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Discussants: Matt Kalaycio, MD1; Sagar Lonial, MD2
From Cleveland Clinic, Cleveland, OH1; Emory University, Atlanta, GA2
Address for correspondence: Matt Kalaycio, MD, Cleveland Clinic Main Campus, Mail Code R32, 9500 Euclid Avenue, Cleveland, OH 44195
E-mail: [email protected]
Biographical sketch:
Dr. Kalaycio has been published in numerous scientific publications including Bone Marrow Transplantation, Journal of Clinical Oncology, and Leukemia. He also is the editor of a book on leukemia and co-editor of a book on clinical malignant hematology. His research interests focus on testing new treatments for leukemia.
Dr. Kalaycio received his degree from West Virginia University School of Medicine in Morgantown. He completed his residency in internal medicine at Mercy Hospital of Pittsburgh and fellowships in hematology and medical oncology and bone marrow transplantation at Cleveland Clinic.
Dr. Lonial is involved in numerous professional organizations including the American Society of Clinical Oncology, American Society of Hematology, and the American Society for Blood and Marrow Transplantation. He serves as Vice Chair of the Myeloma Committee in the Eastern Cooperative Oncology Group and as Chair of the Steering Committee for the Multiple Myeloma Research Consortium. Additionally, he is on the board of directors for the International Myeloma Society, and on the scientific Advisory Board for the International Myeloma Foundation.
New Treatments
Dr. Kalaycio: I would like to spend the remainder of our conversation on some of the exciting new treatments that are coming down the pike for myeloma, both approved and soon to be approved. There were some interesting data presented both at American Society of Hematology (ASH) and at ASCO regarding relapsed refractory myeloma. I think with the varied choices that we have to treat relapsed refractory myeloma, it's unclear what's best.
I don't think anybody knows what's best at this point. Maybe that's going to become clearer, or maybe not, depending on how you look at it. The approach to those patients who have started with 3-drug combinations, got their autotransplant, are on maintenance, and have then progressed is becoming—in my mind—more difficult as we get more options. We don't have a standard approach to these patients at this point, outside of the context of a clinical trial. I'm wondering if you guys have come up with one.
Dr. Lonial: Well, there's no standard algorithm. I think that's because some of it depends in large part on the tempo of relapse. What was the patient's response to their initial therapy? What was their toxicity with initial therapy? For instance, if a patient were to get RVD induction, a single transplant, and then progress on lenalidomide maintenance, my first thought at that point would probably be to use a bortezomib based combination.
I would not give up on bortezomib unless they had a lot of toxicity with their initial bortezomib based approach, in which case I might think about using a carfilzomib based approach—class switching, progressing on an IMiD, switch to a PI in that situation. Then the question is going to be, double it or triple it? That, to me, really represents the big question in early relapse. I talked to you about how I think about classifying patients in the newly diagnosed setting, in terms of three categories.
I think that there are a couple of categories for patients in the early relapse setting as well. Early, to me, means one to three prior lines of therapy. Once you get beyond three prior lines of therapy, you're now in the late or refractory relapse category. I think the real question that's evolving in the myeloma world right now for an early relapse is, is three drugs better than two? I think we've asked this question in the newly diagnosed myeloma setting, and I think we've almost universally answered that three drugs is better than two across the board for newly diagnosed patients. You can pick your partners however you want. In general, I think triplets are better than doublets. In the early relapse setting, it has not been so clear. We now have data from, say the Carfilzomib, Lenalidomide, and Dexamethasone versus Lenalidomide and Dexamethasone for the Treatment of Patients with Relapsed Multiple Myeloma (ASPIRE) trial, which looked at carfilzomib with lenalidomide and dexamethasone (len/dex) versus len/dex.1
We now have data from the Phase III Study of Lenalidomide and Dexamethasone with or Without Elotuzumab to Treat Newly Diagnosed, Previously Untreated Multiple Myeloma (ELOQUENT–2), which looked at elotuzumab len/dex versus len/dex.2 We have data from the Panobinostat or Placebo with Bortezomib and Dexamethasone in Patients with Relapsed Multiple Myeloma (PANORAMA) trial, which looked at panobinostat in combination with bortezomib and dexamethasone versus bortezomib and dexamethasone.3 We have two additional trials that are coming in the near future looking at triplets versus doublets. What we need is longer follow-up on those to see what the survival looks like. My sense is going to be that early relapse is going to start to look like newly diagnosed.
It's going to be the new newly diagnosed in the sense that we're going to want to treat patients aggressively in early relapse—try and put them into a major response, and then try and let that duration of remission last as long as it can. Just as we do for newly diagnosed myeloma patients as well. I don't think we have all the data to make that clear-cut recommendation right now. I think that's a direction that the field is going to be moving in, if we have the supportive data from large randomized trials.
Dr. Kalaycio: It's so difficult to find evidence of an overall survival benefit starting with three drugs versus two. It's going to be harder perhaps, in the relapse setting, to make the case from a survival standpoint because the variables are so many and these patients get treated in so many ways. Getting a randomized trial in a relapse setting for patients who have been treated so many different ways upfront makes it very difficult to—in my mind—create a trial that's clean enough to answer that question definitively. Do you think that overall survival is the marker that we should be analyzing, or should we be looking more at duration of remission, quality of life, things like that?
