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Early versus Late Response in 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: Friday, May 26, 2017


Transcript:

Maria-Victoria Mateos, MD, PhD:
From the general point-of-view, I would say that the quality of the response is very important in the treatment of patients with myeloma. It’s well established that the better the quality of the response, the longer the progression-free survival—and also probably the longest overall survival. As for the question about early versus late relapse, I think that is important but from my personal point-of-view, what is much more important is the quality of the response and knowing if the patient achieves this quality of a response very early or late over the course of the disease.

In my clinical activity, I prefer one patient achieving probably partial response after induction, very good partial response after transplant, and complete response after consolidation. So, the response is improving over the course of the disease. I prefer this type of kinetic response than one patient achieving complete response with minimal residual disease positive after induction; that after transplant and after consolidation, the minimal residual disease stays positive. I think that the important concept is the quality of the response and knowing if the response is achieved earlier or later over the course of the disease.

The better the response, the longer the progression-free survival. But it’s not completely true that when one patient achieves an optimal response very early, the outcome is going to be better. There are some patients in which the good response is achieved very early, but they also immediately relapse. So, what is important is the chemosensitivity; how the response is improving when patients receive such sequence steps of therapy—induction, transplant, consolidation, and maintenance. And this is really important and relevant.

Heinz Ludwig, MD: So, early response has 2 phases. Usually, the majority of patients who have an early response have good prognosis, but there’s a subset of patients who relapse quite fast. And that has been shown already in the 70s. Usually early response is fine, but when you look at different data sets, you see that those patients who achieve a response, there’s a subset of patients who achieve a response only after longstanding therapy, and those patients do very well. The concept doesn’t fit everybody. So, yes, it’s good to have an early response and as fast as possible, but we also have to acknowledge that there’s a significant proportion of patients who do very well and who achieve response only after a while.

I think long-term treatment is now very hot in myeloma debates because it’s not very well-defined. Long-term usually means, when you look at young transplant-eligible patients, maintenance therapy until progression or intolerance. It is not clear whether a shorter period of maintenance in those patients is as good as continuous treatment. We have some indications from one study, from the FIRST study, that long-term benefits, particularly, patients who have a very good response, which is against our previous thinking that you can discontinue treatment there. But the data show if you have a very good response, CR, or very good partial response, you benefit particularly from continuous treatment.

So, again, you have to look at the specifics of your patient, the response characteristics, and then decide. But we don’t have very good studies which compare, for instance, 1-year maintenance and 2-year maintenance with continuous treatment. But we know from old studies that the short-term maintenance significantly impacted PFS and also OS. So, my favorite is, of course, maintenance therapy, which has some end. It may be more complex than that because patients like this say, “When can I stop therapy?” It is always a relief for them, but also for the physician, if you see an end of therapy. We need more data on that, and we probably need more data on the individual patient’s risk and benefit from long-term therapy. We need predictive factors—who benefits from long-term, who benefits from 1 year, who benefits from 2 years, and who doesn’t benefit at all from maintenance because there is a subset of patients who don’t benefit.

Shaji Kumar, MD: In the myeloma field, I think the pattern is shifting towards longer term treatment. Now we don’t really know whether that means 2 years, 3 years, 4 years, or until disease progression. We certainly know in some groups of patients, in the post-transplant setting, the maintenance treatment clearly improves outcome. We know, in the high-risk patients, continued therapy until disease relapse is probably the ideal way to go. So, interestingly, there’s a trend towards using long-term therapy in patients with myeloma. As we study this group further, maybe we will identify a subgroup of patients in whom long-term therapy is not required. But until that is better delineated, I think the default is going to be longer term therapy as long as the patients can tolerate the treatment without any long-term toxicity and any irreversible toxicity.

I think the key thing for long-term therapy is having drugs that can be given without cumulative toxicity, which are convenient to take. So, increasingly, there’s going to be dependence on oral medications, especially combinations of oral medications, or monoclonal antibodies, which can be given less often. And increasingly, there are studies looking at delivering some of those drugs in subcutaneous fashion, which can actually also increase the ease and make the logistics easier.

Maria-Victoria Mateos, MD, PhD: When we prescribe a long-term treatment for a multiple myeloma patient, we explain to him or her that the treatment has to be continued until progression of disease or until toxicity is unacceptable. I think that we have some challenges. One of them is the toxicity profile. Because if we plan a continuous therapy, the tolerability has to be excellent. The side effects have to be minimal. We have to try to preserve the quality of life of the patients, and, if possible, we have to try to maintain patients in their day-to-day living activities. This is a bit of a challenge that we have to try to reach. In addition, another important challenge when we plan a long-term treatment is the adherence to the treatment, and I think that the adherence is clearly related to the toxicity profile. Of course, together with the adherence as well as the toxicity, the efficacy is important. But, if we see efficacy, I think that it is easy to convince the patients to continue on therapy, but we have to ensure that the quality of life and the toxicity profile are excellent.

If we have to plan a long-term treatment for one patient, the route of administration is, of course, a key point. The oral administration is much more convenient. It’s much more important for the patients to try to maintain the quality of life and day-to-day living activities because the oral administration makes it possible to reduce the number of visits to the hospital and the IV administration. It definitely is a plus for the long-term treatment.

