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Relapsed/Refractory Multiple Myeloma: Switching Therapy

Insights From: Kenneth C. Anderson, MD, Dana-Farber Cancer Institute and Harvard Medical School; Rafael Fonseca, MD, Mayo Clinic; Noopur S. Raje, MD, Massachusetts General Hospital Cancer Center
Published: Tuesday, Mar 19, 2019



Transcript: 

Rafael Fonseca, MD: In my opinion, 1 of the most pressing questions in the field of multiple myeloma is, how do we define lenalidomide-refractory status? It is not an easy question. I think when we think about lenalidomide-refractory patients, we have to define whether they’re truly refractory. Now we can see that clinically where patients are getting, say, lenalidomide single agent and they progress, but sometimes the question comes up, for instance, in someone who’s undergoing maintenance.

The more we have learned about the mechanism of action of lenalidomide, we know that patients may be sensitive or not more along the lines of a spectrum than in a very binomial fashion. Let me contrast this, for instance, with patients who have mutations in CML [chronic myelocytic leukemia] who may not respond at all to a TKI [tyrosine kinase inhibitor]. Imatinib will not work just because they have a specific mutation. Myeloma is more gradual, and there’s a spectrum.

Our audience knows that lenalidomide and other IMiDs [immunomodulatory drugs] work through the binding to this protein called cereblon. But the majority of patients who are deemed to be refractory to lenalidomide just don’t have mutations or deletions of cereblon.

So there are other mechanisms that are operating in how lenalidomide works. In our research laboratory we have explored that, and there are some very interesting data that look at the metabolism and reactive oxygen species. So I think there’s a certain threshold, and once you get to that threshold, then the cell starts dying. And sometimes you can get to that threshold faster if you use some of these drugs in combinations. So lenalidomide plus a proteasome inhibitor. And having the ability to test for that will be critical. As we are discussing triplets, and if you’re going to start a patient who has refractory multiple myeloma with carfilzomib/lenalidomide/dex [dexamethasone], and the patient responds, are they responding because of the carfilzomib? Is it the lenalidomide? Is it both? You can easily envision that someone responds, and it’s only the carfilzomib that is providing that benefit.

So I think our ability to test for that is really, really mandatory at this point. We don’t have good markers. My group and others are working toward the development and validation of clinical biomarkers that would allow you to do this prediction. But as of now, it’s a bit of a guessing game. We’re just extrapolating from large data sets to say everyone should get a triplet.

However, because we don’t have those markers, it’s not uncommon that we switch from lenalidomide to pomalidomide when a patient has the suspicion or we have an idea that the patient is refractory to lenalidomide on the basis of our clinical observations alone. There is no question, when you look at the laboratory data and all the studies that have been done in vitro, pomalidomide is a more powerful inhibitor of the pathways that we think are critical for cell death.

Noopur S. Raje, MD: The thought process is that if you’ve been on an IMiD before, you need to change from 1 IMiD to another. And I don’t think that’s necessarily true. I think going from IMiD 1 to IMiD 2, there are adequate data now in the pomalidomide space where most of these patients have been lenalidomide-refractory. In these lenalidomide-refractory patients, you’re still able to capture responses with pomalidomide. Whether it’s with pomalidomide and bortezomib, or whether it’s with pomalidomide and daratumumab, it’s an open question, and you can use either-or. Or carfilzomib, for example. So you can use 1 IMiD after another. You can use 1 proteasome inhibitor after another as well. And it really speaks to the potency of these drugs.

So even if you’ve had bortezomib early, you can be rescued with carfilzomib because carfilzomib is a fairly potent irreversible proteasome inhibitor. So you can use the same class of compound as long as it’s a different compound.

Kenneth C. Anderson, MD: The fortunate news in myeloma is that we actually have the second-generation immunomodulatory drug pomalidomide and the second-generation proteasome inhibitors carfilzomib and ixazomib, and those agents actually were FDA approved because clinical trials showed that they work even when the first-generation treatments don’t. So I’ve mentioned that if you have the 3-drug regimen—lenalidomide, bortezomib, dexamethasone—we can switch to pomalidomide/dexamethasone with either a second-generation proteasome inhibitor, carfilzomib or ixazomib, or a monoclonal antibody, daratumumab or elotuzumab.

