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Therapy Choice at Myeloma Progression

Panelists: Shaji Kumar, MD, Mayo Clinic; Heinz Ludwig, MD, Wilhelminen Cancer Research Institute; Maria Victoria Mateos, MD, PhD, University Hospital of Salamanca
Published: Thursday, Jun 22, 2017


Transcript:

Maria Victoria Mateos, MD, PhD:
In the relapsed and refractory setting, I would select an immunomodulatory drug-based combination when patients have been previously exposed to proteasome inhibitor-based combinations and have not previously received lenalidomide as maintenance after transplant or lenalidomide and dexamethasone as continuous therapy as part of the first line. In this situation, an IMiD, lenalidomide, and dexamethasone would be the backbone to which we have to add a third drug: carfilzomib, ixazomib, elotuzumab, or daratumumab. However, for patients in which the first line of therapy included immunomodulatory drugs—lenalidomide as continuous therapy or lenalidomide after transplant as part of the maintenance—proteasome inhibitors would be the backbone to choose at the moment of relapse.

The approach for slow versus rapid progression is different in real life, because when we have a patient with a rapid relapse in front of us, it is usually a key sign of a very aggressive relapse with a high monoclonal component, with anemia, renal impairments, and sometimes even extramedullary disease. In these patients, what we want is to control the disease as soon as possible. In this situation, we have to choose the optimal combination based on a proteasome inhibitor, an immunomodulatory drug, and dexamethasone, because the combinations based on PIs (proteasome inhibitors) and IMiDs have [a] demonstrated ability to rapidly control the disease, and this is what we want. By contrast, for the slow relapses, we can probably choose another option of therapy, including a monoclonal antibody like elotuzumab. But the rapid control of the disease is not as important as in patients with rapid relapses.

Heinz Ludwig, MD: What is my personal approach for patients with aggressive relapse and those with biochemical relapse? Aggressive relapse needs to be forcefully treated: triple combination if possible, plus an antibody. So, proteasome inhibitor/IMiD/dexamethasone and, if possible, an antibody. Slowly progressing relapse, biochemical relapse, is something which has to be discussed with the patient, because there is no indication that starting treatment early improves survival. Many patients will have to maintain their daily life without the burden of treatment, and you can do this if you can follow them carefully, but you have to have all the means at hand needed to monitor this disease. You should have a skeletal survey with modern technology. From time to time, you have to have the serum free light chain testing. You have to look at all the many other parameters and their well-being.

And if there are signs of progression, then you would argue to your patient that the time has come to start treatment. What you want to prevent is CRAB criteria, mainly the progression of bone disease, renal impairment, hypercalcemia, and anemia. That is easy, because that is probably the most frequent indication for starting therapy in those patients: increasing anemia. So, if the hemoglobin falls by 2 g, then it may be the right time to discuss with your patient re-starting therapy.

Maria Victoria Mateos, MD, PhD: Patients who are not candidates for autologous stem cell transplantation usually receive, in the first line of therapy when they are newly diagnosed, a bortezomib-based combination during a fixed therapy of approximately 1 year or continuous treatment with lenalidomide and dexamethasone. If the first line of therapy is a bortezomib-based combination during a fixed duration, at the moment of relapse, one possibility is to use lenalidomide and dexamethasone as backbone, plus a third drug. And if the patient was sensitive to bortezomib, we can choose a proteasome inhibitor, like carfilzomib or ixazomib, to be combined with lenalidomide and dexamethasone. As we are talking about elderly patients in which convenience and tolerability are key aspects, ixazomib in combination with lenalidomide and dexamethasone is an excellent option.

By contrast, if the nontransplant candidate is coming from continuous therapy with lenalidomide and dexamethasone, the optimal choice at the moment of relapse would be a proteasome inhibitor backbone. So, the patient would probably be a candidate to receive bortezomib/dexamethasone plus something else, carfilzomib/dexamethasone or ixazomib/dexamethasone. What we would not do is repeat treatment with lenalidomide/dexamethasone.

Shaji Kumar, MD: In transplant-ineligible patients, the overall approach to treatment of relapsed myeloma is going to be fairly similar to what we use in the transplant-eligible population. Obviously, with patients who are transplant-ineligible, we are talking about older patients, frailer patients, and patients for whom coming back to the hospital on a regular basis can sometimes be challenging. So, there are some modifications we need to make to our approach in patients who are transplant ineligible and often also have comorbidities.

