Transcript
Zack Bessette: Hello, everyone. This is Zack Bessette, assistant web editor for Journal of Clinical Pathways joined by my colleague, Cameron Kelsall, associate editor of the journal. Our guest today is Natalie S. Callander, MD, Department of Hematology and Oncology at the University of Wisconsin Cancer Center. We’ll be talking to Dr. Callander about her presentation at the latest NCCN Congress of Hematologic Malignancies regarding individualized treatment for patients with relapsed or refractory multiple myeloma. Thank you for joining us today, Dr. Callander.
Patients with multiple myeloma frequently relapse or become refractory to treatments for the disease. What are some of the considerations that physicians need to take into account when determining further treatment options for relapse or refractory patients?
Natalie S. Callander, MD: Well, there are some basic rules. As many people perhaps listening to this know, there are lots of talks out there right now about how to treat relapsed multiple myeloma and I think partly that’s a reflection of how complicated this has become as a reflection I think in part because we’re doing so much better and people are living longer, and then it also has to do with the fact that we have a lot more treatment choices than we ever used to have. And I think it’s, but I think it’s also confusing for people to try to sort of figure out what, in fact, we should be doing. So there are some really basic considerations of how to approach this, and the first is, in my opinion, what kind of relapse you’re dealing with. And the International Myeloma Working Group put out some guidelines a while ago that were published in Lancet Oncology in 2016 and basically, they tried to define relapse for myeloma and used some pretty standard definitions, certainly for clinical relapse where people have, say, a new bone lesion or a fracture, or if they have a new plasmacytoma, if they present with hypercalcemia or new enema or other symptoms that are related to progressive myeloma such as renal failure. And those I think are very straightforward in the sense that patients clearly have a relapse.
But then there are the more subtle relapses, what a lot of people are now terming biochemical progression and this is a situation where patients really are asymptomatic but they’re starting to show elevations either of their monoclonal protein or their light chains and you’re starting to think okay, should I do something or not? So, and there are some considerations for both groups and certainly, people who have a clinical relapse with a new event I think most people feel that, that person needs intervention and it’s not really to be debated.
For the biochemical relapse, there are some more considerations about whether or not you think you could actually watch that patient for a while and that’s appropriate I think when people have what appears to be a more indolent and certainly a biochemical relapse.
Some of the other considerations about what to do for a patient who has relapsed is what was their myeloma like at the beginning. So, patients typically who are that revised ISS stage III patients, those who have bad cytogenetic features or plasma cell leukemia, they tend to relapse very, with a very aggressive relapse and I think most people would agree that those aren’t the patients that you are going to watch. They are certainly the patients that you’re going to intervene upon, even if they just have a biochemical relapse for that group because they just tend to be so refractory.
I think some of the other considerations can be what is the patient’s clinical performance status like now. Are they healthy? Are there other issues? Are they still recovering from side effects related to previous treatments? Apart from biochemical versus a clinical relapse, a lot of people really pay attention to how long was it since their last treatment. So, if somebody is in the middle of receiving an aggressive triplet treatment but they’re progressing while you’re treating them, that’s definitely a different situation than someone who may have completed some therapy and maybe they were on nothing, just on observation, or maybe they were on even some low dose maintenance and that has been ongoing for some time.
The other issues can be in my state, I live in a quite rural state, if you’re planning on therapy for relapse, what are the practical considerations like, can the patient get to clinic okay, do they have insurance coverage for some of the more expensive oral agents, what is their frailty like, are they what we would consider a frail patient versus a more robust patient, and even though this is somewhat of a long list, I think all of these things have to be taken into account. And maybe most importantly would be what’s the availability for a clinical research trial that might be appropriate for this patient as well.
So, I think those, I think most people would take all of those factors into account.
Zack: How has the influx of newly-available multiple myeloma therapeutic options complicated the treatment landscape?
Dr Callander: Well, I think you could look at it that way or else you can say it has given you more opportunities. And I think if you sort of look at the progression of myeloma options over time, we went through many, many years, essentially from about 1959 when, or 1958 when oral melphalan first came about and oral Cytoxan was available then, if you go all the way up to about 2000, if you will, there’s not a lot of choices there. There were the alkylater agents. We had steroids. Interferon was being used. Anthracyclines such as doxorubicin became popular when a regimen named VAD came out in the mid-1980s, so there weren’t a lot of options. But it also meant that for patients relapsing, if they didn’t respond to one of these interventions you were sort of out of gas.
But then what happened with the publication in 1999 of the thalidomide data, we had within a few years now three drugs, three new drugs, bortezomib, thalidomide, and lenalidomide to work with. But in the last, if you look at what’s happened in the last really four years it has really been way more than that. So, we have carfilzomib, we have ixazomib, we have pomalidomide, we have daratumumab, panobinostat and elotuzomab. So we really have a lot more regimens that we can consider and so I think what does get a little difficult here that there are lots of different combinations that one can consider and I think you have to have a little bit of an idea in mind about how do you want to approach this.
