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Antibodies in Combination Therapy for Myeloma

Insights From:Shaji K. Kumar, MD, Mayo Clinic College of Medicine; Peter Voorhees, MD, UNC School of Medicine at Chapel Hill
Published: Friday, Apr 29, 2016


Transcript:

Shaji Kumar, MD:
Daratumumab works through multiple different mechanisms in multiple myeloma, and these are all activation of different immunological pathways, as well as direct killing of the tumor cells by utilizing the immune system. So, it is only natural that we would consider using an immunomodulatory drug in combination with daratumumab. And we already have learned in the context of elotuzumab that when you combine elotuzumab with lenalidomide, it works much better than if you use it as a single agent. Along the same lines, daratumumab was also being compared with lenalidomide. And there were some very interesting data presented at ASH last year where, again, a group of patients with relapsed myeloma—not as heavily pretreated as the ones who are getting the single agent daratumumab, but, again, with a median of a couple lines of prior therapy—these patients were treated with a combination of daratumumab/lenalidomide and dexamethasone.

What was interesting was that almost 80% of those patients had a response to the combination therapy, including almost a third of the patients who had a deep response, they got a complete response. Now, this is not something that we typically see in patients with relapsed/refractory multiple myeloma. Again, many of these patients have gone through a stem cell transplant in the past, and have received other classes of drugs, like proteasome inhibitors and other immunomodulatory drugs. So, the combination clearly appears to have efficacy way beyond what you would have anticipated from either of those agents alone. There’s clear synergy in combining the two drugs. Of course, this is a single-arm trial, so it’s difficult to make too many interpretations based on the data, but clearly provides some exciting and provocative data that then needs to be confirmed in phase III clinical trials. In fact, a phase III trial of daratumumab/lenalidomide and dexamethasone comparing it to lenalidomide and dexamethasone, in relapsed myeloma patients who have had 1 to 3 prior lines of therapy, completed accrual late last year. And, hopefully, we should be hearing the results of that trial by the end of this year.

Daratumumab has also been combined with other myeloma therapies, especially the immunomodulatory drugs as well as the proteasome inhibitors. So, there has been some early data comparing daratumumab in combination with bortezomib and dexamethasone. And this has been tried both in the relapsed-patient population, as well as in the newly-diagnosed myeloma population. The data at this time are fairly sparse in terms of the number of patients that have been treated, so it’s difficult to say for sure how much the combination does compare to either of the drugs. But, what we have learned from these trials is, yes, it can be combined with bortezomib relatively safely without any unanticipated side effects. And we have seen responses in myeloma when this combination is used. How it fares in combination with lenalidomide or other combinations, it’s difficult to address at this point.

Peter Voorhees, MD: Dr. Philippe Moreau presented very exciting data at the 2014 ASH meeting in which daratumumab was combined with a number of different platforms in multiple myeloma. Specifically, daratumumab was combined with melphalan/prednisone/bortezomib. It was combined with bortezomib/thalidomide/dexamethasone. It was also combined with bortezomib/dexamethasone, and lastly pomalidomide/dexamethasone. The primary reason for pursuing the study was to establish the safety of combining daratumumab with these various myeloma platforms, both in the frontline setting, as well as in the relapsed and relapsed/refractory setting. And, importantly, what they showed in that particular study is that daratumumab can readily be incorporated into a number of different varied myeloma platforms quite safely. So, it did not significantly increase the hematologic toxicity that you would expect with the other agents, and importantly, it didn’t make the other side effects, of some of these things, worse, either. For example, the rates of neuropathy with bortezomib-based therapy was the same whether daratumumab was on board or not.

This study established the safety of combining daratumumab with these various regimens, which then spawned a number of different phase III studies that are currently ongoing. So, for example, there’s the MMY3004 study, which is a phase III study looking at bortezomib and dexamethasone with or without daratumumab in relapsed multiple myeloma. There is a frontline phase III study that the Institute for Functional Medicine (IFM) is currently undertaking, looking at bortezomib/thalidomide and dexamethasone with or without daratumumab in a transplant context. There’s a phase III study looking at melphalan/prednisone/bortezomib with or without daratumumab. Daratumumab is basically being combined with just about anything that you can think of in the context of phase III studies.