It’s unusual, but if you’re treating with a doublet—if you were doing lenalidomide/dexamethasone, for example—and the disease grew, then we would switch to the opposite class of drugs. So we would switch if the patient hadn’t had a proteasome inhibitor; we would then start the same. The converse is also true if a patient, for example, had been treated with Velcade and dexamethasone initially and the disease relapsed. Then we would switch to an immunomodulatory drug. So that’s the primary setting in which we might switch there, and switch also might mean, when do we first use antibodies? And that’s adding in daratumumab or elotuzumab to the pomalidomide/dexamethasone, so that’s really a switch since they haven’t had monoclonal antibodies before.

Noopur S. Raje, MD: Carfilzomib is something we are still trying to figure out, regarding the best dosing and the best schedule. There’s no question in my mind that it’s a potent proteasome inhibitor. I think doing it twice a week for 3 weeks is going to be retired. I do think it’s going to be used on a weekly schedule, given that we have been able to go up on the dose of carfilzomib. So we started off with 20 mg/m2 and 27 mg/m2, and we are now using 70 mg/m2. The 70 mg/m2, given once a week, is actually well tolerated.

I think the future of how carfilzomib is going to be used is on a weekly schedule. Now, what dose you use on a weekly schedule would largely depend on what the partner drug is. I tend to use carfilzomib more with an IMiD combination. And I will say that when you use it with an IMiD combination, I don’t think you can go up beyond 56 mg/m2. We have tried 70 mg/m2. We have used it, but typically, most patients do well with the 56 mg/m2 dose with the IMiD because of toxicities or cytopenias associated.

So using carfilzomib on a weekly schedule, depending on what your partner drug is, would kind of tell you what the ideal dose of carfilzomib should be. I do think even in the up-front setting, carfilzomib should be used on a weekly schedule. It’s extremely well tolerated and combines well with most of the drugs. And there are data from ASCO [the American Society of Clinical Oncology Annual Meeting] last year where carfilzomib was used with daratumumab, for example; carfilzomib was used with isatuximab as well on a weekly schedule and was extremely well tolerated, going all the way up to 70 mg/m2.

Kenneth C. Anderson, MD: The benefit of weekly carfilzomib is to both the caregiver and the patient. Until now, we’ve utilized carfilzomib twice a week for 3 weeks in a row with 1 week off, because that’s the original schedule and regimen that was FDA approved. But more recent data suggest that you can safely use single doses of carfilzomib, and even have escalated or higher doses, and use this very safely. This honestly gets equal efficacy, and that’s very important. This is much more user friendly, in terms of clinic time and in terms of the times, you know, patients have to come in to visit us in the clinic for treatment.

Transcript Edited for Clarity
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Transcript: 

Rafael Fonseca, MD: In my opinion, 1 of the most pressing questions in the field of multiple myeloma is, how do we define lenalidomide-refractory status? It is not an easy question. I think when we think about lenalidomide-refractory patients, we have to define whether they’re truly refractory. Now we can see that clinically where patients are getting, say, lenalidomide single agent and they progress, but sometimes the question comes up, for instance, in someone who’s undergoing maintenance.

The more we have learned about the mechanism of action of lenalidomide, we know that patients may be sensitive or not more along the lines of a spectrum than in a very binomial fashion. Let me contrast this, for instance, with patients who have mutations in CML [chronic myelocytic leukemia] who may not respond at all to a TKI [tyrosine kinase inhibitor]. Imatinib will not work just because they have a specific mutation. Myeloma is more gradual, and there’s a spectrum.

Our audience knows that lenalidomide and other IMiDs [immunomodulatory drugs] work through the binding to this protein called cereblon. But the majority of patients who are deemed to be refractory to lenalidomide just don’t have mutations or deletions of cereblon.

So there are other mechanisms that are operating in how lenalidomide works. In our research laboratory we have explored that, and there are some very interesting data that look at the metabolism and reactive oxygen species. So I think there’s a certain threshold, and once you get to that threshold, then the cell starts dying. And sometimes you can get to that threshold faster if you use some of these drugs in combinations. So lenalidomide plus a proteasome inhibitor. And having the ability to test for that will be critical. As we are discussing triplets, and if you’re going to start a patient who has refractory multiple myeloma with carfilzomib/lenalidomide/dex [dexamethasone], and the patient responds, are they responding because of the carfilzomib? Is it the lenalidomide? Is it both? You can easily envision that someone responds, and it’s only the carfilzomib that is providing that benefit.

So I think our ability to test for that is really, really mandatory at this point. We don’t have good markers. My group and others are working toward the development and validation of clinical biomarkers that would allow you to do this prediction. But as of now, it’s a bit of a guessing game. We’re just extrapolating from large data sets to say everyone should get a triplet.