So I think one of the guidelines from the NCCN is when you’re looking at, if you’ve decided a patient needs treatment again, going back to that paradigm, how bad is the relapse. Is it a refractory relapse? In other words, occurring within two months of treatment or are they on treatment at the time? I think most people would say okay, that kind of aggressive relapse requires a triplet intervention whereas a later relapse, perhaps a more indolent relapse, and particularly in a frail patient, you might be trying to use just a couple of agents. But gain, you can look at all this drug availability and say, and point out it gives you more treatment options rather than fewer.
Now, I think given, we now are in a position where there has been some early relapse, phase III trials that give you some very, very, very strong data about what to do in that particular situation. So, what I’m talking about are myeloma patients who may be at their first relapse. We do not think of them as particularly refractory yet and these kinds of trials are out there; that would include the ASPIRE trial, KRD versus RD, there is the TOURMALINE trial, IRD Ixazomib REVLIMID versus RD, there is the ELOQUENT trial, elotuzumab RD versus RD, and then finally, POLLUX daratumumab RD versus RD. And all of these trials gave very strong signals that the triplet was better in terms of both progression-free and in some cases, overall survival. And I think most people, if a patient is not lenalidomide-refractory, would consider one of these for sure as an up-front combination.
And if you are going just by response rate, at least what’s published to date, the highest response rate of all is in that POLLUX trial with that daratumumab RD combination which has about a 93% response rate so it’s quite, it’s quite strong.
If a patient is not able to get lenalidomide, then looking at combinations that use bortezomib, and this is again in early relapse, there are a lot of good choices again so you have the CASTOR trial, daratumumab, bortezomib dexamethasone, versus bortezomib dex, PANORAMA, panobinostat Velcade dex versus Velcade dex. And then there is currently some phase II data looking at elotuzumab Velcade dex and, of course, there’s the ENDEAVOR trial using carfilzomib dex versus Velcade dex.
So, again, those have some pretty reasonable data, perhaps not quite as strong as the len-based regimens but those would also be very reasonable for an early relapse. And that means that we’re talking about patients who really have not manifested themselves to be terribly refractory at this point.
So I think most people would say in a relatively fit patient, those would be, any of those eight trials would be very good ones to consider in terms of a starting point. And then, how you break it down, I think you would say is the patient, do they have residual neuropathy, do they have coverage for lenalidomide, what’s their transportation situation, those kinds of considerations. But I think we have a lot of very strong data for the early relapses for these choices.
What’s, what gets a little bit more difficult is beyond that. Let’s say you’re talking about your second or third or fourth relapse. Then what we really do lack is any sort of testing mechanism that could tell you this particular combination is going to work or this will not work, because I think we all believe that these triplet combinations have synergy and that it’s possible that if a person is resistant to one of the components of the triplet that they might be sensitive though to that combination. So, we still are faced, to a large extent, looking at some trial and error when you’re talking about a later relapse and again, the patients do tend to be more refractory at that point and we’re expecting usually then a shorter progression-free interval as we go through these series of therapies.
Zack: What is the role of stem cell transplant within the new treatment landscape?
Dr Callander: Prior to some of these newer drugs that started to appear in 2013, one of the options that has been present for a number of years has been a second autologous stem cell transplant, and that’s feasible because melphalan has very well-known toxicities and it does appear to be a drug, unlike some others, that you can repeat a second time and actually expect patients to get through that treatment okay. So the use of second transplants has been around for, excuse me, easily, easily more than a decade but there really hadn’t been any randomized data to say that this could be a reasonable approach. And so there was a study from the MRC Group in Great Britain who published follow-up data on their study in 2016 which is looking at a second autologous stem cell transplant for patients who had been at least 18 months out from their first transplant. All of these patients were treated with a combination of bortezomib, doxorubicin, and dexamethasone and then randomized to either that second autologous stem cell transplant, or a maintenance treatment with oral cyclophosphamide. And they were able to show that there was both a progression-free and overall survival advantage for patients going through that second transplant.
But this particular study has been criticized because the oral cyclophosphamide maintenance is not something that’s typically used in the United States, however I think most of the experts in the field of myeloma would say for a patient who has been through, been, say, two years or more out from their transplant, a second transplant can also be quite, quite helpful. And one of the things that I really like about a second transplant talking to patients about this is two factors. One is it gives them usually an opportunity to then go perhaps onto a second sort of maintenance that can be very, very much improving their quality of life. In other words, it’s one thing to be coming in, say, once or twice a week for therapies that are effective, but it’s still a lot of time, and if you could go through a second transplant and then be able to be on a very low intensity maintenance with very few clinic visits, I think everybody really appreciates that.
