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Treatment for Relapsed/Refractory 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 Online: Tuesday, Jun 20, 2017



Transcript:

Shaji Kumar, MD:
As we discussed before, there is increasing complexity in terms of deciding treatment for patients with relapsed myeloma. It’s a good problem and a bad problem. It’s a good problem because we have a lot of different drugs, drug classes, and combinations that have been studied in phase II and phase III clinical trials. It’s a bad problem because now we have to decide amongst those different choices for a given patient, and sometimes it can be difficult. For the most part, I think we should be driven by data from phase III clinical trials. But clearly, in the clinic, there are situations where a particular patient may not fit the profile of the patients who went on a clinical trial, so we really have to depend on the agreed upon data that are available from phase III and phase II trials.

One thing that has become clear over the past few years, when you look at all the phase III clinical trials, is that patients with relapsed disease who get a triplet appear to do much better than patients who get a doublet in terms of progression-free survival, which obviously is to be expected. But more importantly, some of these phase III trials are now showing overall survival benefit in using a triplet compared to a doublet in the setting of relapsed disease.

So, just like what we have done in the newly diagnosed setting, patients, especially the patients in earlier relapses, should be considered for treatment with a triplet. This is also supported based on the biological studies that suggest there’s clonal evolution that happens under the selection pressure from therapy. I think it’s important to try and combine 2 different classes of drugs to get the optimal outcome for patients with relapsed disease.

Now, what are the different classes of drugs that we can combine? Obviously, the proteasome inhibitor and the immunomodulatory drug combination has been studied the most. We have the bortezomib/lenalidomide combination and the ixazomib/lenalidomide combination. We also have the same combinations with pomalidomide. Carfilzomib is another protease inhibitor that has been combined, both with lenalidomide and pomalidomide, and we know that the regimen of carfilzomib/lenalidomide/dexamethasone is quite effective, both in the newly diagnosed setting and in the relapsed setting. Similar data have also been shown with the pomalidomide combination.

Now, we also have the whole new class of monoclonal antibodies, and we have seen the exciting data with both daratumumab and elotuzumab when combined with an immunomodulatory drug or compared to a proteasome inhibitor. So, I look at them as 3 major classes of drugs: the monoclonal antibodies, the proteasome inhibitors, and the immunomodulatory drugs. And at least 2 of those 3 classes should be included in the combinations that we are thinking about for any given patient with relapsed disease.

Obviously, which particular regimen we use for a given patient will depend a lot on what drugs and what kind of toxicities they have seen before. Say if somebody had significant problems with peripheral neuropathy with their initial treatment, we want to use the combination that has the least likelihood of causing peripheral neuropathy. If somebody had a significant rash with immunomodulatory drugs in the past, we want to think about combinations that may not cause that. And so, taking into account the patient characteristics, we can narrow our choice of the triplets down.

Heinz Ludwig, MD: What are the preferred regimens for previously treated patients? This is a simple question, but the answer is very complex because the situation is so complex and the clinical data available are insufficient, because they don’t compare all of the options against each other. So, we have to make our choices based on previous treatment; the response to previous treatment; intolerance to previous treatment; time to next treatment; time to relapse; patient situation, frail or fit; of course, the patients’ preferences; and what is available in your center, which treatment is allowed by your healthcare system or your insurance system. That makes it very complex. There will be no global uniform recommendation for second-, third-, and fourth-line treatment, possibly because of this complexity.

But what you can do—what you are usually doing in your clinical practice—is use your clinical wisdom, and you look at what the patient has had before and what’s helping best. If the patient was on an IMiD (immunomodulator imide), you would likely use a proteasome inhibitor. You have 3 choices. If the patient is willing to come to the institution for a treatment, they will receive bortezomib or carfilzomib. If the patient prefers to stay at home or to continue with their work, to be active, then they will prefer an oral proteasome inhibitor; ixazomib would be the choice, of course. If the patient has a high-risk feature, then again, a proteasome inhibitor, ixazomib/carfilzomib/dexamethasone or bortezomib would be an option.

