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Relapsed/Refractory Multiple Myeloma: Optimal Therapy

Insights From: Kenneth C. Anderson, MD, Dana-Farber Cancer Institute and Harvard Medical School; Rafael Fonseca, MD, Mayo Clinic; Noopur S. Raje, MD, Massachusetts General Hospital Cancer Center
Published: Tuesday, Mar 19, 2019



Transcript: 

Noopur S. Raje, MD: What is the optimal treatment at relapse? There are a lot of caveats out here, right? It really depends on what kind of treatment they’ve had. You brought up RVd [lenalidomide/bortezomib/dexamethasone] followed by, most of our patients would be on REV [Revlimid] maintenance, and it really depends on when that relapse happens. And what is it that a patient is refractory to? Are they refractory to Revlimid because they’ve been on Revlimid maintenance? More than likely. And then a lot of the phase III trials that have gotten approved with the Revlimid combination don’t become relevant in our setting.

Are there folks who had proteasome inhibitor therapy 3 years ahead of time, and can I rechallenge them with a proteasome inhibitor? The answer to that is, yes. Can you reuse treatment you’ve used before? Absolutely. So a lot of it depends on what kind of a relapse it is. Is it a biochemical relapse? Is it an aggressive relapse? Are these patients with high-risk cytogenetic features wherein the relapse is going to be very aggressive and you need to control the disease quickly? Or is it just a little bit of a paraprotein going up? And depending on all of these factors, I think one makes a decision on what the next treatment would be. And typically you like to use a drug that a patient is not refractory to. So, for example, if you’re on REV maintenance, there’s adequate data now to transition to a pomalidomide-based regimen. Now whether you use POM [pomalidomide] with ixazomib or POM with bortezomib, or you use carfilzomib in that space, there are all kinds of options. The good news is we have lots of good options. The bad news is there’s not 1 answer that fits all, and you really have to figure out how the patient is doing.

I think with the data with daratumumab coming more and more up front, the whole paradigm of how we take care of relapses is going to change, and it’s going to change fairly quickly now. With the MAIA trial, DARA [daratumumab] is going to be used up front. So are we going to be using DARA with Pd [pomalidomide/dexamethasone]? Are we going to use KPd [carfilzomib/pomalidomide/dexamethasone]? My sense is we’re going to use more carfilzomib/POM/DEX [dexamethasone] fairly quickly. If carfilzomib comes up front, then what’s the next one we’re going to be using? So this is going to be shifting. And it’s really going to be dependent on what’s available to people up front, what they’ve had up front, and then will change according to what the disease looks at the time of relapse.

Rafael Fonseca, MD: In the setting of relapsed and refractory myeloma, we have a whole range of options that are now available. Some of them commercially for the treatment of our patients, including some clinical trials as well. If you look at what happens with a first line of therapy; so if you take the canonical patient, you’re going to go through about 8 months of pretransplant time where patients get their induction and they get the transplant. The majority of patients can do this and they get their transplant. And then you start looking at a maintenance strategy. You take data, for instance, from the meta-analysis where you’re looking at another 15 months of disease control.

We’re talking about the first relapse being treated sometimes 5 years out from the moment of diagnosis. And, of course, it varies. Maybe it has to be done sooner. Sometimes it could be done later, or never again.

At that point, what we’re doing is mostly using triplet-based combinations. And right now the strategy is really focused on 2 big approaches. One is the combination of daratumumab plus an IMiD [immunomodulatory drug], plus dexamethasone. Regarding the IMiD, there’s some discrepancy for what people think should be the right agent for combination. If you have been using lenalidomide for maintenance, should you use LEN [lenalidomide] at the higher dose? Or should you move on to pomalidomide? We frequently do the latter. Now the second strategy would be the same but with carfilzomib. So carfilzomib/IMiD/dexamethasone with the same considerations for the IMiD.

There are a number of other options that we may consider in this patient population, but I would say those are the 2 main ones. We obviously have the data for elotuzumab, which has proven to be a very well tolerated medication. So one could argue that for a very long indolent relapse, that could be a very good regimen; or ixazomib, because of the aspects of convenience. But that’s what we’re doing. And then, of course, once the person receives this therapy and experiences a progression, what we’re going to try to do is the alternate. If you were using daratumumab, switch to carfilzomib, and vice versa.

Kenneth C. Anderson, MD: If you begin with a triplet, for example, like lenalidomide/bortezomib/ dexamethasone, and if the disease is progressing while the patient is on therapy, it suggests that it’s refractory to those drugs. What’s very fortunate is we have multiple options for which to treat that patient. We have the second-generation immunomodulatory drug pomalidomide and second-generation proteasome inhibitor carfilzomib, for example. So one option would be to treat that patient with pomalidomide, carfilzomib, and dexamethasone.

We also have monoclonal antibodies. And what you have now is similarly either daratumumab or elotuzumab, either one of them now, combined with pomalidomide, the second-generation immunomodulatory drug, and dexamethasone as an FDA-approved option for such a patient. So in RVd-refractory myeloma, we have the opportunity to take pomalidomide/DEX, and either pair it with a second-generation proteasome inhibitor—carfilzomib—or, monoclonal antibodies—daratumumab or elotuzumab.

We have basically 6 different classes of drugs, even today. There are some new ones coming, but the point is that we really need to keep making and developing novel drugs. That, however, should not delay us from using the best possible drugs as early as we can.

The best chance we have for overall response, and, in particular, extent of response is to treat myeloma at the earliest possible stage when there’s the fewest cells and when they’re still sensitive to therapy. So what we do is we get new novel agents and approve them in advanced disease, and then they’re used in relapse, and then they’re used in newly diagnosed patients. And now the novel agents are even being tested in smoldering myeloma. But we should not hold back. We should use scientifically informed combination therapies at the earliest possible opportunity.