Dr. Lonial: Well, I think if you're trying to compare the two versus three, the addition of the new drug, I think progression-free survival (PFS) is the right end point. That's what the U.S. Food and Drug Administration (FDA) has identified as the primary endpoint for most relapsed myeloma trials. I think that the question—Is a triplet better than a doublet?—will require putting together many different phase III trials and trying to analyze that kind of a question. Just to give you a hint of an example, the ASPIRE trial, which looked at carfilzomib len/dex versus len/dex, at least at the early look, suggests there is an improvement in survival for the three drug combination. The ELOQUENT-2 trial, which looked at elotuzumab len/dex versus len/dex, also looks very early like there's a difference in overall survival. PANORAMA does not look like there's a difference in overall survival right now. There are other trials coming that, if you put them in aggregate, you may be able to see that difference you need that may be able to wash across differences in how patients were treated in their frontline approach.
Dr. Kalaycio: There's a smorgasbord of available options that makes it fascinating in trying to read these studies, and trying to make sense out of them. I feel for the clinician in the community trying to figure this out and pick what's best for their particular patient. There are lots of potential options. The most recent one approved by the FDA is the addition of panobinostat to our armamentarium.3,4 We are not clear where it fits in our treatment algorithms and I'm wondering if you've thought about that, and where you think it might fit best.
Dr. Lonial: Yes. I think you're struggling with what I think a lot of people are struggling with, which is, as the data get more mature, we're starting to identify that there are subsets of patients that really may seem to gain benefit from the use of a histone deacetylase inhibitor. There were a couple of analyses presented at the Congress of European Hematology Association (EHA) and at ASCO this year that I think are beginning to clarify some of that for us.5 If you look at the PANORAMA-1 trial (which was the randomized phase III trial of panobinostat in combination with bortezomib and dexamethasone versus bortezomib and dexamethasone) what I think we're starting to see is that in the patients who were exposed to both lenalidomide and bortezomib, that the incremental benefit in PFS for the addition of panobinostat is actually much higher. It's close to 7.8 months now. That's because those are patients who are not gaining as much benefit from retreatment with a PI, and have already been exposed to—or maybe even resistant to—an IMiD in that situation.
Even though these patients didn't stay on therapy for very long, their magnitude of benefit was much longer than for the other subsets of patients in Panorama-1. For the double refractory, or the double exposed subset of patients, the addition of panobinostat seems to be most beneficial. In our own experience, we have partnered panobinostat, not just with bortezomib, but actually with carfilzomib, and have found it to be much better tolerated in combination with carfilzomib.
In fact, Burdeja et al presented some of this data at ASCO this year, and showed that the gastrointestinal toxicity was almost nonexistent in the dose and schedule with which he used panobinostat in combination with carfilzomib.6 I think finding the right partner is really important as well. We have found that for some really high-risk relapses, relapse within a year, aggressive relapses with 17p deletion patients, panobinostat in combination with a PI seems to be a very active combination as well. We're using it right now for those really aggressive high-risk relapses. We may change the partner, but I think we're going to take a little more time to refine who is the best patient population for a histone deacetylase inhibitor in myeloma. I think you're right, it's not clear right now.
Dr. Kalaycio: I agree. I think this will be similar to our learning curve with bortezomib—when first introduced, we gave it intravenously resulting in neurotoxicity, so we learned how to give it subcutaneously to avoid toxicity. I suspect the same will happen with panobinostat and even some of the monoclonals that are soon to be forthcoming.
Dr. Lonial: Yes, I agree.
Dr. Kalaycio: I was impressed by the results of the ELOQUENT trial with elotuzumab in combination. Prior to that, I was unimpressed with elotuzumab as a single agent. I suspect it will get approved in combination, but I don't think that combination is necessarily what people would choose first in the relapse setting. I think it typically would be used with a PI. I'm curious where you think the results of the ELOQUENT trial at ASCO are going to translate into actual practice when it becomes approved?
Dr. Lonial: I think we learned a couple of things from that presentation. We did some of the early phase I work with elotuzumab in combination with an IMiD. The IMiD partnership with a monoclonal antibody is just so strong. I think we've enrolled over 50 patients with IMiDs and antibodies together in combination. The response rate and durability of response is really quite striking.
We have felt left out in myeloma in terms of the fact that we have not had an antibody. In fact, I'm not sure if you've heard my quote about this, but I call it oncologic irony. A disease that makes too much of an antibody doesn’t have an antibody to treat it.
Now we have elotuzumab. Elotuzumab partners very nicely with an IMiD, and not only improves PFS compared to the IMiD dexamethasone combination, but actually seems to prolong the duration of response—even if the depth of response is the same. Just to clarify that, if you take patients that got a partial response (PR) with len/dex, and then look at patients that got a PR with len/dex elotuzumab, the duration of that PR was longer with the antibodies than it was with len/dex alone. The same goes for very good PR or better. This, to me, is the ultimate definition of synergy.
In many trials, it doesn't matter what response level you get to. If you get to that response, whether you were in the control arm or the experimental arm, the PFS is the same. This is one of the first trials that show that the PFS can be dependent on the addition of the immune based treatment or the antibody.
I think that's really a powerful approach. I think it's going to get employed in combination with len/dex. If you think about patients progressing on lenalidomide as a single agent, often times we'll talk about adding in dexamethasone, and adding another agent to that. I think adding len/dex, and adding elotuzumab to that, might be a reasonable approach in the early relapsed myeloma setting as well.
