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When to Treat Smoldering Myeloma

Panelists:Keith Stewart, MD, CHB, Mayo Clinic;William I. Bensinger, MD, Swedish Cancer Institute;Rafael Fonseca, MD, Mayo Clinic;C. Ola Landgren, MD, PhD, Memorial Sloan Kettering Cancer Center;Jatin P. Shah, MD, MD Anderson Cancer Center
Published: Thursday, Jun 30, 2016


Transcript:

Keith Stewart, MD, CHB:
So, just to recap then: we don’t need to wait for CRAB symptoms any more if there’s high-marrow plasmacytosis, high-free light chain, the hemoglobin’s dropping or the proteins are rising, and there’s more and more patients being considered treatable. Let’s just talk about that for a minute, because it’s still in the research realm a little bit. Bill, are you treating smoldering myeloma today? And if so, how?

William I. Bensinger, MD: I’m a little more circumspect about who should be treated. I think that patients who have more than 60% plasma cell involvement, or patients that have lesions on MRI or PET, I think clearly are going to need treatment sooner rather than later. I sort of share Jatin’s concern about the free-light chain alone, because I found it to be rather labile. I’ve seen patients who will have a free-light chain ratio of over 100, and then you’ll check them again in 2 weeks, and it’s now 60. And so what does that mean? They’re no longer over 100. Do they suddenly not need to be treated? And so I’m a little bit concerned about treating a patient just on the basis of the free light chain, that’s all.

Keith Stewart, MD, CHB: I thought in the presentation yesterday, maybe I got this wrong, but that something like 70% of smoldering myeloma patients in that analysis from Mayo got active myeloma within 10 years. Ola, given that they’re basically all going to end up with myeloma at some point, shouldn’t we just treat them all early? Why are we waiting?

C. Ola Landgren, MD, PhD: I think that’s a very good question. I don’t think we really know the answer, what the right thing to do is. So, in my practice, I would not treat the patient with smoldering myeloma outside a clinical trial.

Keith Stewart, MD, CHB: Why is that?

C. Ola Landgren, MD, PhD: Because we don’t know the answer to this question. And I think putting patients on therapy for the wrong reason would not be the right thing to do as a clinician. I do think the research is indicating that probably there are patients that really will benefit from it, but I think we also need to capture that data. So, if we start treating patients outside of a clinical trial, we will never be able to capture it. And I think the downside with that will be we will over treat many patients. I would strongly advocate the trials.

Keith Stewart, MD, CHB: How can you over treat if they’re all going to get myeloma? Is that overtreatment?

C. Ola Landgren, MD, PhD: We know that there are patients that are labeled a smoldering myeloma and that, after very many years of follow-up, they will actually not develop myeloma. So, I think it’s a little bit like in prostate cancer or breast cancer, where you give a lot of therapy for patients that may not need it. We don’t want to go that way with myeloma. We have the chance to stop that.

Keith Stewart, MD, CHB: You’ve actually run a clinical trial where you did treat patients with high-risk smoldering myeloma. Tell us about that, because that was really fascinating.

C. Ola Landgren, MD, PhD: Yes, we have done several studies. The first trial we developed in 2011 was with Kyprolis Rev/Dex (KRD)…

Keith Stewart, MD, CHB: Carfilzomib plus Len/Dex.

C. Ola Landgren, MD, PhD: Carfilzomib, lenalidomide, dexamethasone for 8 cycles. We treated, so far, 17 patients on that trial. We had 100% complete response rate in the first 12. When we added an additional 5, the complete response rate is 16 out of 17. One patient is VGPR (very good patient response). Because the trial was open in 2011, the criteria, at the time, were not there with the 60% cutoff. But I can tell you that that 17th patient that is VGPR was actually 60% plasma-cell infiltration.

We have up to 3 years of follow-up and, to my knowledge, none of those patients have converted back to myeloma. They all remain MRD (minimal residual disease)-negative, the ones that were in complete remission (CR)

Keith Stewart, MD, CHB: I think it’s important to emphasize, this is a fantastic result, right? Three years of complete remission? How many cycles of KRD did you give?

C. Ola Landgren, MD, PhD: We gave 8 cycles, followed by 2 years of maintenance lenalidomide.

Keith Stewart, MD, CHB: No relapse after 3 years, so it does make you wonder.

