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Induction Therapy Considerations in 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 13, 2019



Transcript:

Rafael Fonseca, MD: Another question that has been frequently debated and discussed in the area of myeloma is, how deep should we go? How intense should we go with our regimens? And the more I see the data come back from clinical trials, I think the answer is becoming increasingly clear to me. You have to go for very deep responses. Sometimes when I speak now I use a term. We have to establish Pax Romana for those myeloma cells. And of course, it stands to reason, it’s obvious we have to do it safely, so we have to choose regimens that don’t cause undue toxicity for our patients. But I think we understand the regimens quite a bit better. I think during your induction therapy you should try to achieve that MRD [minimal residual disease]-negative status as possible, as I’ve previously discussed.

As of now, I still make the recommendation for stem cell transplant. Certainly, I put all of my patients on maintenance therapy. One of the questions I still have is whether there’s some value in post-transplant therapy. If someone has residual disease, say someone who’s MRD-positive post stem cell transplant, I would argue, for instance, for a high-risk patient, that just kind of crossing your fingers and going into lenalidomide is probably not enough. So we need more clinical trials in that particular area.

And this is very important because one of the things we’ve learned, and I presented some of this data at the ASH [American Society of Hematology] meeting, is that you cannot assume that you will have the opportunity to establish a second line of treatment or a third line of treatment for a patient for whom you are providing that first line of therapy.

In other words, the attrition between lines of therapy is high. And the reasons for that are multiple. Sometimes the person has a great response, but sometimes they develop comorbidities or have progressive disease in such a way that they’re precluded from receiving that salvage strategy. My common argument here is that if you have drugs A and B, and you show that combination A/B is better, an argument that comes back often is, what if you use A and then save B for later? So the sequencing argument. There may not be time for B, and hopefully we could do that. There are other diseases where this has been done. For instance, in breast cancer. But in myeloma I think you have to put your best foot forward right from the get-go.

When I speak, I have a slide I frequently use. I put an image of soccer and an image of baseball, and I say, “Is it like soccer or baseball?” Because in soccer you put your best players in game number 1. In baseball you can have a lineup or you can have a pitcher on the line that will save the day. Myeloma is like soccer.

Noopur S. Raje, MD: I think what we’ve learned over the last several years is that the depth of response is important, and what we’ve also seen with some of the myeloma treatments is that the depth of response continues to deepen over time. That’s part of the reason why, at least in the transplant-eligible patients, it seems pretty straightforward. You start off with induction treatment and you use transplant as your consolidation. You might use something at the back end, which we also refer to as consolidation, and then you maintain these patients. And along the way, no matter what data set you look at, you will see that there’s a depth in terms of complete responses. There’s a depth in terms of conversion to MRD negativity. And the deeper your responses, the more MRD-negative disease state you get into, the better the outcome is, suggesting that it is important to continue treatment.

In terms of the transplant-ineligible patients, we don’t typically use the words “induction” or “consolidation.” You start off with initial therapy and then you continue therapy for patients with multiple myeloma. And at least the data, as it stands today, recommend that you continue until progression.

Earlier on we talked about 3 drugs versus 4 drugs. Is it time to test 4 drugs? I do think it is time to test 4 drugs. We also talked about MRD testing, and I think it’s really important to use MRD testing as a tool, specifically when you’re using a combination of 3 and 4 drugs, because it is entirely possible that we will not have to continue treatment indefinitely if we can get to a really good depth of response.

The problem, right now, is we don’t know what that depth of response is, right? And we don’t know how long patients need to be treated. That’s why trials that we are doing and we are addressing right now are trials where we’re using MRD as a tool to tailor therapy, we just don’t have the data yet, but to either escalate or de-escalate treatment based on your MRD status. And those things are going to be incredibly useful because there may be a subset of patients where you give a year’s worth of 4-drug combinations, and if you achieve a really good deep response you may not be on anything after. We just don’t know what that is.

We are almost chasing our CML [chronic myeloid leukemia] colleagues, wherein they’ve used MRD testing to try and ascertain the timing or the duration of treatment. So I don’t think we have a good handle on duration of treatment. But given that we have such effective drugs, where we are getting to MRD negativity in a significant proportion of patients, the question is, how long do I need to be MRD negative? And, do I need to have 2 MRD tests a year apart to tell me that I can stop treatment? I don’t think we have data on that yet, but those are the kinds of trials that we should be doing going forward so that we do not subject our patients to undue toxicity from all of these drug combinations that I’m talking about.

