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Transplant-Eligible Multiple Myeloma: Current Treatment

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, Feb 26, 2019



Transcript:

Rafael Fonseca, MD:
When we see patients in our clinic who have newly diagnosed multiple myeloma and that are transplant-eligible, our goals have recently changed. We’re going for the deepest response possible. And that is a decision that is made right from the beginning when you choose a regimen that is going to create the best level of response.

As of now, the standard of care in the United States has been to give induction with a triplet-based combination, mostly in the form of lenalidomide, bortezomib, and dexamethasone followed by autologous stem cell transplant, and then followed by maintenance therapy, which we will discuss later.

This paradigm is being challenged because we do have regimens that are producing a deeper level of response. Some of these regimens are being tested in phase III clinical trials. But at the recent ASH [American Society of Hematology] meeting, we had a number of presentations that showed very exciting results. For example, there’s a study that was presented from Italy that looked at the combination of carfilzomib with lenalidomide and dexamethasone, followed by stem cell transplant, and followed by more of the same, and then maintenance.

Using a threshold of sensitivity of 10-5 for MRD [minimal residual disease], essentially 60% of patients achieve MRD-negative status post-transplant. I think this is a remarkable outcome. And if those patients are able to sustain that MRD-negative status, what is being defined now also by the International Myeloma Working Group a sustained MRD negativity, a fraction of those patients will be cured from their multiple myeloma.

So when I see new patients now in my clinic, number 1, I tell them that we’re going to go for the best possible response. I do discuss the possibility of myeloma being a curable disease. Because if you’re able to achieve these very deep levels of response and sustain that, then the data in the literature show that there’s a possibility that the patients may not need any more intensive therapy. We spend a lot of time arguing about what’s a cure or not. I think it’s mostly arguments about definitional items. But in fact, if you can sustain control of the diseases such that a person can complete a normal lifespan, in my mind the disease is cured. And I think we’re doing that in a fraction of myeloma patients.

Kenneth C. Anderson, MD: There are many regimens that are available for pretransplant treatment. Initial management of multiple myeloma in the transplant-eligible patient is usually with a triplet therapy, very commonly lenalidomide, bortezomib, and dexamethasone. So the immunomodulatory drug lenalidomide, the proteasome, bortezomib, and dexamethasone. It’s common because the overall response rate is nearly 100%. Three-quarters of patients get a very good partial response, and half of patients get a complete response, including patients who are MRD-negative.

Now there can be substitutions. The proteasome inhibitor carfilzomib, together with lenalidomide and dexamethasone, has also been studied and gets similar high rates of overall and extent of response. We now have being presented at the American Society of Hematology in the transplant-eligible patients the addition of monoclonal antibodies to those triplets. So, for example, lenalidomide, bortezomib, and dexamethasone, plus daratumumab. And in clinical trials already is lenalidomide, bortezomib, dexamethasone, and elotuzumab. At this meeting, daratumumab data added to lenalidomide, bortezomib, and dexamethasone was presented in a very small trial, 14 patients. But it does appear that adding monoclonal antibodies to these active triplets can not necessarily increase the overall response rate, because it’s already very high, but can increase the extent of response.

Noopur S. Raje, MD: We’ve come a long way with induction treatments for multiple myeloma, and the good news is we have options now. We have been using a triplet combination of treatments for this patient population for a very long time now. And based on data, we have been using VRd, or RVd, which is lenalidomide with bortezomib and dexamethasone. And there is a SWOG [Southwest Oncology Group] trial now that has compared this triplet to the doublet. Certainly, this trial was done in a transplant-deferred patient population, but nonetheless, the triplet regimen was the better regimen to use. More recently, we have carfilzomib in this space as well, in combination with lenalidomide and dexamethasone. Now most of the data with KRd, or carfilzomib with dexamethasone, are phase II data.

There’s a little bit of data looking at phase III studies, and there is, in fact, an ECOG [Eastern Cooperative Oncology Group] study called the ENDEAVOR trial, which is going to compare RVd to KRd. We don’t have the data on that. As of right now, I think given that bortezomib is approved in the upfront setting, VRd is probably the go-to treatment for the transplant-eligible patient as induction treatment. When it comes to KRd, I certainly use KRd mostly in the context of a clinical trial, only because carfilzomib, as of right now, is not yet approved.

Now the question of which one is better is still open. There’s been retrospective reviews on data looking at KRd versus RVd, and when you do a retrospective review of historical data there’s always a problem with that. There’s a hint of the suggestion that KRd tends to produce better responses, but I think we should wait for the ENDEAVOR trial to see whether we can decide which induction regimen is better, whether it’s KRd or RVd.

Given that we’re routinely using triplets in the treatment of multiple myeloma as induction treatment, the obvious next question is, should we now be using 4 drugs? This has been tried before. Several years back we did a trial with RVd with Cytoxan, for example. That was not a successful endeavor given that Cytoxan actually increased toxicity. And we saw increased mortality in this patient population. So one can argue and say that Cytoxan is probably not the best partner to combine with RVd.

Given that we have monoclonal antibodies now, the next step would be to use triplets in combination with a monoclonal antibody. At this year’s ASH, there were very early data looking at RVd with daratumumab, for example, and earlier at ASCO [the American Society of Clinical Oncology meeting] we’d seen data with KRd and daratumumab. So I do think quadruplets should be tested in this space, and specifically, if you want to try and get a really good response and a deep response even before going to transplant, because there’s enough data to demonstrate that the depth of your response, even pre-transplant, is a prognostic marker in terms of how patients do. So the better the response is, even before a transplant, I think would be a good idea. It needs to be tested though, and we want to make sure that we are not getting undue toxicity by adding more and more drugs.