There are lots of new mechanisms of action and drugs to use in the treatment of myeloma. ... I really like the results that it's showing in preliminary analysis.
Dr. Kalaycio: There are lots of new mechanisms of action and drugs to use in the treatment of myeloma. I think time is going to prevent us getting too much into daratumumab, but I really like the results that it's showing in preliminary analysis.
Dr. Lonial: Yes, daratumumab is a different target than elotuzumab, so it's targeting CD38. We know that CD38 is ubiquitously expressed on plasma cells. We showed at ASCO and EHA this year that in a refractory myeloma patient population—median of five prior lines of therapy—we got single agent activity with daratumumab. About 30% of patients had a response.7
Again, you're right, it's very exciting to have completely new mechanisms of action and drugs. These are patients who really have very few—if any—options left over. They were all double refractory, most of them were triple refractory. The ones that weren't quadruple refractory, were not quadruple refractory because they couldn't get the fourth drug because of toxicity, side effects, or other issues. I think to see responses—even complete responses—in this patient population is really very encouraging. In our experience, bringing it to earlier lines of therapy, partnering it with a PI or with an IMiD, the response rates are really very exciting. I think it's going to be together with elotuzumab. I think these are going to be game changers for us in myeloma.
Dr. Kalaycio: I agree. It's been game changing for oncology in general. Immunotherapies have finally come of age and are certainly coming of age in the treatment of multiple myeloma.
While the prognosis for patients with multiple myeloma has certainly improved, the complexities of treatment are often difficult to manage. Even myeloma experts are challenged with patient selection, practice guidelines, supportive care, and treatment approach. However, with appropriate attention to detail, providers can maximize the benefits obtainable with newer treatments while limiting their adverse effects. For all the advances made in the last decade, the next decade is promising to be even better.
1. Stewart AK, Rajkumar SV, Dimopoulos MA, et al. for the ASPIRE Investigators. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med. 2015;372(2):142–152.
2. Lonial S, Dimopoulos M, Palumbo A, et al. for the ELOQUENT-2 Investigators. Elotuzumab therapy for relapsed or refractory multiple myeloma [published online ahead of print June 2, 2015]. N Engl J Med. Doi:10.1056/NEJMoa1505654.
3. San-Miguel, Hungria VT, Yoon SS, et al. Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trial. Lancet Oncol. 2014;15(11):1195–1206.
4. Richardson PG, Laubach JP, Lonial S, et al. Panobinostat: a novel pan-deactylase inhibitor for the treatment of relapsed or relapsed and refractory multiple myeloma. Expert Rev Anticancer Ther. 2015;15(7):737–748.
5. Einsele H, Richardson PG, Hungria VTM, et al. Subgroup analysis by prior treatment among patients with relapsed or relapsed and refractory multiple myeloma in the PANORAMA 1 study of panobinostat or placebo plus bortezomib and dexamethasone. Abstract presented at 20th Congress of European Hematology Association (EHA); June 11–14, 2015; Vienna, Austria. Abstract S102.
6. Berdeja JG, Gregory T, Matous J, et al. A phase I/II study of the combination of panobinostat and carfilzomib in patients with relapsed or relapsed/refractory multiple myeloma. Abstract presented at 2015 ASCO Annual Meeting; May 29–June 2, 2015; Chicago, IL. Abstract 8513.
7. Lonial S, Weiss B, Usmani S, et al. Phase 2 study or daratumumab (DARA) in patients with ≥3 lines of prior therapy or double refractory multiple myeloma: 54767414MMY2002 (Sirius)*. Abstract presented at 2015 ASCO Annual Meeting; May 29–June 2, 2015; Chicago, IL. Abstract LBA8512.
Discussants: Matt Kalaycio, MD1; Sagar Lonial, MD2
From Cleveland Clinic, Cleveland, OH1; Emory University, Atlanta, GA2
Address for correspondence: Matt Kalaycio, MD, Cleveland Clinic Main Campus, Mail Code R32, 9500 Euclid Avenue, Cleveland, OH 44195
E-mail: [email protected]
Biographical sketch:
Dr. Kalaycio has been published in numerous scientific publications including Bone Marrow Transplantation, Journal of Clinical Oncology, and Leukemia. He also is the editor of a book on leukemia and co-editor of a book on clinical malignant hematology. His research interests focus on testing new treatments for leukemia.
Dr. Kalaycio received his degree from West Virginia University School of Medicine in Morgantown. He completed his residency in internal medicine at Mercy Hospital of Pittsburgh and fellowships in hematology and medical oncology and bone marrow transplantation at Cleveland Clinic.
Dr. Lonial is involved in numerous professional organizations including the American Society of Clinical Oncology, American Society of Hematology, and the American Society for Blood and Marrow Transplantation. He serves as Vice Chair of the Myeloma Committee in the Eastern Cooperative Oncology Group and as Chair of the Steering Committee for the Multiple Myeloma Research Consortium. Additionally, he is on the board of directors for the International Myeloma Society, and on the scientific Advisory Board for the International Myeloma Foundation.
New Treatments
Dr. Kalaycio: I would like to spend the remainder of our conversation on some of the exciting new treatments that are coming down the pike for myeloma, both approved and soon to be approved. There were some interesting data presented both at American Society of Hematology (ASH) and at ASCO regarding relapsed refractory myeloma. I think with the varied choices that we have to treat relapsed refractory myeloma, it's unclear what's best.
