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The Definition and Importance of Long-Term Therapy

Insights From: Ajai Chari, MD, Icahn School of Medicine at Mount Sinai; Andrzej Jakubowiak, MD, PhD, University of Chicago; Sagar Lonial, MD, Winship Cancer Institute of Emory University
Published: Thursday, Jan 03, 2019



Transcript: 

Andrzej Jakubowiak, MD, PhD: Long-term treatment is very much a very generic description of treatment that is meant to be for more than fixed 6, 8, or 9 cycles, which we have had in the past fairly regularly and in some study designs still part of the treatment plan. It wouldn’t be considered long-term treatment. Long-term treatment, or extended treatment, would be considered when we…have treatment until progression. That’s definitely extended treatment. That’s rarely used in newly diagnosed patients who achieve so frequently such good and deep responses that even extended treatment may be fixed. For example, in our KRd [carfilzomib/lenalidomide/dexamethasone] trial, the extended treatment was for 24 cycles, for 24 months, which is very long. But it’s an extended treatment, but it’s not indefinite.

To be able to treat for a long time is actually very important, which is an important addition to our understanding of how to treat myeloma in recent years. There may be 2 aspects or 2 data sets that can support my very general statement. Firstly, for patients who achieve response but not necessarily complete response, the first study—the study conducted in France in which patients were treated with lenalidomide and dexamethasone for 18 months versus until progression—showed that those who were treated until progression had longer progression-free survival, which, it may be interpreted, was reflecting that the patients in good control of the disease had an extended control of the disease if…treatment drugs were still used for an extended period.

The second important observation supporting extended treatment is related to best responses. We have learned, which is another very important observation, that achieving complete response—now we say MRD-negative complete response; MRD stands for “minimal residual disease,” or absence of any detectable disease—that those responses are achieved sometimes very early, but for the most part, analysis has been done in multiple studies. We’ve learned that achievement, or time to achievement, of this deepest response associated with longer remission is, on average, somewhere between 12 and 14 and 16 months, even for most active regimens. Again, this was observed in multiple studies now. In the Kaplan-Meier curves that are evaluating time to a certain level of response—in this case, complete response—we have found that that extended treatment is critical. To just give specific rough estimates, we would have treated patients with KRd for 8 cycles only. At the end of 8 cycles, there is some variability between studies, but probably somewhere between 30% and 40% of patients will achieve complete response.

Extending this treatment beyond 8 cycles increases the rate of complete responses to over 50%, to over even 60%. That is an important observation that, in a different way, supports my initial statement that treating longer rather than shorter is important. Now, I would add to that an important comment. We know from the first study that, indeed, longer treatment was important for prolonging remission. Whether achieving complete response and MRD-negative disease is always as important for every patient is not necessarily established.

But for statistical assessments, patients who achieve that level of response will have to be predicted to have longer remissions. So achieving that level of response will statistically predict for longer remissions. So in both scenarios, longer treatment is important. I think that we may have to potentially start scaling back extended treatment if, for example, certain levels of response are achieved. But that’s the work that is ahead of us, and we don’t have this information.

Transcript Edited for Clarity
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Transcript: 

Andrzej Jakubowiak, MD, PhD: Long-term treatment is very much a very generic description of treatment that is meant to be for more than fixed 6, 8, or 9 cycles, which we have had in the past fairly regularly and in some study designs still part of the treatment plan. It wouldn’t be considered long-term treatment. Long-term treatment, or extended treatment, would be considered when we…have treatment until progression. That’s definitely extended treatment. That’s rarely used in newly diagnosed patients who achieve so frequently such good and deep responses that even extended treatment may be fixed. For example, in our KRd [carfilzomib/lenalidomide/dexamethasone] trial, the extended treatment was for 24 cycles, for 24 months, which is very long. But it’s an extended treatment, but it’s not indefinite.

To be able to treat for a long time is actually very important, which is an important addition to our understanding of how to treat myeloma in recent years. There may be 2 aspects or 2 data sets that can support my very general statement. Firstly, for patients who achieve response but not necessarily complete response, the first study—the study conducted in France in which patients were treated with lenalidomide and dexamethasone for 18 months versus until progression—showed that those who were treated until progression had longer progression-free survival, which, it may be interpreted, was reflecting that the patients in good control of the disease had an extended control of the disease if…treatment drugs were still used for an extended period.

The second important observation supporting extended treatment is related to best responses. We have learned, which is another very important observation, that achieving complete response—now we say MRD-negative complete response; MRD stands for “minimal residual disease,” or absence of any detectable disease—that those responses are achieved sometimes very early, but for the most part, analysis has been done in multiple studies. We’ve learned that achievement, or time to achievement, of this deepest response associated with longer remission is, on average, somewhere between 12 and 14 and 16 months, even for most active regimens. Again, this was observed in multiple studies now. In the Kaplan-Meier curves that are evaluating time to a certain level of response—in this case, complete response—we have found that that extended treatment is critical. To just give specific rough estimates, we would have treated patients with KRd for 8 cycles only. At the end of 8 cycles, there is some variability between studies, but probably somewhere between 30% and 40% of patients will achieve complete response.

Extending this treatment beyond 8 cycles increases the rate of complete responses to over 50%, to over even 60%. That is an important observation that, in a different way, supports my initial statement that treating longer rather than shorter is important. Now, I would add to that an important comment. We know from the first study that, indeed, longer treatment was important for prolonging remission. Whether achieving complete response and MRD-negative disease is always as important for every patient is not necessarily established.

But for statistical assessments, patients who achieve that level of response will have to be predicted to have longer remissions. So achieving that level of response will statistically predict for longer remissions. So in both scenarios, longer treatment is important. I think that we may have to potentially start scaling back extended treatment if, for example, certain levels of response are achieved. But that’s the work that is ahead of us, and we don’t have this information.

Transcript Edited for Clarity
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