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Monoclonal Antibody, Triplet Therapy & Transplant Ineligible

Insights From: Ajai Chari, MD, Icahn School of Medicine at Mount Sinai; Andrzej Jakubowiak, MD, PhD, University of Chicago; Sagar Lonial, MD, Winship Cancer Institute of Emory University
Published: Tuesday, Jan 15, 2019



Transcript:

Ajai Chari, MD:
When we think about drug classes for myeloma, we have steroids, conventional chemo, immunomodulatory drugs, proteasome inhibitors, HDAC [histone deacetylase] inhibitors, and the monoclonal antibody. Until 2015 we had no monoclonal antibodies. Fortunately now we have 2 that are FDA approved. One is elotuzumab, and the second is daratumumab. Elotuzumab does not have single-agent activity, so it’s approved only in combination with lenalidomide and dexamethasone, and so that is challenging because many patients in the United States will not be lenalidomide sensitive.

Going back to symptomatic versus biochemical relapse, if somebody truly has a clinical relapse, ELO-RD [elotuzumab, lenalidomide, and dexamethasone] may not be adequate enough; however, one of the real strengths of ELO-RD is when you compare dexamethasone versus ELO-RD, you see almost no additive toxicity. And that’s really unique about a triplet therapy—when you add a third drug, but you don’t see any additional toxicity, that’s really great for patients.

Daratumumab, of course, has been a tremendous addition for our armamentarium for the treatment of myeloma. Single-agent activity of 20% to 30% response rate, PFS [progression-free survival] of 3 months in their heavily treated patients. But what’s really important about daratumumab is the combinability and safety; it’s been approved now in numerous settings: in frontline with VMP [bortezomib, melphalan, and prednisone], in the relapsed setting with lenalidomide, and with bortezomib, and recently also with pomalidomide. And I’ve also presented data with daratumumab and carfilzomib. So we have a lot of ways daratumumab can be used. And what’s really great about these monoclonals again is that both of the monoclonals typically improve efficacy without adding a lot to toxicity. And that’s what we have been lacking till 2015. So it’s great for patients to have this drug class.

In terms of the use of dexamethasone in lenalidomide-refractory patients, this is an important consideration because we have so many randomized phase III studies, including 4 that had a lenalidomide and dexamethasone backbone: ELOQUENT-3 with the addition of elotuzumab, Tourmaline-MM1 with addition of ixazomib, POLLUX with the addition of daratumumab, and ASPIRE with the addition of carfilzomib. But all 4 of those did not allow lenalidomide-refractory patients. So when we have a patient sitting in front of us in clinic who’s relapsing on lenalidomide, those 4 studies really don’t provide evidence-based medicine to treat them.

And so the dexamethasone cohort is part of the study in which daratumumab was combined with numerous different backbone drugs. It’s a phase I combination study of these compounds. And dexamethasone showed really exciting results, a response rate of approximately 80% with a median of 2 lines of therapy. And really the response rate was no different in the 50 or so patients who were lenalidomide refractory. The PFS of all patients was not reached, whereas the PFS of lenalidomide refractory was 14 months. So I think those are really encouraging data. The toxicity profile is what you would expect from each agent.

So I really like this regimen for salvage because it includes daratumumab, which is an outstanding monoclonal antibody, and carfilzomib, which has been shown in a head-to-head study in ENDEAVOR to be the superior PI. So dexamethasone is a great option. And I would also add that the rate of neutropenia with this regimen is quite low: only 20% compared with much higher rates when we add it with immunomodulatory drugs. Again, this is off-label, not yet approved, but it’s a great option for patients.

When we start patients on triplet therapies, the evidence-based medicine in the studies are all administered until progression. The reality is in the real world, it’s hard to maintain everybody on all drugs forever from a variety of reasons, whether it’s toxicity…physical, emotional, financial, and also the question of how much additive benefit, especially somebody in a good remission.

So my practice in the real world is if somebody has a deep remission or a plateau, do we really need to maintain all 3 drugs? I think many of us drop out the steroids first, because if you ask a myeloma patient which drug you hate the most, it’s usually the steroid. And particularly interesting is when you ask a patient with her family member, are you doing OK on the steroid, the patient often says, “Fine.” But it’s the family member who notices the irritability, the agitation, insomnia.

So steroids, I think, are an easy answer to drop first. And then if you’re trying to eliminate further to go to a single agent, then I think you have to think about the adverse-effect profile. And, for example, if you’re using a daratumumab, pomaliadomide, and dexamethasone combination or a daratumumab, lenalidomide, and dexamethasone combination, and the patient is quite cytopenic, you may want to drop the immunomodulatory drug. If somebody is getting fatigued with a parenteral drug, you may want to maintain the oral drug. So I think those are the typical strategies we use in the real world.

