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Novel Agents for Multiple Myeloma

Panelists: Shaji Kumar, MD, Mayo Clinic; Heinz Ludwig, MD, Wilhelminen Cancer Research Institute; Maria Victoria Mateos, MD, PhD, University Hospital of Salamanca
Published: Wednesday, Jun 28, 2017


Transcript:

Heinz Ludwig, MD:
There are several options for immunotherapy: cell-based immunotherapy, antibody-based immunotherapy, and vaccination, in theory. So, cell-based immunotherapy uses CAR-T cells, for instance. CAR-T cells are developed against certain antigens on myeloma cells, on BCMA. These CAR-T cells have been shown to be extremely active, and 2 companies, at this point of time, are working on a project together with scientists to bring it into the clinic as soon as possible. They will be fantastic. Other approaches to modulate the immune system are very important, just to downregulate the regulatory T cells and to active the killer T cells, which will be important. We will understand it better in the future. We’ll even have antibodies that are intact with regulatory T cells, for instance.

Antibodies, per se, have changed the treatment paradigm because they are already an important part of relapsed/refractory therapies, and they will become part of first-line treatments. And so, we will change our treatment paradigm from a purely conventional treatment backbone to a combination of that backbone plus antibodies. It may be that we use 2 antibodies or even 3 in the future.

These antibodies can be, of course, coupled with taxanes, can be made more active. We can have antibodies against cells, cell antigens, myeloma cell antigens, antigens on the stroma, and particularly against epitopes, which hinder the immune system—these so-called checkpoint inhibitors. And the combination of checkpoint inhibitors with antibodies against tumor antigens or myeloma antigens seems to be very feasible and useful.

In addition, vaccination is another choice, and if that would work, in the future, we would vaccinate every patient with MGUS, or smoldering myeloma. Which vaccines are presently under investigation? Vaccines that use proteins, which inhibit apoptosis of myeloma cells—for instance, BCL-2, BCL-X, or BCL-1. These are proteins that allow the myeloma cell to live forever. So, if you can reduce these proteins, myeloma cells are prone to die. That is the hope. Actually, there are in vivo data that have shown this might be feasible.

You can use vaccines against PD-L1. These are the proteins that inhibit T-cell response. When you vaccinate your patient, he produces his own PD-L1 antibodies. You don’t need an antibody to administer every 2 weeks or so. This is all different testing. In the end, I think modulating the stroma will be very important and will help us to enhance the activity of our conventional therapy.

Maria Victoria Mateos, MD, PhD: There are many promising new agents for the treatment of myeloma patients. After the proteasome inhibitors and immunomodulatory drugs arrived to the myeloma setting more than 10 years ago, we now have second-generation PIs, second-generation immunomodulatory drugs, and even monoclonal antibodies. But, in addition, we have also new agents with different mechanisms of action.

One example is venetoclax, a BCL-2 inhibitor that has demonstrated to be very effective as a single agent in relapsed and refractory myeloma patients having a specific translocation, t(11;14). In addition, venetoclax has been combined with bortezomib and dexamethasone, and the results of the preliminary results are very encouraging in patients with 1 to 3 prior lines of therapy who are bortezomib sensitive. In fact, there is currently an ongoing phase III randomized trial comparing bortezomib/dexamethasone versus bortezomib/dexamethasone plus venetoclax. And this 3-drug-based combination will probably be a new standard of care.

Another promising new agent is selinexor. It’s an XPO1 inhibitor and another new drug that has demonstrated to be effective as a single agent in patients refractory to bortezomib, refractory to immunomodulatory drugs, and refractory to the monoclonal antibodies. In this setting, 20% of the patients responded to single-agent selinexor, and this has been the rationale for it to be combined with proteasome inhibitors. Again, there are preliminary but encouraging results of selinexor in combination with bortezomib and dexamethasone. There is also an ongoing phase III trial, and selinexor will probably be incorporated in the treatment armamentarium for our myeloma patients.

In addition, there are other new agents, like ibrutinib, or new compounds that are going to target the specific mutations or specific abnormalities present in patients with myeloma, but the results aren’t matured yet. We have to wait to have more consolidated results.

Shaji Kumar, MD: A lot has changed with myeloma in the past decade, and I think—based on what we see today—a lot more is going to change in the coming years. It’s a combination of understanding the biology of the disease and understanding how and why the disease behaves differently in different people. That is going to be the key for adapting treatment in patients with myeloma.

So, I think, in the next few years, we are going to treat patients with myeloma differently based on their underlying genetic characteristics. I think there’s certainly a case to be made for more personalized therapy in myeloma based on a better understanding of the biology and the mechanism of action of individual drugs and combinations.

