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Multiple Myeloma: Understanding and Treating Progression

Insights From: Rafael Fonseca, MD, Mayo Clinic; Gareth Morgan, MD, PhD, UAMS Myeloma Institute; Thomas G. Martin, MD, UCSF Helen Diller Family Comprehensive Cancer Center
Published: Thursday, Feb 08, 2018



Transcript: 

Thomas G. Martin, MD: In terms of relapse for multiple myeloma patients, all patients relapse from their initial therapy. We think there are maybe 10% to 20% of people who, 10 years down the line, remain in complete remission where there’s no evidence of progression, and those are the lucky few. But essentially, all of those patients will eventually relapse.

If we try to break down when patients relapse, the high-risk patients are the ones who are going to relapse first. And if we look at just data for patients who have really high-risk disease—like those who have the 17p abnormality, or maybe even patients with plasma-cell leukemia—those patients are usually going to relapse within 18 to 24 months.

If we look at patients who have undergone a single autologous transplant and lenalidomide maintenance, their remission duration is more like 50 months. With primary therapy outside of an autologous transplant, like in the SWOG study, the progression-free survival is around 40 months. I use those as goals for patients to achieve that tell me, do they have good myeloma? Do they have a standard run-of-the-mill myeloma? Or is their myeloma now high risk? Did they really relapse earlier than what we expected? Those are the ways I follow people and assess their response, on how well they’re doing to primary therapy.
              
We know that at relapse, the myeloma biology changes. It changes in ways where if we look at the mutation status from newly diagnosed to first relapse to second relapse, we know that with each relapse patients are gaining more and more mutations. This is probably some genomic instability, and we also know that there are clonal differences and that for each regimen, what comes back is a more resistant clone. It could be resistant just to the regimen that you gave them, or it might be resistant to all of the regimens depending on how fast they’ve gone through their various therapies. But certainly, the clone that is coming back after reach relapse is becoming tougher and tougher and tougher to treat.

Rafael Fonseca, MD: When we have a patient who’s experiencing a relapse post–stem-cell transplant, whether they have been on maintenance or not, the reality is that we have a plethora of options for those patients. If one goes to the NCCN guidelines, you will see that there is a number of options, but primarily, what we’re thinking about are combinations with carfilzomib, carfilzomib as monotherapy, daratumumab combinations, or other combinations that could include elotuzumab or ixazomib, all of which have been proven through phase III clinical trials to be beneficial for patients. In reality, when we look at our patients, unless one is dealing with a very indolent relapse, the majority of patients are going to go through a combination that contains carfilzomib, carfilzomib monotherapy, or a combination with daratumumab, particularly daratumumab plus IMiDs (immunomodulatory drugs).
              
Now, there are other subsets of patients who may benefit from one of the other combinations. For instance, patients with high-risk markers or patients who live far away from the treatment center can do very, very well with ixazomib. In fact, we use that as one of the regimens for maintenance post–stem-cell transplant. But I would say that most of the time, we’re having a conversation with patients between a carfilzomib-based combination and a daratumumab-based combination, both of which have the highest level of evidence that’s provided by the NCCN guidelines.

Gareth Morgan, MD, PhD: At relapse, clearly patients are no longer responding to the treatment, and their disease has come back. The question is, what is the nature of that relapse? Not all relapses are created equally. There are some patients who have explosive disease, for which you may want to select one type of treatment. There are patients who have a slow, indolent relapse, so you may want to watch it or use a different type of gentler treatment. This is all governed by the genetics of the cancer, but also by the duration of time patients had off treatment and the treatment that was used up front. When you’re selecting a regimen for people at relapse, you have to consider the nature of the relapse, the disease-free period, what they were treated with up front, and what side effects they’ve got. And then, by considering all of those factors, it becomes much easier to select a regimen.

There are a number of regimens that have different modes of action. The monoclonal antibodies target the immune system to the surface of the melanoma cell. This is a rather novel mechanism, and you’re taking advantage of the immune system. The IMiD drugs target Ikaros and Aiolos to the proteasome for degradation, so they target the myeloma cells directly and increase the immune affect. Proteasome inhibitors are very important. They target the proteasome, inhibit the cell cycle, stress the endoplasmic reticulin, and affect NF-KappaB signaling. The histone deacetylase (HDAC) inhibitors are anything but histone deacetylase inhibitors. It’s probably better to consider them as just deacetylase inhibitors in what they do to the proteins in the cell. They can target the epigenetic status of the cell as well as target Hsp90 and a variety of proteins in the cell.

Those are their modes of action, but you need to know their side effect profiles. If you’ve had a thrombosis, it’s more difficult to use an IMiD. If you’ve had peripheral neuropathy, using Velcade [bortezomib] is difficult and you should choose a proteasome inhibitor that doesn’t have a neurotoxicity portfolio. The HDAC inhibitors make you anorexic and make it difficult to give other drugs, so they’re difficult to use in combinations. The monoclonal antibodies have the least impactful side effect profile and combine well with IMiDs and/or proteasome inhibitors.

