Case Study: Myeloma at Early Relapse

Dr Joseph Mikhael and expert panel review a case study in early relapse multiple myeloma and the impact of cytogenetics in risk assessment for patients with early relapse multiple myeloma.

Transcript:

Joseph Mikhael, MD: Now, we're going to turn our thinking a little bit more to relapse because that's the focus of today. And in particular, early relapse. I think sometimes we get very excited to talk about frontline therapy and very late relapse with all the new modalities of CAR [chimeric antigen receptor] T-cell therapies and bispecific therapies, but we sometimes forget that most patients land in that 1 to 3 prior line space. To introduce this, I'm going to ask Elisabet if you could just walk us through this first case to get us primed a little bit. I will note to the audience that you do have the option to enter questions into the Q&A box and we'll make sure that we address those, so feel free to do so as we go.

Elisabet Manasanch, MD: Thank you, Joe. So, we're going to go over a very interesting and well-presented case of a patient that could have been treated in an academic center or in the community perfectly with this regimen, a very difficult patient. The patient is a 63-year-old Caucasian female that was diagnosed with stage 2 multiple myeloma. She has a history of being a heavy smoker. In the cytogenetics, in FISH [fluorescence in situ hybridization], what is remarkable is she has a gain of 1q21, she has a very good performance ECOG PS [Eastern Cooperative Oncology Group Performance Status Scale] of 0. Then the patient is treated with a standard regimen for newly diagnosed myeloma, very well accepted, bortezomib, lenalidomide, dexamethasone, and then she follows with an autonomous stem cell transplant, which is what our patients still do these days.

The patient then has a partial remission after this treatment, and she is placed in lenalidomide maintenance therapy. And in the next slide, you can see some of the genes and biological processes that are driven through these gains or amplifications of chromosome 1. And some of these are basically pro-oncogenic biological features. And what we know is that the abnormalities of chromosome 1 in general, in particular 1q, are a very common abnormality. It is found in about 40% of the myeloma patients through FISH, and it's reported as a 1q class, of a 1q21, and when we talk about the gain of 1q, it means that we have 3 copies of this particular area of the chromosome, and if it's an amplification, we have 4 or more copies.

Joseph Mikhael, MD: Great. So that's perfect, thank you for that. That's a fantastic description. And we wanted to focus on chromosome 1 a little bit because as you mentioned, it is so common in 40% of patients. As we used to say, if you don't take the temperature, the patient doesn't have a fever. I think when we weren't looking for this, we didn't recognize how common it was. Now, before I get the take from my 3 colleagues on what this means and what they consider to be high risk, we're now going to go to a polling question from the audience. And I saw that some great questions have come in from the audience. The question is as follows: do you consider gain or amplification in chromosome 1q as a high-risk abnormality at its initial assessment? And it's not just a simple yes or no answer. It's yes for any gain or amplification. So, as Dr Manasanch described, gain means 3 copies, and amplification has 4 or more copies. So yes, to any of that, or only yes if there's amplification, meaning that 3 copies are not enough for you to consider it high risk.

All right, we get more votes in. So, it looks like 70% of the audience thinks that any of this is a risk. So, whether you have the gain or the amplification. About 20% of the audience thinks only if you have the amplification, and 10% to 12% of the audience are saying it's not a high-risk feature at all. So, this is great. Thank you for your answers to that, it's shifting a little bit but still in that same vein, about two-thirds of the audience think that either a gain or an amplification is high risk.

So when we look at the mSMART [stratification for myeloma and risk-adapted therapy] guidelines, which our colleagues at Mayo Clinic have touted for many years, and Keith and I were involved in this in the past, and Sikander is still in the middle of it, we can see that they've listed high-risk features that include the classic translocations of 4;14, 14;16, 14;20, the known deletion 17p or a specific mutation within the p53 gene, but also have listed gain 1q. Now, what colors this a little bit, in addition to those other more clinical features, you see they have Revised ISS [International Staging System] stage 3 plasma cell, a high plasma cell S [synthesis]-phase, and a high-risk signature on gene expression profiling, is this notion below that we have what is sometimes referred to as double hit or triple hit myeloma, where I think we're coming to appreciate that any one of these abnormalities carries some risk, but when you start adding them together, that risk goes up. I just want to pause for a moment here because I know that Keith is a particular expert in the genetics of myeloma. Keith, I know we're going to come back to it in a group discussion in a moment, but if you were an audience member today, how would you answer that question?