These patients are more likely to have underlying hypertension, cardiac disease, diabetes, and other common ailments that we see in older patients. So, the types of agents and the dosing that we use in these patients has to take into account underlying comorbidities. In somebody with diabetes, we certainly want to scale back on the use of steroid medications. In somebody with underlying cardiac dysfunction, we have to be more cognizant about drugs that may have cardiac toxicity. The use of significant amount of fluids in these patients can be especially challenging.

We know that with patients who have underlying respiratory conditions, reactions to some of the monoclonal antibodies can be challenging. These patients need to be watched very closely, and they even need to get their first dose in a more supervised setting because we know that these allergic reactions don’t carry over to the subsequent dosing in the majority of these antibodies. We certainly need to customize therapy for the patient. I don’t think a given drug is absolutely contraindicated in any given setting. Obviously, in somebody with significant heart failure, we don’t want to use a drug that has a risk of heart failure. But for a majority of the drugs that we use in myeloma, we can modify the dose in a fashion that does not increase the toxicity.

Heinz Ludwig, MD: What treatment is available for patients with relapsed disease if transplant is not a choice? And transplant is only a choice for younger patients who have stem cells stored, or for whom you can collect stem cells, so the majority of patients need to have a nontransplant regimen. As mentioned, nowadays they have 29 different regimens that are recommended by the NCCN for use in patients with relapsed/refractory disease, but you will probably use those regimens that have been proven to be highly active and well tolerated.

So, there are a few regimens, and of course, ixazomib/lenalidomide/dexamethasone is one. You can use carfilzomib/dexamethasone. You can use elotuzumab/lenalidomide/dexamethasone. Of course, daratumumab plus lenalidomide/dexamethasone would be an ideal choice. So, these are the major players you consider first, but if they have been used before and patients are relapsing on or after these major players, you have to look for other drugs. You would think about pomalidomide, and you would think about panobinostat in some cases. You would think about them when it comes to, let’s say, the fifth, sixth, or seventh relapse. Then, you are probably left with very little in your pockets. But you still can use what has been developed, such as DCEP (dexamethasone, cyclophosphamide, etoposide, cisplatin), which is continuous therapy for this disease, or VTP (bortezomib plus thalidomide and prednisone). So, that helps a little in many patients, but the results or the remissions are not very long lasting. Finally, you may end up with very good supportive care.

Shaji Kumar, MD: In patients with relapsed myeloma, we have the option of using many of these triplets that have been studied in phase III trials. In a given patient, whether you use a monoclonal antibody-based combination or a proteasome-inhibitor based combination with an immunomodulatory drug depends a lot on the patient’s characteristics, the disease characteristics, as far as the logistics that have been involved with administering therapy.

In a patient who has previously used a proteasome inhibitor or who is currently relapsing on a proteasome inhibitor, my choice would be to use a monoclonal antibody-based therapy. So, let’s say someone had initial treatment with bortezomib/lenalidomide/dexamethasone, had a transplant, and was staying on a bortezomib maintenance. At relapse, I would use a combination like daratumumab/lenalidomide/dexamethasone. Suppose the same patient was relapsing on lenalidomide maintenance, I would consider using a combination of the monoclonal antibody with a proteasome inhibitor. Daratumumab/bortezomib/dexamethasone would be a good combination. Now let’s say somebody is an older patient or a patient who does not want to come to the clinic every week to get an infusion. Then, I would think about using an oral combination like ixazomib/lenalidomide/dexamethasone.

Let’s take a patient who had a bortezomib/lenalidomide/dexamethasone, induction transplant, and was on lenalidomide maintenance. They relapsed. They were treated with a monoclonal antibody-based therapy as a second line of treatment, and now they’re relapsing. If the patient has previously used a monoclonal antibody-based therapy, I would consider using a proteasome inhibitor-based combination and possibly combining that with pomalidomide in that particular setting. I think the 3 main characteristics we need to take into account are the effectiveness of the prior therapy of the particular drug class and the toxicity that patients have seen; the high-risk characteristics of disease relapse; and finally, the logistics of how often patients can come in and get therapy.

The key message when you consider treatment for relapsed myeloma is to try and include at least a class of drug that is different than what was being used in the previous line of therapy. Again, keep the principle of using at least 2 different classes of drugs in a given combination. Switching the class, as well as switching drugs within the same class, is critical when you decide on new therapies. For somebody who is refractory to lenalidomide, making a decision on the optimal regimen, I would use a combination of a monoclonal antibody and a proteasome inhibitor if I can. If I have to use an immunomodulatory drug, then I would certainly move on to a pomalidomide in that setting. Again, in combination with a monoclonal antibody and a proteasome inhibitor.