We’ll have a lot more choices. We can treat patients to a deeper response. We can treat patients longer to keep them in that deeper response and potentially cure some of these patients of the disease. The safety of these new combinations will allow us to use the drugs early on in the course of disease, potentially in patients with high-risk smoldering myeloma—again, increasing the probability that we will cure some of these patients. The ability to give these drugs for longer terms without a cumulative toxicity will also improve the overall quality of life for patients.

Maria Victoria Mateos, MD, PhD: I consider that all myeloma remains today an incurable disease. I think that we are going to be able to offer the cure, if not to all, to some patients with multiple myeloma. This is going to be based, of course, on the combination of novel agents that are emerging for the treatment of patients with myeloma. All of these new combinations are very effective, have excellent toxicity profiles, and are being evaluated in advanced stages of the disease. And in this situation, this combination was effective.

So, the optimal way to move these new regimens to earlier stages of the disease is we probably have to move to the newly diagnosed patients. When all these new combinations based on proteasome inhibitors, IMiDs, corticosteroids, and monoclonal antibodies are going to be administered at the moment of diagnosis, I think we will be able to offer the cure for some patients with myeloma—probably for the standard-risk patients. We probably have to continue investigating in patients with high-risk features because these patients continue being a relevant challenge for us. But most of the patients we have in our clinic every day are standard-risk myeloma patients, and I’m completely sure that we will be able to offer them the cure.

Heinz Ludwig, MD: What is important for the future? We need excellent research, we need very good cooperation between the pharmaceutical and medical scientists, but we also need the support of patients. The patients need to be involved. They need to engage themselves because the more they know about the disease, the better they are able to react when they face complications. We always say patients in low socioeconomic categories or classes are handicapped because of lower income. This is not the real explanation in Europe because all patients here in Europe have access to, I think, reasonable medical care.

But you have to have a mindset that helps you to react, that helps you to understand, that helps you to interact with your care team, and that helps you to get the best out of the options that are available. So, we have to be active; we have to understand that. People have different talents and personalities, and not everybody has these features that are needed to make the best of the options that are available.

That is something patients should know about, because sometimes patients come in and say, “I feel bad, I have bone pain,” but they are not prepared. They do not ask themselves, “What do I want to get out of this conversation, of the consultation?” or “What does the doctor need in order to give me his best choices, to make the best decision for me?” So, that is something. Actually, the future is bright, but we have to be aware that all parts involved in the care—including the patient—have to be as active as possible and have to contribute.

Transcript Edited for Clarity
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Transcript:

Heinz Ludwig, MD:
There are several options for immunotherapy: cell-based immunotherapy, antibody-based immunotherapy, and vaccination, in theory. So, cell-based immunotherapy uses CAR-T cells, for instance. CAR-T cells are developed against certain antigens on myeloma cells, on BCMA. These CAR-T cells have been shown to be extremely active, and 2 companies, at this point of time, are working on a project together with scientists to bring it into the clinic as soon as possible. They will be fantastic. Other approaches to modulate the immune system are very important, just to downregulate the regulatory T cells and to active the killer T cells, which will be important. We will understand it better in the future. We’ll even have antibodies that are intact with regulatory T cells, for instance.

Antibodies, per se, have changed the treatment paradigm because they are already an important part of relapsed/refractory therapies, and they will become part of first-line treatments. And so, we will change our treatment paradigm from a purely conventional treatment backbone to a combination of that backbone plus antibodies. It may be that we use 2 antibodies or even 3 in the future.

These antibodies can be, of course, coupled with taxanes, can be made more active. We can have antibodies against cells, cell antigens, myeloma cell antigens, antigens on the stroma, and particularly against epitopes, which hinder the immune system—these so-called checkpoint inhibitors. And the combination of checkpoint inhibitors with antibodies against tumor antigens or myeloma antigens seems to be very feasible and useful.

In addition, vaccination is another choice, and if that would work, in the future, we would vaccinate every patient with MGUS, or smoldering myeloma. Which vaccines are presently under investigation? Vaccines that use proteins, which inhibit apoptosis of myeloma cells—for instance, BCL-2, BCL-X, or BCL-1. These are proteins that allow the myeloma cell to live forever. So, if you can reduce these proteins, myeloma cells are prone to die. That is the hope. Actually, there are in vivo data that have shown this might be feasible.

You can use vaccines against PD-L1. These are the proteins that inhibit T-cell response. When you vaccinate your patient, he produces his own PD-L1 antibodies. You don’t need an antibody to administer every 2 weeks or so. This is all different testing. In the end, I think modulating the stroma will be very important and will help us to enhance the activity of our conventional therapy.