Importantly, Dr. Chari, and colleagues, presented data at the 2015 ASH meeting, which was basically an expansion of the pomalidomide/dexamethasone/daratumumab patient on the study that I just talked about. So, the rationale of combining daratumumab with an IMiD-based platform, such as pomalidomide, is that we know both lenalidomide and pomalidomide have immunomodulatory effects. Specifically, they both increase the number and activation of natural killer cells, as well as activated T-cells. The thought is you can actually get synergistic myeloma cell kill by targeting the myeloma cells for destruction with the daratumumab, and enhancing the branch of the immune system that’s responsible for antibody-dependent cellular cytotoxicity and getting synergistic effect.

The pomalidomide/dexamethasone/daratumumab study was basically an expansion where 100 total patients were treated. Daratumumab was given at the same dose and schedule that I previously talked about. Pomalidomide was given on days 1 through 21 of the 28 day cycle at a 4 mg dose, and the dexamethasone was given once weekly. And, again, patients were treated until disease progression. And, importantly, again, the side-effect profile was quite good with the inclusion of daratumumab into the regimen. So, the hematologic toxicity, for example, was what one would typically expect with pomalidomide and dexamethasone in this particular patient population. At the time of the ASH presentation, 75 patients of the 100 were evaluable for response, and there was a 71% response rate with the three-drug regimen. And, importantly, there was a 43% rate of what we call very good partial responses or better. In other words, 43% of patients had at least a 90% reduction in their monoclonal protein level with the particular therapy. So, this is a very exciting regimen that we’ll hopefully see more of moving forward.

You’ll certainly see the infusion reactions that we discussed. So, you’ll see the daratumumab-specific reactions, but it does not appear that daratumumab creates clinically significant increased other toxicities when combined with these other platforms. I think that we’ll need to see the phase III readouts to really be able to assess that with absolute certainly. For example, is there increased hematologic toxicity with the use of daratumumab when combined with these various different platforms? There may be, but I think at least in early days, it does appear that it can be combined quite readily with other myeloma platforms. And I would say that daratumumab can be very safely administered to a frailer patient, and I would worry more about the other drugs than I would about the daratumumab in that particular context.

Transcript Edited for Clarity
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Transcript:

Shaji Kumar, MD:
Daratumumab works through multiple different mechanisms in multiple myeloma, and these are all activation of different immunological pathways, as well as direct killing of the tumor cells by utilizing the immune system. So, it is only natural that we would consider using an immunomodulatory drug in combination with daratumumab. And we already have learned in the context of elotuzumab that when you combine elotuzumab with lenalidomide, it works much better than if you use it as a single agent. Along the same lines, daratumumab was also being compared with lenalidomide. And there were some very interesting data presented at ASH last year where, again, a group of patients with relapsed myeloma—not as heavily pretreated as the ones who are getting the single agent daratumumab, but, again, with a median of a couple lines of prior therapy—these patients were treated with a combination of daratumumab/lenalidomide and dexamethasone.

What was interesting was that almost 80% of those patients had a response to the combination therapy, including almost a third of the patients who had a deep response, they got a complete response. Now, this is not something that we typically see in patients with relapsed/refractory multiple myeloma. Again, many of these patients have gone through a stem cell transplant in the past, and have received other classes of drugs, like proteasome inhibitors and other immunomodulatory drugs. So, the combination clearly appears to have efficacy way beyond what you would have anticipated from either of those agents alone. There’s clear synergy in combining the two drugs. Of course, this is a single-arm trial, so it’s difficult to make too many interpretations based on the data, but clearly provides some exciting and provocative data that then needs to be confirmed in phase III clinical trials. In fact, a phase III trial of daratumumab/lenalidomide and dexamethasone comparing it to lenalidomide and dexamethasone, in relapsed myeloma patients who have had 1 to 3 prior lines of therapy, completed accrual late last year. And, hopefully, we should be hearing the results of that trial by the end of this year.

