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Managing Heavily Pretreated R/R Multiple Myeloma

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: Wednesday, Mar 27, 2019



Transcript: 

Noopur S. Raje, MD: Goals of therapy for relapsed and refractory multiple myeloma were different, I would say, even a few months back, when the goal was to try to get a patient into remission and control that remission for as long as possible.

What’s happened is we now have targeted agents and are seeing incredible responses, even in this patient population. So that’s quite remarkable. I would never have imagined doing MRD [minimal residual disease] testing in a relapsed-refractory patient population, and yet, when you saw data with daratumumab, the POLLUX and the CASTOR studies were the first studies that showed us MRD negativity even in the relapsed-refractory space. And more recently, when we’ve used BCMA as a target, where we’ve used conjugated antibodies, we’ve used BiTEs [bispecific T-cell engagers], we’ve used CARs [chimeric antigen receptors], this is a patient population that did not have a whole lot of options. And yet, in this patient population, we’re beginning to see MRD-negative disease. So that is quite remarkable. So the goalpost keeps changing, I think. And the fact that we are seeing MRD-negative disease in this relapsed-refractory patient population is incredible.

Just to put things into context a little bit, you know daratumumab as a single agent gave us a response rate of 30%. If you look at the data with the conjugated BCMA antibody, the response rate of that is in excess of 60%—so doubling as a single-agent antibody. If you look at the CAR T-cell data, the vast majority of patients who are relapsed and refractory to every possible treatment out there were becoming MRD negative. And then if you look at BCMA-BiTE, which was presented at this year’s ASH [American Society of Hematology Annual Meeting & Exposition], again, when they got to a dose level with the AMG 420 drug, they saw MRD-negative disease in the majority of patients.

The question now becomes: You’re seeing depth of response in these patients who have extremely refractory disease. How can you translate this into long-term disease control? And that, I think, is something we need to work on.

Kenneth C. Anderson, MD: The patients with myeloma, because of the availability of novel agents, are often receiving multiple lines of therapy. The thing that has changed over time is the movement from novel agents that are FDA approved in advanced disease, to relapse, and then to initial treatment. And the most recent example of that is daratumumab now being FDA approved as part of initial therapy. We have availability of second-generation agents. So we have pomalidomide, second-generation lenalidomide. We have carfilzomib and ixazomib, second-generation of bortezomib proteasome inhibitor. And we have 2 choices now for monoclonal antibodies: daratumumab or elotuzumab. So that allows us to make combinations of multiple lines of therapy. And so, it’s not uncommon, in academic centers in North America, anyway, to have 5 or 6, or multiple lines of therapy before; in fact, the disease becomes refractory to everything. And even then, we now have clinical protocols of active targeted or immune agents.

Noopur S. Raje, MD: Typically, after multiple lines of therapy your remission duration becomes smaller and smaller, and patients end up developing refractory disease and ultimately succumb to the disease. So the reality even today is myeloma in a subset of patients is actually incurable, where patients will progress, develop refractory disease, and die from their disease. So that does happen, and it happens in about 60% of patients with myeloma, even today.

Rafael Fonseca, MD: Despite the enthusiasm we have for recent developments in myeloma clinical trials with the triplets and other drugs, the sad reality is that a large fraction of patients, or a large majority of our patients, go through different lines of therapy. And then they reach a situation where they have been exposed to all these agents. The term heavily pretreated has been used with some frequency. We talk about the number of lines that a patient may be refractory to.

Now, we do have a number of agents that are being tested in clinical trials. Some of them show significant promise, but I would say it’s either the combination of novel molecules or immunotherapeutic approaches. And in the immunotherapeutic field—I’m just going to use that big tent to describe, of course, CAR T-cells, bispecific antibodies, NK [natural killer] cell-based therapy, as well as some of the vaccination work that is going on. And that is something that is very real. Many clinical trials are being reported in that arena, and hopefully in the near future we’ll have them available just like our colleagues now have for leukemia and lymphoma.

We don’t have them commercially available for multiple myeloma. We’re scrambling to be able to get our patients into those clinical trials. But there are other molecules—among them are selinexor, Melflufen, and others that are currently being tested. Some of them are closer to their approval time.

Selinexor has a very interesting mechanism of action. It really blocks the exits in the membrane of the nucleus of the cell, so that it increases the concentration of genes that we think act as tumor suppressor genes. Now for this XPO1, it’s the pump that gets in and blocks the doors. So even though the cell may not have as much, actually it’s concentrated, and we think that helps in inducing cell death.
There’s a study called the STORM study that has looked at this drug in combination with dexamethasone. They used the schedule where they use selinexor at 80 mg twice per week, and they showed an overall response rate of approximately 26%.

There were some significant issues with toxicity, primarily gastrointestinal toxicity. But just like every other drug, I think there’s a lot of tweaking that can be done, including the administration of this on a weekly basis, as well as some other dose adjustments that hopefully will make this more tolerable for patients. But 26% overall response rate really has been about the benchmark, where every single successful drug that has been used in myeloma started when you looked at patients who have a long history of prior treatment or heavily pretreated patients.

So as we think about selinexor, I think we’re going to see more clinical trials coming forward with this. I anticipate it will be moving forward. And the question is going to be whether selinexor will be considered a backbone or if it’s a very important and good adjunct. To some degree, that’s dexamethasone. That could be selinexor. Potentially, you can even think of daratumumab, which is the rituximab equivalent for multiple myeloma. So if we can find a way to increase the sensitivity of some of the cells to the therapies we already have, we might be able to create more MRD-negative status, and it may take a little bit of selinexor, a sprinkling of selinexor for the frontline patients to now take MRD to even a higher rate. Of course, this needs to be tested only through clinical trials, but I’ll be the first one to say I think they are very exciting data.

