What is the goal of risk stratification in smoldering myeloma? What is the IMWG risk model for SMM? In addition to the variables used to calculate risk in the IMWG model, other factors might be considered when stratifying for HRSMM?

What is risk stratification and smoldering multiple myeloma? What is the goal of risk stratification?

So risk stratification is important particularly when we're thinking about how frequently to follow patients, whether we follow a patient every three months, every six months, every year, how closely to watch them, as well as whether or not we should be thinking about clinical trials for a patient. If a patient is likely to progress to overt multiple myeloma, why wait until they have fractures in their bones and organ damage to treat? And so the existing risk stratification models allow us to better follow patients and manage and provide appropriate care to those who are most likely. Those would benefit most.

It's basically defined by the absence of other things. And that makes it very tricky. Smoldering myeloma is not active myeloma. Smoldering myeloma is not MGUS. And so you have this vast universe of different patients. And every patient diagnosed with smoldering myeloma is different. And it's tricky because we say that some of those patients diagnosed with smoldering myeloma, those cells are capable of chewing into the bone. They are active myeloma right now. We just don't know that they're active myeloma, if that makes sense. Other patients with smoldering myeloma are more like MGUS. These cells are there like a skin mole. They're just growing a little bit more than they should, but inside their DNA, they don't have what it takes to chew into the bones. And I'm happy for that.

So those patients will have a little bit more cells, and I would like to see them more than you see in MGUS, but they stay that way for years and years and don't have any issues. And it's hard because the goal would be for the patient that I initially mentioned, where those cells are capable of chewing. It just hasn't started yet. That's basically active myeloma that's on its way up. I want to intervene on those patients early. For these patients who are going to have basically almost like MGUS for years and years and years, just a few more cells, and you would expect to see what MGUS, those patients, I do not want to intervene.

Because drugs, while they're good for active myeloma, do have side effects. And so we try to identify who are the patients where they're more in this category, where again, the cells are starting to blast off. We just haven't been able to see them in the CT scan or MRIs yet, or any sort of kidney damage, versus here where these patients are quite stable.

How is risk stratification done?

So there are several risk criteria that can be used. They're not perfect. I will openly acknowledge that that is one of the biggest unmet needs of smoldering myeloma. The most common one that you'll hear physicians talk about is something called 20/2/20 or 20/2/20 HR or high risk, or the Mayo criteria. And the idea is that the more of these four factors that someone has, the higher the risk we think of them going from smoldering myeloma to active myeloma, the 20/2/20 HR.

So 20, 20% plasma cells. So if we do a bone marrow biopsy and over 20% of the cells are the smoldering myeloma cells, that's not active myeloma, but that makes me a little bit more concerned that there's less room to negotiate here because it's already 20%. Now, if it does go up to 60%, now we're talking active myeloma, or there may be a spot growing in the bone before then. 20, 2, the two is an m-spike of two or higher. The 20/2/20, 20 would be if the Kappa/lambda ratio is 20 or more in either direction. Again, if it's 100 to more in either direction at diagnosis, that is active myeloma, if it starts to 20 and then becomes 46 to 80, 100 over time, that's actually more controversial. But if it starts at 20 over one year for this patient, maybe a slightly higher risk of having renal issues down the line because they already have such a big mismatch. Kappa is much higher than the lambda, or lambda much higher than the kappa for the free light chains.

So 20/2/20 HR would be high risk. So if they have, you know, everyone with myeloma, the patient's cells are fine. These smoldering myeloma cells by definition have some genomic derangements. That's why they're growing because something is wrong with their DNA. There are certain factors both in smoldering myeloma and active myeloma, that we know make the cells grow more quickly and more aggressively and a bit more resistant to treatment. And those are typically called HRCA, high risk set of genetic abnormalities.

So abnormalities with the DNA or more particularly with the chromosomes, the big pieces of DNA. So if someone has one of those, for example, deletion 17p or t(14;16) or even amplification of 1q, again, these are terms referring to the chromosomes of the smoldering myeloma cells at the excellently high risk. And so basically there are calculators we can do based on 20/2/20 HR. The more of those features that any particular patient's multiple myeloma cells have, the more high risk they're considered. Typically two or more of those I would consider to be high risk.

There are other stratification tools that are out there. The Dana Farber group in Boston has a dynamic score that they look at, that looks at over time what's going on. One group in Spain has talked about looking at circulating tumor cells. You actually can see if you look very carefully with our best technology, you can see small levels of these smoldering cells in the blood that kind of push up from the bone marrow into the blood and come back. The more of those, the more high risk those patients are.

So in terms of how you define high risk, it's controversial. Again, I tend to use 20/2/20 HR. This video is being filmed in July 2024. Depending on when you hear this, that might be irrelevant because it's always changing, and I'm glad that it's changing. And so again, two or more of those four as of right now, I would consider to be high risk, and I would talk to the patient about various strategies for them that in some cases do include treating them.

What is the Pangea Model? The Pangea model is a new risk stratification model that we developed to see if we can improve upon these existing stratification models. Like the 20/2/20 model. The Pangea was a large international initiative that pooled data from as many patients as we could identify with a precursor condition to multiple myeloma that had serial data, so had multiple data from multiple visits over time. What we did is by leveraging that, we saw if we could improve upon the existing models by not only looking at a snapshot of a patient's information in time, which we do in the 20/2/20 model, but we also leverage an individual's trajectory.

The other important feature of Pangea is we wanted to ask the question of, can we accurately predict an individual's risk of progression without the need for a bone marrow biopsy? Many patients don't have that and are not enthusiastic about getting one or getting one with any degree of regularity. And what we found is that indeed, we can improve upon our risk stratification algorithms, particularly when we include as much information as possible about a patient. We include serial data collected over time. And secondly, we can do a pretty good job about predicting risk even without a bone marrow biopsy.

So given the opportunity to enhance an individual's personalized risk of progression to overt multiple myeloma, it was really important for us to make the model available to any patient or clinician who is interested. And so anyone can go to pangeamodels.org, where we have a free online calculator available to the general public so that patients can use that to enter their own information to understand their risk of progression.