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Quadruplet Therapy Prior to Transplant in Myeloma

Panelists: A. Keith Stewart, MB, ChB, Mayo Clinic; Cristina Gasparetto, MD, Duke University Medical Center; Parameswaran Hari, MD, MRCP, MS, Medical College of Wisconsin; Robert Orlowski, MD, PhD, MD Anderson Cancer Center; Noopur Suresh Raje, MD, Massachusetts General Hospital
Published: Friday, Jan 25, 2019



Transcript:

A. Keith Stewart, MB, ChB: Four drug combinations were mentioned, and there were a number of abstracts here at the meeting in which 4 drugs were being employed. Did anything particularly stand out for you?

Rafael Fonseca, MD: Shaji Kumar, MD presented an abstract with introduction of daratumumab plus the triplet Pi/IMiD [proteasome inhibitor/immunomodulatory agent], dexamethasone combination. I don’t think we’re ready. There were a number of other trials so we’re not going to drill down into the details. I think the logic is there. You know if 2 was good, maybe 3 is better; and 4 is going to be even better. But the reality of the new benchmark is MRD [minimal residual disease] negativity.

Now MRD, we’re going to talk more about that later, but getting a deep response is so important that any agent that contributes to that process is going to need to be part of the optimal induction therapy. So what I’m saying is just that sort of the opening, you know the first foray at this 4-drug combinations, but we would have to see, just like what we’re seeing with KRd versus VRd, we’ll have to see that for 4 drugs as well.

A. Keith Stewart, MB, ChB: So you mentioned Dr Kumar’s abstract. He presented on the use of ixazomib, an oral proteasome inhibitor, with lenalidomide and daratumumab, dexamethasone. What did you think of that, Faith?

Faith Davies, MD, MBBCh, MRCP, FRCPath: There has been quite a lot of data being presented on including daratumumab in our up-front regimens. And it certainly seems to be effective. It seems to induce good MRD negativity, and it seems to be very exciting. So I think it’s a drug that’s going to stay. And I think as you we’re saying, we’re going to be in, I guess, a luxurious position of deciding which drug combination is going to be best for our patients, whether we go in an oral route, whether we have an intravenous combination, and then what are their other…

A. Keith Stewart, MB, ChB: I was quite impressed with the Rd/DARA trial data. It was actually better than I thought it would be. It is a very convenient regimen and is, specifically, 3 oral drugs plus what eventually becomes a monthly infusion. Did anybody else feel similarly enamored with that, or do you think this is only for older people?

Adriana Rossi, MD: No, I don’t know that it’s for older people, but I would like to have a better way of distinguishing which patients need that 4-drug therapy. I still have plenty of patients who may even get CyBorD [bortezomib, cyclophosphamide and dexamethasone] and get a CR [complete response] within a couple of cycles. You know, we may not need to do 4 drugs for everybody, but we don’t yet have a good test to decide which ones would or would not. I do think it’s a wonderful challenge to have, that we can pick and choose and find the right triplet for that patient. So it may be age, it may be comorbidity.

A. Keith Stewart, MB, ChB: One of the regimens we’ve all used a lot in the past decade is CyBorD, which is cyclophosphamide based. There was a presentation on cyclophosphamide, bortezomib, and daratumumab with dexamethasone. This is another 4-drug regimen. And I actually got the impression that it was a little bit less effective when we looked at depth of response.

Thomas Martin, MD: I do think that ASH [American Society of Hematology Annual Meeting] 2018 will change the way we practice, in terms of induction therapy for myeloma. No doubt about it. So there are 2. There’s the study that you talked about, VCd plus daratumumab. It was a phase II study. It was done by a community group. And the reason I think it seemed less impressive is because of the way they assessed responses. They assessed it by a computer program that actually has to look at the bone marrow biopsy and decipher the bone biopsy result, and decide whether it’s CR [complete response], or stringent CR, etcetera. So those data are going to improve as that computer program gets better and the doctors get better.

A. Keith Stewart, MB, ChB: I just wondered whether it was partly just real life. These aren’t clinical trial patients, they’re real life patients.

Thomas Martin, MD: I don’t think so. I think that’s part of it. But the other study that was presented was the GRIFFIN study. That’s a large study in the US of RVd plus daratumumab. Actually it was a randomized phase II trial. The patients that they presented were the first 16 patients, the run-in, just to make sure that RVd-DARA was safe and effective. And in those 16 patients the CR stringent rate was over 60%. It was very impressive.

A. Keith Stewart, MB, ChB: Yeah, it was formerly a small number of patients, just to be very clear. But that trial has accrued over 200 patients now.

Thomas Martin, MD: Correct.

A. Keith Stewart, MB, ChB: I was actually very impressed with the data. Adriana, your thoughts on that? Is that going to be our standard of care?