Rafael Fonseca, MD: You know, I’m going to stand with Ola. I think we have to be careful. I probably wouldn’t treat most of the smoldering patients, but I think the studies that refine the risk within smoldering myeloma are helping us a lot. I like to categorize CRAB into the claws of the crabs and the legs of the crabs. And the claws of the crabs for me are the renal failure and the bone disease. And what I mean by that is that’s the dangerous part of CRAB. Anemia and hyperglycemia can be corrected. So, I think we need good biomarkers for renal disease. We have that with a free-light chain assay. We need better biomarkers for bone. But as we incorporate this—and then a dynamic way of following patients—I think you’re right. We shouldn’t let the patient present with a fracture. But then we don’t want to be treating the thousands of patients with smoldering myeloma who are probably not going to progress for many years.

William I. Bensinger, MD: I think there is a concern here about treating smoldering myeloma. What’s changed is we now have drugs that, at least in some very early trials, have shown a difference in outcome, mainly survival, for patients with high-risk smoldering, as they’re defined in the particular trials. But you have to be careful because I think you can over treat patients that may not ever need treatment in their lifetime. And there’s the cost of the drugs and the side effects of the drugs. And that all has to be balanced. So, I think if we can define the patients that need this treatment in the smoldering group, that’s going to be a huge advance.

Keith Stewart, MD, CHB: Give me a summary for the community oncologists of our discussion. Just wrap up here for us, Jatin. What should the community oncologists know what to do with that smoldering myeloma patient today?

Jatin P. Shah, MD: I think it’s important to acknowledge that these are very difficult diagnoses to make, first of all. But I think the key message here is that we are changing now, we are trying to identify patients with a high-risk smoldering myeloma. So, patients who have those features that were defined by Ola—including an MRI lesion, a bone marrow plasmacytosis, or a high-free light chain ratio—and maybe, as you move forward, an evolving process. Those patients are likely to progress in the next 18 to 24 months. It’s very reasonable to start therapy in those patients early to prevent, as Rafael described, the claws of the CRAB, and try and prevent some of the end-organ damage and maintain quality of life for those patients.

Beyond that, for other patients with smoldering disease, I think we want to start treating those patients early—but we need more data. Intuitively, I think, we—as physicians, as patients, as part of the healthcare community—want to treat those patients, but I think we need more data to drive that decision because of the cost of these therapies and the long-term outcomes. There are some side effects with all these drugs. So, I think that we have to be very careful.

We’re excited; that’s where the future may be going, but for now, for those patients, I think the ultra-high-risk patients—as we define—are important to consider for early intervention.

Transcript Edited for Clarity
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Transcript:

Keith Stewart, MD, CHB:
So, just to recap then: we don’t need to wait for CRAB symptoms any more if there’s high-marrow plasmacytosis, high-free light chain, the hemoglobin’s dropping or the proteins are rising, and there’s more and more patients being considered treatable. Let’s just talk about that for a minute, because it’s still in the research realm a little bit. Bill, are you treating smoldering myeloma today? And if so, how?

William I. Bensinger, MD: I’m a little more circumspect about who should be treated. I think that patients who have more than 60% plasma cell involvement, or patients that have lesions on MRI or PET, I think clearly are going to need treatment sooner rather than later. I sort of share Jatin’s concern about the free-light chain alone, because I found it to be rather labile. I’ve seen patients who will have a free-light chain ratio of over 100, and then you’ll check them again in 2 weeks, and it’s now 60. And so what does that mean? They’re no longer over 100. Do they suddenly not need to be treated? And so I’m a little bit concerned about treating a patient just on the basis of the free light chain, that’s all.

Keith Stewart, MD, CHB: I thought in the presentation yesterday, maybe I got this wrong, but that something like 70% of smoldering myeloma patients in that analysis from Mayo got active myeloma within 10 years. Ola, given that they’re basically all going to end up with myeloma at some point, shouldn’t we just treat them all early? Why are we waiting?

C. Ola Landgren, MD, PhD: I think that’s a very good question. I don’t think we really know the answer, what the right thing to do is. So, in my practice, I would not treat the patient with smoldering myeloma outside a clinical trial.

Keith Stewart, MD, CHB: Why is that?

C. Ola Landgren, MD, PhD: Because we don’t know the answer to this question. And I think putting patients on therapy for the wrong reason would not be the right thing to do as a clinician. I do think the research is indicating that probably there are patients that really will benefit from it, but I think we also need to capture that data. So, if we start treating patients outside of a clinical trial, we will never be able to capture it. And I think the downside with that will be we will over treat many patients. I would strongly advocate the trials.