Maria Victoria Mateos, MD, PhD: There are many promising new agents for the treatment of myeloma patients. After the proteasome inhibitors and immunomodulatory drugs arrived to the myeloma setting more than 10 years ago, we now have second-generation PIs, second-generation immunomodulatory drugs, and even monoclonal antibodies. But, in addition, we have also new agents with different mechanisms of action.

One example is venetoclax, a BCL-2 inhibitor that has demonstrated to be very effective as a single agent in relapsed and refractory myeloma patients having a specific translocation, t(11;14). In addition, venetoclax has been combined with bortezomib and dexamethasone, and the results of the preliminary results are very encouraging in patients with 1 to 3 prior lines of therapy who are bortezomib sensitive. In fact, there is currently an ongoing phase III randomized trial comparing bortezomib/dexamethasone versus bortezomib/dexamethasone plus venetoclax. And this 3-drug-based combination will probably be a new standard of care.

Another promising new agent is selinexor. It’s an XPO1 inhibitor and another new drug that has demonstrated to be effective as a single agent in patients refractory to bortezomib, refractory to immunomodulatory drugs, and refractory to the monoclonal antibodies. In this setting, 20% of the patients responded to single-agent selinexor, and this has been the rationale for it to be combined with proteasome inhibitors. Again, there are preliminary but encouraging results of selinexor in combination with bortezomib and dexamethasone. There is also an ongoing phase III trial, and selinexor will probably be incorporated in the treatment armamentarium for our myeloma patients.

In addition, there are other new agents, like ibrutinib, or new compounds that are going to target the specific mutations or specific abnormalities present in patients with myeloma, but the results aren’t matured yet. We have to wait to have more consolidated results.

Shaji Kumar, MD: A lot has changed with myeloma in the past decade, and I think—based on what we see today—a lot more is going to change in the coming years. It’s a combination of understanding the biology of the disease and understanding how and why the disease behaves differently in different people. That is going to be the key for adapting treatment in patients with myeloma.

So, I think, in the next few years, we are going to treat patients with myeloma differently based on their underlying genetic characteristics. I think there’s certainly a case to be made for more personalized therapy in myeloma based on a better understanding of the biology and the mechanism of action of individual drugs and combinations.

We’ll have a lot more choices. We can treat patients to a deeper response. We can treat patients longer to keep them in that deeper response and potentially cure some of these patients of the disease. The safety of these new combinations will allow us to use the drugs early on in the course of disease, potentially in patients with high-risk smoldering myeloma—again, increasing the probability that we will cure some of these patients. The ability to give these drugs for longer terms without a cumulative toxicity will also improve the overall quality of life for patients.

Maria Victoria Mateos, MD, PhD: I consider that all myeloma remains today an incurable disease. I think that we are going to be able to offer the cure, if not to all, to some patients with multiple myeloma. This is going to be based, of course, on the combination of novel agents that are emerging for the treatment of patients with myeloma. All of these new combinations are very effective, have excellent toxicity profiles, and are being evaluated in advanced stages of the disease. And in this situation, this combination was effective.

So, the optimal way to move these new regimens to earlier stages of the disease is we probably have to move to the newly diagnosed patients. When all these new combinations based on proteasome inhibitors, IMiDs, corticosteroids, and monoclonal antibodies are going to be administered at the moment of diagnosis, I think we will be able to offer the cure for some patients with myeloma—probably for the standard-risk patients. We probably have to continue investigating in patients with high-risk features because these patients continue being a relevant challenge for us. But most of the patients we have in our clinic every day are standard-risk myeloma patients, and I’m completely sure that we will be able to offer them the cure.

Heinz Ludwig, MD: What is important for the future? We need excellent research, we need very good cooperation between the pharmaceutical and medical scientists, but we also need the support of patients. The patients need to be involved. They need to engage themselves because the more they know about the disease, the better they are able to react when they face complications. We always say patients in low socioeconomic categories or classes are handicapped because of lower income. This is not the real explanation in Europe because all patients here in Europe have access to, I think, reasonable medical care.

But you have to have a mindset that helps you to react, that helps you to understand, that helps you to interact with your care team, and that helps you to get the best out of the options that are available. So, we have to be active; we have to understand that. People have different talents and personalities, and not everybody has these features that are needed to make the best of the options that are available.

That is something patients should know about, because sometimes patients come in and say, “I feel bad, I have bone pain,” but they are not prepared. They do not ask themselves, “What do I want to get out of this conversation, of the consultation?” or “What does the doctor need in order to give me his best choices, to make the best decision for me?” So, that is something. Actually, the future is bright, but we have to be aware that all parts involved in the care—including the patient—have to be as active as possible and have to contribute.

Transcript Edited for Clarity
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