NDMM Risk-Stratification and Other Factors Informing Treatment Selection


Defining transplant eligibility, explaining the role of transplant in NDMM, and differentiating between high- and low-risk MM.

Dr. Sagar Lonial: So, we've had a lot of discussions here around box one. We haven't really talked a lot about box two. I think, we as a group tend to believe that the transplant offers significant benefit. I would argue, in many ways, that who is transplantable is in the eye of the beholder, and oftentimes, what we know from national data is that about 50% of patients who potentially could be transplant eligible don't even get referred to a transplant site to make that decision. So, Dr. Kaufman, how do you think about yes or no for a transplant in a patient who presents?

Dr. Jonathan L. Kaufman: So, the three things that we look at in consideration of transplant eligibility are age, performance status, and comorbidities. And the reality is that, of those three ages, the least important- And my approach is that most patients who are able to walk into my clinic, who are 75 and younger, are potentially transplant candidates, I would say, and most patients who are over 75 or probably never going to be transplant candidates- Now, when I say- Most, there's a handful of patients over 75 that are clear transplant candidates. So, age is probably the least important of these factors. We think about performance status. When I first meet a patient, they're newly diagnosed myeloma, if they're very sick from myeloma, that's not the performance status I'm thinking about. I'm thinking about what they were six months before diagnosis. Are they active? And we anticipate with our induction therapies that a patient who's sick for myeloma is going to get better and get back in this setting of induction therapy to that performance status. And the third is comorbidities, and for the most part, patients even on dialysis can have autologous transplant, but the comorbidities that prevent people from moving forward with transplant are severe lung disease, heart disease or liver disease.

Dr. Sagar Lonial: And I think the question of what could you do six months or 12 months ago - I go back as far as 12 months ago - that's an easy question to ask, and it's a lot quicker than any frailty index that I know of to assess whether or not a patient can get through. So, actually, I use that question as well. So, Dr. Nooka, let me ask you, we've talked a lot about risk and how we manage risk, how do you define risk? I feel like George Costanza in a Seinfeld episode. And then how do you adjust treatment based on that?

Dr. Ajay Nooka: So, we, typically we use the cytogenetic based risk for stratification. So, asking for in the initial matter or at the time of the diagnosis, do they have a translocation of 4;14, 14;16, 14;20 and deletion 17P. And even in the relapse setting, we are not there yet, but did anybody acquire these abnormalities to gain that risk of the high risk? So, there is one other entity where there's a circulating plasma cells of greater than 5%. In the past it used to be more than 20%. So, to call this a primary plasmas cell leukemia. So, the revised IMWG criteria shows that greater than 5% is good enough to have the bad prognostication. So, we typically use those patients to use the cytogenetic abnormalities to risk stratify them as high risk. So just like have we talked about the boxes in box number three, most of the change happens where these are the patients where, just like how you said before, you cannot let them relapse. If they relapse, the time from the relapse to their death is very, very short. So, the only way to prevent the high risk patients dying and let the high risk patients live the longest possible, is to prevent that relapse. And that's what we are achieving with the combination treatment.

Dr. Sagar Lonial: So, I want to ask you for one slight modification, and we may agree or disagree on this one. So, you mentioned FISH analysis. A lot of groups are switching to sequencing as a potential modality. Do you see a role, any of you guys can answer this, a role for sequencing for 17P mutations, even if they don't have 17P deletion? So P53 mutations?

Dr. Jonathan L. Kauffman: I'll take that. The more you look at the data and the more you take care of patients, you see some high risk patients that they look like high risk, and they do very, very well. And then you see patients that for everything that we're studying, they're standard risk patients and they do poorly, they relapse within a year from transplant. And so, we're clearly not capturing all of the data on both sides. And so, whether it's next-gen sequencing as the technology that helps us or whatever technology, but I think we're behind in optimal risk stratification.

Dr. Sagar Lonial: But most of us probably have access. Most of our audience probably sees leukemia patients at diagnosis and sends out an NGS panel for looking for P53 mutations. I think we as a group are doing that now in addition to our FISH panel to either inform future therapy or know whether they've got a P53 mutation early on. So, Dr. Joseph, we've talked about induction, we've talked about transplant. How do you know that a patient has had a good enough response that they can go on to box number two?

Dr. Nisha Joseph: So, in general, though we're looking for depth of response, a real cutoff to moving forward with transplant for me is a PR, meaning 50% reduction. If we can get to a PR, I move on to transplant and we've looked, other groups have looked at, is it worth giving more therapy and try to get a deeper response if it doesn't really affect outcomes on the back end and you risk losing the response that you've already achieved? So, for me, it's PR. And then for those patients who aren't achieving or achieving a suboptimal response, is thinking strategically about the maintenance strategy, what you're going to do on the back end to then get a deeper response post-transplant.

Dr. Sagar Lonial: And so, I think one other question that often comes up is when you come to our program, you see one of us, are you getting one of us or are you getting all of us? And I think that's an important question. And so, if you guys want to talk through how do we as a group sort of manage these difficult cases, cases that may seem obvious but one of the other ones of us says, no, I've seen this, it looks like this or that. How do we work that as a group?

Dr. Nisha Joseph: Well, I think one thing I'm certainly very fortunate, if you can tell I'm much younger than everyone up here is and have less- I can benefit from your clinical experience is we practice as a group. And so, we tend to practice the same. I can answer some of these questions that you're answering cause we tend to approach myeloma the same way and then we meet weekly and even sometimes more than once a week to talk through these difficult cases, which I think is really helpful. So, though you're seeing one of us, you're likely to be receiving the exact same therapy you'd be receiving if you saw a different one of us in the group, which I think is helpful.

Dr. Jonathan L. Kauffman: I think the other thing that we do is about every six months, we take a look at what the world data says, and we ask the question, should we make a modification? For years, we were using RVD as our triplet post-transplant maintenance. And a large part based on forte, we really switched to KRD. There's a variety of reasons, but that's at least one of the reasons that in a data sub supported way, switches a practice. Now the reality is, is that we debate all the time about what's optimal. But one of the benefits of being in a group is once we've decided our overall strategy, we're all able to implement it.

Dr. Ajay Nooka: I think that the beauty about this homogenous practice, even though we debate, we come to a conclusion, we come to an agreement. Most times, we agree. And then we practice similarly, that allows us for a homogeneous practice and say, when we have these hundreds of patients treated the same way, what are the optimal outcomes that we see? And we compare with the standard of care. If we're doing anything lesser, which never happened, but if we're doing anything lesser, we are ready to change. But if we're doing better than the perceived optimal induction at the time, we want to continue and provide the data to prove that this is the most optimal treatment that will help us to design futuristic clinical trials.

Dr. Jonathan L. Kauffman: And I think that the standard treatment and analysis of our data, I think we'll come up especially with the Dara pom-dex story in the relapse setting that we have some very nice data on. And it's really quite frankly informed our practice. And we wouldn't have had that if we didn't have the standard practice with the uniform data collection.

Dr. Sagar Lonial: And I guess just to wrap this one up. I think when we think about if each of us has seen 1,000 myeloma patients, when we get together and discuss the cases on a weekly basis, you get the collective wisdom of 4,000 myeloma patients, which gives us the opportunity to really each weigh in on how to manage a given case. And that's really, I think, a major strength.

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