Giralt: Yes, you wouldn’t buy a ticket to do it.
Jenny: You can get through it and it's doable but it's not like your favorite thing to do. When it's effective, you really want to consider it. I wonder, as a follow-up question to what you were mentioning before with the African American community, because I know that sometimes their genetics are actually better genetics for myeloma or not as high risk genetics typically. And I just wonder if that would dramatically improve their outcomes if only 25% of them are really getting a transplant if it could make this very dramatic impact on that whole community. It just seems it would.
Dr. Giralt: Remember that African Americans as well as Hispanics present with much more advanced myeloma when they present. But again, I think it's a question of access to care. I think what we as a society have decided that one effort that needs to be done is much more education of both the primary care physician as well as that frontline of medical healthcare providers to make them much more aware of myeloma. I mean we've all seen myeloma patients who have come in now with fractures, infections and renal failures and when you go back in their records, they've had an elevated total protein for a year or two. That requires that we educate our primary care providers that if they have an elevated protein, it needs to be pursued.
Jenny: Let's talk a little bit about immunotherapies because you mentioned them a little bit, vaccines and things like that. There are the checkpoint inhibitors which are now being added to different combinations maybe making it a quad type therapy. There are vaccines. There are dendritic cells. There are the marrow-infiltrating lymphocytes or the MILs and there are the ones that are already approved like elotuzumab and daratumumab and then CAR T cells. Do you want to go over just different categories of those and help us understand how they fit in with transplant, and what you see is the most promising?
Dr. Giralt: I think first we have to go into what of these have activity by themselves? The checkpoint inhibitors as single agents, none of them have a lot of myeloma activity. And we're excited because when we combine them with lenalidomide, they seem to work very well. They make lenalidomide a better drug. Similar to elotuzumab, elotuzumab by itself is not a very active myeloma drug but it makes lenalidomide a better drug. So when you combine them, they're synergistic. You get more activity than what you get with either drug alone. Next we put things in categories of strategies that only work when you have minimal residual disease. If you have active myeloma, 50% plasma cells, there's no amount of vaccines I'm going to give you that's going to make you get rid of those myeloma cells. The vaccines and the dendritic cells and even the MILs are probably strategies that require what we call minimal residual disease. CAR T cells, on the other hand (and there no CAR T cells commercially available for myeloma, they're being explored all over the country) are just beginning. The pioneering work was done by Dr. Kochenderfer at the NCI where they made a BCMA which is called B-cell maturing antigen which is presented in myeloma cells. They made a CAR T cell against that, so any cell that has that BCMA antigen on the surface will be attacked by these serial killer T cells. They are autologous so the patient is the donor for their own T cells but again less than 50 patients have been treated with this cell therapy. It's not commercially available. They've been associated with some severe toxicity so they can only be administered in what we call specialized facilities of cellular therapy or transplant, but we're very excited about it. We think this is another potential game changer. Daratumumab is a game changer. It's a very active drug, very well tolerated. You can combine it with all the other agents that we use. I think daratumumab is rapidly going to go up front but that means that when people relapse, they'll be relapsing resistant to daratumumab.
Jenny: And that CD38, does that disappear sometimes and then the daratumumab doesn’t work anymore?
Dr. Giralt: Correct, exactly. The problem with daratumumab particularly as a single agent is you know how cells are going to become resistant. They just stop expressing CD38.
Jenny: Then it has nothing to go after.
Dr. Giralt: Yes.
Jenny: When you talk about the CAR T cells and that you need to have MRD status, to me that would say well if you can get it --
Dr. Giralt: The vaccines and dendritic cells. CAR T cells are active even with active disease.
Jenny: For all the immunotherapies, there are some like the vaccines, like you said, that you would have to have minimal residual disease, but can you do transplant first and then give those types of therapies afterwards? Because at that point you probably have a suppressed myeloma?