I don't think anybody knows what's best at this point. Maybe that's going to become clearer, or maybe not, depending on how you look at it. The approach to those patients who have started with 3-drug combinations, got their autotransplant, are on maintenance, and have then progressed is becoming—in my mind—more difficult as we get more options. We don't have a standard approach to these patients at this point, outside of the context of a clinical trial. I'm wondering if you guys have come up with one.
Dr. Lonial: Well, there's no standard algorithm. I think that's because some of it depends in large part on the tempo of relapse. What was the patient's response to their initial therapy? What was their toxicity with initial therapy? For instance, if a patient were to get RVD induction, a single transplant, and then progress on lenalidomide maintenance, my first thought at that point would probably be to use a bortezomib based combination.
I would not give up on bortezomib unless they had a lot of toxicity with their initial bortezomib based approach, in which case I might think about using a carfilzomib based approach—class switching, progressing on an IMiD, switch to a PI in that situation. Then the question is going to be, double it or triple it? That, to me, really represents the big question in early relapse. I talked to you about how I think about classifying patients in the newly diagnosed setting, in terms of three categories.
I think that there are a couple of categories for patients in the early relapse setting as well. Early, to me, means one to three prior lines of therapy. Once you get beyond three prior lines of therapy, you're now in the late or refractory relapse category. I think the real question that's evolving in the myeloma world right now for an early relapse is, is three drugs better than two? I think we've asked this question in the newly diagnosed myeloma setting, and I think we've almost universally answered that three drugs is better than two across the board for newly diagnosed patients. You can pick your partners however you want. In general, I think triplets are better than doublets. In the early relapse setting, it has not been so clear. We now have data from, say the Carfilzomib, Lenalidomide, and Dexamethasone versus Lenalidomide and Dexamethasone for the Treatment of Patients with Relapsed Multiple Myeloma (ASPIRE) trial, which looked at carfilzomib with lenalidomide and dexamethasone (len/dex) versus len/dex.1
We now have data from the Phase III Study of Lenalidomide and Dexamethasone with or Without Elotuzumab to Treat Newly Diagnosed, Previously Untreated Multiple Myeloma (ELOQUENT–2), which looked at elotuzumab len/dex versus len/dex.2 We have data from the Panobinostat or Placebo with Bortezomib and Dexamethasone in Patients with Relapsed Multiple Myeloma (PANORAMA) trial, which looked at panobinostat in combination with bortezomib and dexamethasone versus bortezomib and dexamethasone.3 We have two additional trials that are coming in the near future looking at triplets versus doublets. What we need is longer follow-up on those to see what the survival looks like. My sense is going to be that early relapse is going to start to look like newly diagnosed.
It's going to be the new newly diagnosed in the sense that we're going to want to treat patients aggressively in early relapse—try and put them into a major response, and then try and let that duration of remission last as long as it can. Just as we do for newly diagnosed myeloma patients as well. I don't think we have all the data to make that clear-cut recommendation right now. I think that's a direction that the field is going to be moving in, if we have the supportive data from large randomized trials.
Dr. Kalaycio: It's so difficult to find evidence of an overall survival benefit starting with three drugs versus two. It's going to be harder perhaps, in the relapse setting, to make the case from a survival standpoint because the variables are so many and these patients get treated in so many ways. Getting a randomized trial in a relapse setting for patients who have been treated so many different ways upfront makes it very difficult to—in my mind—create a trial that's clean enough to answer that question definitively. Do you think that overall survival is the marker that we should be analyzing, or should we be looking more at duration of remission, quality of life, things like that?
Dr. Lonial: Well, I think if you're trying to compare the two versus three, the addition of the new drug, I think progression-free survival (PFS) is the right end point. That's what the U.S. Food and Drug Administration (FDA) has identified as the primary endpoint for most relapsed myeloma trials. I think that the question—Is a triplet better than a doublet?—will require putting together many different phase III trials and trying to analyze that kind of a question. Just to give you a hint of an example, the ASPIRE trial, which looked at carfilzomib len/dex versus len/dex, at least at the early look, suggests there is an improvement in survival for the three drug combination. The ELOQUENT-2 trial, which looked at elotuzumab len/dex versus len/dex, also looks very early like there's a difference in overall survival. PANORAMA does not look like there's a difference in overall survival right now. There are other trials coming that, if you put them in aggregate, you may be able to see that difference you need that may be able to wash across differences in how patients were treated in their frontline approach.
Dr. Kalaycio: There's a smorgasbord of available options that makes it fascinating in trying to read these studies, and trying to make sense out of them. I feel for the clinician in the community trying to figure this out and pick what's best for their particular patient. There are lots of potential options. The most recent one approved by the FDA is the addition of panobinostat to our armamentarium.3,4 We are not clear where it fits in our treatment algorithms and I'm wondering if you've thought about that, and where you think it might fit best.
Dr. Lonial: Yes. I think you're struggling with what I think a lot of people are struggling with, which is, as the data get more mature, we're starting to identify that there are subsets of patients that really may seem to gain benefit from the use of a histone deacetylase inhibitor. There were a couple of analyses presented at the Congress of European Hematology Association (EHA) and at ASCO this year that I think are beginning to clarify some of that for us.5 If you look at the PANORAMA-1 trial (which was the randomized phase III trial of panobinostat in combination with bortezomib and dexamethasone versus bortezomib and dexamethasone) what I think we're starting to see is that in the patients who were exposed to both lenalidomide and bortezomib, that the incremental benefit in PFS for the addition of panobinostat is actually much higher. It's close to 7.8 months now. That's because those are patients who are not gaining as much benefit from retreatment with a PI, and have already been exposed to—or maybe even resistant to—an IMiD in that situation.
