BETA - Is there a standard of care for SMM? Should smoldering myeloma be treated?

Smoldering myeloma is a really important entity. I do think that we have such amazing therapies that are so highly effective and well tolerated. We really, at all possible, we shouldn't let a patient get crab symptoms, right? Because we've missed the boat. But that goal requires that we can really identify in a very rigorous fashion who's going to actually get it. And so the key in smoldering is really risk stratification. And I think we had some guidelines that we should be 80% at two years. And that's where we started with. And that's where the slim crab came from. That light chain gray sugar over 100 is predictive. And bone man more than 60%. And the MRI lesions. I think the MRI is pretty straightforward because if you don't have good imaging, you're just not diagnosing it correctly. The other two are a little bit more complicated. Bone marrow more than 60%. Keep in mind that myeloma's definition is not just hemoglobin by less than 10. It's also dropped from two by your baseline. So who are these patients that have pristine hemoglobins and yet have marrows that are 60%? I think that most likely that's because of one of two things. It's a sampling issue. You just happen to hit one little pocket of disease. And the other thing that we have to keep in mind is some of this data we came from Europe and in Europe they don't do bone marrow biopsies. They do aspirates. So 60% in the aspirate probably means in the bone marrow was even 80%, 90% because the aspirate tends to underestimate the core. Regardless, I always love the movie photograph analogy. It doesn't matter what happens in one snapshot. It's got to be what happens over time. And I think the other thing to keep in mind is two other things to keep in mind. Most people who are newly diagnosed with myeloma have had that for a long time. So one year prior to the diagnosis, everybody has detectable proteins. Ten years prior, it's 80%. So it's not that this is just coming up and exploding out of nowhere. And the second thing is we cannot conflate myeloma with solid tumors. Solid tumors like breast and colon, yes, you have a single early isolated area. You can take it out. You can't do that with hemalignancies, myelodysplastic syndrome that doesn't require treatment, CLL that does not require treatment, even follicular lymphomas that don't require treatment. And I think we need to do a better job of figuring out, let's get rid of smoldering myeloma. You either have MGUS and disease that doesn't need to be treated or you have disease that needs to be treated. This smoldering is some human artifact that we've created that has no biological basis. We're just chopping up the data into what can be conveniently chopped up every so often and spit out. We're not going to get the good rigorous risk stratification. We'll never get ahead of the therapeutic questions at hand. The standard of care for smoldering myeloma because we still are in the infancy of understanding it better. So we need better risk stratification. Yes, we can use 20 to 20 or evolving M-SPIKE or the Spanish model or the old Mayo model to understand better who are those patients who should be treated. But let's not also stop us from improving on the risk stratification using circulating tumor cells, using high risk genomics, using immune markers, using dynamic models like the Pangea model and not just say, okay, well, we have one option. We have an option that's okay and let's keep improving on it because our patients want to know how to improve on having a precise risk stratification. And then let's improve on our therapy. We know that Orezia lenalidomide or lenalidomide and dexamethasone can improve progression free survival over doing nothing, but that may not be enough for some patients. Let's do precision interception. Some patients may need four drugs. There are RVD or there are KRD. Some patients may need immunotherapy, CAR-T or bispecific antibodies. And some patients may truly benefit from only prevention like lenalidomide alone or vaccines or other options that can really make a difference. So we may have multiple tools in our hands to make sure that we're not just treating all patients the same way. A high risk cytogenetic smoldering myeloma may be very different than a low grade, you know, hyperdeployed smoldering myeloma. The treatment of high risk smoldering myeloma, that is, I will tell you that in every single conference that you go to, or if you're lucky to go to any of our medical conferences, there will probably be a debate about whether to treat or not to treat smoldering myeloma. And that tells you everything about where the field is right now. This is very controversial. But at the same time, I think we're starting to learn so much more about defining who that population is. And I think that's the first step is that still is a little bit of a moving target. It's hard to know exactly who those patients that benefit from treatment are. I think we have some good ideas and certain ways to assess who may be high risk enough, who has that risk of transforming to active myeloma over the next two years. And we define high risk as a 50% risk of transforming to active myeloma. And those patients are the ones that we know are likely to benefit from therapy. The problem is that within that group, there's still a lot of heterogeneity. And there's still a lot of factors that are not taken into account. And so because we don't all agree on who that high risk population is, it makes it difficult to say to any one person, you're the one who needs to be treated. But I think there's very good data that if we were able to say, you are definitely going to become active, that I think I would recommend that you be treated. It's just that I don't know who that person is right now with that much certainty. So the first thing that we've noticed in