The second thing that I’ve found and I think other people have in the field is that if you really have that patient who is quite refractory and may be failing some of the other proteasome inhibitor or other (indisc.) combinations that a second transplant can often in some ways sort of reset the clock and get patients who have active disease back down to a level where it can be more manageable. Again, usually that interval between progression from the first transplant versus progression from the second transplant is going to be shorter for the second, but I think still in the well-selected patients this can be a very good strategy.
Zack: Multiple myeloma has a five-year survival rate of approximately 50%. Is there a reason to believe that this will improve in the coming years? Why or why not?
Dr Callander: Yeah, I think there’s a lot of reason to believe that this is going to continue to improve and not even six or seven years ago when you looked at sort of the average progression after, say, a first autologous stem cell transplant, we would tell patients, and the data would support somewhere around a two-year, two years before they might have progression. Looking at some of the long-term follow-up data from the CLGB trial with a model of initial treatment, followed by stem cell transplant followed by lenalidomide maintenance, in long-term follow-up the average time or the median time for progression is right around 4.5 years. So, that’s very encouraging. It means that patients are going to start off now with a lot longer interval, and what that means is that if they’ve been stable that long, typically at that first relapse as I mentioned we have these great, these choices now that can potentially put people back into a complete remission. And some of these first relapse combinations that I mentioned have response rates that approximate what you can see at diagnosis, so they are quite powerful. So we really think that we have strategies at the first relapse that we can get people back into a very deep response again. So that kind of strategy wasn’t available even shortly ago.
I think the other thing that everybody is very excited about is there’s going to be all sorts of new drugs that are coming about. There are more antibody drugs in the works. There are, there is a drug antibody conjugate targeting B-cell maturation antigen, BCMA. There is a BiTE, there are actually two BiTE antibodies under investigation that will hopefully bring together a patient’s own T cells with a myeloma cell, sort of complementary or sort of the same strategy as the drug blinatumomab that’s approved for ALL.
There is an export inhibitor, Selinexor, that is hopefully, it’s in advanced testing and I think everybody is very excited about this. So I think that we all feel very hopeful that there’s going to be a number of other drugs available and there are certainly other targets that we think are being identified all the time.
Zack: Do gene therapies or CAR T therapies have a place in the landscape?
Dr Callander: There has been investigations into CAR T-cell therapy for myeloma. Some of the initial investigations were done looking at a target for CD19 and this doesn’t appear to be as good a target as we would like. So, BCMA now appears to be the target of choice, and there was some terrific data presented at ASCO this year, one from the Penn group and also from China, indicating very high response rates and durable response rates in patients with relapsed myeloma receiving CAR Ts aimed against BCMA.
I think as your audience may know, there are a number of commercial products that are being investigated for myeloma targeting BCMA and I know of three trials, as well as several centers are manufacturing their own CAR Ts against myeloma, so I think most people feel that this is going to be a terrific way to go.
There are, there is very good data that the CLL drug and now, and to a certain extent the lymphoma drug, venetoclax, may have a role in a sub-population of patients with myeloma who carry the cyclin D1 mutation. There is a whole other list of drugs, but I think CAR T cell therapy right now by and large, patients who have had many, many therapies are being offered this treatment. We expect that this will probably be moved up, but whether this would be, for example, an intervention offered at the first relapse eventually or the second relapse, I think a lot of people think that that may, in fact, happen. So I think these are very exciting times because I think we’re going to have more and more options for patients.
Zack: Are there any other points you would like to make for our audience?
Dr Callander: Yeah, I think one thing that I would recommend is I do think that for oncologists and hematologists in practice, as I tried to sort out in this talk, for those early relapses I think we have a lot of choices that you can feel very confident ordering some of the triplets I mentioned, either bortezomib-based or lenalidomide-based. But I think beyond that, one should really be searching out perhaps maybe a myeloma center to talk about what trials might be available or what kind of second or third-line therapy might be reasonable, is this the time for second transplant. So I think that that’s a time when bringing in perhaps an outside consultant, either in person or on the phone might be a very good thing to consider.
A couple other points I’d just like to make quickly. When you really are deciding, if you will how bad, if I can use that term, a relapse is, it’s often a very good idea to re-assess the patient completely. And by that, not just saying well, what is their M protein or their light chains, but considering imaging such as a PET scan which sometimes can reveal much more extensive disease. We are very much at my institution, encourage getting a second biopsy, a bone marrow biopsy at that point to see how things are going. Sometimes patients can have very little changes in their labs but end up carrying around a lot of myeloma and again, for people who have those more aggressive relapses, that’s a very important thing to know.
I think in summary, there are just a slew of drugs that I haven’t even mentioned that are under investigation right now and I think that we, what I tell my myeloma patients is we really think that we’re going to continue to have more options. We still want to try to stretch that initial treatment out as far as we can in terms of the response and now I think we’re really trying to change, to make that second intervention at the time of relapse last as many years as possible so that we will have healthier and stronger patients by the time that they really have to think about a second or a third-line intervention.
Zack: Alright. Thank you, Dr. Callander, for taking time out of your day to speak with us.