Heinz Ludwig, MD: When do we consider a proteasome inhibitor backbone as compared to an IMiD inhibitor backbone? I think this is important, but only in patients with high-risk cytogenetics where people have clearly shown that proteasome inhibitors overcome at least some part of the negative impact of high-risk cytogenetics. So, a proteasome inhibitor is very important here, but you may combine it with an IMiD as well.

If you want an IMiD combination, I would focus on standard-risk patients without high-risk cytogenetics. But sometimes, you don’t have too many choices after many relapses. So then you go with a pomalidomide/dexamethasone regimen, which seems to be very active in patients with high-risk cytogenetics, particularly a deletion 17p mutation. You may have to add something else to this combination, like cyclophosphamide or even an antibody. So, you have a lot of choices. I understand our desire for a simple algorithm, but my answer to this question is that an algorithm will not be possible in the near future given the plethora of treatment options and the differences in patients, patient characteristics, and biology of the tumors in individual patients. Maybe in the very far future, it will be easier.

Shaji Kumar, MD: Patients with myeloma can relapse with very different tempos of the disease. For the vast majority of patients who relapse, the same principles hold true for treatment. I think what we have learned from the recent clinical trials is that we should certainly consider using triplet combinations. We should use combinations with classes of drugs that are nonoverlapping compared to their prior line of therapy.

Certainly, there’s a subgroup of patients with very indolent and very slow relapse, where we may be able to hold off on therapy for some period of time. But what is more important to characterize separately is a small group of patients who present with very aggressive disease, and these are the patients who present with rapidly increasing monoclonal protein, who presented extramedullary disease, and who may present at the secondary class of leukemia.

These patients had to be treated fairly aggressively, and these are patients where we might try and use some of the older, more conventional chemotherapy-type medications—at least for the initial control of the disease. So, many of us would use combinations like VDD (bortezomib/liposomal doxorubicin/dexamethasone), or combinations that include high-dose alkylators and anthracycline, to try and gain an initial control of the disease, with the understanding that we will follow that up with something less intense that incorporates some of the newer drugs.

Transcript Edited for Clarity
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Transcript:

Maria Victoria Mateos, MD, PhD:
In the relapsed and refractory setting, I would select an immunomodulatory drug-based combination when patients have been previously exposed to proteasome inhibitor-based combinations and have not previously received lenalidomide as maintenance after transplant or lenalidomide and dexamethasone as continuous therapy as part of the first line. In this situation, an IMiD, lenalidomide, and dexamethasone would be the backbone to which we have to add a third drug: carfilzomib, ixazomib, elotuzumab, or daratumumab. However, for patients in which the first line of therapy included immunomodulatory drugs—lenalidomide as continuous therapy or lenalidomide after transplant as part of the maintenance—proteasome inhibitors would be the backbone to choose at the moment of relapse.

The approach for slow versus rapid progression is different in real life, because when we have a patient with a rapid relapse in front of us, it is usually a key sign of a very aggressive relapse with a high monoclonal component, with anemia, renal impairments, and sometimes even extramedullary disease. In these patients, what we want is to control the disease as soon as possible. In this situation, we have to choose the optimal combination based on a proteasome inhibitor, an immunomodulatory drug, and dexamethasone, because the combinations based on PIs (proteasome inhibitors) and IMiDs have [a] demonstrated ability to rapidly control the disease, and this is what we want. By contrast, for the slow relapses, we can probably choose another option of therapy, including a monoclonal antibody like elotuzumab. But the rapid control of the disease is not as important as in patients with rapid relapses.

Heinz Ludwig, MD: What is my personal approach for patients with aggressive relapse and those with biochemical relapse? Aggressive relapse needs to be forcefully treated: triple combination if possible, plus an antibody. So, proteasome inhibitor/IMiD/dexamethasone and, if possible, an antibody. Slowly progressing relapse, biochemical relapse, is something which has to be discussed with the patient, because there is no indication that starting treatment early improves survival. Many patients will have to maintain their daily life without the burden of treatment, and you can do this if you can follow them carefully, but you have to have all the means at hand needed to monitor this disease. You should have a skeletal survey with modern technology. From time to time, you have to have the serum free light chain testing. You have to look at all the many other parameters and their well-being.