Even though these patients didn't stay on therapy for very long, their magnitude of benefit was much longer than for the other subsets of patients in Panorama-1. For the double refractory, or the double exposed subset of patients, the addition of panobinostat seems to be most beneficial. In our own experience, we have partnered panobinostat, not just with bortezomib, but actually with carfilzomib, and have found it to be much better tolerated in combination with carfilzomib.
In fact, Burdeja et al presented some of this data at ASCO this year, and showed that the gastrointestinal toxicity was almost nonexistent in the dose and schedule with which he used panobinostat in combination with carfilzomib.6 I think finding the right partner is really important as well. We have found that for some really high-risk relapses, relapse within a year, aggressive relapses with 17p deletion patients, panobinostat in combination with a PI seems to be a very active combination as well. We're using it right now for those really aggressive high-risk relapses. We may change the partner, but I think we're going to take a little more time to refine who is the best patient population for a histone deacetylase inhibitor in myeloma. I think you're right, it's not clear right now.
Dr. Kalaycio: I agree. I think this will be similar to our learning curve with bortezomib—when first introduced, we gave it intravenously resulting in neurotoxicity, so we learned how to give it subcutaneously to avoid toxicity. I suspect the same will happen with panobinostat and even some of the monoclonals that are soon to be forthcoming.
Dr. Lonial: Yes, I agree.
Dr. Kalaycio: I was impressed by the results of the ELOQUENT trial with elotuzumab in combination. Prior to that, I was unimpressed with elotuzumab as a single agent. I suspect it will get approved in combination, but I don't think that combination is necessarily what people would choose first in the relapse setting. I think it typically would be used with a PI. I'm curious where you think the results of the ELOQUENT trial at ASCO are going to translate into actual practice when it becomes approved?
Dr. Lonial: I think we learned a couple of things from that presentation. We did some of the early phase I work with elotuzumab in combination with an IMiD. The IMiD partnership with a monoclonal antibody is just so strong. I think we've enrolled over 50 patients with IMiDs and antibodies together in combination. The response rate and durability of response is really quite striking.
We have felt left out in myeloma in terms of the fact that we have not had an antibody. In fact, I'm not sure if you've heard my quote about this, but I call it oncologic irony. A disease that makes too much of an antibody doesn’t have an antibody to treat it.
Now we have elotuzumab. Elotuzumab partners very nicely with an IMiD, and not only improves PFS compared to the IMiD dexamethasone combination, but actually seems to prolong the duration of response—even if the depth of response is the same. Just to clarify that, if you take patients that got a partial response (PR) with len/dex, and then look at patients that got a PR with len/dex elotuzumab, the duration of that PR was longer with the antibodies than it was with len/dex alone. The same goes for very good PR or better. This, to me, is the ultimate definition of synergy.
In many trials, it doesn't matter what response level you get to. If you get to that response, whether you were in the control arm or the experimental arm, the PFS is the same. This is one of the first trials that show that the PFS can be dependent on the addition of the immune based treatment or the antibody.
I think that's really a powerful approach. I think it's going to get employed in combination with len/dex. If you think about patients progressing on lenalidomide as a single agent, often times we'll talk about adding in dexamethasone, and adding another agent to that. I think adding len/dex, and adding elotuzumab to that, might be a reasonable approach in the early relapsed myeloma setting as well.
There are lots of new mechanisms of action and drugs to use in the treatment of myeloma. ... I really like the results that it's showing in preliminary analysis.
Dr. Kalaycio: There are lots of new mechanisms of action and drugs to use in the treatment of myeloma. I think time is going to prevent us getting too much into daratumumab, but I really like the results that it's showing in preliminary analysis.
Dr. Lonial: Yes, daratumumab is a different target than elotuzumab, so it's targeting CD38. We know that CD38 is ubiquitously expressed on plasma cells. We showed at ASCO and EHA this year that in a refractory myeloma patient population—median of five prior lines of therapy—we got single agent activity with daratumumab. About 30% of patients had a response.7
Again, you're right, it's very exciting to have completely new mechanisms of action and drugs. These are patients who really have very few—if any—options left over. They were all double refractory, most of them were triple refractory. The ones that weren't quadruple refractory, were not quadruple refractory because they couldn't get the fourth drug because of toxicity, side effects, or other issues. I think to see responses—even complete responses—in this patient population is really very encouraging. In our experience, bringing it to earlier lines of therapy, partnering it with a PI or with an IMiD, the response rates are really very exciting. I think it's going to be together with elotuzumab. I think these are going to be game changers for us in myeloma.
Dr. Kalaycio: I agree. It's been game changing for oncology in general. Immunotherapies have finally come of age and are certainly coming of age in the treatment of multiple myeloma.
While the prognosis for patients with multiple myeloma has certainly improved, the complexities of treatment are often difficult to manage. Even myeloma experts are challenged with patient selection, practice guidelines, supportive care, and treatment approach. However, with appropriate attention to detail, providers can maximize the benefits obtainable with newer treatments while limiting their adverse effects. For all the advances made in the last decade, the next decade is promising to be even better.
Discussants: Matt Kalaycio, MD1; Sagar Lonial, MD2
From Cleveland Clinic, Cleveland, OH1; Emory University, Atlanta, GA2
Address for correspondence: Matt Kalaycio, MD, Cleveland Clinic Main Campus, Mail Code R32, 9500 Euclid Avenue, Cleveland, OH 44195
E-mail: [email protected]
Biographical sketch:
Dr. Kalaycio has been published in numerous scientific publications including Bone Marrow Transplantation, Journal of Clinical Oncology, and Leukemia. He also is the editor of a book on leukemia and co-editor of a book on clinical malignant hematology. His research interests focus on testing new treatments for leukemia.
Dr. Kalaycio received his degree from West Virginia University School of Medicine in Morgantown. He completed his residency in internal medicine at Mercy Hospital of Pittsburgh and fellowships in hematology and medical oncology and bone marrow transplantation at Cleveland Clinic.
Dr. Lonial is involved in numerous professional organizations including the American Society of Clinical Oncology, American Society of Hematology, and the American Society for Blood and Marrow Transplantation. He serves as Vice Chair of the Myeloma Committee in the Eastern Cooperative Oncology Group and as Chair of the Steering Committee for the Multiple Myeloma Research Consortium. Additionally, he is on the board of directors for the International Myeloma Society, and on the scientific Advisory Board for the International Myeloma Foundation.
New Treatments
Dr. Kalaycio: I would like to spend the remainder of our conversation on some of the exciting new treatments that are coming down the pike for myeloma, both approved and soon to be approved. There were some interesting data presented both at American Society of Hematology (ASH) and at ASCO regarding relapsed refractory myeloma. I think with the varied choices that we have to treat relapsed refractory myeloma, it's unclear what's best.
I don't think anybody knows what's best at this point. Maybe that's going to become clearer, or maybe not, depending on how you look at it. The approach to those patients who have started with 3-drug combinations, got their autotransplant, are on maintenance, and have then progressed is becoming—in my mind—more difficult as we get more options. We don't have a standard approach to these patients at this point, outside of the context of a clinical trial. I'm wondering if you guys have come up with one.
Dr. Lonial: Well, there's no standard algorithm. I think that's because some of it depends in large part on the tempo of relapse. What was the patient's response to their initial therapy? What was their toxicity with initial therapy? For instance, if a patient were to get RVD induction, a single transplant, and then progress on lenalidomide maintenance, my first thought at that point would probably be to use a bortezomib based combination.
I would not give up on bortezomib unless they had a lot of toxicity with their initial bortezomib based approach, in which case I might think about using a carfilzomib based approach—class switching, progressing on an IMiD, switch to a PI in that situation. Then the question is going to be, double it or triple it? That, to me, really represents the big question in early relapse. I talked to you about how I think about classifying patients in the newly diagnosed setting, in terms of three categories.
I think that there are a couple of categories for patients in the early relapse setting as well. Early, to me, means one to three prior lines of therapy. Once you get beyond three prior lines of therapy, you're now in the late or refractory relapse category. I think the real question that's evolving in the myeloma world right now for an early relapse is, is three drugs better than two? I think we've asked this question in the newly diagnosed myeloma setting, and I think we've almost universally answered that three drugs is better than two across the board for newly diagnosed patients. You can pick your partners however you want. In general, I think triplets are better than doublets. In the early relapse setting, it has not been so clear. We now have data from, say the Carfilzomib, Lenalidomide, and Dexamethasone versus Lenalidomide and Dexamethasone for the Treatment of Patients with Relapsed Multiple Myeloma (ASPIRE) trial, which looked at carfilzomib with lenalidomide and dexamethasone (len/dex) versus len/dex.1
We now have data from the Phase III Study of Lenalidomide and Dexamethasone with or Without Elotuzumab to Treat Newly Diagnosed, Previously Untreated Multiple Myeloma (ELOQUENT–2), which looked at elotuzumab len/dex versus len/dex.2 We have data from the Panobinostat or Placebo with Bortezomib and Dexamethasone in Patients with Relapsed Multiple Myeloma (PANORAMA) trial, which looked at panobinostat in combination with bortezomib and dexamethasone versus bortezomib and dexamethasone.3 We have two additional trials that are coming in the near future looking at triplets versus doublets. What we need is longer follow-up on those to see what the survival looks like. My sense is going to be that early relapse is going to start to look like newly diagnosed.
It's going to be the new newly diagnosed in the sense that we're going to want to treat patients aggressively in early relapse—try and put them into a major response, and then try and let that duration of remission last as long as it can. Just as we do for newly diagnosed myeloma patients as well. I don't think we have all the data to make that clear-cut recommendation right now. I think that's a direction that the field is going to be moving in, if we have the supportive data from large randomized trials.
Dr. Kalaycio: It's so difficult to find evidence of an overall survival benefit starting with three drugs versus two. It's going to be harder perhaps, in the relapse setting, to make the case from a survival standpoint because the variables are so many and these patients get treated in so many ways. Getting a randomized trial in a relapse setting for patients who have been treated so many different ways upfront makes it very difficult to—in my mind—create a trial that's clean enough to answer that question definitively. Do you think that overall survival is the marker that we should be analyzing, or should we be looking more at duration of remission, quality of life, things like that?
