Rounds with Investigators 2012 | Multiple Myeloma
QUESTION: Are there biomarkers to indicate who should be treated and whom we can observe in MGUS or smoldering myeloma?
DR JEFFREY WOLF: This was a tremendous controversy at the last myeloma meetings in Paris, because there was clearly a group of myeloma experts that wasn’t satisfied with just plain films. We’ve been doing plain films since William Rankin developed them, right, 100 years ago. We have better imaging technology. And I don't know if you’re going to have a smoldering myeloma case, but I think it becomes very important in the case of smoldering myeloma, for example, where if you only define it based on plain films, you’ve got a lot of people who are smoldering who really aren’t smoldering. They’re being called smoldering, but they’ve got active lesions. There were people in the audience who said, “Positive PET scan, positive MRI, they’ve got myeloma. They need treatment,” and then there were some others who simply said, “The definition is abnormal plain films, and they have smoldering disease until they have an abnormal plain film.”
DR NEIL LOVE: So any other questions? Let’s go on to Raymond’s case.
DR CHARLES FARBER: I’d like to hear what Jeff says.
DR JEFFREY ZONDER: Actually, I agree with that. But if you use the definition of smoldering myeloma that’s out there, for a large group of patients I think you know what you can expect in terms of the natural history for that group of patients. The question you’re bringing up is whether it might be possible to tease that apart and could you find somebody who meets the classical definition of smoldering myeloma who would actually be at higher risk. Who’s the group that really does go on to develop symptomatic disease? And could you find out that some of them really had findable, measurable lesions using better imaging?
DR WOLF: And in that case, you treat them and you prevent. How many of us have seen that patient with smoldering myeloma who comes in with a cord compression or had smoldering myeloma who comes in with renal insufficiency?
DR ZONDER: I have to admit that I, in my own practice, a patient who meets the definition of smoldering myeloma, I don’t universally get a PET scan as part of their staging. However, when somebody has a surprisingly high M protein or one of those rare smoldering cases where instead of 15 or 20 or 25% plasma cells in the marrow you get this really heavily involved marrow, because we all have those, the patient who meets smoldering criteria but is 50% involved. I actually go to extra lengths to image their bones.
DR LOVE: Okay. Now we’ve got to do Steve’s case. Hold on, Raymond, as long as you guys got into smoldering. Why don’t you throw out your case?
DR RAYMOND LOBINS: Could I ask a quick question first? And my case kind of was an issue of this question as well. When you have a patient who you’re not going to use zoledronic acid with, when you look at the data on bortezomib — there are at least 2 studies that say because it works through NF-kappa-beta, and osteoclasts kind of work the same way, do you ever give bortezomib in a regimen where you’re not going to give zoledronic acid to try to, quote/unquote, protect the bones? Because there are a couple of trials to say that bortezomib kind of helps protect the bones as well.
DR LOVE: Jeff Wolf?
DR WOLF: I don’t use it that way.
DR LOVE: Okay. Steve, can you just kind of put out your case there in terms of a smoldering case? That’s your 78-year-old.
DR STEVEN HAGER: Yes, 78-year-old lady, presented to me in October of 2009 with hypercalcemia. At that time, she was taking vitamin D and calcium for osteoporosis. She had a parathyroid hormone, which was within normal range. She was taken off the calcium and still remained hypercalcemic. At that time, she was referred to me.
She had a bone marrow biopsy at that time. She had normal blood counts also at that time, and it revealed 20% monoclonal plasma cells. The cytogenetics and FISH at that time were negative. Further workup included bone survey at that time. And beta-2 microglobulin was normal —
DR WOLF: I’m sorry. The bone survey was normal.
DR HAGER: Correct. That’s in 2009. I did get a PET scan just recently, so I see your point. But SPEP at that time revealed a very small M-spike of 0.08 grams, and it was IgG lambda. She was followed at that time. She has comorbidities, I should say, of congestive heart failure, which was well compensated, hypertension and valvular heart disease, status post a valve replacement. This is a well-functioning lady, but she comes in with a walker. And she prefers noninvolvement. She’s very happy the way it is. So at that time the decision was made to follow.
