Docwire News spoke with Thomas G. Martin, MD, Professor of Medicine and Associate Director of the Myeloma Program at the University of California, San Francisco, about how high-risk multiple myeloma is identified, and how this classification has changed over time.

Docwire News: How is high-risk MM defined and identified? 

Dr. Martin: High-risk myeloma has, I’d say, undergone some variability in definitions over the last five to 10 years. I think most of us are now coming to a more uniform definition. The International Myeloma Working Group (IMWG) came up with a position paper a few years ago that defined “high-risk” based on FISH abnormalities from the bone marrow biopsy examination. And the FISH (fluorescence in situ hybridization) results that were associated with high-risk disease were the translocation 4;14, deletion 17 or 17p, the translocation 14;16, translocation 14;20, non hyperdiploidy and 1q gain. And all those abnormalities were identified to confer the worst prognosis overall. And if you take all of those abnormalities, that would define about 20% to maybe as high as 30% of patients with multiple myeloma.

Now there’s also been a variety of staging systems, but the revised International Staging System (ISS) actually tries to group patients into risk. And I think a lot of us have gravitated towards the revised ISS stage three group as really being the highest risk patient group. And that’s defined actually, as patients who are ISS stage three, so they have to have a beta two microglobulin that’s greater than 5.5, and they have to have either an elevated lactate dehydrogenase (LDH), or they have to have a translocation 4;14, 14;16, or a 17p deletion. So if you’d take the revised ISS stage three, we actually can narrow it down to about 6–10% of patients.

We, like the Lymphoma Group, have also come up with some other definitions. We now describe a double hit myeloma. It was actually initially described by the Arkansas Myeloma Group, and they described it as two groups of patients. Patients who had a 17p deletion and then on the other allele, the non-deleted allele would have a mutation in the p53 gene, and that was considered a double hit. So two 17 hits per se. And then the other double hit they described was basically if they had revised ISS stage three disease, and they had a 1q gain, that was their other double hit. And those patients, they showed survival curves over time for treatment at Arkansas, which a lot was total therapy. They didn’t do so well. The Mayo Clinic, in their smart definition has offered a different definition of double hit. And that is just to have two of these high risk abnormalities, which makes it a little easier, because we don’t really do sequencing of the allele that’s not deleted in patients that have the 17p deletion.

One controversy also has been what level of 17p deletion is really important? Because you’ll get it back FISH and it’ll say, “This has been found in 5% of the plasma cells examined.” And is that really a 17p deletion? Is that really a high-risk? And some people think it has to be more than 20%, but it goes up to as many as 60%. Some have defined it as more than 60% of the cells have to have the 17p deletion. So there still is a little controversy on that ground. But that in general is how we’ve defined kind of the novel high-risk or the new day high-risk definition.