high risk smoldering myeloma is that there are two large randomized studies that actually showed that indeed treatment is better than observation. These were the lenalidomide and dexamethasone study by the Spanish group, as well as the lenalidomide alone versus observation by the ECoC study by Sagar-Lonial. Those two were wonderful because for the first time, we understand that if you treat early, you can actually make a difference in progression-free survival and in one of them, in overall survival. The problem is the criteria of what is considered high risk smoldering. So both studies use very different criteria. One of them even included intermediate and low risk smoldering myeloma. So we really don't know the true answer of who are the patients who will benefit the most from this intervention. The second question is, well, should we really treat very high risk patients with single agent lenalidomide? Is that okay or not? Because if you just said that smoldering myeloma, extremely high risk, looks like myeloma, I don't want to treat myeloma with only one drug. If I'm going to intervene, I want to intervene with everything I have, which is three drugs, even four drugs now, so that I do not cause clonal resistance. I do not cause worsening of the disease. So there is a hesitation of using this as a standard of care. I think it's a very good first step. It's a proof of concept, but let's improve on it before we consider it a standard of care. So I think it's important to talk to your doctor about clinical trials and about should I really consider being treated or not? It's a very important question. I personally would think if I have a precursor condition, what are you waiting for? Why are you waiting for me to have end organ damage and fall apart and have fractures instead of treating early? Yet, if you think about it, the standard of care still is do nothing, watch and wait until you have end organ damage, until you have myeloma. And we're trying to change that, but we have to change it through clinical trials. And there's a misconception of trials, meaning, oh, you're experimenting. Actually, all the drugs that we use in small drink myeloma are drugs that are well known, approved, have been tested already in myeloma. And we're just bringing them earlier to ask the question, if we treat earlier, can we truly cure the disease or prevent progression, prevent the damage that happens by waiting until you have end organ damage? Now we need many studies. We need things to be approved until this becomes a standard of care. But by contributing to it, you are contributing to changing the way we think. But not only that, you are actually giving benefit to yourself if you are eligible and you're interested because you are actually getting active therapy that could potentially prevent myeloma from progressing. I think it's very important to get a second opinion. Not that your local doctor is not good, your local doctor is excellent, but he has so many different cancers to treat. And in fact, M. gus and small drink is considered something that you just watch and wait and you don't do anything. So they don't know about all of those new options or they do know them, but they don't have everything there. And that's why an expert may give you all those options and may discuss in details what are the risks, what are the markers to look for and what are the clinical trial options that we are offering now. And I think it doesn't hurt to just get that information and be empowered with information before you make your decision on whether this is what you want to do locally or not. I think you can email us anytime at Dana Farber. You can go on our website. There are many other websites that give you information for myeloma. Again, it's very important to know which website and how you get your data. But we're happy to help. And this is why we're here to say we're happy to give a second opinion at any time. We're happy to be part of that discussion, whether you do indeed have a risk of progression and you need to be on therapy or your risk is very low and continue on observation and enjoy life. Many of the patients who come and see me, they will say, is my family at risk of developing myeloma? Are my sons and daughters going to have this? And the answer is we don't know. We know that there is a higher risk of developing MGUS or myeloma in certain families. So there could be potentially some association, but we don't have an actual gene that we say, yes, this is inherited and this causes multiple myelomas. So it's not like breast cancer where you have the BRCA mutations and you know that this happens. We're working on that. In fact, the PROMIS study is the first study that we look for family members of people who have myeloma or MGUS to see if they're at risk, if they have a higher incidence and what is that genetic connection between them so that we can understand it better. And until then, we do not advocate to screen family members, but we would advocate that you go on the PROMIS study and be part of it. Okay. I think that's good. For an individual who is diagnosed with small ring myeloma coming to my clinic, one of the first questions patients ask is, what am I going to do next? Do I need treatment? And the answer is that at the current time, there is not yet any FDA approved drug for the indication of small ring myeloma. Looking at guidelines, looking at the NCCN guideline, looking at other myeloma working group guidelines, all the guidelines have as the default to monitor the patients, to do a bone marrow biopsy, to do a PET CT or whole body MRI, and to do blood tests. If all the workup excludes multiple myeloma, this would formally be a small ring myeloma diagnosis. The guidelines would further recommend retesting the blood, say on a three month basis. If the marker stays stable, another year of about a three month interval would be the standard of care. