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Managing Smoldering Myeloma

Panelists:Ajai Chari, MD, Mount Sinai Hospital; Sagar Lonial, MD, Emory University School of Medicine; Paul G. Richardson, MD, Harvard Medical School; Jatin J. Shah, MD, MD Anderson Cancer Center; Keith Stewart, MD, CHB, Mayo Clinic
Published: Wednesday, Jan 27, 2016


Transcript:

Keith Stewart, MB, CHB:
So, we have this condition we all see in our clinic, we call smoldering myeloma, which is people who clearly have cancer on their bone marrow, myeloma on their bone marrow, and yet we choose to watch and wait. There are some of those patients who will progress very quickly, we know from experience.

Should those patients be treated, Dr. Lonial, high risk? Well first of all, how would you define high-risk smoldering myeloma, briefly, and would you treat it?

Sagar Lonial, MD: So I think high-risk smoldering myeloma, in my view, using an objective set of data really follows the ECOG Mayo criteria that we use in the current ECOG trial, which is randomizing patients between observation and single-agent lenalidomide. That looks at three criteria, greater than 10% plasma cells, M spike greater than 3, and a free light chain ratio greater than 8, or less than 1.25. And, if you have all three of those, your risk of progression is very high.

Median time is about 2-1/2 to 3 years. If you have only one of those, your median time to progression is greater than 10 years. So that's a good way to risk stratify patients. It's simple. These are all tests that we do regularly. It doesn't include complex imaging.

I think the question about treating them is much more difficult. I think for patients who fit into the regular smoldering myeloma category, the standard of care remains observation, and it remains close observation.

Keith Stewart, MB, CHB: Let me stop you with that. Does everybody agree with that? Would you treat a high-risk smoldering myeloma patient?

Jatin J. Shah, MD: That's important knowledge. That's actually one of the most difficult diagnoses to make, quite frankly. So, for a community oncologist who sees breast cancer and prostate cancer, it's rather clear-cut when to treat and when not to treat. So, I would say we need to acknowledge that this is actually a very difficult decision.

We see referrals all the time about confirming is it smoldering or active myeloma. So, I think it's important to acknowledge. And, so, as we get into these nuances that we talk about here, I think it becomes very challenging to apply this clinically, quite frankly. So, when you get down to the high-risk smoldering, it's also important that the criteria have changed, right, in the last six years.

Keith Stewart, MB, CHB: Yeah, speak that. There are some new criteria that have come out which suggest if it's not smoldering, you should just treat straightaway.

Jatin J. Shah, MD: Yeah, absolutely. So I think we recategorize or identified a subset of patients with ultra-high risk myeloma, and those are patients with a pre-light chain ratio greater than 100, a bone marrow plasmacytosis more than 60%, and lytic lesions on MRI more than one on PET scan. And those are patients who have a very high risk of progression in the first 18 to 24 months.

Keith Stewart, MB, CHB: So those patients should be treated today.

Jatin J. Shah, MD: So that's what the new IMGG criteria suggests, yes. And, then we have the leftover smoldering intermediate and high-risk patients. And, so for those patients, I agree with Dr. Lonial that those patients, for now, should be observed unless they're on a clinical trial.

Keith Stewart, MB, CHB: How many feel differently? How many feel we should be treating more aggressively, early? We don't watch breast cancer for very long before we treat it.

Paul G. Richardson, MD: Well, I think there are various strategies, Keith. But, I agree completely with Jatin that the on protocol approach makes the most sense until we can dissect the best answers from the various opportunities we have.

Our own experience has been that the use of monoclonal antibodies experimentally in this setting has been quite favorable. But like everything, as you move into then combining an antibody with immunomodulatory therapy, we've been struck that whilst the combination is very active, you know out of the box have come some interesting and challenging toxicities.

So, it kind of sharply defines that one has to be careful. And I think the immune-oncologic space in smoldering is very attractive. But, again, it gets to this question of toxicity benefit, and we have to be appropriately perspective in how we evaluate patients in that regard.