Keith Stewart, MD, CHB: How can you over treat if they’re all going to get myeloma? Is that overtreatment?

C. Ola Landgren, MD, PhD: We know that there are patients that are labeled a smoldering myeloma and that, after very many years of follow-up, they will actually not develop myeloma. So, I think it’s a little bit like in prostate cancer or breast cancer, where you give a lot of therapy for patients that may not need it. We don’t want to go that way with myeloma. We have the chance to stop that.

Keith Stewart, MD, CHB: You’ve actually run a clinical trial where you did treat patients with high-risk smoldering myeloma. Tell us about that, because that was really fascinating.

C. Ola Landgren, MD, PhD: Yes, we have done several studies. The first trial we developed in 2011 was with Kyprolis Rev/Dex (KRD)…

Keith Stewart, MD, CHB: Carfilzomib plus Len/Dex.

C. Ola Landgren, MD, PhD: Carfilzomib, lenalidomide, dexamethasone for 8 cycles. We treated, so far, 17 patients on that trial. We had 100% complete response rate in the first 12. When we added an additional 5, the complete response rate is 16 out of 17. One patient is VGPR (very good patient response). Because the trial was open in 2011, the criteria, at the time, were not there with the 60% cutoff. But I can tell you that that 17th patient that is VGPR was actually 60% plasma-cell infiltration.

We have up to 3 years of follow-up and, to my knowledge, none of those patients have converted back to myeloma. They all remain MRD (minimal residual disease)-negative, the ones that were in complete remission (CR)

Keith Stewart, MD, CHB: I think it’s important to emphasize, this is a fantastic result, right? Three years of complete remission? How many cycles of KRD did you give?

C. Ola Landgren, MD, PhD: We gave 8 cycles, followed by 2 years of maintenance lenalidomide.

Keith Stewart, MD, CHB: No relapse after 3 years, so it does make you wonder.

Rafael Fonseca, MD: You know, I’m going to stand with Ola. I think we have to be careful. I probably wouldn’t treat most of the smoldering patients, but I think the studies that refine the risk within smoldering myeloma are helping us a lot. I like to categorize CRAB into the claws of the crabs and the legs of the crabs. And the claws of the crabs for me are the renal failure and the bone disease. And what I mean by that is that’s the dangerous part of CRAB. Anemia and hyperglycemia can be corrected. So, I think we need good biomarkers for renal disease. We have that with a free-light chain assay. We need better biomarkers for bone. But as we incorporate this—and then a dynamic way of following patients—I think you’re right. We shouldn’t let the patient present with a fracture. But then we don’t want to be treating the thousands of patients with smoldering myeloma who are probably not going to progress for many years.

William I. Bensinger, MD: I think there is a concern here about treating smoldering myeloma. What’s changed is we now have drugs that, at least in some very early trials, have shown a difference in outcome, mainly survival, for patients with high-risk smoldering, as they’re defined in the particular trials. But you have to be careful because I think you can over treat patients that may not ever need treatment in their lifetime. And there’s the cost of the drugs and the side effects of the drugs. And that all has to be balanced. So, I think if we can define the patients that need this treatment in the smoldering group, that’s going to be a huge advance.

Keith Stewart, MD, CHB: Give me a summary for the community oncologists of our discussion. Just wrap up here for us, Jatin. What should the community oncologists know what to do with that smoldering myeloma patient today?

Jatin P. Shah, MD: I think it’s important to acknowledge that these are very difficult diagnoses to make, first of all. But I think the key message here is that we are changing now, we are trying to identify patients with a high-risk smoldering myeloma. So, patients who have those features that were defined by Ola—including an MRI lesion, a bone marrow plasmacytosis, or a high-free light chain ratio—and maybe, as you move forward, an evolving process. Those patients are likely to progress in the next 18 to 24 months. It’s very reasonable to start therapy in those patients early to prevent, as Rafael described, the claws of the CRAB, and try and prevent some of the end-organ damage and maintain quality of life for those patients.

Beyond that, for other patients with smoldering disease, I think we want to start treating those patients early—but we need more data. Intuitively, I think, we—as physicians, as patients, as part of the healthcare community—want to treat those patients, but I think we need more data to drive that decision because of the cost of these therapies and the long-term outcomes. There are some side effects with all these drugs. So, I think that we have to be very careful.

We’re excited; that’s where the future may be going, but for now, for those patients, I think the ultra-high-risk patients—as we define—are important to consider for early intervention.

Transcript Edited for Clarity
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