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Treating Transplant-Ineligible 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: Monday, Mar 04, 2019



Transcript:

Kenneth C. Anderson, MD:
The patients who are transplant-ineligible also really need to benefit from our novel agents. I actually did an educational session at the American Society of Hematology [ASH] annual meeting this year [2018], which really informed and educated caregivers on how to assess the concept of frailty. Frailty is not just performance status. It involves many features of the disease, but, in particular, it can classify patients either as fit or frail. And the reason that’s important is frailty in patients with myeloma has been as important or actually even more important than age or cytogenetics as a risk factor. So if we actually have a frail patient who’s not eligible for transplant, which is not uncommon—they’re elderly and they have comorbidities, for example—we can dose adjust the drugs so that they can receive triplet therapies.

I’ll mention to you that a common doublet therapy that has been popularized is lenalidomide/dexamethasone [RD] given continuously. That was as a consequence of the first trial, a randomized trial of lenalidomide/dexamethasone continuously versus lenalidomide/dexamethasone for 18 months, versus melphalan and prednisone and thalidomide [MPT].

So lenalidomide/dexamethasone continuously was superior and was a standard of care. But we have 2 or maybe more options coming where triplets are commonly used in myeloma. The most common one right now is called Revlimid/Velcade/dexamethasone, or lenalidomide/bortezomib/dexamethasone, where the doses have been reduced. It’s called RVd-lite, because the doses have been reduced—15 mg of lenalidomide daily for 2 weeks, dexamethasone 20 mg orally once a week, and Velcade at 1.3 mm per meter squared weekly. This RVd-lite can really achieve responses and be well tolerated on the other in myeloma.

Now I’ll mention one clinical trial that was presented at the American Society of Hematology annual meeting as a late-breaking abstract. It’s a triplet where daratumumab was added to lenalidomide and dexamethasone for the first time in the transplant-ineligible patients. And in that setting, the lenalidomide/dexamethasone progression-free survival was 31.9 months. When you added daratumumab, it was not yet reached. That particular study showed a 45% reduction in the rate of progression or death when one added daratumumab to lenalidomide and dexamethasone.

I mention this because this is an example. In addition to RVd-lite, or lenalidomide/bortezomib/dexamethasone, daratumumab/lenalidomide/dexamethasone, as of this time, appears to be a very active and well tolerated initial therapy in transplant-ineligible patients.

Noopur S. Raje, MD: In the transplant-ineligible patients, we’ve made a lot of advances more recently, which is reassuring because most of us talk about survival in myeloma, which has improved significantly, and most of us attribute that survival to transplant.

At this year’s ASH, we saw, for the first time, data that were presented from the MAIA trial. This was a step up from the first data. Now if you go back to the first data, this was a trial that, for the first time, showed us that continuous therapy in multiple myeloma makes a difference. That was a study that compared RD for a stipulated timeframe, RD continuous, and then compared it to MPT. The RD continuous regimen was the winner in that arm, and that was considered sort of the standard of care.

So building up on this first trial, really nice data were presented at this year’s ASH. This was the MAIA trial, where the control arm was RD continuously. And the addition of daratumumab, the monoclonal antibody, to the RD arm raised the question of, is that going to make a difference? What you have is a remarkable benefit, in terms of a progression-free survival. The RD arm had a survival of about 30 months or so for a median follow up of about 27 months. And the median for the RD/daratumumab arm has not yet been reached. It’s close to about 70%, 75% or so, which is quite remarkable in this patient population.

Clearly we haven’t seen the overall survival data. It’s too early. But given that this was generally well tolerated, you’ve only added on a monoclonal antibody, you did not compound the toxicity of RD by adding on the daratumumab. This is going to be a practice-changing trial in the future, I think. And I do think people are going to be using daratumumab in combination with RD, specifically if you look at the fantastic progression-free survival benefit that we’re seeing in our patients.

Rafael Fonseca, MD: A number of clinical trials show that triplets are better than doublets, and there are exceptions to this. Individuals who are frail, who have a number of comorbidities may be better off treated with the doublet, and there’s quite a bit of subjectivity in how we would go about choosing such patients. But I would say for the standard nontransplant candidate, a triplet will be better. Now, how’s that done? Well, there are a number of approaches. In the United States we’ve used mostly a combination of bortezomib/lenalidomide/dexamethasone—the RVd or VRd. And then there’s the “lite” word added to that because there’s some dose adjustment that is done for the elderly.

