What factors should be considered when stratifying a patient as high risk or standard risk?
There's a lot of different biologic features that determine risk. People who have disease outside the bone marrow presentation have a higher risk. Patients who present with kidney impairment that doesn't reverse have higher risk. Patients who do not respond to first line therapy have higher risk, and patients with disease that comes back within one year of starting therapy are at higher risk.
Having said all that about those clinical variables, in which age is included as a higher risk feature, most risk systems that physicians use in myeloma are biologically based. Those six biologic variables are beta-2 microglobulin, albumin, LDH, and the three genetic abnormalities Del(17p), 4;14, and 1q+. I think these are factors that each patient needs to understand if they want a more in-depth grasp of how physicians are perceiving their disease activity.
Risk stratification in myeloma means, can we determine who's going to do well with our treatments and who's not? There are usually different ways of doing it, but high risk and standard risk is one way. Back in the day, there was the ISS paper which used beta-2 microglobulin and albumin. That was the stage one, two, and three. Then that was reiterated with the addition of LDH and FISH, and that was also categorized as stages one through three. In JCO 2022, they incorporated chromosome one abnormalities, so now we have four different categories. These are the ways we classify them, and some people refer to risk in terms of these factors. Some refer specifically to genomic risk like cytogenetics/FISH, and some refer to clinical risk like extramedullary disease or plasma cell leukemia. Those are the different ways of looking at risk at baseline.
An important aspect of making a long-term plan for the management of multiple myeloma is to establish what we call a risk classification or stratification. What we mean by that is that we like to study the cells, the myeloma cells, and their biology, primarily their genetics, to see if they are a form or flavor of myeloma that turns out to be more aggressive. We have a number of markers we look for when we test the bone marrow for risk markers. These risk markers include some of the translocations: chromosomes 4;14, 14;16, 14;20. We also know abnormalities of chromosome one, particularly many extra copies of chromosome one, the long arm of chromosome one, or deletions of the short arm of chromosome one. These seem to be associated with more aggressive myeloma. Last but not least, and very important, are abnormalities of chromosome 17. There's a gene there called p53, known as the guardian of the genome. If that gene is gone, then the cells can mutate more. These are things that we look for very carefully as we perform risk stratification.
It is critically important for patients to know that being high risk is not a 100% determinant. What I mean by that is it doesn't say that if you're high risk, then chemotherapy is worthless. No, we can still have very good outcomes with high-risk disease, even without those markers. But you can still have very good outcomes. In fact, I can think of several patients of mine who had the high-risk markers, and now I think they are potentially cured because they are many years out without evidence of detectable disease. This should be a reminder to pay more attention and consider more intensive strategies, but it's not a 100% determinant of what will happen.
