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The Future of Immunotherapy in Myeloma

Insights From:Shaji K. Kumar, MD, Mayo Clinic College of Medicine; Peter Voorhees, MD, UNC School of Medicine at Chapel Hill
Published: Wednesday, Jun 01, 2016


Transcript:

Peter Voorhees, MD:
Patients with smoldering multiple myeloma that are high risk of developing symptomatic disease certainly are a group of patients that we have a lot of interest in these newer therapies. We certainly want to apply therapies that are, first of all, safe to use. Not everybody with smoldering multiple myeloma is going to go on to develop symptomatic disease very quickly, so you want to apply a strategy that is safe but also effective. In that context, daratumumab, for example, is an excellent strategy to evaluate in this particular setting. And there’s an ongoing randomized study looking at three different dosing schedules of daratumumab in patients, who have smoldering multiple myeloma, that are at somewhat higher risk of progression to symptomatic disease.

I think there’s very strong data on the use of lenalidomide and dexamethasone for patients with smoldering multiple myeloma that are high risk of developing symptomatic disease. And there’s an ongoing study adding elotuzumab to the lenalidomide/dexamethasone backbone to see if that will further improve upon the results with lenalidomide and dexamethasone. I think that there’s also a lot of interest in vaccine-based strategies in this particular context as well, and vaccines in combination with these monoclonal antibodies would be another exciting area of investigation.

Shaji Kumar, MD: The era of monoclonal antibodies in multiple myeloma is just beginning, and daratumumab and elotuzumab are the first two monoclonal antibodies to be approved for use in multiple myeloma. However, there is a whole slew of monoclonal antibodies that are currently going through clinical trials. The one that is closest to clinic is a drug called isatuximab, which is very similar to daratumumab in terms of the target. That monoclonal antibody also targets CD38 that’s present on the monoclonal plasma cells. It is unclear how much this monoclonal antibody differs from daratumumab in terms of its toxicity profile and efficacy. However, in the single-arm trials that have been performed with isatuximab, both in the single agent as well as in combination with lenalidomide and dexamethasone, there has been significant efficacy in patients with relapsed and refractory multiple myeloma. So, there are phase III clinical trials that are being initiated looking at isatuximab in combination with lenalidomide/dexamethasone, as well as other drugs. It seems to be very well tolerated based on the data that we have from the single-arm trials.

Now, in addition to these, what we call naked antibodies—which are basically antibodies which utilize the immune system to act on the tumor cells—there are also antibodies that are being developed that conjugate a toxin to a monoclonal antibody. There are several of those antibodies currently being developed. There’s one that uses an antibody similar to elotuzumab, where it’s been conjugated with a toxin. There’s another antibody that is targeted against a molecule called CD56 that’s present on many of these plasma cells, and that has been conjugated or attached to a toxin, which then is delivered to the myeloma cell by virtue of the fact that proteins present on the tumor cells.

In addition to the monoclonal antibodies, there are several other immunotherapy approaches that are currently being evaluated in multiple myeloma. The one that has caught the excitement of a lot of people has been the CAR T-cell therapy. Now, CAR T- cells have shown some phenomenal results in patients with acute leukemia, which would not have been expected based on the current therapies that we have available for that disease. And more recently, there has been a report of a single patient where the use of CAR T-cell resulted in eradication of the myeloma cells way beyond what we would have expected with the type of therapies that patient had seen previously, while it’s a single agent. That is an anecdotal report, so we clearly cannot read too much into it, but that has given enough excitement.

CAR T-cells can be developed against a variety of different proteins on the myeloma cells. The one report that has been published used CAR T-cells that’s targeted against what we call a CD19, which is similar to what has been done in leukemia. There are several clinical trials that are ongoing that are using CAR T-cells engineered against different antigens. Many of them are unique to myeloma, and we are hoping that the results from these ongoing clinical trials would be as we hope based on the initial reports.

In addition to the CAR T-cells, there are other approaches that are being used. Vaccination strategies have been tried in this disease for a long period of time, but I think we have a better sense of the type of antigens that we need to target for developing vaccines in myeloma. There are several trials that are looking at vaccination strategies in conjunction with autologous stem cell transplant for myeloma. Now, clearly patients who undergo an autologous peripheral blood stem cell transplant have significant disease control. And their immune system tends to come back to a normal phase, much more than in patients who are getting other types of therapy. So, that does provide a unique platform for us to examine some of these vaccination strategies and dendritic cell strategies, many of which are currently in process.