Keith Stewart, MD: I would have selected none of the above because you're right, Joe, the bottom box is the key one. First of all, I'll say that the FISH scale does a terrible job of reporting the adverse applications, that is a totally unreliable and probably community practice, even worse than what is in our academic centers. So, I think that presence is a high-risk feature on its own. It's not in my mind high-risk if that's all you find, because it's 45% of our patients. However, if it's present, it would be additive to any of the other mutations so 1q plus something else in my mind is high risk. On its own, I tend to treat it as an intermediate risk.

Joseph Mikhael, MD: Any other thoughts from our other 2 colleagues here?

Elisabet Manasanch, MD: I think that sometimes the evaluation of the abnormalities in chromosome 1 is difficult. I completely agree with Keith, if you have a high-risk abnormality and abnormalities in chromosome 1, it can be not just a gain on 1q. That is a patient that we treat as high-risk. But I think that it's true that we don't have such a reliable method to test this. But I think if you're in the community and you ask your pathologist or the companies that are doing the FISH testing to include probes that would measure this area, for example, in some of the probes sometimes it's reported paths that can use 1p, some gene in chromosome 1. But chromosome 1 abnormalities I think overall are not good in myeloma and they're very common and that also includes deletions and again, gains or amplifications of basically extra copies of parts of the chromosome or the entire chromosome are usually not good in myeloma.

Joseph Mikhael, MD: With maybe the exception of a true hyperdiploid state where we do see these chess pieces in the standard risk.

Elisabet Manasanch, MD: Correct. Yes. Only hyperdiploid.

Joseph Mikhael, MD: Sikander, your thoughts?

Sikander Ailawadhi, MD: I havea couple of thoughts. Obviously, Keith and Elisabet pointed out the most important things. I think especially what we discussed with our community partners that it's very important for, first of all, the lab, whatever the pathology specimens send, to include probes for chromosome 1. I think we get it done routinely and obviously with mSMART we've had a gain in 1q included as a high risk forever and ever. But the thought is that if you don't look for it, you don't find it. Just like you mentioned, Joe. And so, knowing whether abnormalities exist or not, 1q gain exists or not, is extremely important. Linking it with other abnormalities is, again, very important.

What I can say is whenever we look at large databases, registries, etc, it comes out clear that chromosome 1 patients do behave differently and that's where, when we start breaking them apart into one with 13, one with this, one double hip, one with a triple hip. I think we break it down into smaller subsets, so it does play an important role. But I agree that by itself it may not be that important. But we really need to look for it. We need to understand our patients need to be aware as well.

Joseph Mikhael, MD: Great questions. Great comments from all of you about ensuring that the testing is done better. I think Keith raised that in particular. But I hope that we'll have a bit of an evolution where we'll be able to more clearly distinguish amplification from just a gain. Because I do think that probably in and of itself may be a high-risk feature. But I totally agree with all the comments you made.

Let me just quickly remind us of the case. So the patient that Elisabet shared with us got their VRd [Velcade, Revlimid, and dexamethasone], and got maintenance therapy with lenalidomide. But now here, unfortunately, 1 year after lenalidomide, we're running into trouble. So, before I even go into the details, someone asked a good question here which was, “How long do you plan to give lenalidomide? Do you plan to give it indefinitely?” As some of us know, coming up at the ASH [American Society of Hematology] annual meeting, there's some discussion and some studies looking at do we stop lenalidomide at 3 years. Do we stop it at 4 years? Do we stop it at 5 years? Do you, if someone is tolerating it, plan to prescribe lenalidomide forever? Or do you prescribe lenalidomide for 3, 4, or 5 years? Or what is your approach? I'll start with you, Elisabet.