Dr. Lonial: Well, I think if you're trying to compare the two versus three, the addition of the new drug, I think progression-free survival (PFS) is the right end point. That's what the U.S. Food and Drug Administration (FDA) has identified as the primary endpoint for most relapsed myeloma trials. I think that the question—Is a triplet better than a doublet?—will require putting together many different phase III trials and trying to analyze that kind of a question. Just to give you a hint of an example, the ASPIRE trial, which looked at carfilzomib len/dex versus len/dex, at least at the early look, suggests there is an improvement in survival for the three drug combination. The ELOQUENT-2 trial, which looked at elotuzumab len/dex versus len/dex, also looks very early like there's a difference in overall survival. PANORAMA does not look like there's a difference in overall survival right now. There are other trials coming that, if you put them in aggregate, you may be able to see that difference you need that may be able to wash across differences in how patients were treated in their frontline approach.
Dr. Kalaycio: There's a smorgasbord of available options that makes it fascinating in trying to read these studies, and trying to make sense out of them. I feel for the clinician in the community trying to figure this out and pick what's best for their particular patient. There are lots of potential options. The most recent one approved by the FDA is the addition of panobinostat to our armamentarium.3,4 We are not clear where it fits in our treatment algorithms and I'm wondering if you've thought about that, and where you think it might fit best.
Dr. Lonial: Yes. I think you're struggling with what I think a lot of people are struggling with, which is, as the data get more mature, we're starting to identify that there are subsets of patients that really may seem to gain benefit from the use of a histone deacetylase inhibitor. There were a couple of analyses presented at the Congress of European Hematology Association (EHA) and at ASCO this year that I think are beginning to clarify some of that for us.5 If you look at the PANORAMA-1 trial (which was the randomized phase III trial of panobinostat in combination with bortezomib and dexamethasone versus bortezomib and dexamethasone) what I think we're starting to see is that in the patients who were exposed to both lenalidomide and bortezomib, that the incremental benefit in PFS for the addition of panobinostat is actually much higher. It's close to 7.8 months now. That's because those are patients who are not gaining as much benefit from retreatment with a PI, and have already been exposed to—or maybe even resistant to—an IMiD in that situation.
Even though these patients didn't stay on therapy for very long, their magnitude of benefit was much longer than for the other subsets of patients in Panorama-1. For the double refractory, or the double exposed subset of patients, the addition of panobinostat seems to be most beneficial. In our own experience, we have partnered panobinostat, not just with bortezomib, but actually with carfilzomib, and have found it to be much better tolerated in combination with carfilzomib.
In fact, Burdeja et al presented some of this data at ASCO this year, and showed that the gastrointestinal toxicity was almost nonexistent in the dose and schedule with which he used panobinostat in combination with carfilzomib.6 I think finding the right partner is really important as well. We have found that for some really high-risk relapses, relapse within a year, aggressive relapses with 17p deletion patients, panobinostat in combination with a PI seems to be a very active combination as well. We're using it right now for those really aggressive high-risk relapses. We may change the partner, but I think we're going to take a little more time to refine who is the best patient population for a histone deacetylase inhibitor in myeloma. I think you're right, it's not clear right now.
Dr. Kalaycio: I agree. I think this will be similar to our learning curve with bortezomib—when first introduced, we gave it intravenously resulting in neurotoxicity, so we learned how to give it subcutaneously to avoid toxicity. I suspect the same will happen with panobinostat and even some of the monoclonals that are soon to be forthcoming.
Dr. Lonial: Yes, I agree.
Dr. Kalaycio: I was impressed by the results of the ELOQUENT trial with elotuzumab in combination. Prior to that, I was unimpressed with elotuzumab as a single agent. I suspect it will get approved in combination, but I don't think that combination is necessarily what people would choose first in the relapse setting. I think it typically would be used with a PI. I'm curious where you think the results of the ELOQUENT trial at ASCO are going to translate into actual practice when it becomes approved?
Dr. Lonial: I think we learned a couple of things from that presentation. We did some of the early phase I work with elotuzumab in combination with an IMiD. The IMiD partnership with a monoclonal antibody is just so strong. I think we've enrolled over 50 patients with IMiDs and antibodies together in combination. The response rate and durability of response is really quite striking.
We have felt left out in myeloma in terms of the fact that we have not had an antibody. In fact, I'm not sure if you've heard my quote about this, but I call it oncologic irony. A disease that makes too much of an antibody doesn’t have an antibody to treat it.
Now we have elotuzumab. Elotuzumab partners very nicely with an IMiD, and not only improves PFS compared to the IMiD dexamethasone combination, but actually seems to prolong the duration of response—even if the depth of response is the same. Just to clarify that, if you take patients that got a partial response (PR) with len/dex, and then look at patients that got a PR with len/dex elotuzumab, the duration of that PR was longer with the antibodies than it was with len/dex alone. The same goes for very good PR or better. This, to me, is the ultimate definition of synergy.
In many trials, it doesn't matter what response level you get to. If you get to that response, whether you were in the control arm or the experimental arm, the PFS is the same. This is one of the first trials that show that the PFS can be dependent on the addition of the immune based treatment or the antibody.
I think that's really a powerful approach. I think it's going to get employed in combination with len/dex. If you think about patients progressing on lenalidomide as a single agent, often times we'll talk about adding in dexamethasone, and adding another agent to that. I think adding len/dex, and adding elotuzumab to that, might be a reasonable approach in the early relapsed myeloma setting as well.
There are lots of new mechanisms of action and drugs to use in the treatment of myeloma. ... I really like the results that it's showing in preliminary analysis.