The only caution I would add is that if somebody is truly high-risk, you may not want to reduce too much because I think we know that with high-risk patients, it’s not that they don’t get a response or a deep response; it’s the durability. So we don’t want to be complacent in a high-risk patient and say, “Oh, I’ve had a great response. Let me dial back everything.” I think in high-risk patients, it’s important to maintain at least the doublet. Perhaps you can omit the steroid, but I think the 2-drug maintenance is important.

When we think about slow versus rapid progression, in a way this is reminiscent of the biochemical versus clinical relapse. But I would add that for all of these considerations, we really should think about not only the crab symptoms and the rate but also making sure that the [radiological] assessment has been done. Because sometimes we may label somebody as a slow progression or as a biochemical progression, but if they have radiological progression on a PET [positron emission tomography] scan or an MRI [magnetic resonance imaging], skeletal surveys we know are not very helpful.

But if they have new radiological disease, even if it’s asymptomatic, that really should be treated more aggressively. But if somebody has been scanned and has no radiological disease, and if they have no crab symptoms, then we can put them into the biochemical slow-relapse category, and that one patient could consider again the same considerations we had for biochemical, thinking about up titrating the lenalidomide, for example, adding steroids, perhaps adding elotuzumab or ixazomib or something like that. But I think if somebody again has a rapid progression, high risk, symptomatic we really need to use active drugs and change up all the backbone drugs as well.

In transplant-ineligible patients, relapse is even more challenging because the big difference now is you have additional host factors. So you have the same disease in prior therapy-related issues that you do with younger transplant eligible patients. But now we add the complexity of whatever made them transplant and ineligible is likely going to make their medical care more challenging. Is it the heart failure, is it the lung problems like COPD [chronic obstructive pulmonary disease], is it the renal function or their performance status—whatever those things are, it really affects their outcome. So we have to be mindful of doses, combinations, and modifications.

So there’s a frailty index that’s available online if somebody is uncertain about what to do. But if it’s a patient who’s frail, doses should be minimized. For example, twice-weekly bortezomib is never well tolerated in this population. Weekly bortezomib, there are some concerns that older patients may have more cardiac issues. And so not that carfilzomib is a bad drug, but because older patients have more cardiac issues, we may see more cardiac toxicity with carfilzomib. The immunomodulatory drug should probably be reduced for safety. We have to be mindful of thrombotic prophylaxis because of poor performance status. So those are examples of things we need to consider in this population that’s unique to them.

Transcript edited for clarity.
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Transcript:

Ajai Chari, MD:
When we think about drug classes for myeloma, we have steroids, conventional chemo, immunomodulatory drugs, proteasome inhibitors, HDAC [histone deacetylase] inhibitors, and the monoclonal antibody. Until 2015 we had no monoclonal antibodies. Fortunately now we have 2 that are FDA approved. One is elotuzumab, and the second is daratumumab. Elotuzumab does not have single-agent activity, so it’s approved only in combination with lenalidomide and dexamethasone, and so that is challenging because many patients in the United States will not be lenalidomide sensitive.

Going back to symptomatic versus biochemical relapse, if somebody truly has a clinical relapse, ELO-RD [elotuzumab, lenalidomide, and dexamethasone] may not be adequate enough; however, one of the real strengths of ELO-RD is when you compare dexamethasone versus ELO-RD, you see almost no additive toxicity. And that’s really unique about a triplet therapy—when you add a third drug, but you don’t see any additional toxicity, that’s really great for patients.

Daratumumab, of course, has been a tremendous addition for our armamentarium for the treatment of myeloma. Single-agent activity of 20% to 30% response rate, PFS [progression-free survival] of 3 months in their heavily treated patients. But what’s really important about daratumumab is the combinability and safety; it’s been approved now in numerous settings: in frontline with VMP [bortezomib, melphalan, and prednisone], in the relapsed setting with lenalidomide, and with bortezomib, and recently also with pomalidomide. And I’ve also presented data with daratumumab and carfilzomib. So we have a lot of ways daratumumab can be used. And what’s really great about these monoclonals again is that both of the monoclonals typically improve efficacy without adding a lot to toxicity. And that’s what we have been lacking till 2015. So it’s great for patients to have this drug class.

In terms of the use of dexamethasone in lenalidomide-refractory patients, this is an important consideration because we have so many randomized phase III studies, including 4 that had a lenalidomide and dexamethasone backbone: ELOQUENT-3 with the addition of elotuzumab, Tourmaline-MM1 with addition of ixazomib, POLLUX with the addition of daratumumab, and ASPIRE with the addition of carfilzomib. But all 4 of those did not allow lenalidomide-refractory patients. So when we have a patient sitting in front of us in clinic who’s relapsing on lenalidomide, those 4 studies really don’t provide evidence-based medicine to treat them.