If the patient is frail, an ixazomib combination with lenalidomide/dexamethasone would be an option. And, of course, we have these antibodies now, and they should be, and will be, combined with individual backbones in the future. I foresee everybody working in this field, foresee that we will follow the lymphoma paradigm. We’ll have a backbone plus an antibody in the induction, and when it comes to patients with relapsed/refractory disease, we will have a backbone plus an antibody or possibly plus 2 antibodies. So, the field is evolving and what is optimal today will be overcome tomorrow because there is so much going on, such an evolution of new treatments, and also a better understanding of the disease.

Maria Victoria Mateos, MD, PhD: When we have a patient with relapsed and refractory myeloma in front of us, I think that there is not any preferred regime. What we have to do is consider the type of relapse. If the relapse is a biochemical or very aggressive relapse, we have to consider the prior lines of therapy, the efficacy, the cumulative toxicity, and, of course, the options of therapy we have to treat to our patient in relapse.

Now, we know that, for patients relapsing after 1 to 3 prior lines of therapy, we are going to be able to choose among different combinations. We have to consider the features of the disease, the patient’s preferences, and the baseline characteristics of the disease to try to individualize the choice and to make the optimal choice for the patient.

The election of an optimal regimen at the moment of relapse is going to be influenced by the prior line of therapy. The first scenario would be for patients receiving a proteasome inhibitor-based combination in the first line of therapy without previous exposition to lenalidomide. In this situation, at the moment of first relapse, the best option would be a lenalidomide/dexamethasone-based combination. We can choose between carfilzomib/lenalidomide/dexamethasone, ixazomib/lenalidomide/dexamethasone, daratumumab/lenalidomide/dexamethasone, or elotuzumab/lenalidomide/dexamethasone. Considering the patient’s characteristics, the baseline characteristics of the disease, and the patient’s preferences, we can choose one or another.

By contrast, if a patient is coming from lenalidomide as continuous therapy or lenalidomide as maintenance after transplant, at the moment of relapse, what we are not going to do is repeat lenalidomide/dexamethasone plus something else. In this situation, we would probably choose a proteasome inhibitor-based combination like carfilzomib/dexamethasone or, probably in the near future, bortezomib/dexamethasone plus daratumumab.

Transcript Edited for Clarity
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Transcript:

Shaji Kumar, MD:
As we discussed before, there is increasing complexity in terms of deciding treatment for patients with relapsed myeloma. It’s a good problem and a bad problem. It’s a good problem because we have a lot of different drugs, drug classes, and combinations that have been studied in phase II and phase III clinical trials. It’s a bad problem because now we have to decide amongst those different choices for a given patient, and sometimes it can be difficult. For the most part, I think we should be driven by data from phase III clinical trials. But clearly, in the clinic, there are situations where a particular patient may not fit the profile of the patients who went on a clinical trial, so we really have to depend on the agreed upon data that are available from phase III and phase II trials.

One thing that has become clear over the past few years, when you look at all the phase III clinical trials, is that patients with relapsed disease who get a triplet appear to do much better than patients who get a doublet in terms of progression-free survival, which obviously is to be expected. But more importantly, some of these phase III trials are now showing overall survival benefit in using a triplet compared to a doublet in the setting of relapsed disease.

So, just like what we have done in the newly diagnosed setting, patients, especially the patients in earlier relapses, should be considered for treatment with a triplet. This is also supported based on the biological studies that suggest there’s clonal evolution that happens under the selection pressure from therapy. I think it’s important to try and combine 2 different classes of drugs to get the optimal outcome for patients with relapsed disease.

Now, what are the different classes of drugs that we can combine? Obviously, the proteasome inhibitor and the immunomodulatory drug combination has been studied the most. We have the bortezomib/lenalidomide combination and the ixazomib/lenalidomide combination. We also have the same combinations with pomalidomide. Carfilzomib is another protease inhibitor that has been combined, both with lenalidomide and pomalidomide, and we know that the regimen of carfilzomib/lenalidomide/dexamethasone is quite effective, both in the newly diagnosed setting and in the relapsed setting. Similar data have also been shown with the pomalidomide combination.