Peter Voorhees, MD: I think it’s a very exciting time in multiple myeloma. I think the advent of elotuzumab in combination with lenalidomide and dexamethasone, and daratumumab monotherapy for more heavily pretreated patients, is just the first step. You’re going to see these agents being used earlier in the course of the disease and in novel combinations moving forward. In addition, I think as we learn more about how the immune system is suppressed as cancers develop, we’ve developed new therapeutics that can be used to treat not just multiple myeloma but other malignancies as well. So, for example, there’s a lot of excitement about checkpoint inhibitors in a variety of different malignancies, and certainly in multiple myeloma as well. At our ASH meeting in 2015, there was very exciting data presented looking at the combination of lenalidomide and dexamethasone with pembrolizumab, and pomalidomide/dexamethasone with pembrolizumab.

There’s very exciting data on the use of CAR T-cell therapies in multiple myeloma that were presented at ASH. So, the NCI group showed very exciting preliminary data on a CAR T-cell program recognizing B-cell maturation antigen on the surface of myeloma cells, and they saw an early signal of activity particularly with higher T-cell doses. I think you’re going to see an explosion in the area of immuno-oncology in multiple myeloma over the next 5 to 10 years, and it will be very exciting to combine these different immunomodulatory drugs over the course of time. For example, combining IMiDs with the monoclonal antibodies, combining these things with checkpoint inhibitors, and seeing if these therapeutics can enhance the effects of the CAR T-cell therapies moving forward. I think we’ve done a great job as far as developing the proteasome inhibitors. We’ve done a great job developing the IMiDs. I think the next wave of the future is in immuno-oncology in multiple myeloma.

Shaji Kumar, MD: The cost of therapy is a very hot topic currently in the cancer world. We all constantly see the reports about how much cancer drugs cost, and how much it adds to the cost of therapy in general, especially when you use many of these drugs in combination. We already know that the drugs that we had available before, like the proteasome inhibitors and the immunomodulatory drugs, are fairly expensive. And when you combine them, the cost of therapy becomes extremely high. The addition of a monoclonal antibody only adds to that cost burden in this disease. So, I think it’s very important for us to think about how we can become more cost effective. The use of the appropriate combinations to get the maximum benefit is more and more important when we factor in the cost of the drugs.

There’s obviously ongoing debate as to what is considered an appropriate cost, and how do we measure it, and the right cost in the context of the efficacy of these drugs. I think that’s going to be a debate that’s constantly ongoing, but I think from a physician and the patient perspective, it’s important for us to focus on how we can get the best therapy for the patient. At the same time we need to keep in mind what particular or unique combination of drugs can achieve the best benefit, and at the same time keep the drug cost low. Obviously, as many of these drugs go generic, the overall cost of combinations will go down, and that will enable us to incorporate these new drugs into the combinations that may include some old drugs, which are less expensive.

Transcript Edited for Clarity
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Transcript:

Peter Voorhees, MD:
Patients with smoldering multiple myeloma that are high risk of developing symptomatic disease certainly are a group of patients that we have a lot of interest in these newer therapies. We certainly want to apply therapies that are, first of all, safe to use. Not everybody with smoldering multiple myeloma is going to go on to develop symptomatic disease very quickly, so you want to apply a strategy that is safe but also effective. In that context, daratumumab, for example, is an excellent strategy to evaluate in this particular setting. And there’s an ongoing randomized study looking at three different dosing schedules of daratumumab in patients, who have smoldering multiple myeloma, that are at somewhat higher risk of progression to symptomatic disease.

I think there’s very strong data on the use of lenalidomide and dexamethasone for patients with smoldering multiple myeloma that are high risk of developing symptomatic disease. And there’s an ongoing study adding elotuzumab to the lenalidomide/dexamethasone backbone to see if that will further improve upon the results with lenalidomide and dexamethasone. I think that there’s also a lot of interest in vaccine-based strategies in this particular context as well, and vaccines in combination with these monoclonal antibodies would be another exciting area of investigation.

Shaji Kumar, MD: The era of monoclonal antibodies in multiple myeloma is just beginning, and daratumumab and elotuzumab are the first two monoclonal antibodies to be approved for use in multiple myeloma. However, there is a whole slew of monoclonal antibodies that are currently going through clinical trials. The one that is closest to clinic is a drug called isatuximab, which is very similar to daratumumab in terms of the target. That monoclonal antibody also targets CD38 that’s present on the monoclonal plasma cells. It is unclear how much this monoclonal antibody differs from daratumumab in terms of its toxicity profile and efficacy. However, in the single-arm trials that have been performed with isatuximab, both in the single agent as well as in combination with lenalidomide and dexamethasone, there has been significant efficacy in patients with relapsed and refractory multiple myeloma. So, there are phase III clinical trials that are being initiated looking at isatuximab in combination with lenalidomide/dexamethasone, as well as other drugs. It seems to be very well tolerated based on the data that we have from the single-arm trials.

