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On the Horizon for Multiple Myeloma

Insights From:Shaji K. Kumar, MD, Mayo Clinic College of Medicine; Peter Voorhees, MD, UNC School of Medicine at Chapel Hill
Published: Wednesday, May 25, 2016


Transcript:

Shaji Kumar, MD:
Drugs that are found to be effective for treatment of relapsed multiple myeloma eventually find their way to the treatment of newly diagnosed myeloma as well. As with other drugs, monoclonal antibodies are no exception, and they have also been tried in newly diagnosed multiple myeloma. The ELOQUENT-1 trial looked at the combination of elotuzumab/lenalidomide/dexamethasone, comparing it to lenalidomide and dexamethasone in newly diagnosed multiple myeloma. That trial has completed accrual, and we don’t have the complete results of that phase III trial. Similarly, daratumumab has also been combined with lenalidomide and dexamethasone, comparing it with lenalidomide and dexamethasone in newly diagnosed multiple myeloma in patients who are not eligible to undergo stem cell transplant. This particular trial is currently enrolling and is almost a third of its way through. We probably won’t hear the results of that combination in the newly diagnosed myeloma for probably a couple of years.

But, increasingly, there are trials that are being planned looking at the combination of daratumumab with other very effective regimens. So, one of the most effective regimens that we have for use in newly diagnosed multiple myeloma is a combination of bortezomib/lenalidomide and dexamethasone. Now, this is a combination that has been shown to improve the overall survival in patients with newly diagnosed myeloma. There are clinical trials that are currently looking at combining daratumumab with either the triplet of bortezomib/lenalidomide/dexamethasone, or carfilzomib/lenalidomide/dexamethasone, or ixazomib/lenalidomide/dexamethasone. So, these are all trials that are currently under way. But, as we have seen with relapsed multiple myeloma, we are quite excited about these combinations in the upfront setting where we think it can really make a difference with the natural history of the disease.

Peter Voorhees, MD: For first-relapse patients, there’s a number of different phase III studies that are ongoing, incorporating daratumumab into standard myeloma platforms. One of them I’ve already alluded to. This is the MMY3004 study, looking at bortezomib/dexamethasone with or without daratumumab for patients with relapsed multiple myeloma. And this is for patients that typically have received one to three prior lines of therapy. So, I think it will be very interesting to see the readout of that particular study. There’s also the MMY3003 study, which is a study looking at the combination of lenalidomide/dexamethasone and daratumumab for patients with one to three prior therapies for their multiple myeloma. And that’s a study that actually finished enrolling quite some time ago now. We’ll hopefully get a readout on that sometime in the very near future. I think you’re going to see daratumumab move to first relapse and earlier treatment sooner rather than later.

Certainly there’s a lot of interest in developing improved maintenance strategies. So, there’s a couple of different ways that you can look at this. One is to improve on existing maintenance therapies. Certainly, the most data that we currently have—at least as far as phase III studies are concerned—is the use of lenalidomide as a maintenance therapy, either given after recovery from autologous stem cell transplantation or even in the non-transplant setting, as well. The question is, can we build on that success? And, again, given the synergy of IMiDs with monoclonal antibody therapeutics, there certainly is a lot of interest in combining antibodies—such as daratumumab and elotuzumab—to a lenalidomide platform to see if you can improve on the progression-free survival, and potentially overall survival seen with the use of lenalidomide maintenance as a single agent.

In addition, it’s important to recognize that not everybody tolerates lenalidomide as maintenance therapy for their disease. It’s also important to recognize that there is a low but real increased risk of secondary cancers with lenalidomide maintenance therapy, particularly given after melphalan-based therapy. So, it’s also important that we explore other therapeutic strategies in the maintenance setting, perhaps without lenalidomide, to see if we can also improve progression-free survival and potentially overall survival, but in a way that might be better tolerated for long-term administration. And daratumumab would certainly be interesting to study in that particular context.