Now, we also have the whole new class of monoclonal antibodies, and we have seen the exciting data with both daratumumab and elotuzumab when combined with an immunomodulatory drug or compared to a proteasome inhibitor. So, I look at them as 3 major classes of drugs: the monoclonal antibodies, the proteasome inhibitors, and the immunomodulatory drugs. And at least 2 of those 3 classes should be included in the combinations that we are thinking about for any given patient with relapsed disease.

Obviously, which particular regimen we use for a given patient will depend a lot on what drugs and what kind of toxicities they have seen before. Say if somebody had significant problems with peripheral neuropathy with their initial treatment, we want to use the combination that has the least likelihood of causing peripheral neuropathy. If somebody had a significant rash with immunomodulatory drugs in the past, we want to think about combinations that may not cause that. And so, taking into account the patient characteristics, we can narrow our choice of the triplets down.

Heinz Ludwig, MD: What are the preferred regimens for previously treated patients? This is a simple question, but the answer is very complex because the situation is so complex and the clinical data available are insufficient, because they don’t compare all of the options against each other. So, we have to make our choices based on previous treatment; the response to previous treatment; intolerance to previous treatment; time to next treatment; time to relapse; patient situation, frail or fit; of course, the patients’ preferences; and what is available in your center, which treatment is allowed by your healthcare system or your insurance system. That makes it very complex. There will be no global uniform recommendation for second-, third-, and fourth-line treatment, possibly because of this complexity.

But what you can do—what you are usually doing in your clinical practice—is use your clinical wisdom, and you look at what the patient has had before and what’s helping best. If the patient was on an IMiD (immunomodulator imide), you would likely use a proteasome inhibitor. You have 3 choices. If the patient is willing to come to the institution for a treatment, they will receive bortezomib or carfilzomib. If the patient prefers to stay at home or to continue with their work, to be active, then they will prefer an oral proteasome inhibitor; ixazomib would be the choice, of course. If the patient has a high-risk feature, then again, a proteasome inhibitor, ixazomib/carfilzomib/dexamethasone or bortezomib would be an option.

If the patient is frail, an ixazomib combination with lenalidomide/dexamethasone would be an option. And, of course, we have these antibodies now, and they should be, and will be, combined with individual backbones in the future. I foresee everybody working in this field, foresee that we will follow the lymphoma paradigm. We’ll have a backbone plus an antibody in the induction, and when it comes to patients with relapsed/refractory disease, we will have a backbone plus an antibody or possibly plus 2 antibodies. So, the field is evolving and what is optimal today will be overcome tomorrow because there is so much going on, such an evolution of new treatments, and also a better understanding of the disease.

Maria Victoria Mateos, MD, PhD: When we have a patient with relapsed and refractory myeloma in front of us, I think that there is not any preferred regime. What we have to do is consider the type of relapse. If the relapse is a biochemical or very aggressive relapse, we have to consider the prior lines of therapy, the efficacy, the cumulative toxicity, and, of course, the options of therapy we have to treat to our patient in relapse.

Now, we know that, for patients relapsing after 1 to 3 prior lines of therapy, we are going to be able to choose among different combinations. We have to consider the features of the disease, the patient’s preferences, and the baseline characteristics of the disease to try to individualize the choice and to make the optimal choice for the patient.

The election of an optimal regimen at the moment of relapse is going to be influenced by the prior line of therapy. The first scenario would be for patients receiving a proteasome inhibitor-based combination in the first line of therapy without previous exposition to lenalidomide. In this situation, at the moment of first relapse, the best option would be a lenalidomide/dexamethasone-based combination. We can choose between carfilzomib/lenalidomide/dexamethasone, ixazomib/lenalidomide/dexamethasone, daratumumab/lenalidomide/dexamethasone, or elotuzumab/lenalidomide/dexamethasone. Considering the patient’s characteristics, the baseline characteristics of the disease, and the patient’s preferences, we can choose one or another.

By contrast, if a patient is coming from lenalidomide as continuous therapy or lenalidomide as maintenance after transplant, at the moment of relapse, what we are not going to do is repeat lenalidomide/dexamethasone plus something else. In this situation, we would probably choose a proteasome inhibitor-based combination like carfilzomib/dexamethasone or, probably in the near future, bortezomib/dexamethasone plus daratumumab.

Transcript Edited for Clarity
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