And so the dexamethasone cohort is part of the study in which daratumumab was combined with numerous different backbone drugs. It’s a phase I combination study of these compounds. And dexamethasone showed really exciting results, a response rate of approximately 80% with a median of 2 lines of therapy. And really the response rate was no different in the 50 or so patients who were lenalidomide refractory. The PFS of all patients was not reached, whereas the PFS of lenalidomide refractory was 14 months. So I think those are really encouraging data. The toxicity profile is what you would expect from each agent.

So I really like this regimen for salvage because it includes daratumumab, which is an outstanding monoclonal antibody, and carfilzomib, which has been shown in a head-to-head study in ENDEAVOR to be the superior PI. So dexamethasone is a great option. And I would also add that the rate of neutropenia with this regimen is quite low: only 20% compared with much higher rates when we add it with immunomodulatory drugs. Again, this is off-label, not yet approved, but it’s a great option for patients.

When we start patients on triplet therapies, the evidence-based medicine in the studies are all administered until progression. The reality is in the real world, it’s hard to maintain everybody on all drugs forever from a variety of reasons, whether it’s toxicity…physical, emotional, financial, and also the question of how much additive benefit, especially somebody in a good remission.

So my practice in the real world is if somebody has a deep remission or a plateau, do we really need to maintain all 3 drugs? I think many of us drop out the steroids first, because if you ask a myeloma patient which drug you hate the most, it’s usually the steroid. And particularly interesting is when you ask a patient with her family member, are you doing OK on the steroid, the patient often says, “Fine.” But it’s the family member who notices the irritability, the agitation, insomnia.

So steroids, I think, are an easy answer to drop first. And then if you’re trying to eliminate further to go to a single agent, then I think you have to think about the adverse-effect profile. And, for example, if you’re using a daratumumab, pomaliadomide, and dexamethasone combination or a daratumumab, lenalidomide, and dexamethasone combination, and the patient is quite cytopenic, you may want to drop the immunomodulatory drug. If somebody is getting fatigued with a parenteral drug, you may want to maintain the oral drug. So I think those are the typical strategies we use in the real world.

The only caution I would add is that if somebody is truly high-risk, you may not want to reduce too much because I think we know that with high-risk patients, it’s not that they don’t get a response or a deep response; it’s the durability. So we don’t want to be complacent in a high-risk patient and say, “Oh, I’ve had a great response. Let me dial back everything.” I think in high-risk patients, it’s important to maintain at least the doublet. Perhaps you can omit the steroid, but I think the 2-drug maintenance is important.

When we think about slow versus rapid progression, in a way this is reminiscent of the biochemical versus clinical relapse. But I would add that for all of these considerations, we really should think about not only the crab symptoms and the rate but also making sure that the [radiological] assessment has been done. Because sometimes we may label somebody as a slow progression or as a biochemical progression, but if they have radiological progression on a PET [positron emission tomography] scan or an MRI [magnetic resonance imaging], skeletal surveys we know are not very helpful.

But if they have new radiological disease, even if it’s asymptomatic, that really should be treated more aggressively. But if somebody has been scanned and has no radiological disease, and if they have no crab symptoms, then we can put them into the biochemical slow-relapse category, and that one patient could consider again the same considerations we had for biochemical, thinking about up titrating the lenalidomide, for example, adding steroids, perhaps adding elotuzumab or ixazomib or something like that. But I think if somebody again has a rapid progression, high risk, symptomatic we really need to use active drugs and change up all the backbone drugs as well.

In transplant-ineligible patients, relapse is even more challenging because the big difference now is you have additional host factors. So you have the same disease in prior therapy-related issues that you do with younger transplant eligible patients. But now we add the complexity of whatever made them transplant and ineligible is likely going to make their medical care more challenging. Is it the heart failure, is it the lung problems like COPD [chronic obstructive pulmonary disease], is it the renal function or their performance status—whatever those things are, it really affects their outcome. So we have to be mindful of doses, combinations, and modifications.

So there’s a frailty index that’s available online if somebody is uncertain about what to do. But if it’s a patient who’s frail, doses should be minimized. For example, twice-weekly bortezomib is never well tolerated in this population. Weekly bortezomib, there are some concerns that older patients may have more cardiac issues. And so not that carfilzomib is a bad drug, but because older patients have more cardiac issues, we may see more cardiac toxicity with carfilzomib. The immunomodulatory drug should probably be reduced for safety. We have to be mindful of thrombotic prophylaxis because of poor performance status. So those are examples of things we need to consider in this population that’s unique to them.

Transcript edited for clarity.
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