Kenneth C. Anderson, MD: The duration of therapy is a consideration when you are initially treating a patient who’s eligible for transplantation. The major thing to remember here is that the novel agents, lenalidomide, in particular, an immunomodulatory drug, if given repeatedly can actually suppress or inhibit, compromise the ability to collect autologous peripheral blood stem cells. So most protocols usually treat with lenalidomide-containing therapies for 3 or 4 cycles, often until maximal response. But we avoid utilizing prolonged treatment with immunomodulatory drug-containing regimens like lenalidomide because we don’t want to compromise collection of stem cells. Having said that, we, in the old days, would use cyclophosphamide mobilization. Now we have G-CSF [granulocyte colony-stimulating factor] that’s added and can help us. And we have plerixafor also, which can be utilized. So it’s very rare nowadays that we can’t collect autologous cells in adequate numbers for stem cell transplant.

I actually wouldn’t recommend, in the era of novel therapies, any patients for double transplantation. The only evidence that we have that is remaining or pointing in the direction that a double transplant might help patients is from a European Myeloma Network trial, where they actually showed that in patients who had 2 transplants, there was a benefit versus 1 transplant. But honestly, in that clinical trial, patients did not receive the state-of-the-art novel therapies as part of their initial treatment. So putting it plainly, in the United States there was a clinical trial of lenalidomide/bortezomib/dexamethasone [RVd], followed by a single transplant and lenalidomide maintenance. The second arm was lenalidomide/bortezomib/dexamethasone, stem cell transplant, RVd, or lenalidomide/bortezomib/dexamethasone consolidation, and lenalidomide maintenance.  And the third arm was the same induction, 2 transplants, and then lenalidomide maintenance. And there was no difference. It was called the StaMINA trial in the United States. But it tells you if you use novel therapy, triplet therapies, initially, the value of a double transplant is really not appreciated any longer.

Transcript Edited for Clarity
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Transcript:

Rafael Fonseca, MD: Another question that has been frequently debated and discussed in the area of myeloma is, how deep should we go? How intense should we go with our regimens? And the more I see the data come back from clinical trials, I think the answer is becoming increasingly clear to me. You have to go for very deep responses. Sometimes when I speak now I use a term. We have to establish Pax Romana for those myeloma cells. And of course, it stands to reason, it’s obvious we have to do it safely, so we have to choose regimens that don’t cause undue toxicity for our patients. But I think we understand the regimens quite a bit better. I think during your induction therapy you should try to achieve that MRD [minimal residual disease]-negative status as possible, as I’ve previously discussed.

As of now, I still make the recommendation for stem cell transplant. Certainly, I put all of my patients on maintenance therapy. One of the questions I still have is whether there’s some value in post-transplant therapy. If someone has residual disease, say someone who’s MRD-positive post stem cell transplant, I would argue, for instance, for a high-risk patient, that just kind of crossing your fingers and going into lenalidomide is probably not enough. So we need more clinical trials in that particular area.

And this is very important because one of the things we’ve learned, and I presented some of this data at the ASH [American Society of Hematology] meeting, is that you cannot assume that you will have the opportunity to establish a second line of treatment or a third line of treatment for a patient for whom you are providing that first line of therapy.

In other words, the attrition between lines of therapy is high. And the reasons for that are multiple. Sometimes the person has a great response, but sometimes they develop comorbidities or have progressive disease in such a way that they’re precluded from receiving that salvage strategy. My common argument here is that if you have drugs A and B, and you show that combination A/B is better, an argument that comes back often is, what if you use A and then save B for later? So the sequencing argument. There may not be time for B, and hopefully we could do that. There are other diseases where this has been done. For instance, in breast cancer. But in myeloma I think you have to put your best foot forward right from the get-go.

When I speak, I have a slide I frequently use. I put an image of soccer and an image of baseball, and I say, “Is it like soccer or baseball?” Because in soccer you put your best players in game number 1. In baseball you can have a lineup or you can have a pitcher on the line that will save the day. Myeloma is like soccer.