The debate about sequencing therapy versus combination therapy is one that’s discussed quite frequently. What I would say is this: there’s absolutely no question that the combination therapies produce, in general, better overall response rates. In addition to that, you see a higher rate of what we call good-quality responses, so patients who have a much deeper response to therapy. And generally speaking, you see an improvement in progression-free survival and duration of remission as well. So, for those patients with relapsed disease that are experiencing active morbidity related to their disease, or perhaps have a more explosive progression, that’s the kind of patient where you really want a regimen that’s going to have a higher likelihood of working, and producing a deep response, and maintaining that response long in order to benefit the patient. I think you can very strongly argue in favor of combination strategy. Now, whether or not combination therapy improves overall survival compared to sequential therapy is a debatable situation.

Certainly, the ASPIRE data looking at the combination of lenalidomide and dexamethasone versus carfilzomib/lenalidomide and dexamethasone would suggest an overall survival advantage with the addition of carfilzomib to the lenalidomide/dexamethasone platform. However, many of the patients that were treated on that particular study were ex-US, and did not have access to carfilzomib-based therapy at the time of progression if they were assigned to the lenalidomide/dexamethasone arm. So, I think it remains an open question. I think it remains a very important question to answer. And I think a great way to answer this question would be to do a study, for example, of pomalidomide and dexamethasone, followed by daratumumab monotherapy at the time of progression versus pomalidomide/dexamethasone and daratumumab from the beginning. In addition, you could also have a third arm where you treat with pomalidomide and dexamethasone, and at the time of progression, you add in the daratumumab but keep the pomalidomide going to see whether or not—although the pomalidomide in that situation may have lost activity against the myeloma itself—it may actually enhance the effects of the daratumumab. So, a study like that would be a terrific one, and would help answer that question.

Shaji Kumar, MD: One of the difficulties with the monoclonal antibodies is that patients have to come in and get the infusion over a period of time, and that obviously takes a significant chunk of time out of people’s daily life. One of the approaches that has been looked at in a variety of different injectable drugs has been the ability to give it subcutaneously. We already know that in the context of bortezomib in myeloma, going from the IV to subcutaneous formulation has not only made it easier, but also significantly diminished the side effects. Along those lines, there have been attempts to try and give the daratumumab subcutaneously.

So, there are ongoing trials with daratumumab which are looking at a special type of injector to actually give the drug under the skin. And the particular process will allow us to give a relatively large volume of drug under the skin, which would obviate the need for infusion, potentially decrease the infusion reaction problems, and also decrease the amount of time the patients have to spend in the chemotherapy room.

Transcript Edited for Clarity
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Transcript:

Shaji Kumar, MD:
Drugs that are found to be effective for treatment of relapsed multiple myeloma eventually find their way to the treatment of newly diagnosed myeloma as well. As with other drugs, monoclonal antibodies are no exception, and they have also been tried in newly diagnosed multiple myeloma. The ELOQUENT-1 trial looked at the combination of elotuzumab/lenalidomide/dexamethasone, comparing it to lenalidomide and dexamethasone in newly diagnosed multiple myeloma. That trial has completed accrual, and we don’t have the complete results of that phase III trial. Similarly, daratumumab has also been combined with lenalidomide and dexamethasone, comparing it with lenalidomide and dexamethasone in newly diagnosed multiple myeloma in patients who are not eligible to undergo stem cell transplant. This particular trial is currently enrolling and is almost a third of its way through. We probably won’t hear the results of that combination in the newly diagnosed myeloma for probably a couple of years.

But, increasingly, there are trials that are being planned looking at the combination of daratumumab with other very effective regimens. So, one of the most effective regimens that we have for use in newly diagnosed multiple myeloma is a combination of bortezomib/lenalidomide and dexamethasone. Now, this is a combination that has been shown to improve the overall survival in patients with newly diagnosed myeloma. There are clinical trials that are currently looking at combining daratumumab with either the triplet of bortezomib/lenalidomide/dexamethasone, or carfilzomib/lenalidomide/dexamethasone, or ixazomib/lenalidomide/dexamethasone. So, these are all trials that are currently under way. But, as we have seen with relapsed multiple myeloma, we are quite excited about these combinations in the upfront setting where we think it can really make a difference with the natural history of the disease.