Elisabet Manasanch, MD: I think that what you were saying is very important and I think that this is a patient that is relapsing seemingly quite quickly, has creatinine that is increasing, has a fracture in L2 second lumbar vertebrae. And so we want to give a treatment that is off the shelf, and we can get very quickly that is going to also reduce most of the myeloma very quickly, and that within 2 weeks can cut this down by quite a lot.

Joseph Mikhael, MD: Absolutely. Sorry, I was asking you before you knew about this relapse, what is your plan for lenalidomide maintenance? Are you giving it for a defined period of time or indefinitely?

Elisabet Manasanch, MD: We usually continue it indefinitely unless there's some tolerance issue, or if the patient starts relapsing, we need a biochemical relapse or relapse like this patient is experiencing, which is with some symptoms.

Joseph Mikhael, MD: Keith, how about you?

Keith Stewart, MD: I have almost no patients that take it forever. I tend to find a reason to stop around 2 or 3 years, such as rising MCP [medical care plan], dropping platelets, tolerance, and complete remission. I can't think of very many patients I've treated that go more than 3 or 4 years maximum taking lenalidomide.

Joseph Mikhael, MD: Sikander?

Sikander Ailawadhi, MD: I don't go with a time-limited treatment. Either ongoing, if the patient is tolerating and none of these issues show up like Keith is bringing up. Or most recently, with larger studies that are looking at maintenance, MRD [measurable residual disease]-driven maintenance, etc. Those data are not yet prime, but those studies are not yet ready. But we've started toying with the idea of looking for MRD-negative. Again, if there's sustained MRD-negative, it would be 6 months to 12 months. Should we be stopping lenalidomide? I feel comfortable with those kinds of discussions. I don't think there is one size that fits all, but those discussions have started happening more and more frequently with patients now.

Joseph Mikhael, MD: Excellent. I believe hopefully we’ll go towards stopping lenalidomide. If it's an opportunity to give patients nothing for a period of time, then that's very good. There’s one other question I want to address from the Q&A box. Keith, I'll get you to answer this one because I know you've written about this and talked about this before. Someone is saying, in light of what we said for frontline therapy, that the exposure to melphalan in the transplants can potentially yield other genetic mutations. Is that something that you're considering in your mind now? Do you think that's going to play a feature in the future, whether or not we continue doing transplants?

Keith Stewart, MD: You know, it clearly causes genetic damage throughout the cancer cell and the normal cells of a human to give high dose melphalan. However, it hasn't really translated into a very significant problem, as most of our patients end up dying of their myeloma, not something else. There is a background of acute leukemia that comes on later, but I think it's still small enough that we've tended to think the good for the bad transplant outweighs that.

Having said that, as our therapies improve, I'm all for getting rid of high-dose melphalan. I think it is genotoxic and at the end of the day, we'd be much better off without it. But for now, we're still transplanting, and the background DNA damage doesn't seem to be as important as controlling the myeloma.

Joseph Mikhael, MD: Great. Thanks so much, Keith. I also appreciated your comment of when that person is on lenalidomide maintenance, we do have to be a little bit on higher alert for any potential second primary malignancy, which would include MDS [myelodysplastic syndromes]. So, watching that MCV [mean corpuscular volume], watching the blood counts. But also, any particular GU [genitourinary] malignancy, any evidence of blood in the urine, or urinary symptoms that may be consistent with that.

There was one other question that I'll quickly address, which was what about dexamethasone? We keep talking about always using dexamethasone and I have to say that I try to tell my patients that dexamethasone is like the booster rockets on the shuttle. Really helpful for those first few cycles but there is a very strong impetus now to have a reduction. I've even joked this week that our clinic is going to be renamed, instead of The Myeloma Clinic, The Dexamethasone Reduction Service. I think we do find ourselves so often doing that and we are now even embarking on protocols where people are only given dexamethasone for the first 2 or 3 cycles. So, I would encourage, particularly our colleagues in the community, to assess how much you’re starting dose should be but also to have a plan in most patients to have that dexamethasone reduced, if not discontinued, within 2 to 6 months of the beginning of that therapy.

