Why does the list of chromosomal abnormalities that are consider high risk change or evolve over time?

In a previous HealthTree University lesson, we explored the latest list of chromosomal and gene abnormalities classified as high risk biomarkers. But did you know this list isn't set in stone? In this lesson, we'll uncover why these genetic abnormalities change over time. What drives these updates, how new research reshapes our understanding, and what it means for myeloma treatment and risk assessment. 

Why does the list of chromosomal abnormalities that are considered high-risk change or evolve over time?

Our definition of what high risk is has evolved over time. Way back when we used to look at, honestly mostly like, patient factors. We would, you know, it was and it was really based on, like, how aggressively the disease was already behaving at the time of diagnosis because most patients 30, 40 years ago weren't diagnosed in an asymptomatic state. They were already diagnosed when they had symptoms. Right. And so, you know, if they were more, if they had more severe anemia, if they had more severe kidney dysfunction, if they had terrible skeletal disease, those things imparted prognosis, you know, then, and then we recognize other things like, actually the Mayo group was very fundamental in this. We recognized that disease characteristics by cell biology characteristics, markers that reflected like increased cell turnover and aggressiveness. So like that, that would predict tumor growth. They could measure some things like that. And our original ISS staging system, was based on those things. So like beta-2 microglobulin. Later we included LDH which is a marker of cell turnover also. Mayo Clinic had a proliferation index that they would look at, which we know other centers weren't using, but it measured sort of the same idea.

After that, it was recognized that even within each prognostic group that we thought we understood pretty well, if certain chromosomal changes were present or absent, it affected prognosis. And so the revised ISS staging system incorporated cytogenetic changes measured by FISH testing. And so there were three high risk cytogenetic features: if you had deletions 17, if you had translocations between chromosomes four and 14, or 14 and 16, if those are present, that upstaged you. And so the highest risk, revised ISS stage three, incorporated those findings.

Moving forward, our current iteration of the revised ISS staging system, a second version of it. Now, we've recognized, and this might be I think, one of the more important realizations that we've had as a myeloma community, is that these risk factors stack on each other. So now we have this point-based system where if you have two high risk set of genetic features, it's worse than if you have one, and that's worse than if you have none. And so based on this point system, we've actually gotten better at discerning not just the very best risk and the very worst risk, but in the middle, we're teasing it apart into sort of like a low intermediate and high intermediate. So we're getting more refined.

And I think what we're hearing about now, in presentations and in papers, we're thinking about myeloma as double hit and triple hit, and that refers to the number of high risk set of genetic features. The reason why these things are in flux is that what is prognostic for outcome is dependent on what treatment is available. As treatment improves and begins to neutralize the bad effect of certain abnormalities, whether that's genetics or high LDH or extra medullary disease or plasma cell leukemia, what is prognostic significance is going to change. So it should be expected over time that there will be fluidity in what is a high risk abnormality as treatment continues to improve.

So as an example, if we could cure myeloma then there would be no high risk abnormalities at all because everyone would be cured. And it's completely irrelevant what's prognostic. Unfortunately we're not at that point. And so we identify high risk abnormalities. But it's important to keep in mind that different high risk abnormalities depend on the available therapies that you're receiving.

Our technology has also been in flux in terms of identifying high risk abnormalities. When we first addressed the treatment of patients with multiple myeloma, we used metaphase cytogenetics. And we focused on deletion 13. And deletion 13 was thought to be a significant high risk abnormality. As we introduced new agents into the treatment of multiple myeloma and moved from metaphase cytogenetics to FISH, deletion 13 by FISH became completely unimportant. And so we still find loss of chromosome 13 by FISH, but it carries no prognostic significance at all. And that's likely because now we're identifying other abnormalities that are probably more important. But also because of the introduction of new agents such as bortezomib and lenalidomide, that have neutralized the adverse impact of the genetic abnormality.

And unfortunately right now when you look at most trials, the high risk abnormalities are profoundly prognostic in terms of how long you will go without myeloma being out of control. But it hasn't been very good at directing treatment. When you look at the way patients are being treated, they're being treated in a certain way, oftentimes without much input on high risk. Where high risk is actually being used in the clinic is in the determination of maintenance treatment. It's very common in many academic medical centers that for standard risk myeloma, we're using one medicine for maintenance, but now with high risk, there's a movement, although it hasn't been fully validated by multiple studies, to use two agents for maintenance therapy.

We often, and I get into this debate with some of my colleagues about defining high risk disease. I had a very good debate with a colleague who said, you know, Brian, even though you have better genetic characteristics, high risk disease was high risk disease ten years ago. It's the same high risk disease today. It's still high risk. And my argument against that was it's only high risk because you haven't found the right drug to treat that particular population of cells.

As an example, 15 or 20 years ago, if a patient had a deletion of chromosome 13, it was considered a very high risk marker. That is, there tended to be poor outcome in people that had that genetic characteristic of having either a portion or an entire missing chromosome 13. When the proteasome inhibitors came along—velcade, carfilzomib, ixazomib—all of those proteasome inhibitors ended up being reasonably effective even in the patients with chromosome 13 deletion. So the chromosome 13 deletion, as a definition of high risk disease, was only high risk prior to the advent of proteasome inhibitors that now were pretty effective in treating those high risk diseases.

So now, as we continue to start analyzing markers of high risk disease, I think that some of the new therapies that are going to come along and that are currently being tested are going to start chipping away. You're going to say, you know, that genetic characteristic was high risk, but now this particular drug is now reasonably effective in treating that. And the ultimate goal would be to chip away at high risk so that all of the high risk now becomes standard risk. All of the standard risk starts becoming low risk and treatable.

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You can watch the other basic genetics and cancerb tumor biology lessons by clicking the link in the description.