Dr. Giralt: I'm glad you bring that up because I think one of the things we talk about, there are all these great treatments but eventually many patients get to the end of the line. And now we've been struggling with what do we do with these patients . Many of them are young and fit. Many times what we've been doing is what we call Hail Mary donor transplants which generally don’t work. If you just say, okay, because it's a lot to ask of the donor cells. We can get people in remission but those remissions don’t last very long in people who have multiply relapsed/refractory myeloma. Now, we've been thinking that this is maybe a reasonable place to explore these immune therapeutic options after a donor transplant, an allogeneic transplant, which is the first successfully described immunotherapy. People with acute leukemia get cured. Chronic myelogenous leukemia get cured. Myeloma patients have been cured with donor transplants. The question is how can we make the platform safer? We do some density conditioning that has made the platform safer. There's a national study with reduced intensity conditioning for high-risk myeloma up front followed by a randomization to ixazomib or placebo. We're looking at people with more advanced disease. This is following the work Dr. Guenther Koehne has done on a platform what we call CD34 selection which is the best way of preventing graft-versus-host disease and afterwards do an immunotherapy with a checkpoint blocker. Again, we hope that study may be opening towards the end of next year.
Jenny: And he has that WT1 vaccine that he does with allo and he's trying to bring that to auto, right? Auto transplant?
Dr. Giralt: To bring it up for auto and to bring it up to people who have had only one to three prior relapses.
Jenny: How close is that trial coming in to the autologous transplant setting?
Dr. Giralt: We just finished the first vaccination trial. The WT1-CTL was a donor transplant trial which also has just finished. We're looking at the data and those follow-on studies will probably happen towards the end of next year too. We're just looking at the data.
Jenny: You mentioned that lenalidomide, I know a lot of times lenalidomide is talked about like not only does it kill the myeloma cells, but in some way it boosts the immune system. Do all of the IMiDs do that as well like pomalidomide, does it give the same reaction to the immune system to use that and is that why it's used as maintenance therapy because it's boosting the immune system that go fight all the residual cells that might crop up after you do transplant, or is it just the anti-myeloma effect that you're looking at?
Dr. Giralt: I think we've all recognized that the immunomodulatory drugs are immunomodulatory drugs. They modulate the immune system. We know that thalidomide was the first maintenance used. Randomized trials showed it could potentially beneficial but it was associated with severe side effects particularly neurocognitive dysfunction, constipation, rash and neuropathy. Now, the immunomodulatory effects of thalidomide are relatively modest. Lenalidomide is a much more potent immunomodulatory and actually we think one of the reasons why checkpoint blockade seems to work particularly well with lenalidomide in combination is because of that, because it's a way of modulating the immune system and making patient's immune cells more active against the patient's myeloma. I can't tell you we've figured it out. We have not. I think this is more an empiric observation but we're all very excited about what the Spanish group showed with the combination of checkpoint blockade and lenalidomide and steroids. It was very well tolerated and they had a very high response rate with good remission duration. I think it is reasonable to start studying checkpoint blockade particularly in people with high-risk disease. I think what we have to recognize is that a good proportion of patients that RVD induction, high-dose melphalan and lenalidomide maintenance alone will put them in a complete remission that can last an average of six to seven years.
Jenny: That's really impressive compared to where it's been.
Dr. Giralt: Oh, definitely.
Jenny: So impressive. And then you look at these other things that you could add. What you're saying is that you have to be careful about the different combinations. Maybe we can talk about just combination therapies outside of the immunotherapies like panobinostat or selinexor or some of these other different things that you can do for consolidation. You talked about the three that are pretty standard for the induction. But are there other things that are being considered or in your opinion should be considered for either post-transplant and maybe it's not just lenalidomide maintenance that could really extend your remission even longer?
Dr. Giralt: Definitely. I think there are a lot of things starting from dara to going all the way to panobinostat. But I think one is that there's the challenge of how do you show these are effective? And two is if we were to do the randomized trial and particularly in the upfront setting, a randomized trial to show a survival benefit for a thousand patients for 10 years and it's difficult to see who would pay for it. We actually again are discussing with our friends from Takeda a study where people who are on lenalidomide maintenance and have not achieved the complete response after nine months, we add ixazomib. The idea there is again the goal is to achieve the deepest response possible. If lenalidomide maintenance is not enough, maybe we should add another drug. What that drug is we don’t know. We're trying to identify which are the ones that are potentially active and then the idea would be to do a randomized phase 2 trial to pick a winner.
