BETA - How is mass spectrometry being used to monitor myeloma response? What is MASS-FIX?

Mass spectrometry might sound complex, but it's actually a super smart tool scientists use to figure out what's in a sample. Like, how much of a certain chemical or protein is there? It's used in all kinds of areas, from checking for toxins in food to solving crimes. At the Mayo Clinic, a researcher used this powerful technology to measure the myeloma protein in the blood, helping doctors see how well treatment is working. In this HealthTree University video, you'll learn how this tool works, why it's so sensitive, and how it's helping in the fight against myeloma. How is mass spectrometry being used to monitor myeloma response? So traditionally, the different myeloma proteins in the blood were detected using a method called serum protein electrophoresis, where the proteins were separated based on their electrical charge. And this allowed us to look at them very coarsely. Then we had antibody-based techniques, like serum immunofixation, which allowed us to tell which protein was abnormal, and even light chain-based techniques, which would tell us if the free kappa or free lambda were involved in the serum of the patients that were diagnosed. Over time, the technology has developed where we can use mass spectrometry, which uses the weight or the mass of the protein to very accurately detect myeloma proteins. And in fact, we can now detect them, quantify them, and even discriminate them from therapeutic antibodies that patients are receiving, which was very difficult until a few years ago. So this technology called mass spectrometry comes in several flavors, but is readily performed on the patient's peripheral blood and can tell us not only what type of abnormal protein might be there, but it also allows us to discriminate it from other antibodies the patient may be For example, some patients getting diuretumumab, it can actually discriminate, is the protein banned from diuretumumab, or is this the patient's actual disease? So these sorts of situations are very important. Not only that, it is 10 times more sensitive than the antibody-based methods like serum immunofixation. So in patients that have a negative serum immunofixation, they can sometimes still pick up disease by the mass spec method, and therefore it is more sensitive. In fact, some institutions have completely shifted over to using just mass spec instead of serum immunofixation electrophoresis, and we use a combination of the two at the moment. The primary method which multiple myeloma has been monitored is the use of the serum protein electrophoresis. This is a technique that separates all of your blood proteins based on their electrical charge. The myeloma proteins all have the same electrical charge, so when they're separated out, they're all separated to one area and it results in the so-called peak or spike. The technology of separating proteins by charge was first developed 90 years ago, so the technology is extremely old. But it's not the only way to separate proteins. Proteins can be separated based on their weight, and again myeloma proteins all weigh the same because they're all produced by a single cell, a specific myeloma population, what we call a clone, but it's the myeloma cancer cell. They all make the same protein, they have the same weight, and so if you separate them by weight, it's another way of identifying the protein. Mass spectrometry actually is a technique that separates proteins by their mass or weight. The really interesting thing about it is that it's more than 10 times more sensitive than electrophoresis. For those of you who monitor your proteins, you know that a protein can be 1 gram or 2 grams or 0.5 grams, but the lowest level is 0.3 grams. You can't get more sensitive than that. With mass spectrometry, we can get 30 times more sensitive and measure down to 0.01 grams. It's even more important than that because plus, we're able to separate not only the proteins, we can actually separate out the drugs that you're receiving. So we can see Darzalex in your blood, Toclistumab in your blood, Talquetumab, any antibody is detectable by mass spectrometry. And since we know the weight of the drug, we know what protein in your blood is the treatment versus what is the disease protein. At the end of the day, mass spectrometry is a much more sensitive method of detecting the level of the myeloma protein in your blood. Mass spectrometry is often available through laboratories across the United States, but it requires a requisite number of samples. To make it effective for hospitals to offer the test, it requires volume. And so many hospitals will simply mail it to a reference laboratory, and they're all available throughout the United States where you can get information. Where I work, we use it routinely, and we actually no longer do the serum protein electrophoresis at all. All we do is mass spectrometry because it is faster, it is actually less expensive, and provides a heightened level of information. Mass spectrometry is not a standard of care, in part because the equipment itself is extremely expensive. Even though running each test is quite inexpensive, it would not be considered a standard of care. But that really is primarily an issue of education and acceptance by laboratory chemists that do these tests. And I think it should replace it because other than the cost, there really shouldn't be any barriers to implement this test widely across the globe. I believe that mass spectrometry should be the standard of care in the future once it's adopted. Again, the major resistance is equipment costs. They're really quite substantial, and mass spectrometry is hideously expensive. And then of course there's a barrier for its widespread implementation. There's also some technical expertise that's required. The machine just doesn't spit an answer out for you. It does require review and interpretation. But it is so much more sensitive that I don't know why we wouldn't be moving away from myeloma protein assessment by electrical charge to myeloma assessment based on weight. What is the sensitivity of identifying residual myeloma cells by mass spectrometry compared to finding residual myeloma cells by MRD testing using next-generation sequencing? At the moment, most studies show that it's a complement to the MRD testing. We do the MRD testing from bone marrow at the moment, and we do it by next-generation sequencing. And we can typically find even one in a million cells that are from myeloma at that resolution. There are studies showing that there are few patients where the MRD test can miss and show negative results, and then the mass spec shows that the patient may still have disease. I think that sort of discordance tells us that there's some complementarity to these two methods, but it's only applicable for a small proportion of patients. It offers the future potential of being used for minimal residual disease. Today, minimal residual disease requires a bone marrow examination to determine if there's any residual myeloma. But when you start having extremely sensitive techniques of measuring what the myeloma cell makes, the protein, it's another way of looking at very, very small levels of myeloma. And we hope that in the future we may be able to monitor patients for achieving very, very good responses by looking at their blood instead of having to do a bone marrow. What does mass fix? One of my colleagues, Dave Murray, brilliant guy, came up with this idea that using mass spectrometry, one could potentially identify a given patient's monoclonal protein by using sort of this very large desktop machine called a MALDI. It basically separates proteins by charge and mass. And basically, we just, you know, there's a little bit of work that you do. You put it in these little tubes and you put it in a well in the machine, and a laser shoots at it, and you get these patterns. And you can actually identify the monoclonal protein. And the really nice thing is that you can identify a specific mass charge, we call it, of a given patient's monoclonal protein. And so if they have a G-kappa and they're getting a therapeutic antibody like their Atumumab, we can easily tell the difference in mass charge and discern whether it's the drug versus the patient's protein. And actually at Mayo now we don't even do immunofixation anymore. We're doing just this mass fix because we find that it's more sensitive and more specific than the typical immunofixation tests. So when we follow myeloma patients, the workhorses are the serum protein electrophoresis, and that is sort of a quantitative assay. So somebody says, you know, my M-spike is two grams, three grams, whatever. You get that off of the S-pep, but then when you can't really see it anymore, or if you want to know exactly what type it is, is it an A-kappa, a G-lambda, whatever, you do immunofixation. So for us, the mass fix is replacing that immunofixation. So we can, we do it for saying what is the monoclonal protein, and then also is it there or not. And it's very, very good at finding little monoclonal proteins, which is very helpful.