What is plasma cell percentage? Why is it useful to have this information?

Plasma cells are found in your bone marrow. They are a type of white blood cell which produces antibodies that fight disease and infection in your body. Myeloma is a cancer of plasma cells. When these plasma cells become myeloma cells, they prevent the normal production of antibodies, which leaves your body's immune system weakened and more susceptible to infection.

What is plasma cell percentage?

Plasma cell percentage is a very important number in multiple myeloma. I would say multiple myeloma itself is kind of a number game. Plasma cells normally present in the bone marrow. And the normal amount of plasma cells in the bone marrow is less than 1%. They have an important function. They serve as an immune system. They help us to create immunoglobulins. And this is that monoclonal protein, that we see in the blood or urine if and when patients have myeloma or precursors of myeloma. Why the plasma cell percentage is very important is because this is how we define the disease itself. Anything is more than 1% that less than 10% is considered to be an MGUS, monoclonal gammopathy of uncertain clinical significance, and anything above 10% would be considered either smoldering or active multiple myeloma. The way, how we determine the plasma cell percentage is we look at the bone marrow in very rare circumstances, if someone has an aggressive disease, we could see the plasma cells floating around in peripheral blood. And that's always bad. Right. But, mostly we would do the bone marrow biopsy and there are several tests that we do at the bone marrow. First of all, look at the morphology. We just do the sample, we spread and do this slide, stained it and looked under the microscope. And then we can calculate the percentage of this plasma cells in comparison with the rest of the nucleated cells and calculate that percentage. And like I said it should be in the normal circumstances. It should be less than 1% of non clonal plasma cells. After that we use a study called immunohistochemistry or flow cytometry. Then we can particularly stain them for the certain proteins in the cell surface, CD138 CD56. And those proteins allow us to differentiate the plasma cells, especially clonal plasma cells, from the rest of the nucleated cells in the bone marrow. Those are the two most important studies that we would use for the differentiation of the plasma cell percentages. We use additional study from the bone marrow, but they are more related to, the FISH studies, fluorescent in situ hybridization or next gen sequencing, but those are used more for the genetics, not that for the plasma cell percentage identification. The plasma cell percentage, you know, our bone marrow when you do a biopsy and you look at it, there's a liquid part and a solid part. You can determine, you can try and estimate the plasma cell percentage either way, the most accurate way actually is looking at the solid part, the the slices you make slices of the biopsy and stain it. You're looking at the soft part in the middle of the. That's what you're sampling, the soft part in the middle of the bone. And everybody's bone marrow is made up of, some cells and some fat. And, I, I remember being taught the 50:50 rule. It's actually the 50-50-50 rule. When you're about 50, your bone marrow is about 50% cells and about 50% fat. Everything else in our bodies, as we get older, the percentage of fat, tends to tends to go up over time. So older patients may have less cellularity in their bone marrow, a relatively larger percentage of fat in the bone marrow. When you're counting the percentage of plasma cells, you're looking at the cellular component only, and you're estimating, okay, of of the cells in the bone marrow that we're counting what percentage of the, of our plasma cells. It's a very manual thing. You stain them with markers, some of the same markers that we would that we actually use as targets, like CD38 or CD138, you can do stains of the cell of the marrow, and then you can count the cells that stain positive. And those are the plasma cells. You can also do sort of fancier sorting with a test called flow cytometry on the liquid part that you pull out at the same time. But the problem is that that sample sometimes gets diluted by just blood. And so what you're measuring isn't necessarily all bone marrow on the on the liquid part. So flow cytometry, even though it is a more precise way of sorting cells, it may underestimate the percentage of plasma cells due to the artifact of the, you know, from from how the samples collected.

When you talk about plasma cells, are we talking about malignant plasma cells?