Dr. Kalaycio: There are lots of new mechanisms of action and drugs to use in the treatment of myeloma. I think time is going to prevent us getting too much into daratumumab, but I really like the results that it's showing in preliminary analysis.
Dr. Lonial: Yes, daratumumab is a different target than elotuzumab, so it's targeting CD38. We know that CD38 is ubiquitously expressed on plasma cells. We showed at ASCO and EHA this year that in a refractory myeloma patient population—median of five prior lines of therapy—we got single agent activity with daratumumab. About 30% of patients had a response.7
Again, you're right, it's very exciting to have completely new mechanisms of action and drugs. These are patients who really have very few—if any—options left over. They were all double refractory, most of them were triple refractory. The ones that weren't quadruple refractory, were not quadruple refractory because they couldn't get the fourth drug because of toxicity, side effects, or other issues. I think to see responses—even complete responses—in this patient population is really very encouraging. In our experience, bringing it to earlier lines of therapy, partnering it with a PI or with an IMiD, the response rates are really very exciting. I think it's going to be together with elotuzumab. I think these are going to be game changers for us in myeloma.
Dr. Kalaycio: I agree. It's been game changing for oncology in general. Immunotherapies have finally come of age and are certainly coming of age in the treatment of multiple myeloma.
While the prognosis for patients with multiple myeloma has certainly improved, the complexities of treatment are often difficult to manage. Even myeloma experts are challenged with patient selection, practice guidelines, supportive care, and treatment approach. However, with appropriate attention to detail, providers can maximize the benefits obtainable with newer treatments while limiting their adverse effects. For all the advances made in the last decade, the next decade is promising to be even better.
1. Stewart AK, Rajkumar SV, Dimopoulos MA, et al. for the ASPIRE Investigators. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med. 2015;372(2):142–152.
2. Lonial S, Dimopoulos M, Palumbo A, et al. for the ELOQUENT-2 Investigators. Elotuzumab therapy for relapsed or refractory multiple myeloma [published online ahead of print June 2, 2015]. N Engl J Med. Doi:10.1056/NEJMoa1505654.
3. San-Miguel, Hungria VT, Yoon SS, et al. Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trial. Lancet Oncol. 2014;15(11):1195–1206.
4. Richardson PG, Laubach JP, Lonial S, et al. Panobinostat: a novel pan-deactylase inhibitor for the treatment of relapsed or relapsed and refractory multiple myeloma. Expert Rev Anticancer Ther. 2015;15(7):737–748.
5. Einsele H, Richardson PG, Hungria VTM, et al. Subgroup analysis by prior treatment among patients with relapsed or relapsed and refractory multiple myeloma in the PANORAMA 1 study of panobinostat or placebo plus bortezomib and dexamethasone. Abstract presented at 20th Congress of European Hematology Association (EHA); June 11–14, 2015; Vienna, Austria. Abstract S102.
6. Berdeja JG, Gregory T, Matous J, et al. A phase I/II study of the combination of panobinostat and carfilzomib in patients with relapsed or relapsed/refractory multiple myeloma. Abstract presented at 2015 ASCO Annual Meeting; May 29–June 2, 2015; Chicago, IL. Abstract 8513.
7. Lonial S, Weiss B, Usmani S, et al. Phase 2 study or daratumumab (DARA) in patients with ≥3 lines of prior therapy or double refractory multiple myeloma: 54767414MMY2002 (Sirius)*. Abstract presented at 2015 ASCO Annual Meeting; May 29–June 2, 2015; Chicago, IL. Abstract LBA8512.
1. Stewart AK, Rajkumar SV, Dimopoulos MA, et al. for the ASPIRE Investigators. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med. 2015;372(2):142–152.
2. Lonial S, Dimopoulos M, Palumbo A, et al. for the ELOQUENT-2 Investigators. Elotuzumab therapy for relapsed or refractory multiple myeloma [published online ahead of print June 2, 2015]. N Engl J Med. Doi:10.1056/NEJMoa1505654.
3. San-Miguel, Hungria VT, Yoon SS, et al. Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trial. Lancet Oncol. 2014;15(11):1195–1206.
4. Richardson PG, Laubach JP, Lonial S, et al. Panobinostat: a novel pan-deactylase inhibitor for the treatment of relapsed or relapsed and refractory multiple myeloma. Expert Rev Anticancer Ther. 2015;15(7):737–748.
5. Einsele H, Richardson PG, Hungria VTM, et al. Subgroup analysis by prior treatment among patients with relapsed or relapsed and refractory multiple myeloma in the PANORAMA 1 study of panobinostat or placebo plus bortezomib and dexamethasone. Abstract presented at 20th Congress of European Hematology Association (EHA); June 11–14, 2015; Vienna, Austria. Abstract S102.
6. Berdeja JG, Gregory T, Matous J, et al. A phase I/II study of the combination of panobinostat and carfilzomib in patients with relapsed or relapsed/refractory multiple myeloma. Abstract presented at 2015 ASCO Annual Meeting; May 29–June 2, 2015; Chicago, IL. Abstract 8513.
7. Lonial S, Weiss B, Usmani S, et al. Phase 2 study or daratumumab (DARA) in patients with ≥3 lines of prior therapy or double refractory multiple myeloma: 54767414MMY2002 (Sirius)*. Abstract presented at 2015 ASCO Annual Meeting; May 29–June 2, 2015; Chicago, IL. Abstract LBA8512.