Jenny: Let's talk about clinical trial construction because you said you have to be really careful about how those are constructed especially in this age of all these different drugs. As a specialist and as a transplant expert, how do you go about helping craft these trials? Because I know you're on these committees that are helping to create and structure these trials and you're trying to do it collaboratively and not duplicate so you don’t waste time, but how do you do that?
Dr. Giralt: There's a lot of talking going on now. There's the myeloma intergroup that is sponsored by the BMT CTN, that's Blood and Marrow Transplant Clinical Trials Network. The idea is that we never want to have multiple large studies being run at the same time and none of them accruing appropriately. We want to always try to have what we call “no gap” between trials which means that we always want to have an important myeloma study up and running for all patients. Our current frontline for the national study is DETERMINATION, that's the early versus late transplant, being led by Paul Richardson through the ALLIANCE. There's a next generation study which is a vaccine study looking at myeloma dendritic cell vaccine. This is being run only in select centers because they have GMP facilities. It's a very interesting concept of really immunizing you against your own myeloma. The next generation of studies will probably be looking at different maintenance strategies. So really we sit down in a room and we talk - what are the things we think our patients need? And more and more patients are requesting, look, we really want something that's risk adapted and more personalized. So a lot of what patients are asking is could you please advise me if it is possible that I can stop my Revlamid? And the answer is we don't know. We think that MRD assessment will be very important in allowing us to decide who could potentially stop their Revlimid or their lenalidomide after many years. I would say it's work in progress. There is a lot of negotiation done behind the scenes but we all want the same. We want to move the field as quick as possible. We are learning that victims of our success at some of these studies we need to have early endpoints because they'll be going on forever if we're looking -- I mean the average remission now for a patient with upfront myeloma is four years.
Jenny: Wow, yeah, that's hard. So you're trying to do a study and you're trying to get a study results back, but you don't want to wait 10 or 15 years for those study results to come back before you know the answer.
Dr. Giralt: Yes.
Jenny: Another doctor talked about using minimal residual disease as one of those endpoints to say, okay, if patients hit a certain minimal residual disease, then what? Then have we accomplished something here?
Dr. Giralt: Correct. But what we think it means may not be what it means, and that's why you need to show it. It's the same thing we did with chronic myelogenous leukemia. When people were getting molecular remissions and everybody was happy, but you kept it until it stopped working. And now after people have had five years of being consistently molecularly negative, people are starting to stop the drug and being monitored and since it's a blood test, I mean it's a lot easier. What they've shown is that half of the patients do not progress and the half that progress, you can easily re-control them by reinstalling the drug, but on average you may get one or two years of a drug holiday which I think everybody liked.
Jenny: Oh, yeah, it's really important. You feel like a person again when you have that. Let me ask you about some of these other things that I'm not familiar with, so other things that might impact the bone marrow environment when you think about transplants. I ran across filgrastim.
Dr. Giralt: The GCSF you use to mobilize the stem cells.
Jenny: Oh, okay. Now I know what that is then. I just wasn't familiar with that name. I know there are studies being done to manipulate the bone marrow environment and make it less friendly. Is there anything happening in the transplant world to incorporate that? Because you're really taking everybody down to nothing again in transplant and then rebuilding. Is there something that can be done in the bone marrow environment at that low point to protect?
Dr. Giralt: The answer is we don't. A lot of things people have looked at, is the bone marrow microenvironment protecting the myeloma cells? And there are suggestions that they actually do because they may actually shut off the immune response. And that's one of the reasons why people want to explore checkpoint blockade in the context of a transplant platform to see if they can enhance immune recovery. Two, we know that the bone marrow microenvironment plays a role in myeloma survival. If we can manipulate those factors that give myeloma an advantage over normal cells, we might be able to "even the playing field" and give patients a better response. And then I think finally filgrastim is a great mobilizing agent, but I mean from what we've looked at, it hasn't changed the microenvironm that may change the microenvironment substantially and they may make a difference, and it's a question of studying it.