Ajai Chari, MD: I would like to just point out that with the three new criteria we just have better technology for picking up bone lesion. And the bone marrow, notwithstanding the heterogeneity and sampling issues of a bone marrow sample, 60% I would buy. But, I think the free light chain ratio is a little bit different.

Keith Stewart, MB, CHB: I was sitting here thinking, I still challenge somebody has a free light chain of 110.

Ajai Chari, MD: Right. And issues in that include things like, what is lead time bias? How long has this patient already had a free light chain? So particularly for the community oncologist, if they've already had a free light chain ratio of over 100 for two years, do you need to start treating them just because we have a consensus statement saying that?

And I think it's important to remember that we don't have phase III prospective studies showing that this particular population, because at the end of the day, it's all about risk and benefit: what is the benefit and what is the risk of the therapy you're implementing?

And, are you making a dent in that patient's overall survival and natural history? Because the argument would be, if you follow these patients closely, you could even say, maybe we should randomize them to monthly follow-up and intervene.

Sagar Lonial, MD: But, remember the risk in these patients is renal failure. So, it's not often; I mean if you look at the Spanish Trial, the randomized Len/Dex versus observation, which I think is not the answer.

Ajai Chari, MD: Correct.

Sagar Lonial, MD: But many of the patients in the control arm presented with renal failure, and those patients were being watched relatively frequently.

Paul G. Richardson, MD: And interestingly, also, Sagar, many of them, in fact that lead CRAB-defining event was actually bone disease.

Jatin J. Shah, MD: Agreed, yes.

Paul G. Richardson, MD: And, I think that the important message I've always found, too, is that, you know, again, if I have a smoldering patient with osteopenia, I'm very comfortable recommending appropriately, with the usual caveats, bisphosphonate use.

I'm particularly interested in that because I think actually beyond the simple effect on bone, this is intriguing evidence that bisphosphonates may have a favorable impact on the gamma T-cell population. So, in fact, hypothetically, they have an immunological platform as well. So, it's just interesting.

Sagar Lonial, MD: Yeah.

Keith Stewart, MB, CHB: So, let me summarize again. I think I just want to make sure we wrap up for the watching physicians. The general sense is that we still don't treat smoldering myeloma. So we may have a lower threshold for people with the high blast plasmacytosis, and certainly for people who have evidence of disease on board. But, for the most part, we still recommend watchful waiting in this population.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity
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Transcript:

Keith Stewart, MB, CHB:
So, we have this condition we all see in our clinic, we call smoldering myeloma, which is people who clearly have cancer on their bone marrow, myeloma on their bone marrow, and yet we choose to watch and wait. There are some of those patients who will progress very quickly, we know from experience.

Should those patients be treated, Dr. Lonial, high risk? Well first of all, how would you define high-risk smoldering myeloma, briefly, and would you treat it?

Sagar Lonial, MD: So I think high-risk smoldering myeloma, in my view, using an objective set of data really follows the ECOG Mayo criteria that we use in the current ECOG trial, which is randomizing patients between observation and single-agent lenalidomide. That looks at three criteria, greater than 10% plasma cells, M spike greater than 3, and a free light chain ratio greater than 8, or less than 1.25. And, if you have all three of those, your risk of progression is very high.

Median time is about 2-1/2 to 3 years. If you have only one of those, your median time to progression is greater than 10 years. So that's a good way to risk stratify patients. It's simple. These are all tests that we do regularly. It doesn't include complex imaging.

I think the question about treating them is much more difficult. I think for patients who fit into the regular smoldering myeloma category, the standard of care remains observation, and it remains close observation.

Keith Stewart, MB, CHB: Let me stop you with that. Does everybody agree with that? Would you treat a high-risk smoldering myeloma patient?

Jatin J. Shah, MD: That's important knowledge. That's actually one of the most difficult diagnoses to make, quite frankly. So, for a community oncologist who sees breast cancer and prostate cancer, it's rather clear-cut when to treat and when not to treat. So, I would say we need to acknowledge that this is actually a very difficult decision.

We see referrals all the time about confirming is it smoldering or active myeloma. So, I think it's important to acknowledge. And, so, as we get into these nuances that we talk about here, I think it becomes very challenging to apply this clinically, quite frankly. So, when you get down to the high-risk smoldering, it's also important that the criteria have changed, right, in the last six years.

