How is multiple myeloma staged? What is the Revised International Staging System (R-ISS)?

How is myeloma staged? What is the Revised International Staging System?

Great question. Once we establish the diagnosis of any cancer, the next task is to determine the extent of the disease and what's the disease burden. The best way to determine that in a reproducible way is to assess the speed of the disease. For that, myeloma specialists and the International Myeloma Working Group have developed the international staging system.

A quick note about why myeloma is staged the way it is: in cases of solid tumors, like breast cancer, staging is done based on the size of the tumor. But in myeloma, since it affects the whole body, you can't stage that way. Myeloma is a complicated disease, which is why it's been difficult to create a staging system that applies to all myeloma patients.

The original myeloma staging system took into account albumin and beta-2 microglobulin. The newest version, the Revised International Staging System (ISS), includes another blood marker, LDH, and considers the high-risk genetics of the disease. As we learn more about myeloma, the staging may continue to evolve.

The original international staging system was based on data from clinical trials and observations and showed that two factors—beta-2 microglobulin and serum albumin—determine the stage of the disease. High beta-2 microglobulin or low albumin indicates a more advanced stage.

For example, a patient is classified as ISS stage one when their beta-2 microglobulin level is less than 3.5 or their serum albumin is 3.5 or higher. ISS stage three is characterized by a very high beta-2 microglobulin level of more than 5.5.

And in between was ISS stage two, but then, we and others learned that there are additional factors like LDH, level of protein, that we all have in our blood, but it can go up in certain cancers, including multiple myeloma. So people started taking into consideration LDH level. Another important factor is cytogenetics. Those chromosomal abnormalities.

So the revised ISS staging system, international staging system, took into consideration and took into account not just beta-2 microglobulin and albumin, but also, chromosomal abnormalities on FISH studies, as well as LDH level.

So in very simple terms, in revised ISS, stage one is what was the old ISS stage one, that is low beta-2 microglobulin and normal to high albumin. But with that, these patients should also have normal LDH and they should not have any high-risk chromosomal abnormalities.

And there are three of those that are incorporated in the revised ISS staging system: deletion 17p, which we all know is a high-risk abnormality, translocation 4;14 and translocation 14;16. So patients should not have either of these three and should have normal LDH in addition to the old ISS stage one.

On the other hand, ISS stage three patients would have or revised ISS stage three patients would have the old ISS stage three plus either a high LDH level. And then each institution has its own upper limit of normal. And if it is above that limit, it is high LDH. And that would put patient in revised ISS stage three or and or patient at one of those three chromosomal abnormalities on FISH studies that I outlined: deletion 17p, translocation 4;14, or translocation 14;16.

And then of course, those who do not follow either a revised ISS stage one or revised ISS stage three are revised ISS stage two.