Jenny: Let's talk about your clinical trials that you're running or involved in the creation of. Which ones are you working on and which ones are the most exciting to you? I'm sure they're all exciting if you're working on them.
Dr. Giralt: We have two, let's say, big initiatives and they're all one falls under the increasing access rubric and the other one calls on the improving outcomes. Increasing access is we're really trying to explore the reason why patients don't want to proceed to transplant. Many of them has fear of staying in the hospital. We now have a robust outpatient transplant program. We're actually beginning a pilot trial, homebound transplant program where patients are treated at home if they're within certain zip codes. We send the nurse practitioners to them. Very exciting, very interesting, still early on but at least it breaks down one of the barriers I don't want to stay in the hospital 20 days. The improving outcome we're looking at (a) making the transplant more effective, getting people into a deeper response. There are three strategies: one, improve the induction so Dr. Landgren and Dr. Korde are leading a carfilzomib, len, dex induction. Two, looking at minimal residual disease assessment as our endpoint. Three, we're trying to optimize the melphalan by doing this pk melphalan trial. And then four, we have different what we call post-transplant strategies. One is the vaccine. It's called BMT CTN 1401. Two, we have the lenalidomide, ixazomib study that we're working on. And then for patients whose disease has relapsed, we really think that particularly for younger patients with good donors, we should be exploring donor transplants. Dr. Koehne is bringing his follow-up studies about the intensive conditioning regimen with the CD34 selected graft which is much easier. It does not cause graft-versus-host disease and then followed by post-transplant immunotherapy with either donor lymphocyte infusions or WT1 CTLs. We're going to expand that to more relapsed patients looking at checkpoint blockade. And then the other big area for us is to flatten the symptom burden curve. You went through this twice so you know the fatigue, the nausea. I mean we just finished a study of acupuncture, and I can't share the results but they're very interesting. Dr. Bill Redd from Mount Sinai just finished a study of light therapy for patients with fatigue. We're expanding those observations to the post-transplant setting, and we're actually going to expand it to prevent fatigue from transplant with light therapy during the procedure. This is the light that they use for submarines and seasonal depression, so it'll be very interesting. Most of the symptoms that people feel after an autologous transplant are driven by a cytokine called Interleukin-6, and we actually now have a study that's hopefully soon to begin in six months to nine months looking at blocking IL-6 with monoclonal antibodies. It's going to be supported by Johnson & Johnson. Hopefully, we'll be able to make transplants easier. The idea that we make symptom burden a lot easier, if we flatten that symptom burden curve, more and more patients will feel comfortable proceeding to a transplant.
Jenny: I want patients to know. I mean I've done two of them and so it's not fun but you can get through it and it's doable. Sometimes patients get emotionally disturbed about getting a transplant, but it's something that you can do so. I want to stress to patients that it is something that they can do. So how would patients seek out the best transplant plus options for them?
Dr. Giralt: It's an interesting question. I think one is obviously I would go to the clinicaltrials.gov is the best place to start, but it's difficult for patients to navigate it. I would actually start with your local transplant center. See what's available to you locally. The patient advocacy groups are a great source of information, the Multiple Myeloma Research Foundation, the International Myeloma Foundation. Myeloma Crowd has a website, right?
Dr. Giralt: So the Myeloma Crowd website probably has information on clinical trials too. And this is where I think that early referral to the transplant specialist makes a difference because a transplant specialist will know what trials are available across the country, and will make an assessment with the patient. Is it worth your while to travel over there? Or should you get this trial over here which I can offer you? And then patients can make an informed decision about what's available. But you're right, that it's not easy. It's not easy to navigate that system.