Coming back to our patient; as Elisabet noted, this patient unfortunately is relapsing rather aggressively. The M [monoclonal] spike has reappeared. The white chain is going up. They're anemic. Their creatinine is now up to 1.5 with a GFR [glomerular filtration rate] of less than 50 and they do have a fracture at L2, based on a PET [positron emission tomography] scan, with a performance status of 1. We've talked a little bit about this, but the gist is a discussion. In general, I think with this patient, it's obvious that we've got to treat them. But Sikander, are you, at the first hint of any biochemical relapse, tending to jump in and treat? Or are you more of a wait-and-watch kind of individual? Or does risk status influence that decision?

Sikander Ailawadhi, MD: Joe, absolutely. All of the above. I would say the very fact that this patient is progressing so soon after transplant and on maintenance, I think I would feel a little uncomfortable waiting and watching. So even if this was a slow progression but soon after transplant, I think I would be very concerned, because that is giving us an idea about the biological behavior of this case. In fact, just yesterday I had a patient who's about 160 days out of the transplant. Has, incidentally, 1q positive with a 13 deletion, and he was on dual agent maintenance and is progressing literally 5 months, 6 months, after the transplant. So, although that is a slow progression that patient was at, I'm very concerned. On the other hand, if the patient's been on treatment for 2 or 3 years with the regimen and now has a slow biochemical progression, I think that is a different disease. I think that's a different case. That's how we handle it. But with this one, I'm quite concerned. And I think it's the biological behavior that I'm most concerned about.

Joseph Mikhael, MD: What concerns you, Keith, the most in early relapse? Sikander noted the fact that it happened within a year, about a year after the transplant. What other features might make you think that this is more of an aggressive or a high-risk relapse?

Keith Stewart, MD: Obviously, one is worried about kidney function as a predominant thing so this is a pretty clear-cut case where the treatment needs to get started. I am very quick to move to new therapies when things start to rise. In some ways, the treatments we have available today are better than the treatments people started with in terms of the use of daratumumab if they haven't received it. The use of carfilzomib. The use of T [thymus]-cell engaging therapies. So, I very quickly switch gears and move on to the next thing. And in terms of this patient, I think just the fact they're relapsing so quickly is ominous. I think this patient's declaring themselves, despite their genetics being neutral, to be a high-risk patient.

Joseph Mikhael, MD: This is really helpful. I'm hearing lots of themes from you, which are all really important. I do think there is a general trend in the myeloma community, to be more aggressive at early relapse than we used to be in the sense that now we have better treatments. We don't necessarily just go back and give this person VRd again. Now we have new treatments and new options.

This leads us to our next polling question. which says: what regimen are you most likely to recommend for this patient with early relapse while on lenalidomide maintenance after VRd induction and transplant? So, they're relapsing 1 year afterward. Will you go to daratumumab plus carfilzomib and dexamethasone [DaraKd]? Will you go to isatuximab plus carfilzomib and dexamethasone [IsaKd]? Will you go to daratumumab/pomalidomide and dexamethasone [DPd]? Will you go to isatuximab/pomalidomide and dexamethasone [IsaPD]? Or option number 5, will you go to selinexor/bortezomib and dexamethasone [selinexorVd]? Or perhaps there is another option. I will show you some of the results of the data of the studies that are behind these 5 options, but let's first see what the audience thinks with respect to the next line of therapy. And then I'm going to ask our presenters here what they think.

As it's starting to come in, no surprise. There's quite a spread here. It looks like there's no 1 major winner, but we do have a little over half of the people going to daratumumab plus carfilzomib and dexamethasone. And another 25-30% saying isatuximab/carfilzomib and dexamethasone. So, there definitely seems to be an endorsement here of carfilzomib and a CD38 [cluster of differentiation 38] antibody, be it daratumumab or isatuximab. There are a few votes for DPd, very few, if any, for IsaPD, and just very few also for selinexorVd. And no one has chosen the other.

So the bottom line here, it looks like DaraKd is at the top of the chain but there's considerable support for IsaKd, which I'm going to suggest is not surprising. And I'll share with you now a little bit about what we have in our NCCN [National Comprehensive Cancer Network] guidelines.

Transcript edited for clarity.

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