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Relapse Therapy: Incremental Change Versus Different Regimen

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: Tuesday, Jan 15, 2019



Transcript:

Sagar Lonial, MD:
Management of relapse has really become quite complicated. And I think that one of the factors that one needs to think about when a patient becomes symptomatic or needs therapy is, what has their prior therapy dictated? So if they are a patient who has not been on maintenance therapy, then lenalidomide- or bortezomib- or carfilzomib-based options become sort of the primary go-tos. And there are lots of different phase III trials that support each of those. If a patient has progressed on lenalidomide-based maintenance, then pomalidomide-based combinations become an option, as do, again, bortezomib or carfilzomib or ixazomib.

Certainly, in our practice, one of the things that we think about very seriously is bringing antibodies such as daratumumab into the first relapsed setting. It then becomes a matter of, what’s the partner for [daratumumab]? And in our practice it has traditionally been pomalidomide. Pomalidomide and daratumumab has been our go-to for many of these patients, who relapsed in their first relapsed setting. But one could use bortezomib and daratumumab. And there are emerging data on carfilzomib and daratumumab as well. You could use carfilzomib at high dose, as the ENDEAVOR trial did. There are a number of different options that one could do, and what I would suggest is coming up with a routine practice and just sticking with that algorithm as you go forward.

As a patient relapses, you may see small signs that a patient is progressing with biochemical relapse, even in the context of salvage therapy. In those situations you may add back the dexamethasone if you’ve tapered it off. Or you may go back up on a dose of a medicine that you had tapered down. Or in the case of daratumumab, you may go from once a month back to once a week for a short period of time to see if you can recapture a response.

The situation, when I think about really disregarding what I’m currently on and changing to something completely different, really has to do with symptomatic relapse. So if a patient is rapidly rising or their hemoglobin is dropping or the kidneys are starting to become at risk, I’m going to throw away whatever I’m doing and start with something different.

Andrzej Jakubowiak, MD, PhD: When a patient is found to have IMWG [International Myeloma Working Group] criteria of progression of the disease, not only timing of next therapy is important but what to do. And I would like to maybe present the spectrum of choices. And in this context I generally feel that if there are available choices, which are potentially among the best available at any given stage of disease—for example, some new triplet regimens or new regimens with newer agents established—the disease is very active. My rule is that at any given time, I’m trying to apply potentially tolerable treatments for the patient with, perhaps, new agents, based on the data that we have from given regimen reports and what has been previously published.
So we can achieve as much control of the disease at that stage of therapy as we can. Because that’s eventually our goal: achieving control of the disease, eliminating risk of organ damage or reversing emerging organ damage if that has already started to happen, and then potentially achieving, again—like in newly diagnosed patients—as deep a response as we can. Because it is associated with longer remission and for as much time as possible. If I had even active triplet regimen, if I go to the newer regimen, I’d rather make 2 changes than 1 change in the regimen or potentially even fewer.
But there are variables. That’s very much a patient-specific choice, for which we think hard and try to make at the time of this discussion. What are the different prior conditions this patient has, comorbidities, other components of health, previous toxicities of drugs, and previous history of drug effectiveness. These are affecting our choices. And on top of that, we also have some knowledge how certain subsets of disease will be responding to certain classes of drugs, which may potentially direct our choices.
I am not a big fan of incremental change of drug dosing at the time of progression. It may be applicable if too-deep declines of doses were done for, perhaps, toxicity, which I generally don’t favor. For example, somebody is on drug X for very high doses or optimal doses for about 8 months. But then just to avoid toxicities, we cut the drug by more than 50%, and it’s well tolerated but at some point stops working. For these patients maybe escalation to optimal dose would be considered. I would not necessarily be too…opposed to that. But if one approaches disease that we should be treating patients with given regimen as close to tolerated dose as possible with optimized mild toxicities, then there is no room really for escalation. And I think that that may potentially limit, in my practice, escalation of any drugs as treatment intervention.
Sagar Lonial, MD: When we think about proteasome inhibitor-based options, we’ve got bortezomib, which is typically given on a twice-a-week schedule, although in many combinations is now being used on a once-a-week schedule. And the main adverse effect of bortezomib is neuropathy. When we think about dosing carfilzomib, most of the trials have looked at twice-a-week dosing of carfilzomib, which tends to become a little troublesome over the long haul. Patients don’t like coming into the office that often.

There was recently a study that demonstrated that once-a-week carfilzomib dosing was better than twice-a-week dosing at a lower dose for carfilzomib. And that the adverse effect profile was not appreciably different. And what I think that brings to the table is the ability to deliver carfilzomib, which we know has much less neurotoxicity associated with it in a more patient-friendly schedule of once a week. And that is being adopted by a number of groups at this time.