Peter Voorhees, MD: For first-relapse patients, there’s a number of different phase III studies that are ongoing, incorporating daratumumab into standard myeloma platforms. One of them I’ve already alluded to. This is the MMY3004 study, looking at bortezomib/dexamethasone with or without daratumumab for patients with relapsed multiple myeloma. And this is for patients that typically have received one to three prior lines of therapy. So, I think it will be very interesting to see the readout of that particular study. There’s also the MMY3003 study, which is a study looking at the combination of lenalidomide/dexamethasone and daratumumab for patients with one to three prior therapies for their multiple myeloma. And that’s a study that actually finished enrolling quite some time ago now. We’ll hopefully get a readout on that sometime in the very near future. I think you’re going to see daratumumab move to first relapse and earlier treatment sooner rather than later.

Certainly there’s a lot of interest in developing improved maintenance strategies. So, there’s a couple of different ways that you can look at this. One is to improve on existing maintenance therapies. Certainly, the most data that we currently have—at least as far as phase III studies are concerned—is the use of lenalidomide as a maintenance therapy, either given after recovery from autologous stem cell transplantation or even in the non-transplant setting, as well. The question is, can we build on that success? And, again, given the synergy of IMiDs with monoclonal antibody therapeutics, there certainly is a lot of interest in combining antibodies—such as daratumumab and elotuzumab—to a lenalidomide platform to see if you can improve on the progression-free survival, and potentially overall survival seen with the use of lenalidomide maintenance as a single agent.

In addition, it’s important to recognize that not everybody tolerates lenalidomide as maintenance therapy for their disease. It’s also important to recognize that there is a low but real increased risk of secondary cancers with lenalidomide maintenance therapy, particularly given after melphalan-based therapy. So, it’s also important that we explore other therapeutic strategies in the maintenance setting, perhaps without lenalidomide, to see if we can also improve progression-free survival and potentially overall survival, but in a way that might be better tolerated for long-term administration. And daratumumab would certainly be interesting to study in that particular context.

The debate about sequencing therapy versus combination therapy is one that’s discussed quite frequently. What I would say is this: there’s absolutely no question that the combination therapies produce, in general, better overall response rates. In addition to that, you see a higher rate of what we call good-quality responses, so patients who have a much deeper response to therapy. And generally speaking, you see an improvement in progression-free survival and duration of remission as well. So, for those patients with relapsed disease that are experiencing active morbidity related to their disease, or perhaps have a more explosive progression, that’s the kind of patient where you really want a regimen that’s going to have a higher likelihood of working, and producing a deep response, and maintaining that response long in order to benefit the patient. I think you can very strongly argue in favor of combination strategy. Now, whether or not combination therapy improves overall survival compared to sequential therapy is a debatable situation.

Certainly, the ASPIRE data looking at the combination of lenalidomide and dexamethasone versus carfilzomib/lenalidomide and dexamethasone would suggest an overall survival advantage with the addition of carfilzomib to the lenalidomide/dexamethasone platform. However, many of the patients that were treated on that particular study were ex-US, and did not have access to carfilzomib-based therapy at the time of progression if they were assigned to the lenalidomide/dexamethasone arm. So, I think it remains an open question. I think it remains a very important question to answer. And I think a great way to answer this question would be to do a study, for example, of pomalidomide and dexamethasone, followed by daratumumab monotherapy at the time of progression versus pomalidomide/dexamethasone and daratumumab from the beginning. In addition, you could also have a third arm where you treat with pomalidomide and dexamethasone, and at the time of progression, you add in the daratumumab but keep the pomalidomide going to see whether or not—although the pomalidomide in that situation may have lost activity against the myeloma itself—it may actually enhance the effects of the daratumumab. So, a study like that would be a terrific one, and would help answer that question.

Shaji Kumar, MD: One of the difficulties with the monoclonal antibodies is that patients have to come in and get the infusion over a period of time, and that obviously takes a significant chunk of time out of people’s daily life. One of the approaches that has been looked at in a variety of different injectable drugs has been the ability to give it subcutaneously. We already know that in the context of bortezomib in myeloma, going from the IV to subcutaneous formulation has not only made it easier, but also significantly diminished the side effects. Along those lines, there have been attempts to try and give the daratumumab subcutaneously.

So, there are ongoing trials with daratumumab which are looking at a special type of injector to actually give the drug under the skin. And the particular process will allow us to give a relatively large volume of drug under the skin, which would obviate the need for infusion, potentially decrease the infusion reaction problems, and also decrease the amount of time the patients have to spend in the chemotherapy room.

Transcript Edited for Clarity
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