Transcript Edited for Clarity
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Transcript: 

Noopur S. Raje, MD: What is the optimal treatment at relapse? There are a lot of caveats out here, right? It really depends on what kind of treatment they’ve had. You brought up RVd [lenalidomide/bortezomib/dexamethasone] followed by, most of our patients would be on REV [Revlimid] maintenance, and it really depends on when that relapse happens. And what is it that a patient is refractory to? Are they refractory to Revlimid because they’ve been on Revlimid maintenance? More than likely. And then a lot of the phase III trials that have gotten approved with the Revlimid combination don’t become relevant in our setting.

Are there folks who had proteasome inhibitor therapy 3 years ahead of time, and can I rechallenge them with a proteasome inhibitor? The answer to that is, yes. Can you reuse treatment you’ve used before? Absolutely. So a lot of it depends on what kind of a relapse it is. Is it a biochemical relapse? Is it an aggressive relapse? Are these patients with high-risk cytogenetic features wherein the relapse is going to be very aggressive and you need to control the disease quickly? Or is it just a little bit of a paraprotein going up? And depending on all of these factors, I think one makes a decision on what the next treatment would be. And typically you like to use a drug that a patient is not refractory to. So, for example, if you’re on REV maintenance, there’s adequate data now to transition to a pomalidomide-based regimen. Now whether you use POM [pomalidomide] with ixazomib or POM with bortezomib, or you use carfilzomib in that space, there are all kinds of options. The good news is we have lots of good options. The bad news is there’s not 1 answer that fits all, and you really have to figure out how the patient is doing.

I think with the data with daratumumab coming more and more up front, the whole paradigm of how we take care of relapses is going to change, and it’s going to change fairly quickly now. With the MAIA trial, DARA [daratumumab] is going to be used up front. So are we going to be using DARA with Pd [pomalidomide/dexamethasone]? Are we going to use KPd [carfilzomib/pomalidomide/dexamethasone]? My sense is we’re going to use more carfilzomib/POM/DEX [dexamethasone] fairly quickly. If carfilzomib comes up front, then what’s the next one we’re going to be using? So this is going to be shifting. And it’s really going to be dependent on what’s available to people up front, what they’ve had up front, and then will change according to what the disease looks at the time of relapse.

Rafael Fonseca, MD: In the setting of relapsed and refractory myeloma, we have a whole range of options that are now available. Some of them commercially for the treatment of our patients, including some clinical trials as well. If you look at what happens with a first line of therapy; so if you take the canonical patient, you’re going to go through about 8 months of pretransplant time where patients get their induction and they get the transplant. The majority of patients can do this and they get their transplant. And then you start looking at a maintenance strategy. You take data, for instance, from the meta-analysis where you’re looking at another 15 months of disease control.

We’re talking about the first relapse being treated sometimes 5 years out from the moment of diagnosis. And, of course, it varies. Maybe it has to be done sooner. Sometimes it could be done later, or never again.

At that point, what we’re doing is mostly using triplet-based combinations. And right now the strategy is really focused on 2 big approaches. One is the combination of daratumumab plus an IMiD [immunomodulatory drug], plus dexamethasone. Regarding the IMiD, there’s some discrepancy for what people think should be the right agent for combination. If you have been using lenalidomide for maintenance, should you use LEN [lenalidomide] at the higher dose? Or should you move on to pomalidomide? We frequently do the latter. Now the second strategy would be the same but with carfilzomib. So carfilzomib/IMiD/dexamethasone with the same considerations for the IMiD.

There are a number of other options that we may consider in this patient population, but I would say those are the 2 main ones. We obviously have the data for elotuzumab, which has proven to be a very well tolerated medication. So one could argue that for a very long indolent relapse, that could be a very good regimen; or ixazomib, because of the aspects of convenience. But that’s what we’re doing. And then, of course, once the person receives this therapy and experiences a progression, what we’re going to try to do is the alternate. If you were using daratumumab, switch to carfilzomib, and vice versa.

Kenneth C. Anderson, MD: If you begin with a triplet, for example, like lenalidomide/bortezomib/ dexamethasone, and if the disease is progressing while the patient is on therapy, it suggests that it’s refractory to those drugs. What’s very fortunate is we have multiple options for which to treat that patient. We have the second-generation immunomodulatory drug pomalidomide and second-generation proteasome inhibitor carfilzomib, for example. So one option would be to treat that patient with pomalidomide, carfilzomib, and dexamethasone.

We also have monoclonal antibodies. And what you have now is similarly either daratumumab or elotuzumab, either one of them now, combined with pomalidomide, the second-generation immunomodulatory drug, and dexamethasone as an FDA-approved option for such a patient. So in RVd-refractory myeloma, we have the opportunity to take pomalidomide/DEX, and either pair it with a second-generation proteasome inhibitor—carfilzomib—or, monoclonal antibodies—daratumumab or elotuzumab.

We have basically 6 different classes of drugs, even today. There are some new ones coming, but the point is that we really need to keep making and developing novel drugs. That, however, should not delay us from using the best possible drugs as early as we can.

The best chance we have for overall response, and, in particular, extent of response is to treat myeloma at the earliest possible stage when there’s the fewest cells and when they’re still sensitive to therapy. So what we do is we get new novel agents and approve them in advanced disease, and then they’re used in relapse, and then they’re used in newly diagnosed patients. And now the novel agents are even being tested in smoldering myeloma. But we should not hold back. We should use scientifically informed combination therapies at the earliest possible opportunity.

Transcript Edited for Clarity
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