Transcript Edited for Clarity
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Transcript:

Maria-Victoria Mateos, MD, PhD:
From the general point-of-view, I would say that the quality of the response is very important in the treatment of patients with myeloma. It’s well established that the better the quality of the response, the longer the progression-free survival—and also probably the longest overall survival. As for the question about early versus late relapse, I think that is important but from my personal point-of-view, what is much more important is the quality of the response and knowing if the patient achieves this quality of a response very early or late over the course of the disease.

In my clinical activity, I prefer one patient achieving probably partial response after induction, very good partial response after transplant, and complete response after consolidation. So, the response is improving over the course of the disease. I prefer this type of kinetic response than one patient achieving complete response with minimal residual disease positive after induction; that after transplant and after consolidation, the minimal residual disease stays positive. I think that the important concept is the quality of the response and knowing if the response is achieved earlier or later over the course of the disease.

The better the response, the longer the progression-free survival. But it’s not completely true that when one patient achieves an optimal response very early, the outcome is going to be better. There are some patients in which the good response is achieved very early, but they also immediately relapse. So, what is important is the chemosensitivity; how the response is improving when patients receive such sequence steps of therapy—induction, transplant, consolidation, and maintenance. And this is really important and relevant.

Heinz Ludwig, MD: So, early response has 2 phases. Usually, the majority of patients who have an early response have good prognosis, but there’s a subset of patients who relapse quite fast. And that has been shown already in the 70s. Usually early response is fine, but when you look at different data sets, you see that those patients who achieve a response, there’s a subset of patients who achieve a response only after longstanding therapy, and those patients do very well. The concept doesn’t fit everybody. So, yes, it’s good to have an early response and as fast as possible, but we also have to acknowledge that there’s a significant proportion of patients who do very well and who achieve response only after a while.

I think long-term treatment is now very hot in myeloma debates because it’s not very well-defined. Long-term usually means, when you look at young transplant-eligible patients, maintenance therapy until progression or intolerance. It is not clear whether a shorter period of maintenance in those patients is as good as continuous treatment. We have some indications from one study, from the FIRST study, that long-term benefits, particularly, patients who have a very good response, which is against our previous thinking that you can discontinue treatment there. But the data show if you have a very good response, CR, or very good partial response, you benefit particularly from continuous treatment.

So, again, you have to look at the specifics of your patient, the response characteristics, and then decide. But we don’t have very good studies which compare, for instance, 1-year maintenance and 2-year maintenance with continuous treatment. But we know from old studies that the short-term maintenance significantly impacted PFS and also OS. So, my favorite is, of course, maintenance therapy, which has some end. It may be more complex than that because patients like this say, “When can I stop therapy?” It is always a relief for them, but also for the physician, if you see an end of therapy. We need more data on that, and we probably need more data on the individual patient’s risk and benefit from long-term therapy. We need predictive factors—who benefits from long-term, who benefits from 1 year, who benefits from 2 years, and who doesn’t benefit at all from maintenance because there is a subset of patients who don’t benefit.

Shaji Kumar, MD: In the myeloma field, I think the pattern is shifting towards longer term treatment. Now we don’t really know whether that means 2 years, 3 years, 4 years, or until disease progression. We certainly know in some groups of patients, in the post-transplant setting, the maintenance treatment clearly improves outcome. We know, in the high-risk patients, continued therapy until disease relapse is probably the ideal way to go. So, interestingly, there’s a trend towards using long-term therapy in patients with myeloma. As we study this group further, maybe we will identify a subgroup of patients in whom long-term therapy is not required. But until that is better delineated, I think the default is going to be longer term therapy as long as the patients can tolerate the treatment without any long-term toxicity and any irreversible toxicity.

I think the key thing for long-term therapy is having drugs that can be given without cumulative toxicity, which are convenient to take. So, increasingly, there’s going to be dependence on oral medications, especially combinations of oral medications, or monoclonal antibodies, which can be given less often. And increasingly, there are studies looking at delivering some of those drugs in subcutaneous fashion, which can actually also increase the ease and make the logistics easier.

Maria-Victoria Mateos, MD, PhD: When we prescribe a long-term treatment for a multiple myeloma patient, we explain to him or her that the treatment has to be continued until progression of disease or until toxicity is unacceptable. I think that we have some challenges. One of them is the toxicity profile. Because if we plan a continuous therapy, the tolerability has to be excellent. The side effects have to be minimal. We have to try to preserve the quality of life of the patients, and, if possible, we have to try to maintain patients in their day-to-day living activities. This is a bit of a challenge that we have to try to reach. In addition, another important challenge when we plan a long-term treatment is the adherence to the treatment, and I think that the adherence is clearly related to the toxicity profile. Of course, together with the adherence as well as the toxicity, the efficacy is important. But, if we see efficacy, I think that it is easy to convince the patients to continue on therapy, but we have to ensure that the quality of life and the toxicity profile are excellent.

If we have to plan a long-term treatment for one patient, the route of administration is, of course, a key point. The oral administration is much more convenient. It’s much more important for the patients to try to maintain the quality of life and day-to-day living activities because the oral administration makes it possible to reduce the number of visits to the hospital and the IV administration. It definitely is a plus for the long-term treatment.

Transcript Edited for Clarity
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