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Case Study 1: The Value of KRd in Multiple Myeloma

Insights From: Rafael Fonseca, MD, Mayo Clinic; Gareth Morgan, MD, PhD, UAMS Myeloma Institute; Thomas G. Martin, MD, UCSF Helen Diller Family Comprehensive Cancer Center
Published: Thursday, Mar 01, 2018



Transcript: 

Rafael Fonseca, MD: In the case we discussed, one could make the argument that continuation of a proteasome inhibitor remains an important aspect of the therapy. The t(14;16) is only in a very small subset of myeloma patients. This is about 5% of all cases, but it remains one of the most challenging subsets of this population. We have learned that for t(4;14), continuation of proteasome inhibitors results in significant improvements in survival of patients, so much so that under some classifications, this is no longer considered a high-risk marker. Now, we know less about t(14;16), but one could postulate that given what we know for t(4;14), one may want to consider the continuation of a proteasome inhibitor in a patient with t(14;16).

We need to develop additional clinical trials and targets for t(14;16). One of the things we know is that this subtype has the highest rate of mutation. When you look at all myelomas, particularly at the CoMMpass data, we have learned that t(14;16) has the highest rate of mutations, which probably means those cases have the highest rate of neoantigens. I know we’re in a pause right now, but the idea of immunotherapy, such as checkpoint inhibitors, seems pretty appealing for this patient population. Maybe they could be early adopters of CAR T-cell therapies or the like.

Gareth Morgan, MD, PhD: The way I interpret the data about the efficacy of proteasome inhibitors is that if you look at them together, carfilzomib gives you the best responses and the deepest responses and has the best side effect profile. In this patient who has already seen Velcade [bortezomib], it’s a perfectly reasonable option to go for a combination containing carfilzomib. It’s also reasonable to expect that that patient will do at least as well with RVd, but probably better because of the trial data supporting the efficacy of that combination.

Even though this patient has seen a proteasome inhibitor before, proteasome inhibition is one of the backbones of therapy in multiple myeloma. Even though we have a range of different drugs, it is quite clear that proteasome inhibitors and IMiD drugs and transplantation constitute the mainstays of treatment, and carfilzomib is a very excellent proteasome inhibitor.

Thomas G. Martin, MD: In this young patient with high-risk disease who received RVd as induction therapy followed by autologous transplant and maintenance, once they develop relapse, you have to select a therapy. This patient was started on carfilzomib, lenalidomide, and dexamethasone (or KRd) for their relapsed disease. I think that’s an excellent strategy for relapse in this setting. This is a patient who has had first relapse. There are data from the ASPIRE trial, which was updated at ASH 2017, that show patients who had KRd for relapse, especially at their first relapse, had the best progression-free survival and the best overall survival advantage. So, I think it’s a perfect strategy for this patient.

The ASPIRE trial was for patients who were randomized to receive either the triplet of carfilzomib, lenalidomide, and dexamethasone (or KRd) versus a doublet of lenalidomide and dexamethasone. These were patients experiencing their first to third relapse, so 1 to 3 prior lines of therapy. In this study, we had an initial publication in the New England Journal of Medicine that showed a progression-free survival advantage for those getting KRd. In fact, at that time, the PFS was 26 months. That was the longest progression-free survival ever published as a relapsed therapy in patients with multiple myeloma.

Now, those data were updated at ASH in 2017. The update of the data showed that, in fact, there’s actually a survival advantage to choosing KRd versus Rd as initial therapy for relapsed disease. It’s pretty remarkable that they saw an overall survival advantage. The overall survival was 48 months for those getting KRd and 40 months for those getting Rd. Now, the overall survival advantage was even greater if you chose KRd as being your first therapy. The advantage was more in the 11-and-a-half to 12-month range. There was really quite a bit of advantage in choosing KRd as the first-relapse therapy.

Rafael Fonseca, MD: A question that one could pose is, should we switch to something different, like pomalidomide instead of lenalidomide? That’s a very, very important question. From what we know, pomalidomide is able to rescue situations where lenalidomide was already showing a lack of activity. Now, we have learned recently that the activity of IMiDs is not an all-or-nothing phenomenon. There are multiple mechanisms through which IMiDs work. My lab has been involved in some of this work, and we think it’s almost like you reach a threshold of pressure on the cell. In our case, we think that’s through oxidative stress. And you can reach a certain threshold, but it’s just not quite enough to induce apoptosis. That’s why sometimes you may have someone who’s refectory to lenalidomide and then refractory to a PI. If you combine it, you can push that cell over that limit. Well, the same would be true with pomalidomide.

The reason that question is critical is because, in that case, you want to make sure you still have that drug to be used later in case lenalidomide would still be effective. Something that I think we need to work on quite urgently are biomarkers that would tell us whether each one of those drugs is working individually. You could imagine a situation where someone is going to be proposed regimens, such as KRd, and that person could respond very nicely, but without a biomarker, you don’t know if it was the KRd or the Kd. If that was the case, then that arm may just add toxicity and cost to the regimen. Potentially, in some of those patients, we would know that the lenalidomide doesn’t work but the pomalidomide works. So, developing those biomarkers will allow you to tailor your therapy better, particularly with regards to resistance. That would be a very important step forward in the care of myeloma patients.