Noopur S. Raje, MD: I think what we’ve learned over the last several years is that the depth of response is important, and what we’ve also seen with some of the myeloma treatments is that the depth of response continues to deepen over time. That’s part of the reason why, at least in the transplant-eligible patients, it seems pretty straightforward. You start off with induction treatment and you use transplant as your consolidation. You might use something at the back end, which we also refer to as consolidation, and then you maintain these patients. And along the way, no matter what data set you look at, you will see that there’s a depth in terms of complete responses. There’s a depth in terms of conversion to MRD negativity. And the deeper your responses, the more MRD-negative disease state you get into, the better the outcome is, suggesting that it is important to continue treatment.

In terms of the transplant-ineligible patients, we don’t typically use the words “induction” or “consolidation.” You start off with initial therapy and then you continue therapy for patients with multiple myeloma. And at least the data, as it stands today, recommend that you continue until progression.

Earlier on we talked about 3 drugs versus 4 drugs. Is it time to test 4 drugs? I do think it is time to test 4 drugs. We also talked about MRD testing, and I think it’s really important to use MRD testing as a tool, specifically when you’re using a combination of 3 and 4 drugs, because it is entirely possible that we will not have to continue treatment indefinitely if we can get to a really good depth of response.

The problem, right now, is we don’t know what that depth of response is, right? And we don’t know how long patients need to be treated. That’s why trials that we are doing and we are addressing right now are trials where we’re using MRD as a tool to tailor therapy, we just don’t have the data yet, but to either escalate or de-escalate treatment based on your MRD status. And those things are going to be incredibly useful because there may be a subset of patients where you give a year’s worth of 4-drug combinations, and if you achieve a really good deep response you may not be on anything after. We just don’t know what that is.

We are almost chasing our CML [chronic myeloid leukemia] colleagues, wherein they’ve used MRD testing to try and ascertain the timing or the duration of treatment. So I don’t think we have a good handle on duration of treatment. But given that we have such effective drugs, where we are getting to MRD negativity in a significant proportion of patients, the question is, how long do I need to be MRD negative? And, do I need to have 2 MRD tests a year apart to tell me that I can stop treatment? I don’t think we have data on that yet, but those are the kinds of trials that we should be doing going forward so that we do not subject our patients to undue toxicity from all of these drug combinations that I’m talking about.

Kenneth C. Anderson, MD: The duration of therapy is a consideration when you are initially treating a patient who’s eligible for transplantation. The major thing to remember here is that the novel agents, lenalidomide, in particular, an immunomodulatory drug, if given repeatedly can actually suppress or inhibit, compromise the ability to collect autologous peripheral blood stem cells. So most protocols usually treat with lenalidomide-containing therapies for 3 or 4 cycles, often until maximal response. But we avoid utilizing prolonged treatment with immunomodulatory drug-containing regimens like lenalidomide because we don’t want to compromise collection of stem cells. Having said that, we, in the old days, would use cyclophosphamide mobilization. Now we have G-CSF [granulocyte colony-stimulating factor] that’s added and can help us. And we have plerixafor also, which can be utilized. So it’s very rare nowadays that we can’t collect autologous cells in adequate numbers for stem cell transplant.

I actually wouldn’t recommend, in the era of novel therapies, any patients for double transplantation. The only evidence that we have that is remaining or pointing in the direction that a double transplant might help patients is from a European Myeloma Network trial, where they actually showed that in patients who had 2 transplants, there was a benefit versus 1 transplant. But honestly, in that clinical trial, patients did not receive the state-of-the-art novel therapies as part of their initial treatment. So putting it plainly, in the United States there was a clinical trial of lenalidomide/bortezomib/dexamethasone [RVd], followed by a single transplant and lenalidomide maintenance. The second arm was lenalidomide/bortezomib/dexamethasone, stem cell transplant, RVd, or lenalidomide/bortezomib/dexamethasone consolidation, and lenalidomide maintenance.  And the third arm was the same induction, 2 transplants, and then lenalidomide maintenance. And there was no difference. It was called the StaMINA trial in the United States. But it tells you if you use novel therapy, triplet therapies, initially, the value of a double transplant is really not appreciated any longer.

Transcript Edited for Clarity
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