High-risk multiple myeloma (MM) is defined by genetic abnormalities and clinical features that are associated with inferior outcomes. While risk stratification helps guide treatment decisions, these classifications remain an approximation rather than a definitive predictor of prognosis.

When we talk about MM—assuming the decision has been made that this patient has active disease and needs treatment—it is important to use a risk stratification approach because, historically, we know that patients with high-risk disease have had a greater likelihood of experiencing inferior outcomes. However, the difference in outcomes (ie, the percentage of patients who respond to treatment) is not as apparent today given that many treatments for MM are so effective. Where you see a significant difference is in the durability of response.

There are many ways to think about high-risk disease. The classic approach is to look at genetic markers that include chromosome translocations (namely t[4;14] and t[14;16]), chromosome 17 abnormalities at the locus of TP53, and/or other secondary changes such as chromosome 1 abnormalities. New classification recommendations from the International Myeloma Society (IMS) and the International Myeloma Working Group (IMWG) propose identifying high-risk MM by the presence of at least 1 of the following abnormalities: a chromosome 17 deletion (with a >20% clonal fraction) and/or TP53 mutation; an IgH translocation (ie, t[4;14], t[14;16], or t[14;20]), along with chromosome 1 abnormalities (ie, 1q+ and/or del[1p32]); the monoallelic deletion of the short arm of chromosome 1 (ie, del[1p32]), along with another chromosome 1 abnormality (ie, biallelic del[1p32] or 1q+); or elevated levels of β2 microglobulin (ie, >5.5 mg/L). These patients also need to have normal creatinine levels because abnormal renal function will also elevate the β2 microglobulin.

Features such as age and comorbidities can also contribute to adverse outcomes and have been incorporated into what we call “functional high risk.” These are patients with MM who respond initially—sometimes achieving very deep responses—but then experience a very early relapse, usually within 1 or 2 years after the completion of therapy.

I think that risk classifications will continue to be used to approximate patient outcomes, but it is important to recognize that risk classification is not 100% deterministic. We may see patients who fit these high-risk criteria yet still achieve very good outcomes; then there are other patients who have favorable profiles but begin to show features of functional high risk.

As we think about these risk factors, people have asked, “Well, you are describing a series of variables, but what happens if a patient with MM exhibits more than one?” And that has led to the use of the term “ultra-high risk.” There is less consensus here, but the idea is that, as patients acquire additional genetic or clinical factors, they may be classified as ultra-high risk. A simple way to define this is when a patient has 2 or more high-risk factors, reflecting the cumulative effect of negative prognostic features.

There is an infinite number of permutations of how you can start aggregating negative factors to define who might be an ultra-high-risk patient. Being high risk or ultra-high risk does not preclude patients from having a favorable long-term outcome, it is just that it is less likely. The best way to provide optimal results for these patients is with the attainment of sustained repeated measurements of measurable residual disease negativity.