Jenny: Right. To make it simpler, we've partnered with a company called SparkCures. It's someone whose mother died of myeloma and he's an entrepreneur, so he created this amazing system that lets you find myeloma clinical trials very easily and in simple language. He makes sure he vets them so that he knows if they're open or closed and sometimes clinicaltrials.gov is not always updated.
Dr. Giralt: I think I love that. That's a great initiative.
Jenny: It's great and he's done a fabulous job creating it. I've had several doctors say, I pretended to be a high-risk smoldering 80-year-old woman or whatever and I found all the trials that I was looking for. That's one way. But I want patients to know that there is a big difference between getting care and referral information from a myeloma specialist and a myeloma transplant specialist versus a local oncologist, in my opinion and in my experience. My local oncologist that diagnosed me had maybe 15 myeloma patients and then the facility that was just in my hometown that had the myeloma specialist had 400 myeloma patients. My husband made the comment it's like talking to the high school basketball coach versus the NBA coach. There is so much depth of information that he had that wasn't available through that local center. I would just say to patients, if they need to travel, they can stay at apartments or something near your facility or how does the travel work when they come to your center for transplant? When someone travels to New York to come to have a transplant at Memorial Sloan Kettering, they have apartments or some place they can stay during that transplant process?
Dr. Giralt: The Hope Lodge provides housing, but for the outpatient transplant program we lease two rooms from New York Presbyterian Guest Facility. If we need to lease more because there are more patients in the outpatient transplant program, we will do so and those are covered by the insurance.
Jenny: Okay, that's great. Well, I want to leave some time for caller questions, but do you have any final conclusions that you would like to share with patients who are listening?
Dr. Giralt: I think, one, for those of you who are listening, particularly those that are recently diagnosed, there is great hope and there have been major advances. The myeloma that we treat today is totally different from the myeloma we were treating 20 years ago because there's so many new treatments, but the treatment philosophies haven't changed. Our goal is to give patients the longest life with the best quality of life with a minimum treatment necessary. Now, the surrogate for that is to achieve a major response, a complete remission. For most patients, the best way to achieve a complete remission is triple drug induction, consolidation with high-dose melphalan and then continued therapy with lenalidomide. We do think that this is now a backbone and that we can make significant improvements. Moreover, we think that there may be patients in which the treatment strategy doesn't follow that paradigm. And that's why it's essential for us to continue to encourage patients to participate in clinical trials so we can try to find the best treatment strategy for every myeloma patient of tomorrow. And remember that the treatments of today were developed because patients before you participated in a clinical trial that allowed us to make significant advances.
Jenny: Excellent. Well, we're thrilled that you are working so hard on our behalf to extend life for patients and that's what we all want.
Dr. Giralt: You're welcome.
Jenny: Fantastic. I would like to invite people who are listening to call in with a question. If you have a question for Dr. Giralt, you can call 347-637-2631 and press 1 on your keypad. Go ahead with your question.
Caller: Hi, Jenny and Dr. Giralt. This is Jack. I'm wondering, could you put your crystal ball on, Dr. Giralt, and tell us about maybe ASH presentations that we should look at that might effect changes or updates to myeloma patient treatments over the next year or so?
Dr. Giralt: I think definitely the update of the randomized trial of early versus late transplant, the HOVON EMN trial is worth going. All the trials that have to do with upfront daratumumab are definitely worth listening to. I think the hardest ones I think the salvage trials, again there's going to be a lot going on and for many patients what they've told me when they've gone to ASH is they get lost because it's just so much of an alphabet soup, and sometimes you have no ways of putting things in perspective. I would say, look, updates of the older trials particularly updates of the ASPIRE trial, updates of the POLLUX trial, those are very informative first because these are probably going to become FDA approved and commercially available. And second, they give patients an idea of how really effective these treatments are over the long term. I've been asked by patients, well, if I only had a couple of hours to go, where should I go? I would say go to the educational sessions on Saturday and Sunday, the ones that are focusing on myeloma and plasma cells disorders because I think in that hour and a half or those two hours, you will get I would say a condensed cliff notes version of what's happening in the myeloma field today and what's probably going to be shown at ASH.
