What testing will my doctor order to determine if my treatment is working? What is the International Myeloma Working Group (IMWG) response criteria?

What testing will my doctor order to determine if my treatment is working?

So when someone starts a new treatment where there are multiple myeloma, there's several different types of tests that one can monitor to see if the treatments are working. So typically when we're looking for response for the monoclonal protein or that abnormal protein that's produced by the plasma cells and multiple myeloma, one will order something called a protein electrophoresis and this can be done in both the blood as well as the urine. And so monitoring how big that monoclonal protein is within the protein electrophoresis tells us a lot of information for response. There's also the free light chain levels that could be monitored. We look at both the absolute or the actual number of the free light chains that is elevated as well as a ratio, because other things like for example, kidney disease or kidney impairment can affect both free light chains. So that ratio is really important. So monitoring the protein electrophoresis as well as the freeway chains are important to looking at response. And then of course, depending on how one presented with multiple myeloma. So if one had high calcium levels or a low red blood cell count and anemia or, renal disease with high creatinine, we would want to monitor to see those kind of layups, to see the responses for if your blood counts are any better or if your kidney function is getting better. So another test that can be ordered is the quantitative immunoglobulins. And this isn't part of response criteria, typically, but it also can be monitored for when one is responding. You'll see a decrease in these immunoglobulins as well. If they were involved. So, for example, if one has their abnormal protein is an IgG kappa or not, one can monitor the IgG levels after receiving treatment to see how that has been decreasing as well. In rare cases there can be non secretary myeloma where that abnormal protein isn't demonstrated within the protein electrophoresis or the free light chain elevations or even within the urine protein electrophoresis as well. And so in that case, it's a little harder to assess response. And really a bone marrow biopsy is your best bet, seeing how involved your plasma cells are. Before the start of diagnosis compared to when one is being treated. The bone marrow involvement of your plasma cells could give a lot of information. If someone has what we call as plasmcytoma or masses of the plasma cells as well, then that can be assessed with imaging. So whether it's a plasmacytoma that is outside of the bone or even just bony involvement of the myeloma, that could be monitored over time as well with imaging.

What is the IMWG’s response criteria?

So it comes to the response criteria of multiple myeloma. There are a lot of challenges, obviously, for patients to understand. In summary, it is basically showing how much of the myeloma that was there in the beginning of the total sum and mass of cells, how much has that been reduced. The last step that we can show is a 25% reduction. Usually what we measure is the monoclonal protein in serum and in urine. When you have 25% reduction or more, then we call it at least a minimal response. In patients who have a 50% reduction, we call it a partial response. In patients who have a 90% reduction, it's a bit more complex than that. But in general, we can say 90% reduction is so-called very good partial remission. And if we cannot measure anything anymore in blood and urine with the most sensitive techniques that we have, then we call it a complete remission. To have this criteria, we also have to do a bone marrow biopsy and show that there is less than 5% plasma cells in the bone marrow that would complete the complete remission definition. What we also have is a so-called stringent, complete remission, where also the ratio of the light chains is negative. And in the immune histochemistry and from the bone marrow, we see that there are no monoclonal plasma cells left and no cancerous cells left with microscopy. The next step is the minimal residual disease negativity, and there are also different levels. But the most important is to know that we use machines like either next generation sequencing or next generation flow cytometry, where we put a number, a large number of cells, for example, 100,000 or 1 million cells. And if there is no myeloma cell in this 100,000 or 1 million cells, then we call it minimal residual disease negativity. And we also have to add what sensitivity did we use. And the less important factor is that we do imaging, we do usually PET-CT for follow up and we see if the PET-CT is negative, we call it imaging negative. And we know that if we do MRD assessment from the bone marrow, we also have to do an imaging because we might miss something, because the bone marrow biopsy is only one area where we do the biopsy. It is very representative, but it's not 100%. So it makes sense to do a bone marrow biopsy for MRD assessment plus an imaging. And if both are negative, we know the patients have a very good prognosis. And the last thing I want to mention is that some patients have kind of sequential MRD assessments from the bone marrow biopsies, for example, six or 12 months apart. And if they are both negative for MRD assessment, then we call it sustained imaging negativity. And in a lot of studies, we can see that patients with a sustained MRD negativity have the best prognosis of all.

Are remission and response the same?

What does it mean to be in remission? Oftentimes confused amongst patients. They are very surprised if they tell them they have achieved a remission. There's not really much of a difference between response and remission. Response is to therapy. Remission is the remaining amount of myeloma, but the response basically leads to the remission. And I personally tell my patients, and it might be a little bit more philosophical than the research question, that even a partial remission is a remission and even a minimal remission. A minimal response is a remission. It is, of course, we want to achieve the deepest remission possible because that's the closest to a cure we can come. But I think even achieving a reduction, especially later lines of treatment, it's helpful to achieve some kind of remission. And then there's even in clinical trials, sometimes there are clinical response rates, clinical benefit rates which show that a patient is staying stable in a certain area. And patients who had a lot of lines of treatment, sometimes you've been happy to just keep them on a low level of disease that doesn't harm their body and they can still survive longer. The International Myeloma Group developed a standardized response criteria that is used worldwide. This chart summarizes the criteria needed for each level and response. The International Myeloma Working Group established this criteria in order to facilitate precise comparison of efficacy between new treatment strategies and trials, incorporate the serum free light chain assay to include assessment of patients with oligosecretory and non-secretory disease, provide stricter definitions of complete response (CR), and provide classifications that would improve detail and correcting consistencies in prior response criteria. This criteria reconciles various previously used systems for assessing response and has been universally adopted.