Transcript Edited for Clarity 
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Transcript: 

Rafael Fonseca, MD: In the case we discussed, one could make the argument that continuation of a proteasome inhibitor remains an important aspect of the therapy. The t(14;16) is only in a very small subset of myeloma patients. This is about 5% of all cases, but it remains one of the most challenging subsets of this population. We have learned that for t(4;14), continuation of proteasome inhibitors results in significant improvements in survival of patients, so much so that under some classifications, this is no longer considered a high-risk marker. Now, we know less about t(14;16), but one could postulate that given what we know for t(4;14), one may want to consider the continuation of a proteasome inhibitor in a patient with t(14;16).

We need to develop additional clinical trials and targets for t(14;16). One of the things we know is that this subtype has the highest rate of mutation. When you look at all myelomas, particularly at the CoMMpass data, we have learned that t(14;16) has the highest rate of mutations, which probably means those cases have the highest rate of neoantigens. I know we’re in a pause right now, but the idea of immunotherapy, such as checkpoint inhibitors, seems pretty appealing for this patient population. Maybe they could be early adopters of CAR T-cell therapies or the like.

Gareth Morgan, MD, PhD: The way I interpret the data about the efficacy of proteasome inhibitors is that if you look at them together, carfilzomib gives you the best responses and the deepest responses and has the best side effect profile. In this patient who has already seen Velcade [bortezomib], it’s a perfectly reasonable option to go for a combination containing carfilzomib. It’s also reasonable to expect that that patient will do at least as well with RVd, but probably better because of the trial data supporting the efficacy of that combination.

Even though this patient has seen a proteasome inhibitor before, proteasome inhibition is one of the backbones of therapy in multiple myeloma. Even though we have a range of different drugs, it is quite clear that proteasome inhibitors and IMiD drugs and transplantation constitute the mainstays of treatment, and carfilzomib is a very excellent proteasome inhibitor.

Thomas G. Martin, MD: In this young patient with high-risk disease who received RVd as induction therapy followed by autologous transplant and maintenance, once they develop relapse, you have to select a therapy. This patient was started on carfilzomib, lenalidomide, and dexamethasone (or KRd) for their relapsed disease. I think that’s an excellent strategy for relapse in this setting. This is a patient who has had first relapse. There are data from the ASPIRE trial, which was updated at ASH 2017, that show patients who had KRd for relapse, especially at their first relapse, had the best progression-free survival and the best overall survival advantage. So, I think it’s a perfect strategy for this patient.

The ASPIRE trial was for patients who were randomized to receive either the triplet of carfilzomib, lenalidomide, and dexamethasone (or KRd) versus a doublet of lenalidomide and dexamethasone. These were patients experiencing their first to third relapse, so 1 to 3 prior lines of therapy. In this study, we had an initial publication in the New England Journal of Medicine that showed a progression-free survival advantage for those getting KRd. In fact, at that time, the PFS was 26 months. That was the longest progression-free survival ever published as a relapsed therapy in patients with multiple myeloma.

Now, those data were updated at ASH in 2017. The update of the data showed that, in fact, there’s actually a survival advantage to choosing KRd versus Rd as initial therapy for relapsed disease. It’s pretty remarkable that they saw an overall survival advantage. The overall survival was 48 months for those getting KRd and 40 months for those getting Rd. Now, the overall survival advantage was even greater if you chose KRd as being your first therapy. The advantage was more in the 11-and-a-half to 12-month range. There was really quite a bit of advantage in choosing KRd as the first-relapse therapy.

Rafael Fonseca, MD: A question that one could pose is, should we switch to something different, like pomalidomide instead of lenalidomide? That’s a very, very important question. From what we know, pomalidomide is able to rescue situations where lenalidomide was already showing a lack of activity. Now, we have learned recently that the activity of IMiDs is not an all-or-nothing phenomenon. There are multiple mechanisms through which IMiDs work. My lab has been involved in some of this work, and we think it’s almost like you reach a threshold of pressure on the cell. In our case, we think that’s through oxidative stress. And you can reach a certain threshold, but it’s just not quite enough to induce apoptosis. That’s why sometimes you may have someone who’s refectory to lenalidomide and then refractory to a PI. If you combine it, you can push that cell over that limit. Well, the same would be true with pomalidomide.

The reason that question is critical is because, in that case, you want to make sure you still have that drug to be used later in case lenalidomide would still be effective. Something that I think we need to work on quite urgently are biomarkers that would tell us whether each one of those drugs is working individually. You could imagine a situation where someone is going to be proposed regimens, such as KRd, and that person could respond very nicely, but without a biomarker, you don’t know if it was the KRd or the Kd. If that was the case, then that arm may just add toxicity and cost to the regimen. Potentially, in some of those patients, we would know that the lenalidomide doesn’t work but the pomalidomide works. So, developing those biomarkers will allow you to tailor your therapy better, particularly with regards to resistance. That would be a very important step forward in the care of myeloma patients.

Transcript Edited for Clarity 
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