How is smoldering multiple myeloma stratified?

How is smoldering multiple myeloma stratified?

Smoldering Myeloma was lumped into just one category where we knew people who had more than 10% plasma cells, but no myeloma defining events like renal failure, high calcium bone lesions or anemia. And they would fall into this category of sleeping myeloma or smoldering myeloma, which is not really causing damage to the body. And we knew that 10% of these patients each year would evolve into active disease. But now, as we're learning more about how myeloma behaves, we're identifying factors or variables that change this risk. And we can now divide that into more categories and identify out of all the people who have smoldering myeloma, which population is really at higher risk of transforming into smoldering into active myeloma? And which ones are going to behave more like an MGUS or just going to do their thing and not really cause any damage to the body.

And there's a lot of different groups that have done their own way of measuring this risk category and stratifying patients based on those criteria. But that poses a problem when it comes to doing clinical trials, because whenever we do a clinical trial, we can only study a specific therapy. And then when somebody else does a clinical trial with different criteria, it's hard to compare. And technically, it's hard to compare studies because we don't use the same patient population. There's a lot of variables in it. But even if you throw in even different criteria as to what's considered high risk, intermediate risk or low risk, then that just makes it so confusing.

Now we're trying to reach a consensus. Okay? These are the categories that we're going to use. These are the criteria that we're going to use. And IMWG came up with this category where there's three specific things that are easy to monitor, to simplify things that do have an impact, and the risk of it evolving to active myeloma, that is one than the how high your M spike is or the apparent protein, how high your light chains are, and the ratio of the affected light chains that are being produced by the myeloma cell compared to the unaffected light chain and also the amount of bone marrow involvement.

So that 2/20/20 is a simplified way of trying to categorize this where M spike greater than two bone marrow involvement of 20% or greater and a light chain ratio abnormality greater than 20 are the three points. Each one gains a point, and depending on how many points you have is whether you are low risk, intermediate risk or high risk, and then to incorporate mutations. Since we know that genes play a key role in how likely they are to evolve to active disease or how aggressive they're going to behave, we've added that as well.

And people who have translocation 4;14 or translocation 14;16 1q gain or deletion 13. Mutations that we've seen we can incorporate into this. So that adds a fourth point. And now we have low risk, intermediate low, intermediate and high risk. And there's a big difference because the low risk is just a 6% chance each year of transforming into active myeloma. While the high risk can vary between 44 and 60% chance of transforming to active myeloma in the course of two years.

So those are the ones that we need to be following more closely and need to be making sure that we're keeping a close eye on. And I think that by having this structure now, we can now do clinical trials in different parts of the world using this similar diagnostic criteria categories, categorizing these smoldering patients so that we can then make a lot of progress. And how we can prevent smoldering patients transforming into active myeloma, trying to nip it in the bud before it actually becomes an active problem.

Is the fourth criteria of mutations widely accepted or is only the 2/20/20 criteria used? So that's a thing that is in process that 2/20/20 is something that I think is gaining more traction. Incorporating the mutations is also gaining more traction. But that doesn't necessarily mean that everybody is using it and it's going to take some time. But I hope that this is going to be something that everybody's going to adopt. Now that IMWG is trying to support that.

Why do categories change? Is this a good or bad? I think the categories of myeloma, Smoldering Myeloma and MGUS are going to be changing for the next years to come. And it's been changing for the last year because it's a disease that we still have a lot of uncertainties about. We don't know a lot of things of how it behaves, why it behaves, what causes it.

And what we know now is much more than what we knew ten years ago. And we are still learning a lot and there's still a lot of uncertainties. So as we learn about the disease and how it behaves and what makes it behave that way, we have to adapt as we gain more knowledge is something that we have to incorporate to what we're doing so that we can use it to better things.

If we start with the same categories of what smoldering is and what myeloma is and not considering these new knowledge, then we're never going to evolve. We're never going to advance. So it's always important to be evolving. Yes, it's tricky because a lot of the times what we know now and the way we categorize things now might be very different in 20 years ago. So we can't go back and compare things, but we can stay stuck. We always have to continue to progress because that's going to help advance to the science.