BETA - Are there any biomarkers that will help predict smoldering multiple myeloma (SMM) to active multiple myeloma (MM)

Yeah, it's a great question. So we know currently the one that is approved by the International Myeloma Working Group is 22-20, 20% plasma cells, 20 light chain ratio and 2 grams of M-spike. However, when it was published, it was done at one time point at the time that you diagnose a patient. And we know that the dynamic progression, the serial sampling of a patient is much more important. Think of it more of a video rather than a one time shot, rather than one picture. You're looking at a video of a patient and you do want that timeline to understand better the dynamics of progression. And those people who, every time you see them, their numbers are ticking up, although they did not meet the 22-20, I'm really worried about high risk and going on to active disease. Also, there are so many other factors. Soon we will be talking about a new model that we developed called the Pangea model. And that's based on the dynamic mechanisms of progression. So we put in trajectory models, trying to basically create your own risk calculator based on your own percentage of plasma cells. Or if you don't have a bone marrow, then we can still do it without it based on M-spike, based on light chain, but also age and hemoglobin and creatinine and not using it as a one time value, but as your trajectory of how the numbers have changed, the kinetics of how those changed. And every time you go to your doctor, you can put in your own risk calculator and see how your numbers look like. And it behaves much better in predicting progression, even better than the 22-20 at different time points, which is the rolling model of 22-20. So we're hoping that will be available to everyone to use, hopefully all patients, but also all physicians, so that they can have better precision of predicting what is their number. And then hopefully soon we will have other things circulating tumor cells, the genomics of the patient, high risk cytogenetics or not, the mutation status. If they have a KRAS mutation or a P53, the immune system, if we develop better immune biomarkers, all of this put together will give us that precise risk stratification for patients. It's hard to know what high risk small-dream myeloma is because there are so many criteria. There was the Kyl criteria, which had three grams protein, 10% plasma cells and light chain ratio that's elevated. There was also the Spanish data of an immunoparesis and the number of plasma cells being abnormal. There's a new clinical data that was presented by the International Myeloma Working Group that talks about the 20% plasma cells, two grams protein and a light chain ratio of 20. And all of those are excellent markers, but they're clinical markers and they do not add the biology into it. We are now showing new data that says that genomic markers are also important in predicting who will progress and who is not going to progress. And that includes mutations in the map kinase pathway, myc translocations or amplifications, as well as DNA repair mutations, which are like the P53 mutation and others. And we're hoping that with the genomic data and the clinical data, we can better predict who is truly high risk so that we're not over treating patients who should not be treated. And we're also not under treating patients who will progress very rapidly to overt myeloma. The hope is that we can offer this as a clinical test in the near future and patients can actually have a better prediction of who will progress in their lifetime. High risk small-drain myeloma is a group of people who are within the small-drain myeloma disease, which is the 10% plasma cells, but they have characteristics that indicate likely they have a very high chance of developing myeloma. So that means either a very high number of plasma cells in the bone marrow, a very high M-spike, a high light-chain ratio or bad cytogenetics. Now, that's an area where we're still changing the criteria. So there is the Mayo Clinic criteria, the Spanish criteria, 10,000 other criteria, and we can put them all together. And we're still working on understanding better what characterizes a patient to have potentially a high chance of developing myeloma. We've actually worked on genomic studies that can be added to the clinical data that we know so far to improve on understanding who is truly at risk of developing myeloma in the next couple of years. Some patients with smoldering myeloma have markers of increased risk of progression to active multiple myeloma. And for some of those markers, the risk of progression is high enough that we think that it would be a good idea to start treatment while their disease is still smoldering and before it has a chance to become active. In general, the marker that's most indicative of a very high risk of progression to active myeloma is a percentage of plasma cells in the bone marrow that's greater than 60%. In addition, other markers can include a very high level of serum-free light chains with a ratio of the abnormal to the normal light chain greater than 100 or the presence of more than three focal lesions on MRI scans of the body. There is a lot of debate still among oncologists of exactly which of these should be used as an indication to start treatment for smoldering myeloma. But there's no question that each of them increases the risk of earlier progression to active myeloma. So multiple myeloma is one of a few cancers that has a known precursor condition. It was proposed over 50 years ago that there are monoclonal proteins in the blood. In 1978, the terminology of monoclonal gamopathy, undetermined significance, was proposed in the literature. When this was created, soon after, there were cases that didn't fit with the definition. So there had to be an extra entity proposed in the literature. Based on six cases from a chart review, a research letter was published in 1980 suggesting that these could be called something different, smoldering myeloma. Over time, more and more information was collected for individuals that fit this little group and it turned out that many of these individuals unfortunately developed myeloma. It also turned out that the monoclonal gamopathy had a lower risk of conversion compared to this smoldering category. To this day, people are focusing on the amount of protein that you see in the blood or the number of cells that you can count with your eyes in the microscope. All these markers are basically indicators of the amount of the disease. And all the so-called risk factors show that if there is more of these precursor cells versus if there are fewer of these precursor cells, the risk is higher for progression if there are more of them. What is happening right now is that there are a lot of investigations using modern technologies with sequencing-based approaches and so forth, trying to see if genomic characterisation, even in low amounts of disease, can identify individuals that will progress. And if all the individuals that have slightly higher amounts, higher volume of precursor disease, if all of them will progress or not. There is data published over the past 12 to 18 months indicating that with very sophisticated sequencing, it's possible to identify cases that will progress within two years or so. And patients that have precursor disease that don't have these markers, with over 15 years of follow-up, there is no progression yet. So where is the field going? So what's happening right now is that these novel insights are being expanded to be confirmed and expanded into larger cohorts. The field is wrestling with these questions. So my prediction is that most likely, I think, small ring myeloma will not exist in the future. I think we will have the monoclonal gum apathy and we will have the multiple myeloma. And I think these tests will bring clarity to the space of who is programmed to progress and not. So this is an area of a lot of investigation and there is also a lot of controversy. And the future will tell where the field will go. I mentioned that more advanced sequencing of low amounts of disease cells reveals that there are two entities. There is the progressive and non-progressive precursor disease. As the field is moving forward, as more data is being generated, if these larger efforts will confirm and expand on these observations, this will erase the terminology of small ring myeloma. It will make it monoclonal gum apathy and it will make it myeloma. And we are talking about an earlier detection of multiple myeloma. In addition to this, people have been studying the immune system. There is less information on the role of the immune system in this setting. But there are some papers showing that there are differences in the immune cells in the normal immune system of individuals with a non-progressive versus the progressive disease. There are problems studying it because you have the presence of these cells. And if there are more of these cells, the cells could probably change the immune system. So it's not known what's the hen and what's the egg here. Is it the cells that change the immune system or is it the immune system that allows the cells to become more and more active? It's very hard to do these types of investigations. Maybe different types of laboratory models could be done. I could think that maybe having mouse models where you could move cells across different mice to see if more active cells put in another environment maybe would change the immune system and so forth. Obviously, there will be limitations with those models as well because humans and mice are different. It's very hard to do these types of experiments. There are a lot of investigations ongoing in this field as well.