And I saw her every few months, and then when data came out, which I’m sure these gentlemen will — with the use, I believe it’s thalidomide in smoldering myeloma that I saw a couple of trials. I offered her lenalidomide, but she refused at that time. And we still follow her. Her last M-spike was 0.0 — I think 0.88. So it did go up by a tiny amount. Her PET scan was just 2 months ago, and that was completely normal.
DR LOVE: So, Jeff Zonder, you want to comment on this? And also, can you talk a little bit about what we know about IMiDs? I’ve seen lenalidomide was reported at ASH. I’m not sure about thalidomide in smoldering myeloma.
DR ZONDER: Thalidomide was studied in smoldering myeloma at the Mayo Clinic and ECOG a long time ago. And it was a small Phase II experience. And what they showed was that you can — predictably, you can lower M proteins and cause thalidomide-related toxicity. And it was felt that the balance was such that they didn’t proceed with that. I mean, that’s the data that I’m aware of, of thalidomide in smoldering myeloma.
DR LOVE: How about lenalidomide?
DR WOLF: Mateos’ randomized trial.
DR ZONDER: Right. So there was the Spanish group, has done a randomized study of lenalidomide and dexamethasone versus observation in patients with what they call high-risk asymptomatic multiple myeloma. And they defined that in a way that’s a bit different than we do. They looked at the height of the M protein spike. They also looked at the percentage of aberrant plasma cells compared to normal plasma cells in the bone marrow. They have a very specific definition —
DR WOLF: You could look at the rate of increase of protein.
DR ZONDER: I don’t recall that, but the definition, that isn’t exactly I think what standard American practice generally — how we think about these patients. Nonetheless, they defined a high-risk subset. And in that study, there was a delay in the progression to symptomatic myeloma and there was ultimately a small survival benefit.
DR WOLF: It was huge.
DR WOLF: It was 95% versus 76% at 3 years.
DR ZONDER: Progression.
DR WOLF: I think survival.
DR LOVE: Kathryn, can you pull it up? We’ll pull it up and see. I didn’t remember survival.
DR ZONDER: So from my standpoint the problem with that study is that the survival — and again, maybe it has to do with the way they defined their patients. But the survival in the observation group is not what we would have expected.
DR WOLF: That’s the point.
DR ZONDER: And so I mean I would expect observed patients, a patient like this, to have a higher survival rate than what we saw in that study, a higher likelihood of 3-year survival.
DR LOVE: Just to be clear, before I go to Jeff Wolf, do you agree with Steve offering lenalidomide to this patient?
DR ZONDER: I only do that in the context of a study.
DR LOVE: Jeff Wolf?
DR WOLF: So what I need to hear, Steve, is what happened to her calcium.
DR ZONDER: I want to know about that, too.
DR WOLF: Is it still up? You said it was up when she came off calcium supplement. She still had an elevated calcium. What is it we don’t believe about CRAB criteria?
DR LOVE: Does she still have an elevated calcium now?
DR HAGER: No, she doesn’t.
DR LOVE: She does not. Okay.
DR WOLF: So it was related to the supplement? Because I heard you say it continued to be elevated. That’s why she got referred to you.
DR HAGER: Correct. Her calcium dropped. It was — she was not given any bisphosphonates. It’s just that it dropped by itself. It was mildly elevated. It was like 10.8. Yes.
DR ZONDER: Actually, I don’t think a normal PTH in this situation is normal. I would have expected it to be —
DR WARREN BRENNER: Low.
DR ZONDER: Right? Low. So I was actually wondering if she had a little bit of hyperparathyroidism.
DR WOLF: But I’d like to get back to the issue of the definition of smoldering, because I have 2 comments, 1 for Steve and 1 for you, Jeff. If, indeed, her calcium had remained up, would you have treated her?