Now, in addition to these, what we call naked antibodies—which are basically antibodies which utilize the immune system to act on the tumor cells—there are also antibodies that are being developed that conjugate a toxin to a monoclonal antibody. There are several of those antibodies currently being developed. There’s one that uses an antibody similar to elotuzumab, where it’s been conjugated with a toxin. There’s another antibody that is targeted against a molecule called CD56 that’s present on many of these plasma cells, and that has been conjugated or attached to a toxin, which then is delivered to the myeloma cell by virtue of the fact that proteins present on the tumor cells.

In addition to the monoclonal antibodies, there are several other immunotherapy approaches that are currently being evaluated in multiple myeloma. The one that has caught the excitement of a lot of people has been the CAR T-cell therapy. Now, CAR T- cells have shown some phenomenal results in patients with acute leukemia, which would not have been expected based on the current therapies that we have available for that disease. And more recently, there has been a report of a single patient where the use of CAR T-cell resulted in eradication of the myeloma cells way beyond what we would have expected with the type of therapies that patient had seen previously, while it’s a single agent. That is an anecdotal report, so we clearly cannot read too much into it, but that has given enough excitement.

CAR T-cells can be developed against a variety of different proteins on the myeloma cells. The one report that has been published used CAR T-cells that’s targeted against what we call a CD19, which is similar to what has been done in leukemia. There are several clinical trials that are ongoing that are using CAR T-cells engineered against different antigens. Many of them are unique to myeloma, and we are hoping that the results from these ongoing clinical trials would be as we hope based on the initial reports.

In addition to the CAR T-cells, there are other approaches that are being used. Vaccination strategies have been tried in this disease for a long period of time, but I think we have a better sense of the type of antigens that we need to target for developing vaccines in myeloma. There are several trials that are looking at vaccination strategies in conjunction with autologous stem cell transplant for myeloma. Now, clearly patients who undergo an autologous peripheral blood stem cell transplant have significant disease control. And their immune system tends to come back to a normal phase, much more than in patients who are getting other types of therapy. So, that does provide a unique platform for us to examine some of these vaccination strategies and dendritic cell strategies, many of which are currently in process.

Peter Voorhees, MD: I think it’s a very exciting time in multiple myeloma. I think the advent of elotuzumab in combination with lenalidomide and dexamethasone, and daratumumab monotherapy for more heavily pretreated patients, is just the first step. You’re going to see these agents being used earlier in the course of the disease and in novel combinations moving forward. In addition, I think as we learn more about how the immune system is suppressed as cancers develop, we’ve developed new therapeutics that can be used to treat not just multiple myeloma but other malignancies as well. So, for example, there’s a lot of excitement about checkpoint inhibitors in a variety of different malignancies, and certainly in multiple myeloma as well. At our ASH meeting in 2015, there was very exciting data presented looking at the combination of lenalidomide and dexamethasone with pembrolizumab, and pomalidomide/dexamethasone with pembrolizumab.

There’s very exciting data on the use of CAR T-cell therapies in multiple myeloma that were presented at ASH. So, the NCI group showed very exciting preliminary data on a CAR T-cell program recognizing B-cell maturation antigen on the surface of myeloma cells, and they saw an early signal of activity particularly with higher T-cell doses. I think you’re going to see an explosion in the area of immuno-oncology in multiple myeloma over the next 5 to 10 years, and it will be very exciting to combine these different immunomodulatory drugs over the course of time. For example, combining IMiDs with the monoclonal antibodies, combining these things with checkpoint inhibitors, and seeing if these therapeutics can enhance the effects of the CAR T-cell therapies moving forward. I think we’ve done a great job as far as developing the proteasome inhibitors. We’ve done a great job developing the IMiDs. I think the next wave of the future is in immuno-oncology in multiple myeloma.

Shaji Kumar, MD: The cost of therapy is a very hot topic currently in the cancer world. We all constantly see the reports about how much cancer drugs cost, and how much it adds to the cost of therapy in general, especially when you use many of these drugs in combination. We already know that the drugs that we had available before, like the proteasome inhibitors and the immunomodulatory drugs, are fairly expensive. And when you combine them, the cost of therapy becomes extremely high. The addition of a monoclonal antibody only adds to that cost burden in this disease. So, I think it’s very important for us to think about how we can become more cost effective. The use of the appropriate combinations to get the maximum benefit is more and more important when we factor in the cost of the drugs.

There’s obviously ongoing debate as to what is considered an appropriate cost, and how do we measure it, and the right cost in the context of the efficacy of these drugs. I think that’s going to be a debate that’s constantly ongoing, but I think from a physician and the patient perspective, it’s important for us to focus on how we can get the best therapy for the patient. At the same time we need to keep in mind what particular or unique combination of drugs can achieve the best benefit, and at the same time keep the drug cost low. Obviously, as many of these drugs go generic, the overall cost of combinations will go down, and that will enable us to incorporate these new drugs into the combinations that may include some old drugs, which are less expensive.

Transcript Edited for Clarity
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