Adriana Rossi, MD: Well, again, I think it probably will be, but it would be nice to know in whom we actually need the fourth drug, and which 3 drug combinations…

A. Keith Stewart, MB, ChB: You don’t think everybody uses it?

Adriana Rossi, MD: I don’t think everybody needs to be treated the same. I think the new…

A. Keith Stewart, MB, ChB: Why would you not add a fourth drug if the response rates are higher and depth of response is better? What would stop you?

Adriana Rossi, MD: Well one of the things is the financial toxicity of trying to get 4 of these drugs for everybody. And as our patients are living longer and we ascribe to continuous therapy, also, how long are you going to go with 4? And when you peal back, which ones do you peal back?

A. Keith Stewart, MB, ChB: You draw out the dreaded. Let’s stay away from this a little bit. Toxicity, Rafael, when adding a fourth drug. I was impressed. There was quite a lot of infection when one added daratumumab. In that RVd/DARA trial there was 25%. We saw fairly significant infection—pneumonia.

Rafael Fonseca, MD: Everyone likes DARA. We’re putting it in combinations, but one has to remember that hypo gamma and other affects in the immune system we have yet to understand. And oftentimes we’ve seen some patients of course who were heavily pretreated. So I don’t think the signal has been as clear. But now we have to be careful about that. Now the one interesting thing is that we now think about infection prophylaxis from myeloma in the front line. There’s a study with levofloxacin from a year ago. Should they be on the trimethoprim for, you know? Should they be on fluconazole? They all need to be on acyclovir. So they’re going to take as many pills now for prevention as they’re taking for primary therapy. But it is a challenge that we need to be mindful about.

A. Keith Stewart, MB, ChB: Faith, what is your experience? Do you find early infection to be a problem?

Faith Davies, MD, MBBCh, MRCP, FRCPath: Yeah. No, I mean I think as you mentioned, the pneumonia is the one. And so we really need to be observant for that, and I think that, as you said, we need to do prophylaxis. But I think we prophylax in other disease areas without batting an eyelid, so why shouldn’t we do it in myeloma?

A. Keith Stewart, MB, ChB: What about Levaquin? Has everybody started using Levaquin again?

Thomas Martin, MD: With induction therapy I definitely use Levaquin. And I will say on the infection risk, there are 2 time periods that we have to worry about. Its induction therapy, and then maintenance-based therapy. And most of the infection is during induction, and that’s why I do use Levaquin during that period of time, and Bactrim receptor for PCP [pneumocystis pneumonia] prophylaxis.

What I think we really need to look at as we use daratumumab is maintenance-based therapy. Are we going to see late pneumonias and late complications? That is going to really, in my mind, be the key for this.

Transcript edited for clarity.

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Transcript:

A. Keith Stewart, MB, ChB: Four drug combinations were mentioned, and there were a number of abstracts here at the meeting in which 4 drugs were being employed. Did anything particularly stand out for you?

Rafael Fonseca, MD: Shaji Kumar, MD presented an abstract with introduction of daratumumab plus the triplet Pi/IMiD [proteasome inhibitor/immunomodulatory agent], dexamethasone combination. I don’t think we’re ready. There were a number of other trials so we’re not going to drill down into the details. I think the logic is there. You know if 2 was good, maybe 3 is better; and 4 is going to be even better. But the reality of the new benchmark is MRD [minimal residual disease] negativity.

Now MRD, we’re going to talk more about that later, but getting a deep response is so important that any agent that contributes to that process is going to need to be part of the optimal induction therapy. So what I’m saying is just that sort of the opening, you know the first foray at this 4-drug combinations, but we would have to see, just like what we’re seeing with KRd versus VRd, we’ll have to see that for 4 drugs as well.

A. Keith Stewart, MB, ChB: So you mentioned Dr Kumar’s abstract. He presented on the use of ixazomib, an oral proteasome inhibitor, with lenalidomide and daratumumab, dexamethasone. What did you think of that, Faith?

Faith Davies, MD, MBBCh, MRCP, FRCPath: There has been quite a lot of data being presented on including daratumumab in our up-front regimens. And it certainly seems to be effective. It seems to induce good MRD negativity, and it seems to be very exciting. So I think it’s a drug that’s going to stay. And I think as you we’re saying, we’re going to be in, I guess, a luxurious position of deciding which drug combination is going to be best for our patients, whether we go in an oral route, whether we have an intravenous combination, and then what are their other…

A. Keith Stewart, MB, ChB: I was quite impressed with the Rd/DARA trial data. It was actually better than I thought it would be. It is a very convenient regimen and is, specifically, 3 oral drugs plus what eventually becomes a monthly infusion. Did anybody else feel similarly enamored with that, or do you think this is only for older people?