Transcript edited for clarity.
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Transcript:

Rafael Fonseca, MD:
When we see patients in our clinic who have newly diagnosed multiple myeloma and that are transplant-eligible, our goals have recently changed. We’re going for the deepest response possible. And that is a decision that is made right from the beginning when you choose a regimen that is going to create the best level of response.

As of now, the standard of care in the United States has been to give induction with a triplet-based combination, mostly in the form of lenalidomide, bortezomib, and dexamethasone followed by autologous stem cell transplant, and then followed by maintenance therapy, which we will discuss later.

This paradigm is being challenged because we do have regimens that are producing a deeper level of response. Some of these regimens are being tested in phase III clinical trials. But at the recent ASH [American Society of Hematology] meeting, we had a number of presentations that showed very exciting results. For example, there’s a study that was presented from Italy that looked at the combination of carfilzomib with lenalidomide and dexamethasone, followed by stem cell transplant, and followed by more of the same, and then maintenance.

Using a threshold of sensitivity of 10-5 for MRD [minimal residual disease], essentially 60% of patients achieve MRD-negative status post-transplant. I think this is a remarkable outcome. And if those patients are able to sustain that MRD-negative status, what is being defined now also by the International Myeloma Working Group a sustained MRD negativity, a fraction of those patients will be cured from their multiple myeloma.

So when I see new patients now in my clinic, number 1, I tell them that we’re going to go for the best possible response. I do discuss the possibility of myeloma being a curable disease. Because if you’re able to achieve these very deep levels of response and sustain that, then the data in the literature show that there’s a possibility that the patients may not need any more intensive therapy. We spend a lot of time arguing about what’s a cure or not. I think it’s mostly arguments about definitional items. But in fact, if you can sustain control of the diseases such that a person can complete a normal lifespan, in my mind the disease is cured. And I think we’re doing that in a fraction of myeloma patients.

Kenneth C. Anderson, MD: There are many regimens that are available for pretransplant treatment. Initial management of multiple myeloma in the transplant-eligible patient is usually with a triplet therapy, very commonly lenalidomide, bortezomib, and dexamethasone. So the immunomodulatory drug lenalidomide, the proteasome, bortezomib, and dexamethasone. It’s common because the overall response rate is nearly 100%. Three-quarters of patients get a very good partial response, and half of patients get a complete response, including patients who are MRD-negative.

Now there can be substitutions. The proteasome inhibitor carfilzomib, together with lenalidomide and dexamethasone, has also been studied and gets similar high rates of overall and extent of response. We now have being presented at the American Society of Hematology in the transplant-eligible patients the addition of monoclonal antibodies to those triplets. So, for example, lenalidomide, bortezomib, and dexamethasone, plus daratumumab. And in clinical trials already is lenalidomide, bortezomib, dexamethasone, and elotuzumab. At this meeting, daratumumab data added to lenalidomide, bortezomib, and dexamethasone was presented in a very small trial, 14 patients. But it does appear that adding monoclonal antibodies to these active triplets can not necessarily increase the overall response rate, because it’s already very high, but can increase the extent of response.

Noopur S. Raje, MD: We’ve come a long way with induction treatments for multiple myeloma, and the good news is we have options now. We have been using a triplet combination of treatments for this patient population for a very long time now. And based on data, we have been using VRd, or RVd, which is lenalidomide with bortezomib and dexamethasone. And there is a SWOG [Southwest Oncology Group] trial now that has compared this triplet to the doublet. Certainly, this trial was done in a transplant-deferred patient population, but nonetheless, the triplet regimen was the better regimen to use. More recently, we have carfilzomib in this space as well, in combination with lenalidomide and dexamethasone. Now most of the data with KRd, or carfilzomib with dexamethasone, are phase II data.

There’s a little bit of data looking at phase III studies, and there is, in fact, an ECOG [Eastern Cooperative Oncology Group] study called the ENDEAVOR trial, which is going to compare RVd to KRd. We don’t have the data on that. As of right now, I think given that bortezomib is approved in the upfront setting, VRd is probably the go-to treatment for the transplant-eligible patient as induction treatment. When it comes to KRd, I certainly use KRd mostly in the context of a clinical trial, only because carfilzomib, as of right now, is not yet approved.

Now the question of which one is better is still open. There’s been retrospective reviews on data looking at KRd versus RVd, and when you do a retrospective review of historical data there’s always a problem with that. There’s a hint of the suggestion that KRd tends to produce better responses, but I think we should wait for the ENDEAVOR trial to see whether we can decide which induction regimen is better, whether it’s KRd or RVd.

Given that we’re routinely using triplets in the treatment of multiple myeloma as induction treatment, the obvious next question is, should we now be using 4 drugs? This has been tried before. Several years back we did a trial with RVd with Cytoxan, for example. That was not a successful endeavor given that Cytoxan actually increased toxicity. And we saw increased mortality in this patient population. So one can argue and say that Cytoxan is probably not the best partner to combine with RVd.

Given that we have monoclonal antibodies now, the next step would be to use triplets in combination with a monoclonal antibody. At this year’s ASH, there were very early data looking at RVd with daratumumab, for example, and earlier at ASCO [the American Society of Clinical Oncology meeting] we’d seen data with KRd and daratumumab. So I do think quadruplets should be tested in this space, and specifically, if you want to try and get a really good response and a deep response even before going to transplant, because there’s enough data to demonstrate that the depth of your response, even pre-transplant, is a prognostic marker in terms of how patients do. So the better the response is, even before a transplant, I think would be a good idea. It needs to be tested though, and we want to make sure that we are not getting undue toxicity by adding more and more drugs.

Transcript edited for clarity.
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