In European countries the combination of bortezomib, melphalan, and prednisone has been one of the backbones for the elderly patients. So a study was published and has been discussed in greater detail, including at the recent ASH meeting—the so-called ALCYONE study—where they looked at the combination of bortezomib/melphalan/prednisone plus daratumumab, showing the superiority of that combination. Dr Meletios Dimopoulos presented the data. It’s over 700 patients. And at least from the data we can see that the median progression-free survival was not reached. I believe they had a follow up of about 27 months. Whereas it was 19 months for the triplet combination there with bortezomib, melphalan, and prednisone.

Now that’s a regimen we’re not using as much in the United States just because we don’t use melphalan, but as we’re discussing, the alternative is the combination of daratumumab, lenalidomide, and dexamethasone—the so-called MAIA study—which really has very interesting and positive results. I think, and I know there’s a range of opinions here, but I think this is practice changing. I think this is a new standard and that’s what I’m doing for most of my patients.

Now, to some degree, the ALCYONE study was not as impactful here in the United States, just because we don’t use melphalan. But there’s a lot of lessons buried there. There are 2 that I would like to highlight. Number 1, just like the MAIA study, they found that the majority of patients are standard-risk. In both studies it’s about 85%. This is a very important fact because a high-risk disease is more common in the younger population, and the older population is more commonly composed of patients that have standard-risk disease, including hyperdiploidy. This has been published now for over 10, 15 years. We know this data to be very solid. Now this is very relevant because we need to understand the impact of risk stratification as we select some of these combinations.

So, for instance, if you have some of these high-risk markers, as we have traditionally done, do you still include a proteasome inhibitor? These are very important questions that need to be considered as we select some of those regimens. And I think we need to look also at other aspects of long-term toxicities. The studies, even though, again, we’re not using the melphalan, will give us a good representation of what some of the potential toxicities might be for these regimens. All in all, it’s a great time for multiple myeloma because of the progress that continues to show up at our meetings.

Transcript edited for clarity.
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Transcript:

Kenneth C. Anderson, MD:
The patients who are transplant-ineligible also really need to benefit from our novel agents. I actually did an educational session at the American Society of Hematology [ASH] annual meeting this year [2018], which really informed and educated caregivers on how to assess the concept of frailty. Frailty is not just performance status. It involves many features of the disease, but, in particular, it can classify patients either as fit or frail. And the reason that’s important is frailty in patients with myeloma has been as important or actually even more important than age or cytogenetics as a risk factor. So if we actually have a frail patient who’s not eligible for transplant, which is not uncommon—they’re elderly and they have comorbidities, for example—we can dose adjust the drugs so that they can receive triplet therapies.

I’ll mention to you that a common doublet therapy that has been popularized is lenalidomide/dexamethasone [RD] given continuously. That was as a consequence of the first trial, a randomized trial of lenalidomide/dexamethasone continuously versus lenalidomide/dexamethasone for 18 months, versus melphalan and prednisone and thalidomide [MPT].

So lenalidomide/dexamethasone continuously was superior and was a standard of care. But we have 2 or maybe more options coming where triplets are commonly used in myeloma. The most common one right now is called Revlimid/Velcade/dexamethasone, or lenalidomide/bortezomib/dexamethasone, where the doses have been reduced. It’s called RVd-lite, because the doses have been reduced—15 mg of lenalidomide daily for 2 weeks, dexamethasone 20 mg orally once a week, and Velcade at 1.3 mm per meter squared weekly. This RVd-lite can really achieve responses and be well tolerated on the other in myeloma.

Now I’ll mention one clinical trial that was presented at the American Society of Hematology annual meeting as a late-breaking abstract. It’s a triplet where daratumumab was added to lenalidomide and dexamethasone for the first time in the transplant-ineligible patients. And in that setting, the lenalidomide/dexamethasone progression-free survival was 31.9 months. When you added daratumumab, it was not yet reached. That particular study showed a 45% reduction in the rate of progression or death when one added daratumumab to lenalidomide and dexamethasone.