First, everybody has plasma cells in their marrow. And so a normal number of plasma cells is 1 to 2%. And, traditionally we consider anything up to 5% to be normal as long as they're not clonal plasma cells. You can determine the clonality of plasma cells by looking at the, light chains on the immunoglobulins, the, the antibody proteins that they produce. You can also deduce that they're clonal based on the presence or absence of these FISH findings. There's chromosomal abnormalities that we were talking about before. So if if there's no evidence of colonality, anything up to 5% could be considered normal. If there is coloniality in the bone area, if there is an abnormal population of plasma cells, then you have a plasma cell this greater. But if it's in that low range, if it's still in the 1 or 2 or 5% range, even all the way up to 10%, we call that monoclonal gammapothy of uncertain significance or MGUS. As long as a patient doesn't have symptoms, they don't have the like the bone or kidney or blood count symptoms of multiple myeloma. There are some patients whose bone marrow plasma cell percentage actually has increased to being north of 10%. We say 10% is a cutoff for myeloma. But if you don't have symptoms, people in that range we call smoldering myeloma. Those patients are definitely at increased risk for developing symptoms in the future compared to MGUS patients. But you still don't necessarily treat them just because they hit some arbitrary 10%. Nothing magic happens at 10%. And, the guidance on using that 10% cutoff, it is intended to be a soft number if you have 8% plasma cells, 6% plasma cells, but bone lesions or cast nephropathy, injuring your kidneys, you have myeloma. Even if you don't have 10% plasma cells. Likewise, as I just said, I mean, you could have 20% plasma cells or 25% plasma cells. And if you have no symptoms, you don't have treatment requiring myeloma. You have smoldering myeloma.

Is having a higher amount of plasma cells necessarily a worse prognosis? Is the location of plasma cell prognostic?

The percentage of plasma cells does not necessarily reflect how those plasma cells are going to respond to therapy that, that has to do with sort of, molecular, abnormality is, you know, within them, within the plasma cell the plasma cell biology more than the plasma cell number. When multiple myeloma is no longer confined to the bone marrow, and you start to see those plasma cells spilling over into the blood, plasma cell leukemia would be the term for that. It when it's a lot of plasma cells or when it, found in other organs, if you have tissue masses that aren't arising, you know, from bone directly but are actually like in organs, I mean, if you have, a tumor of plasma cells in your liver when you're first diagnosed, store in the lining of your lung or something like that. That's called extra medullary myeloma. And having extra medullary myeloma or circulating plasma cells in your peripheral blood. That's those are high risk features. And we didn't talk about those when we were talking about risk. But if you have those. That is high risk disease. And the one of the hardest, things about making progress in those situations is, for instance, patients with plasma cell leukemia routinely excluded from myeloma trials. It's it's there's they're not part of those trials at all. And so instead of having them be a subset of huge trials exploring, important new therapies and combinations, but we end up getting our a bunch of very small trials, and we're lucky if we can explore those same combinations in those patients. So it's a it's an example of a patient subset who is like most in need of new treatments, who, who, who are routinely excluded from trials. It's, something where we really have to address as a field.

How often should plasma cell percentage be measured?

So we do test at the diagnosis. So we do test if we need to make the diagnosis, if we, if we are suspecting someone have a plasma cells is crazier, regardless if it's active myeloma, smoldering multiple myeloma, or, precursors with MGUS. So, we could do that if we are strongly suspecting that we have a high risk disease. If someone, is relapsing, you know, if we're really suspecting unusual relapse or someone is relapsing in a little bit unusual way would bony lesions, but no presence of the protein in a, in the, blood or the urine. So we often test that if patients are going through the stem cell transplant, we prefer to test that it's not mandatory, but we prefer to test it just so we know the baseline. How much of the disease was cleared up with induction therapy before we transplanting the patient and use that more as an addition or new baseline, we also are able to obtain that important information with next gen sequencing or evaluate for the presence of the minimal residual disease, which would be more of a genetic study. And that is, something that we also are able to yield, from the bone marrow.

Why is plasma cell percentage measured?

So measuring plasma cells in the bone marrow is important to get the diagnosis correct. So less than 10% mgus more than 10% myeloma. If there is no end organ damage. Then it's smoldering myeloma. If there is end organ damage myeloma that requires treatment. The chances of requiring treatment increase as the number of plasma cells increase. And there's a move afoot to change the definition from 10 to 20%. So it is important, I would argue strongly that you should use the plasma cells as well as the M spike to monitor the disease. And my practice would be to do imaging and the bone marrow annually to check how people are doing, because then it's very good. If you have no abnormalities on the imaging, you don't have anything positive with MRD testing. You're looking very good for the next year and you can relax and forget about your myeloma to a certain extent.

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