Keith Stewart, MB, CHB: Yeah, speak that. There are some new criteria that have come out which suggest if it's not smoldering, you should just treat straightaway.

Jatin J. Shah, MD: Yeah, absolutely. So I think we recategorize or identified a subset of patients with ultra-high risk myeloma, and those are patients with a pre-light chain ratio greater than 100, a bone marrow plasmacytosis more than 60%, and lytic lesions on MRI more than one on PET scan. And those are patients who have a very high risk of progression in the first 18 to 24 months.

Keith Stewart, MB, CHB: So those patients should be treated today.

Jatin J. Shah, MD: So that's what the new IMGG criteria suggests, yes. And, then we have the leftover smoldering intermediate and high-risk patients. And, so for those patients, I agree with Dr. Lonial that those patients, for now, should be observed unless they're on a clinical trial.

Keith Stewart, MB, CHB: How many feel differently? How many feel we should be treating more aggressively, early? We don't watch breast cancer for very long before we treat it.

Paul G. Richardson, MD: Well, I think there are various strategies, Keith. But, I agree completely with Jatin that the on protocol approach makes the most sense until we can dissect the best answers from the various opportunities we have.

Our own experience has been that the use of monoclonal antibodies experimentally in this setting has been quite favorable. But like everything, as you move into then combining an antibody with immunomodulatory therapy, we've been struck that whilst the combination is very active, you know out of the box have come some interesting and challenging toxicities.

So, it kind of sharply defines that one has to be careful. And I think the immune-oncologic space in smoldering is very attractive. But, again, it gets to this question of toxicity benefit, and we have to be appropriately perspective in how we evaluate patients in that regard.

Ajai Chari, MD: I would like to just point out that with the three new criteria we just have better technology for picking up bone lesion. And the bone marrow, notwithstanding the heterogeneity and sampling issues of a bone marrow sample, 60% I would buy. But, I think the free light chain ratio is a little bit different.

Keith Stewart, MB, CHB: I was sitting here thinking, I still challenge somebody has a free light chain of 110.

Ajai Chari, MD: Right. And issues in that include things like, what is lead time bias? How long has this patient already had a free light chain? So particularly for the community oncologist, if they've already had a free light chain ratio of over 100 for two years, do you need to start treating them just because we have a consensus statement saying that?

And I think it's important to remember that we don't have phase III prospective studies showing that this particular population, because at the end of the day, it's all about risk and benefit: what is the benefit and what is the risk of the therapy you're implementing?

And, are you making a dent in that patient's overall survival and natural history? Because the argument would be, if you follow these patients closely, you could even say, maybe we should randomize them to monthly follow-up and intervene.

Sagar Lonial, MD: But, remember the risk in these patients is renal failure. So, it's not often; I mean if you look at the Spanish Trial, the randomized Len/Dex versus observation, which I think is not the answer.

Ajai Chari, MD: Correct.

Sagar Lonial, MD: But many of the patients in the control arm presented with renal failure, and those patients were being watched relatively frequently.

Paul G. Richardson, MD: And interestingly, also, Sagar, many of them, in fact that lead CRAB-defining event was actually bone disease.

Jatin J. Shah, MD: Agreed, yes.

Paul G. Richardson, MD: And, I think that the important message I've always found, too, is that, you know, again, if I have a smoldering patient with osteopenia, I'm very comfortable recommending appropriately, with the usual caveats, bisphosphonate use.

I'm particularly interested in that because I think actually beyond the simple effect on bone, this is intriguing evidence that bisphosphonates may have a favorable impact on the gamma T-cell population. So, in fact, hypothetically, they have an immunological platform as well. So, it's just interesting.

Sagar Lonial, MD: Yeah.

Keith Stewart, MB, CHB: So, let me summarize again. I think I just want to make sure we wrap up for the watching physicians. The general sense is that we still don't treat smoldering myeloma. So we may have a lower threshold for people with the high blast plasmacytosis, and certainly for people who have evidence of disease on board. But, for the most part, we still recommend watchful waiting in this population.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity
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