And if there are signs of progression, then you would argue to your patient that the time has come to start treatment. What you want to prevent is CRAB criteria, mainly the progression of bone disease, renal impairment, hypercalcemia, and anemia. That is easy, because that is probably the most frequent indication for starting therapy in those patients: increasing anemia. So, if the hemoglobin falls by 2 g, then it may be the right time to discuss with your patient re-starting therapy.

Maria Victoria Mateos, MD, PhD: Patients who are not candidates for autologous stem cell transplantation usually receive, in the first line of therapy when they are newly diagnosed, a bortezomib-based combination during a fixed therapy of approximately 1 year or continuous treatment with lenalidomide and dexamethasone. If the first line of therapy is a bortezomib-based combination during a fixed duration, at the moment of relapse, one possibility is to use lenalidomide and dexamethasone as backbone, plus a third drug. And if the patient was sensitive to bortezomib, we can choose a proteasome inhibitor, like carfilzomib or ixazomib, to be combined with lenalidomide and dexamethasone. As we are talking about elderly patients in which convenience and tolerability are key aspects, ixazomib in combination with lenalidomide and dexamethasone is an excellent option.

By contrast, if the nontransplant candidate is coming from continuous therapy with lenalidomide and dexamethasone, the optimal choice at the moment of relapse would be a proteasome inhibitor backbone. So, the patient would probably be a candidate to receive bortezomib/dexamethasone plus something else, carfilzomib/dexamethasone or ixazomib/dexamethasone. What we would not do is repeat treatment with lenalidomide/dexamethasone.

Shaji Kumar, MD: In transplant-ineligible patients, the overall approach to treatment of relapsed myeloma is going to be fairly similar to what we use in the transplant-eligible population. Obviously, with patients who are transplant-ineligible, we are talking about older patients, frailer patients, and patients for whom coming back to the hospital on a regular basis can sometimes be challenging. So, there are some modifications we need to make to our approach in patients who are transplant ineligible and often also have comorbidities.

These patients are more likely to have underlying hypertension, cardiac disease, diabetes, and other common ailments that we see in older patients. So, the types of agents and the dosing that we use in these patients has to take into account underlying comorbidities. In somebody with diabetes, we certainly want to scale back on the use of steroid medications. In somebody with underlying cardiac dysfunction, we have to be more cognizant about drugs that may have cardiac toxicity. The use of significant amount of fluids in these patients can be especially challenging.

We know that with patients who have underlying respiratory conditions, reactions to some of the monoclonal antibodies can be challenging. These patients need to be watched very closely, and they even need to get their first dose in a more supervised setting because we know that these allergic reactions don’t carry over to the subsequent dosing in the majority of these antibodies. We certainly need to customize therapy for the patient. I don’t think a given drug is absolutely contraindicated in any given setting. Obviously, in somebody with significant heart failure, we don’t want to use a drug that has a risk of heart failure. But for a majority of the drugs that we use in myeloma, we can modify the dose in a fashion that does not increase the toxicity.

Heinz Ludwig, MD: What treatment is available for patients with relapsed disease if transplant is not a choice? And transplant is only a choice for younger patients who have stem cells stored, or for whom you can collect stem cells, so the majority of patients need to have a nontransplant regimen. As mentioned, nowadays they have 29 different regimens that are recommended by the NCCN for use in patients with relapsed/refractory disease, but you will probably use those regimens that have been proven to be highly active and well tolerated.

So, there are a few regimens, and of course, ixazomib/lenalidomide/dexamethasone is one. You can use carfilzomib/dexamethasone. You can use elotuzumab/lenalidomide/dexamethasone. Of course, daratumumab plus lenalidomide/dexamethasone would be an ideal choice. So, these are the major players you consider first, but if they have been used before and patients are relapsing on or after these major players, you have to look for other drugs. You would think about pomalidomide, and you would think about panobinostat in some cases. You would think about them when it comes to, let’s say, the fifth, sixth, or seventh relapse. Then, you are probably left with very little in your pockets. But you still can use what has been developed, such as DCEP (dexamethasone, cyclophosphamide, etoposide, cisplatin), which is continuous therapy for this disease, or VTP (bortezomib plus thalidomide and prednisone). So, that helps a little in many patients, but the results or the remissions are not very long lasting. Finally, you may end up with very good supportive care.