What is antibody interference?

There are a lot of nuances with our reliance on the protein level and on the myeloma cells themselves. One, the proteins stick around for a while. I have many patients where their bone marrow is completely clear of myeloma, but the M spike is still stuck. It's not quite 0.1 for months afterwards. Why is that? Because M spike is an antibody. Antibodies are designed to stick around for months. That can often happen where someone is still in a VGPR or nearly a CR. You still see a little bit of the antibody there and that's okay and that's completely okay. And I wouldn't change anything differently based on that alone, because the limitation really of our response criteria is more so than have our drugs. The other nuance to keep in mind about them, that comes up quite a bit in the modern era of us using monoclonal antibodies as treatments, is that the monoclonal antibody that's therapeutic can actually show up on the M spike. So this is confusing for patients. But, I view it as somewhat poetic that the myeloma cells, by definition, produce this junk antibody, and we make a different antibody that looks just like it, that attacks the myeloma back. Practically speaking, particularly for patients with IgG kappa myeloma, daratumumab, for example, darzalex is itself a monoclonal antibody, just doing an aspect, just taking your proteins or running them across an electrical gel, looking at what type of antibody and how big they are. You cannot tell what IgG kappa is from the myeloma versus from the daratumumab itself. Some of my patients may have an M spike of 0.1 for years and never quite be a complete response on daratumumab maintenance, and that's okay. So I think at the end of the day, the response criteria are important for the blood work, but the IMWG appropriately also looks to the bone marrow. So if you do a bone marrow biopsy, that's really important. And so to confirm a complete response (CR), which is my word for remission, to be in remission with a bone marrow biopsy should be negative. The IMWG does have an additional criteria for patients in the bone marrow where you can assess for measurable residual disease (MRD). If you listen to the podcast, listen to this video, there are many resources in HealthTree, but MRD is a constantly evolving topic. But you can, within CR or within VGPR, kind of say, look, is this MRD positive or is this MRD negative? And that's another level of credential. Another layer of depth of response. That's maybe a story for another day.

What is a stringent complete remission?

Stringent CR trials use it. I think most of us in clinical practice aren't as preoccupied with. It's a stringent, complete response within complete response. A complete response was developed before the advent of free light chains being readily available. So basically a stringent CR would be that the you’re in a CR and a complete response to bone now showed less than 5% of the abnormal cells and the ratio of capital lambda is normal to free light chains. I will say that when my patient on clinical trials, that matters a lot because clinical trials go by the book of how ambulatory response criteria are defined. In real life, as I'm alluding to, life is never that simple. Stringent CR are sometimes patients who have kidney disease that can affect the normal ratio of kappa and lambda. So you may actually see that the kappa and lambda are not quite where they need to be. They never qualify. Stringent CR they're kind of stuck in the modern era. I would say that for patient newly diagnosed today, the VGPR, CR and stringent CR all do relatively the same in my book because you've knocked out the myeloma cells enough and any difference between some narrow difference in the M spike being 0.1 versus faint versus zero or the free light chains being slightly off and therefore not stringent CR versus being normal and therefore a CR is largely a function of our response criteria more than of the underlying myeloma disease biology. So I would say if you’re not, if there was a video and you're like, man, I'm not in stringent CR just at a CR. Fine. If you're looking at the video, I'm like, I'm only in a VGPR, I'm not an CR. Fine. I was in all those things in the modern era of therapy, patients like that will do excellently.

Is there a test that can distinguish antibody interference from therapy from the myeloma antibody?

So if you are interested. So I joke to patients that the lawyers go by the end of the criteria by the book and me, I just kind of go with kind of a gestalt feeling of everything. But let's say if you have a lawyer inside and you really want to know for sure, is this a CR or is the interference from daratumumab that again, could show up on the SPEP assay. There are tests that can do it. So there are drug specific assays, something called Hydrashift, that can help differentiate between how much of the M spike is from the daratumumab versus from the actual myeloma M spike. We also can run mass spectrometry, so we actually can do some fancy testing, something like kind of forensic science basically to actually look at the blood and see what's what. For example, the Mayo Clinic does have a test like that anyone in the country, the doctor, gets under blood to.  My caveat I would say to that is, again, when someone's M spike is 0.1 and their bone marrow is clear, I don't think it's going to change my management to know where that residual M spike coming from. Because even if that's two myeloma, let's say we do I that is the myeloma protein. The myeloma protein can stick around for six months even when the bone marrow is negative and the protein itself is not the cancer. So I would say that, yes, it is possible and I have done it in certain situations to go and try to differentiate what is the myeloma protein versus what is the actual therapeutic drug. But at the end of the day, if someone's M spike is 0.1, they're in a great spot. And if you do the bone marrow biopsy, they're negative. That's in my mind a thousand times more important than what the blood is showing.