Daratumumab has also been combined with other myeloma therapies, especially the immunomodulatory drugs as well as the proteasome inhibitors. So, there has been some early data comparing daratumumab in combination with bortezomib and dexamethasone. And this has been tried both in the relapsed-patient population, as well as in the newly-diagnosed myeloma population. The data at this time are fairly sparse in terms of the number of patients that have been treated, so it’s difficult to say for sure how much the combination does compare to either of the drugs. But, what we have learned from these trials is, yes, it can be combined with bortezomib relatively safely without any unanticipated side effects. And we have seen responses in myeloma when this combination is used. How it fares in combination with lenalidomide or other combinations, it’s difficult to address at this point.

Peter Voorhees, MD: Dr. Philippe Moreau presented very exciting data at the 2014 ASH meeting in which daratumumab was combined with a number of different platforms in multiple myeloma. Specifically, daratumumab was combined with melphalan/prednisone/bortezomib. It was combined with bortezomib/thalidomide/dexamethasone. It was also combined with bortezomib/dexamethasone, and lastly pomalidomide/dexamethasone. The primary reason for pursuing the study was to establish the safety of combining daratumumab with these various myeloma platforms, both in the frontline setting, as well as in the relapsed and relapsed/refractory setting. And, importantly, what they showed in that particular study is that daratumumab can readily be incorporated into a number of different varied myeloma platforms quite safely. So, it did not significantly increase the hematologic toxicity that you would expect with the other agents, and importantly, it didn’t make the other side effects, of some of these things, worse, either. For example, the rates of neuropathy with bortezomib-based therapy was the same whether daratumumab was on board or not.

This study established the safety of combining daratumumab with these various regimens, which then spawned a number of different phase III studies that are currently ongoing. So, for example, there’s the MMY3004 study, which is a phase III study looking at bortezomib and dexamethasone with or without daratumumab in relapsed multiple myeloma. There is a frontline phase III study that the Institute for Functional Medicine (IFM) is currently undertaking, looking at bortezomib/thalidomide and dexamethasone with or without daratumumab in a transplant context. There’s a phase III study looking at melphalan/prednisone/bortezomib with or without daratumumab. Daratumumab is basically being combined with just about anything that you can think of in the context of phase III studies.

Importantly, Dr. Chari, and colleagues, presented data at the 2015 ASH meeting, which was basically an expansion of the pomalidomide/dexamethasone/daratumumab patient on the study that I just talked about. So, the rationale of combining daratumumab with an IMiD-based platform, such as pomalidomide, is that we know both lenalidomide and pomalidomide have immunomodulatory effects. Specifically, they both increase the number and activation of natural killer cells, as well as activated T-cells. The thought is you can actually get synergistic myeloma cell kill by targeting the myeloma cells for destruction with the daratumumab, and enhancing the branch of the immune system that’s responsible for antibody-dependent cellular cytotoxicity and getting synergistic effect.

The pomalidomide/dexamethasone/daratumumab study was basically an expansion where 100 total patients were treated. Daratumumab was given at the same dose and schedule that I previously talked about. Pomalidomide was given on days 1 through 21 of the 28 day cycle at a 4 mg dose, and the dexamethasone was given once weekly. And, again, patients were treated until disease progression. And, importantly, again, the side-effect profile was quite good with the inclusion of daratumumab into the regimen. So, the hematologic toxicity, for example, was what one would typically expect with pomalidomide and dexamethasone in this particular patient population. At the time of the ASH presentation, 75 patients of the 100 were evaluable for response, and there was a 71% response rate with the three-drug regimen. And, importantly, there was a 43% rate of what we call very good partial responses or better. In other words, 43% of patients had at least a 90% reduction in their monoclonal protein level with the particular therapy. So, this is a very exciting regimen that we’ll hopefully see more of moving forward.

You’ll certainly see the infusion reactions that we discussed. So, you’ll see the daratumumab-specific reactions, but it does not appear that daratumumab creates clinically significant increased other toxicities when combined with these other platforms. I think that we’ll need to see the phase III readouts to really be able to assess that with absolute certainly. For example, is there increased hematologic toxicity with the use of daratumumab when combined with these various different platforms? There may be, but I think at least in early days, it does appear that it can be combined quite readily with other myeloma platforms. And I would say that daratumumab can be very safely administered to a frailer patient, and I would worry more about the other drugs than I would about the daratumumab in that particular context.

Transcript Edited for Clarity
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