Transcript Edited for Clarity.
 
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Transcript:

Sagar Lonial, MD:
Management of relapse has really become quite complicated. And I think that one of the factors that one needs to think about when a patient becomes symptomatic or needs therapy is, what has their prior therapy dictated? So if they are a patient who has not been on maintenance therapy, then lenalidomide- or bortezomib- or carfilzomib-based options become sort of the primary go-tos. And there are lots of different phase III trials that support each of those. If a patient has progressed on lenalidomide-based maintenance, then pomalidomide-based combinations become an option, as do, again, bortezomib or carfilzomib or ixazomib.

Certainly, in our practice, one of the things that we think about very seriously is bringing antibodies such as daratumumab into the first relapsed setting. It then becomes a matter of, what’s the partner for [daratumumab]? And in our practice it has traditionally been pomalidomide. Pomalidomide and daratumumab has been our go-to for many of these patients, who relapsed in their first relapsed setting. But one could use bortezomib and daratumumab. And there are emerging data on carfilzomib and daratumumab as well. You could use carfilzomib at high dose, as the ENDEAVOR trial did. There are a number of different options that one could do, and what I would suggest is coming up with a routine practice and just sticking with that algorithm as you go forward.

As a patient relapses, you may see small signs that a patient is progressing with biochemical relapse, even in the context of salvage therapy. In those situations you may add back the dexamethasone if you’ve tapered it off. Or you may go back up on a dose of a medicine that you had tapered down. Or in the case of daratumumab, you may go from once a month back to once a week for a short period of time to see if you can recapture a response.

The situation, when I think about really disregarding what I’m currently on and changing to something completely different, really has to do with symptomatic relapse. So if a patient is rapidly rising or their hemoglobin is dropping or the kidneys are starting to become at risk, I’m going to throw away whatever I’m doing and start with something different.

Andrzej Jakubowiak, MD, PhD: When a patient is found to have IMWG [International Myeloma Working Group] criteria of progression of the disease, not only timing of next therapy is important but what to do. And I would like to maybe present the spectrum of choices. And in this context I generally feel that if there are available choices, which are potentially among the best available at any given stage of disease—for example, some new triplet regimens or new regimens with newer agents established—the disease is very active. My rule is that at any given time, I’m trying to apply potentially tolerable treatments for the patient with, perhaps, new agents, based on the data that we have from given regimen reports and what has been previously published.
So we can achieve as much control of the disease at that stage of therapy as we can. Because that’s eventually our goal: achieving control of the disease, eliminating risk of organ damage or reversing emerging organ damage if that has already started to happen, and then potentially achieving, again—like in newly diagnosed patients—as deep a response as we can. Because it is associated with longer remission and for as much time as possible. If I had even active triplet regimen, if I go to the newer regimen, I’d rather make 2 changes than 1 change in the regimen or potentially even fewer.
But there are variables. That’s very much a patient-specific choice, for which we think hard and try to make at the time of this discussion. What are the different prior conditions this patient has, comorbidities, other components of health, previous toxicities of drugs, and previous history of drug effectiveness. These are affecting our choices. And on top of that, we also have some knowledge how certain subsets of disease will be responding to certain classes of drugs, which may potentially direct our choices.
I am not a big fan of incremental change of drug dosing at the time of progression. It may be applicable if too-deep declines of doses were done for, perhaps, toxicity, which I generally don’t favor. For example, somebody is on drug X for very high doses or optimal doses for about 8 months. But then just to avoid toxicities, we cut the drug by more than 50%, and it’s well tolerated but at some point stops working. For these patients maybe escalation to optimal dose would be considered. I would not necessarily be too…opposed to that. But if one approaches disease that we should be treating patients with given regimen as close to tolerated dose as possible with optimized mild toxicities, then there is no room really for escalation. And I think that that may potentially limit, in my practice, escalation of any drugs as treatment intervention.
Sagar Lonial, MD: When we think about proteasome inhibitor-based options, we’ve got bortezomib, which is typically given on a twice-a-week schedule, although in many combinations is now being used on a once-a-week schedule. And the main adverse effect of bortezomib is neuropathy. When we think about dosing carfilzomib, most of the trials have looked at twice-a-week dosing of carfilzomib, which tends to become a little troublesome over the long haul. Patients don’t like coming into the office that often.

There was recently a study that demonstrated that once-a-week carfilzomib dosing was better than twice-a-week dosing at a lower dose for carfilzomib. And that the adverse effect profile was not appreciably different. And what I think that brings to the table is the ability to deliver carfilzomib, which we know has much less neurotoxicity associated with it in a more patient-friendly schedule of once a week. And that is being adopted by a number of groups at this time.

Transcript Edited for Clarity.
 
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