DR HAGER: I would have pushed much harder.
DR LOVE: Would you have?
DR WOLF: Yes. What makes me crazy about the way we look at myeloma — and it’s not just you. It’s some investigators, too — is that we don’t believe the CRAB criteria. That is, when we see lytic lesions, fine. When we see renal disease, fine. But I see people who have anemia and docs are attributing it to a million other things than their myeloma. And yet it’s really related to their myeloma. They’re loath to start therapy just based on anemia. And I’ve seen people with slightly high calciums, where they ignore those, too.
DR LOVE: This lady was taking calcium, though.
DR WOLF: Yes. But I think that we undertreat smoldering myeloma. We overdiagnose smoldering myeloma.
DR WOLF: Right.
DR WOLF: And I’m going to go back to the Spanish study, and I’m going to pull the curves, if you guys haven’t found it. I’m going to show you those curves.
DR WOLF: Those curves diverged in the first month.
DR LOVE: Was this survival or progression? What was it?
DR KATHRYN ZIEL: Ninety-three percent in those in the continuous lenalidomide arm versus 76% in the —
DR LOVE: Yep. You got it.
DR WOLF: Overall survival. Was I close?
DR LOVE: Yes. You got it.
DR ZONDER: Which is totally unexpected.
DR WOLF: But if you look at the curves, it’s unexpected. If you look at those curves, there are patients who progress in a month or 3 months. You don’t think they went from smoldering to active in a month. They had disease. If they had done PET scans or MRIs, they would have found those lesions. And a month or 2 later, they can see them on x-ray. So I think that we underdiagnose smoldering by not doing the proper imaging.
And in that study, 40% of the patients on the observation arm, within 2 years, had developed active myeloma. That’s an unacceptable number. Some of them had renal disease as well. They went on dialysis. And that’s what I see. I’m just sick, Jeff, of seeing patients who are sent to me, who have been followed with smoldering for 3 years and now are paraplegic. I’ve got one of those who comes in on dialysis. I’ve got one of those. I just think that the term “smoldering” has to be redefined using better imaging and these people have to be watched more carefully.
DR LOVE: I want to ask Jeff Zonder in a second about the trial that’s looking at this. I think it’s an ECOG trial. But just to clarify, you get an email from Steve. He shoots you this email, “I’ve got this lady. She was hypercalcemic, but she was taking calcium. Now she’s normocalcemic.” What would you say about lenalidomide?
DR WOLF: I think in this case, if she truly has a normal calcium now, normal hemoglobin, normal renal function and no lytic lesions on PET, this woman should not get treated. This woman does have smoldering disease.
DR LOVE: What’s the trial that’s going on? I don't know if either of you are participating in it.
DR ZONDER: We’re not participating in the —
DR LOVE: The ECOG trial.
DR ZONDER: There’s an ECOG trial.
DR LOVE: Can either of you comment on that?
DR WOLF: I’m not participating.
DR LOVE: In terms of the criteria, the entry criteria and —
DR ZONDER: It’s patients with the criteria for smoldering myeloma or high-risk MGUS.
DR LOVE: And lenalidomide —
DR WOLF: And what kind of imaging are they using?
DR ZONDER: I don't know the answer to that question.
DR LOVE: And it’s lenalidomide?
DR ZONDER: It’s lenalidomide — I don’t know the answer to this. I don't know if it’s lenalidomide with dex. I think it’s just lenalidomide.
DR LOVE: So I want to go on to Raymond’s case, but any questions at this point, Steve?
DR HAGER: How would you define high-risk MGUS?
DR ZONDER: High-risk MGUS is patients who have over a gram and a half of protein, patients who have anything but an IgG paraprotein.
DR BRENNER: FISH? Abnormal free light chain.
DR ZONDER: Abnormal free light chain. I chose the other one. FISH, actually, cytogenetics aren’t incorporated into the definition. So, when they need treatment, it predicts the duration of their response, but I don’t think there are great data to show that it predicts the duration of smoldering state.