Transcript Edited for Clarity 
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Transcript: 

Thomas G. Martin, MD: In terms of relapse for multiple myeloma patients, all patients relapse from their initial therapy. We think there are maybe 10% to 20% of people who, 10 years down the line, remain in complete remission where there’s no evidence of progression, and those are the lucky few. But essentially, all of those patients will eventually relapse.

If we try to break down when patients relapse, the high-risk patients are the ones who are going to relapse first. And if we look at just data for patients who have really high-risk disease—like those who have the 17p abnormality, or maybe even patients with plasma-cell leukemia—those patients are usually going to relapse within 18 to 24 months.

If we look at patients who have undergone a single autologous transplant and lenalidomide maintenance, their remission duration is more like 50 months. With primary therapy outside of an autologous transplant, like in the SWOG study, the progression-free survival is around 40 months. I use those as goals for patients to achieve that tell me, do they have good myeloma? Do they have a standard run-of-the-mill myeloma? Or is their myeloma now high risk? Did they really relapse earlier than what we expected? Those are the ways I follow people and assess their response, on how well they’re doing to primary therapy.
              
We know that at relapse, the myeloma biology changes. It changes in ways where if we look at the mutation status from newly diagnosed to first relapse to second relapse, we know that with each relapse patients are gaining more and more mutations. This is probably some genomic instability, and we also know that there are clonal differences and that for each regimen, what comes back is a more resistant clone. It could be resistant just to the regimen that you gave them, or it might be resistant to all of the regimens depending on how fast they’ve gone through their various therapies. But certainly, the clone that is coming back after reach relapse is becoming tougher and tougher and tougher to treat.

Rafael Fonseca, MD: When we have a patient who’s experiencing a relapse post–stem-cell transplant, whether they have been on maintenance or not, the reality is that we have a plethora of options for those patients. If one goes to the NCCN guidelines, you will see that there is a number of options, but primarily, what we’re thinking about are combinations with carfilzomib, carfilzomib as monotherapy, daratumumab combinations, or other combinations that could include elotuzumab or ixazomib, all of which have been proven through phase III clinical trials to be beneficial for patients. In reality, when we look at our patients, unless one is dealing with a very indolent relapse, the majority of patients are going to go through a combination that contains carfilzomib, carfilzomib monotherapy, or a combination with daratumumab, particularly daratumumab plus IMiDs (immunomodulatory drugs).
              
Now, there are other subsets of patients who may benefit from one of the other combinations. For instance, patients with high-risk markers or patients who live far away from the treatment center can do very, very well with ixazomib. In fact, we use that as one of the regimens for maintenance post–stem-cell transplant. But I would say that most of the time, we’re having a conversation with patients between a carfilzomib-based combination and a daratumumab-based combination, both of which have the highest level of evidence that’s provided by the NCCN guidelines.

Gareth Morgan, MD, PhD: At relapse, clearly patients are no longer responding to the treatment, and their disease has come back. The question is, what is the nature of that relapse? Not all relapses are created equally. There are some patients who have explosive disease, for which you may want to select one type of treatment. There are patients who have a slow, indolent relapse, so you may want to watch it or use a different type of gentler treatment. This is all governed by the genetics of the cancer, but also by the duration of time patients had off treatment and the treatment that was used up front. When you’re selecting a regimen for people at relapse, you have to consider the nature of the relapse, the disease-free period, what they were treated with up front, and what side effects they’ve got. And then, by considering all of those factors, it becomes much easier to select a regimen.

There are a number of regimens that have different modes of action. The monoclonal antibodies target the immune system to the surface of the melanoma cell. This is a rather novel mechanism, and you’re taking advantage of the immune system. The IMiD drugs target Ikaros and Aiolos to the proteasome for degradation, so they target the myeloma cells directly and increase the immune affect. Proteasome inhibitors are very important. They target the proteasome, inhibit the cell cycle, stress the endoplasmic reticulin, and affect NF-KappaB signaling. The histone deacetylase (HDAC) inhibitors are anything but histone deacetylase inhibitors. It’s probably better to consider them as just deacetylase inhibitors in what they do to the proteins in the cell. They can target the epigenetic status of the cell as well as target Hsp90 and a variety of proteins in the cell.

Those are their modes of action, but you need to know their side effect profiles. If you’ve had a thrombosis, it’s more difficult to use an IMiD. If you’ve had peripheral neuropathy, using Velcade [bortezomib] is difficult and you should choose a proteasome inhibitor that doesn’t have a neurotoxicity portfolio. The HDAC inhibitors make you anorexic and make it difficult to give other drugs, so they’re difficult to use in combinations. The monoclonal antibodies have the least impactful side effect profile and combine well with IMiDs and/or proteasome inhibitors.

Transcript Edited for Clarity 
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