Shaji Kumar, MD: In patients with relapsed myeloma, we have the option of using many of these triplets that have been studied in phase III trials. In a given patient, whether you use a monoclonal antibody-based combination or a proteasome-inhibitor based combination with an immunomodulatory drug depends a lot on the patient’s characteristics, the disease characteristics, as far as the logistics that have been involved with administering therapy.

In a patient who has previously used a proteasome inhibitor or who is currently relapsing on a proteasome inhibitor, my choice would be to use a monoclonal antibody-based therapy. So, let’s say someone had initial treatment with bortezomib/lenalidomide/dexamethasone, had a transplant, and was staying on a bortezomib maintenance. At relapse, I would use a combination like daratumumab/lenalidomide/dexamethasone. Suppose the same patient was relapsing on lenalidomide maintenance, I would consider using a combination of the monoclonal antibody with a proteasome inhibitor. Daratumumab/bortezomib/dexamethasone would be a good combination. Now let’s say somebody is an older patient or a patient who does not want to come to the clinic every week to get an infusion. Then, I would think about using an oral combination like ixazomib/lenalidomide/dexamethasone.

Let’s take a patient who had a bortezomib/lenalidomide/dexamethasone, induction transplant, and was on lenalidomide maintenance. They relapsed. They were treated with a monoclonal antibody-based therapy as a second line of treatment, and now they’re relapsing. If the patient has previously used a monoclonal antibody-based therapy, I would consider using a proteasome inhibitor-based combination and possibly combining that with pomalidomide in that particular setting. I think the 3 main characteristics we need to take into account are the effectiveness of the prior therapy of the particular drug class and the toxicity that patients have seen; the high-risk characteristics of disease relapse; and finally, the logistics of how often patients can come in and get therapy.

The key message when you consider treatment for relapsed myeloma is to try and include at least a class of drug that is different than what was being used in the previous line of therapy. Again, keep the principle of using at least 2 different classes of drugs in a given combination. Switching the class, as well as switching drugs within the same class, is critical when you decide on new therapies. For somebody who is refractory to lenalidomide, making a decision on the optimal regimen, I would use a combination of a monoclonal antibody and a proteasome inhibitor if I can. If I have to use an immunomodulatory drug, then I would certainly move on to a pomalidomide in that setting. Again, in combination with a monoclonal antibody and a proteasome inhibitor.

Heinz Ludwig, MD: When do we consider a proteasome inhibitor backbone as compared to an IMiD inhibitor backbone? I think this is important, but only in patients with high-risk cytogenetics where people have clearly shown that proteasome inhibitors overcome at least some part of the negative impact of high-risk cytogenetics. So, a proteasome inhibitor is very important here, but you may combine it with an IMiD as well.

If you want an IMiD combination, I would focus on standard-risk patients without high-risk cytogenetics. But sometimes, you don’t have too many choices after many relapses. So then you go with a pomalidomide/dexamethasone regimen, which seems to be very active in patients with high-risk cytogenetics, particularly a deletion 17p mutation. You may have to add something else to this combination, like cyclophosphamide or even an antibody. So, you have a lot of choices. I understand our desire for a simple algorithm, but my answer to this question is that an algorithm will not be possible in the near future given the plethora of treatment options and the differences in patients, patient characteristics, and biology of the tumors in individual patients. Maybe in the very far future, it will be easier.

Shaji Kumar, MD: Patients with myeloma can relapse with very different tempos of the disease. For the vast majority of patients who relapse, the same principles hold true for treatment. I think what we have learned from the recent clinical trials is that we should certainly consider using triplet combinations. We should use combinations with classes of drugs that are nonoverlapping compared to their prior line of therapy.

Certainly, there’s a subgroup of patients with very indolent and very slow relapse, where we may be able to hold off on therapy for some period of time. But what is more important to characterize separately is a small group of patients who present with very aggressive disease, and these are the patients who present with rapidly increasing monoclonal protein, who presented extramedullary disease, and who may present at the secondary class of leukemia.

These patients had to be treated fairly aggressively, and these are patients where we might try and use some of the older, more conventional chemotherapy-type medications—at least for the initial control of the disease. So, many of us would use combinations like VDD (bortezomib/liposomal doxorubicin/dexamethasone), or combinations that include high-dose alkylators and anthracycline, to try and gain an initial control of the disease, with the understanding that we will follow that up with something less intense that incorporates some of the newer drugs.

Transcript Edited for Clarity
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