I mention this because this is an example. In addition to RVd-lite, or lenalidomide/bortezomib/dexamethasone, daratumumab/lenalidomide/dexamethasone, as of this time, appears to be a very active and well tolerated initial therapy in transplant-ineligible patients.

Noopur S. Raje, MD: In the transplant-ineligible patients, we’ve made a lot of advances more recently, which is reassuring because most of us talk about survival in myeloma, which has improved significantly, and most of us attribute that survival to transplant.

At this year’s ASH, we saw, for the first time, data that were presented from the MAIA trial. This was a step up from the first data. Now if you go back to the first data, this was a trial that, for the first time, showed us that continuous therapy in multiple myeloma makes a difference. That was a study that compared RD for a stipulated timeframe, RD continuous, and then compared it to MPT. The RD continuous regimen was the winner in that arm, and that was considered sort of the standard of care.

So building up on this first trial, really nice data were presented at this year’s ASH. This was the MAIA trial, where the control arm was RD continuously. And the addition of daratumumab, the monoclonal antibody, to the RD arm raised the question of, is that going to make a difference? What you have is a remarkable benefit, in terms of a progression-free survival. The RD arm had a survival of about 30 months or so for a median follow up of about 27 months. And the median for the RD/daratumumab arm has not yet been reached. It’s close to about 70%, 75% or so, which is quite remarkable in this patient population.

Clearly we haven’t seen the overall survival data. It’s too early. But given that this was generally well tolerated, you’ve only added on a monoclonal antibody, you did not compound the toxicity of RD by adding on the daratumumab. This is going to be a practice-changing trial in the future, I think. And I do think people are going to be using daratumumab in combination with RD, specifically if you look at the fantastic progression-free survival benefit that we’re seeing in our patients.

Rafael Fonseca, MD: A number of clinical trials show that triplets are better than doublets, and there are exceptions to this. Individuals who are frail, who have a number of comorbidities may be better off treated with the doublet, and there’s quite a bit of subjectivity in how we would go about choosing such patients. But I would say for the standard nontransplant candidate, a triplet will be better. Now, how’s that done? Well, there are a number of approaches. In the United States we’ve used mostly a combination of bortezomib/lenalidomide/dexamethasone—the RVd or VRd. And then there’s the “lite” word added to that because there’s some dose adjustment that is done for the elderly.

In European countries the combination of bortezomib, melphalan, and prednisone has been one of the backbones for the elderly patients. So a study was published and has been discussed in greater detail, including at the recent ASH meeting—the so-called ALCYONE study—where they looked at the combination of bortezomib/melphalan/prednisone plus daratumumab, showing the superiority of that combination. Dr Meletios Dimopoulos presented the data. It’s over 700 patients. And at least from the data we can see that the median progression-free survival was not reached. I believe they had a follow up of about 27 months. Whereas it was 19 months for the triplet combination there with bortezomib, melphalan, and prednisone.

Now that’s a regimen we’re not using as much in the United States just because we don’t use melphalan, but as we’re discussing, the alternative is the combination of daratumumab, lenalidomide, and dexamethasone—the so-called MAIA study—which really has very interesting and positive results. I think, and I know there’s a range of opinions here, but I think this is practice changing. I think this is a new standard and that’s what I’m doing for most of my patients.

Now, to some degree, the ALCYONE study was not as impactful here in the United States, just because we don’t use melphalan. But there’s a lot of lessons buried there. There are 2 that I would like to highlight. Number 1, just like the MAIA study, they found that the majority of patients are standard-risk. In both studies it’s about 85%. This is a very important fact because a high-risk disease is more common in the younger population, and the older population is more commonly composed of patients that have standard-risk disease, including hyperdiploidy. This has been published now for over 10, 15 years. We know this data to be very solid. Now this is very relevant because we need to understand the impact of risk stratification as we select some of these combinations.

So, for instance, if you have some of these high-risk markers, as we have traditionally done, do you still include a proteasome inhibitor? These are very important questions that need to be considered as we select some of those regimens. And I think we need to look also at other aspects of long-term toxicities. The studies, even though, again, we’re not using the melphalan, will give us a good representation of what some of the potential toxicities might be for these regimens. All in all, it’s a great time for multiple myeloma because of the progress that continues to show up at our meetings.

Transcript edited for clarity.
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