Transcript Edited for Clarity
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Transcript: 

Noopur S. Raje, MD: Goals of therapy for relapsed and refractory multiple myeloma were different, I would say, even a few months back, when the goal was to try to get a patient into remission and control that remission for as long as possible.

What’s happened is we now have targeted agents and are seeing incredible responses, even in this patient population. So that’s quite remarkable. I would never have imagined doing MRD [minimal residual disease] testing in a relapsed-refractory patient population, and yet, when you saw data with daratumumab, the POLLUX and the CASTOR studies were the first studies that showed us MRD negativity even in the relapsed-refractory space. And more recently, when we’ve used BCMA as a target, where we’ve used conjugated antibodies, we’ve used BiTEs [bispecific T-cell engagers], we’ve used CARs [chimeric antigen receptors], this is a patient population that did not have a whole lot of options. And yet, in this patient population, we’re beginning to see MRD-negative disease. So that is quite remarkable. So the goalpost keeps changing, I think. And the fact that we are seeing MRD-negative disease in this relapsed-refractory patient population is incredible.

Just to put things into context a little bit, you know daratumumab as a single agent gave us a response rate of 30%. If you look at the data with the conjugated BCMA antibody, the response rate of that is in excess of 60%—so doubling as a single-agent antibody. If you look at the CAR T-cell data, the vast majority of patients who are relapsed and refractory to every possible treatment out there were becoming MRD negative. And then if you look at BCMA-BiTE, which was presented at this year’s ASH [American Society of Hematology Annual Meeting & Exposition], again, when they got to a dose level with the AMG 420 drug, they saw MRD-negative disease in the majority of patients.

The question now becomes: You’re seeing depth of response in these patients who have extremely refractory disease. How can you translate this into long-term disease control? And that, I think, is something we need to work on.

Kenneth C. Anderson, MD: The patients with myeloma, because of the availability of novel agents, are often receiving multiple lines of therapy. The thing that has changed over time is the movement from novel agents that are FDA approved in advanced disease, to relapse, and then to initial treatment. And the most recent example of that is daratumumab now being FDA approved as part of initial therapy. We have availability of second-generation agents. So we have pomalidomide, second-generation lenalidomide. We have carfilzomib and ixazomib, second-generation of bortezomib proteasome inhibitor. And we have 2 choices now for monoclonal antibodies: daratumumab or elotuzumab. So that allows us to make combinations of multiple lines of therapy. And so, it’s not uncommon, in academic centers in North America, anyway, to have 5 or 6, or multiple lines of therapy before; in fact, the disease becomes refractory to everything. And even then, we now have clinical protocols of active targeted or immune agents.

Noopur S. Raje, MD: Typically, after multiple lines of therapy your remission duration becomes smaller and smaller, and patients end up developing refractory disease and ultimately succumb to the disease. So the reality even today is myeloma in a subset of patients is actually incurable, where patients will progress, develop refractory disease, and die from their disease. So that does happen, and it happens in about 60% of patients with myeloma, even today.

Rafael Fonseca, MD: Despite the enthusiasm we have for recent developments in myeloma clinical trials with the triplets and other drugs, the sad reality is that a large fraction of patients, or a large majority of our patients, go through different lines of therapy. And then they reach a situation where they have been exposed to all these agents. The term heavily pretreated has been used with some frequency. We talk about the number of lines that a patient may be refractory to.

Now, we do have a number of agents that are being tested in clinical trials. Some of them show significant promise, but I would say it’s either the combination of novel molecules or immunotherapeutic approaches. And in the immunotherapeutic field—I’m just going to use that big tent to describe, of course, CAR T-cells, bispecific antibodies, NK [natural killer] cell-based therapy, as well as some of the vaccination work that is going on. And that is something that is very real. Many clinical trials are being reported in that arena, and hopefully in the near future we’ll have them available just like our colleagues now have for leukemia and lymphoma.

We don’t have them commercially available for multiple myeloma. We’re scrambling to be able to get our patients into those clinical trials. But there are other molecules—among them are selinexor, Melflufen, and others that are currently being tested. Some of them are closer to their approval time.

Selinexor has a very interesting mechanism of action. It really blocks the exits in the membrane of the nucleus of the cell, so that it increases the concentration of genes that we think act as tumor suppressor genes. Now for this XPO1, it’s the pump that gets in and blocks the doors. So even though the cell may not have as much, actually it’s concentrated, and we think that helps in inducing cell death.
There’s a study called the STORM study that has looked at this drug in combination with dexamethasone. They used the schedule where they use selinexor at 80 mg twice per week, and they showed an overall response rate of approximately 26%.

There were some significant issues with toxicity, primarily gastrointestinal toxicity. But just like every other drug, I think there’s a lot of tweaking that can be done, including the administration of this on a weekly basis, as well as some other dose adjustments that hopefully will make this more tolerable for patients. But 26% overall response rate really has been about the benchmark, where every single successful drug that has been used in myeloma started when you looked at patients who have a long history of prior treatment or heavily pretreated patients.

So as we think about selinexor, I think we’re going to see more clinical trials coming forward with this. I anticipate it will be moving forward. And the question is going to be whether selinexor will be considered a backbone or if it’s a very important and good adjunct. To some degree, that’s dexamethasone. That could be selinexor. Potentially, you can even think of daratumumab, which is the rituximab equivalent for multiple myeloma. So if we can find a way to increase the sensitivity of some of the cells to the therapies we already have, we might be able to create more MRD-negative status, and it may take a little bit of selinexor, a sprinkling of selinexor for the frontline patients to now take MRD to even a higher rate. Of course, this needs to be tested only through clinical trials, but I’ll be the first one to say I think they are very exciting data.

Transcript Edited for Clarity
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