Adriana Rossi, MD: No, I don’t know that it’s for older people, but I would like to have a better way of distinguishing which patients need that 4-drug therapy. I still have plenty of patients who may even get CyBorD [bortezomib, cyclophosphamide and dexamethasone] and get a CR [complete response] within a couple of cycles. You know, we may not need to do 4 drugs for everybody, but we don’t yet have a good test to decide which ones would or would not. I do think it’s a wonderful challenge to have, that we can pick and choose and find the right triplet for that patient. So it may be age, it may be comorbidity.

A. Keith Stewart, MB, ChB: One of the regimens we’ve all used a lot in the past decade is CyBorD, which is cyclophosphamide based. There was a presentation on cyclophosphamide, bortezomib, and daratumumab with dexamethasone. This is another 4-drug regimen. And I actually got the impression that it was a little bit less effective when we looked at depth of response.

Thomas Martin, MD: I do think that ASH [American Society of Hematology Annual Meeting] 2018 will change the way we practice, in terms of induction therapy for myeloma. No doubt about it. So there are 2. There’s the study that you talked about, VCd plus daratumumab. It was a phase II study. It was done by a community group. And the reason I think it seemed less impressive is because of the way they assessed responses. They assessed it by a computer program that actually has to look at the bone marrow biopsy and decipher the bone biopsy result, and decide whether it’s CR [complete response], or stringent CR, etcetera. So those data are going to improve as that computer program gets better and the doctors get better.

A. Keith Stewart, MB, ChB: I just wondered whether it was partly just real life. These aren’t clinical trial patients, they’re real life patients.

Thomas Martin, MD: I don’t think so. I think that’s part of it. But the other study that was presented was the GRIFFIN study. That’s a large study in the US of RVd plus daratumumab. Actually it was a randomized phase II trial. The patients that they presented were the first 16 patients, the run-in, just to make sure that RVd-DARA was safe and effective. And in those 16 patients the CR stringent rate was over 60%. It was very impressive.

A. Keith Stewart, MB, ChB: Yeah, it was formerly a small number of patients, just to be very clear. But that trial has accrued over 200 patients now.

Thomas Martin, MD: Correct.

A. Keith Stewart, MB, ChB: I was actually very impressed with the data. Adriana, your thoughts on that? Is that going to be our standard of care?

Adriana Rossi, MD: Well, again, I think it probably will be, but it would be nice to know in whom we actually need the fourth drug, and which 3 drug combinations…

A. Keith Stewart, MB, ChB: You don’t think everybody uses it?

Adriana Rossi, MD: I don’t think everybody needs to be treated the same. I think the new…

A. Keith Stewart, MB, ChB: Why would you not add a fourth drug if the response rates are higher and depth of response is better? What would stop you?

Adriana Rossi, MD: Well one of the things is the financial toxicity of trying to get 4 of these drugs for everybody. And as our patients are living longer and we ascribe to continuous therapy, also, how long are you going to go with 4? And when you peal back, which ones do you peal back?

A. Keith Stewart, MB, ChB: You draw out the dreaded. Let’s stay away from this a little bit. Toxicity, Rafael, when adding a fourth drug. I was impressed. There was quite a lot of infection when one added daratumumab. In that RVd/DARA trial there was 25%. We saw fairly significant infection—pneumonia.

Rafael Fonseca, MD: Everyone likes DARA. We’re putting it in combinations, but one has to remember that hypo gamma and other affects in the immune system we have yet to understand. And oftentimes we’ve seen some patients of course who were heavily pretreated. So I don’t think the signal has been as clear. But now we have to be careful about that. Now the one interesting thing is that we now think about infection prophylaxis from myeloma in the front line. There’s a study with levofloxacin from a year ago. Should they be on the trimethoprim for, you know? Should they be on fluconazole? They all need to be on acyclovir. So they’re going to take as many pills now for prevention as they’re taking for primary therapy. But it is a challenge that we need to be mindful about.

A. Keith Stewart, MB, ChB: Faith, what is your experience? Do you find early infection to be a problem?

Faith Davies, MD, MBBCh, MRCP, FRCPath: Yeah. No, I mean I think as you mentioned, the pneumonia is the one. And so we really need to be observant for that, and I think that, as you said, we need to do prophylaxis. But I think we prophylax in other disease areas without batting an eyelid, so why shouldn’t we do it in myeloma?

A. Keith Stewart, MB, ChB: What about Levaquin? Has everybody started using Levaquin again?

Thomas Martin, MD: With induction therapy I definitely use Levaquin. And I will say on the infection risk, there are 2 time periods that we have to worry about. Its induction therapy, and then maintenance-based therapy. And most of the infection is during induction, and that’s why I do use Levaquin during that period of time, and Bactrim receptor for PCP [pneumocystis pneumonia] prophylaxis.

What I think we really need to look at as we use daratumumab is maintenance-based therapy. Are we going to see late pneumonias and late complications? That is going to really, in my mind, be the key for this.

Transcript edited for clarity.
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