However, because we don’t have those markers, it’s not uncommon that we switch from lenalidomide to pomalidomide when a patient has the suspicion or we have an idea that the patient is refractory to lenalidomide on the basis of our clinical observations alone. There is no question, when you look at the laboratory data and all the studies that have been done in vitro, pomalidomide is a more powerful inhibitor of the pathways that we think are critical for cell death.

Noopur S. Raje, MD: The thought process is that if you’ve been on an IMiD before, you need to change from 1 IMiD to another. And I don’t think that’s necessarily true. I think going from IMiD 1 to IMiD 2, there are adequate data now in the pomalidomide space where most of these patients have been lenalidomide-refractory. In these lenalidomide-refractory patients, you’re still able to capture responses with pomalidomide. Whether it’s with pomalidomide and bortezomib, or whether it’s with pomalidomide and daratumumab, it’s an open question, and you can use either-or. Or carfilzomib, for example. So you can use 1 IMiD after another. You can use 1 proteasome inhibitor after another as well. And it really speaks to the potency of these drugs.

So even if you’ve had bortezomib early, you can be rescued with carfilzomib because carfilzomib is a fairly potent irreversible proteasome inhibitor. So you can use the same class of compound as long as it’s a different compound.

Kenneth C. Anderson, MD: The fortunate news in myeloma is that we actually have the second-generation immunomodulatory drug pomalidomide and the second-generation proteasome inhibitors carfilzomib and ixazomib, and those agents actually were FDA approved because clinical trials showed that they work even when the first-generation treatments don’t. So I’ve mentioned that if you have the 3-drug regimen—lenalidomide, bortezomib, dexamethasone—we can switch to pomalidomide/dexamethasone with either a second-generation proteasome inhibitor, carfilzomib or ixazomib, or a monoclonal antibody, daratumumab or elotuzumab.

It’s unusual, but if you’re treating with a doublet—if you were doing lenalidomide/dexamethasone, for example—and the disease grew, then we would switch to the opposite class of drugs. So we would switch if the patient hadn’t had a proteasome inhibitor; we would then start the same. The converse is also true if a patient, for example, had been treated with Velcade and dexamethasone initially and the disease relapsed. Then we would switch to an immunomodulatory drug. So that’s the primary setting in which we might switch there, and switch also might mean, when do we first use antibodies? And that’s adding in daratumumab or elotuzumab to the pomalidomide/dexamethasone, so that’s really a switch since they haven’t had monoclonal antibodies before.

Noopur S. Raje, MD: Carfilzomib is something we are still trying to figure out, regarding the best dosing and the best schedule. There’s no question in my mind that it’s a potent proteasome inhibitor. I think doing it twice a week for 3 weeks is going to be retired. I do think it’s going to be used on a weekly schedule, given that we have been able to go up on the dose of carfilzomib. So we started off with 20 mg/m2 and 27 mg/m2, and we are now using 70 mg/m2. The 70 mg/m2, given once a week, is actually well tolerated.

I think the future of how carfilzomib is going to be used is on a weekly schedule. Now, what dose you use on a weekly schedule would largely depend on what the partner drug is. I tend to use carfilzomib more with an IMiD combination. And I will say that when you use it with an IMiD combination, I don’t think you can go up beyond 56 mg/m2. We have tried 70 mg/m2. We have used it, but typically, most patients do well with the 56 mg/m2 dose with the IMiD because of toxicities or cytopenias associated.

So using carfilzomib on a weekly schedule, depending on what your partner drug is, would kind of tell you what the ideal dose of carfilzomib should be. I do think even in the up-front setting, carfilzomib should be used on a weekly schedule. It’s extremely well tolerated and combines well with most of the drugs. And there are data from ASCO [the American Society of Clinical Oncology Annual Meeting] last year where carfilzomib was used with daratumumab, for example; carfilzomib was used with isatuximab as well on a weekly schedule and was extremely well tolerated, going all the way up to 70 mg/m2.

Kenneth C. Anderson, MD: The benefit of weekly carfilzomib is to both the caregiver and the patient. Until now, we’ve utilized carfilzomib twice a week for 3 weeks in a row with 1 week off, because that’s the original schedule and regimen that was FDA approved. But more recent data suggest that you can safely use single doses of carfilzomib, and even have escalated or higher doses, and use this very safely. This honestly gets equal efficacy, and that’s very important. This is much more user friendly, in terms of clinic time and in terms of the times, you know, patients have to come in to visit us in the clinic for treatment.

Transcript Edited for Clarity
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