Caller: Thank you very much.
Jenny: Okay, thanks for your question. Our second caller, go ahead with your question.
Caller: Yes, my name is Vivian and my husband has myeloma. He is 73, got it back two and a half years ago, and they considered the transplant where we are in South Carolina too late for age at 70. I had a couple questions. What MRD, what does that really include to be in a residual, like does that include all the lab work? Or what do you have to have to have a residual?
Dr. Giralt: For minimal residual disease assessment, thank you very much for the question. I know sometimes we speak in jargon.
Caller: I should know. I'm a nurse.
Dr. Giralt: Let's first argue that at this time we say their age is no longer a limitation. As long as you have a good functional status, you should be considered for transplant. We actually transplant up to the age of 80. And many people over 80 just don't want to be transplanted because they are not interested in it. Response or MRD in myeloma is defined by how much myeloma protein you have left and how much myeloma cells in the bone marrow you have left. When you achieve a complete remission, it means that we haven't found any myeloma protein in the blood or in the urine, and then we look at the bone marrow and the bone marrow has less than 5% plasma cells.
Caller: When we do the test?
Dr. Giralt: When you have less than 5%.
Caller: For the M protein, does that come into a big play?
Dr. Giralt: The M protein is zero in the urine and in the blood and the bone marrow shows less than 5% plasma cells. But now they know that even if your bone marrow has less than 5% plasma cells, with these special techniques, we can identify, we can see myeloma cells. So those are two techniques. One is called flow cytometry, and the other one is called next-gen sequencing. They can detect one in one million myeloma cells, so one myeloma cell in a million normal cells. We say you have minimal residual disease is despite being in a complete remission when we do these special techniques, we can still see myeloma cells.
Caller: Oh, so you would have to go in and aspirate some bone marrow?
Dr. Giralt: Yes, you have to get a bone marrow done to be able to do the assessment for minimal residual disease.
Caller: My husband has been off of Revlimid for a year and he was very allergic to the Velcade, so they took him off everything for one year. His M protein went up from zero to 0.1 to 0.2. They still didn’t put him on anything.
Dr. Giralt: What I've always told people in this, since I'm not seeing your husband, I mean usually we can't make specific recommendations on individual patients. This is something to discuss with your doctor. In general, many of us would say that unless you have what we call disease progression which means that the myeloma my protein goes up to 0.5 or more, it is reasonable to not start treatment unless there are other reasons for which you wanted to start.
Caller: Can you still have side effects from being off of the chemo for a year?
Dr. Giralt: It depends on the side effects that people have. Sometimes people had side effects to a drug in a specific situation. They don't have it when they're re-challenged depending on the type of side effects.
Caller: Thank you very much. Appreciate it.
Dr. Giralt: You're welcome.
Jenny: Okay, thanks for your question and thanks for your answer. We'll take our last caller question, please go ahead.
Caller: Hi, Dr. Giralt. I just have a quick question. You mentioned that age is no longer a limitation, but the fitness level is. So how fit do you have to be especially if you're over 65?
Dr. Giralt: We ask all the patients over 65 to actually be seen by a geriatrician. We do a comprehensive geriatric assessment. In general, if patients are independent in their activities of daily living and their performance status is 80 or above, they're good candidates for a transplant regardless of their age.
Caller: Great, thank you.
Dr. Giralt: You're welcome.
Jenny: Okay, thank you. Well, Dr. Giralt, thank you for taking an hour with us today. We really appreciate it. It was jam-packed with information.
Dr. Giralt: Thank you for what you do with the Myeloma Crowd.
Jenny: Well, thank you. It's great to talk to people like you directly to learn exactly what's happening in myeloma research and not having to wait for your papers to come out later. It's just fabulous. We really thank you for all you're doing for us.
Dr. Giralt: You're welcome.
Jenny: Okay. Take care.
Dr. Giralt: Thank you, Jenny.
Jenny: Thank you for listening to another episode of Myeloma Crowd Radio. Join us for future shows to learn more about the latest in myeloma research and what it means for you.
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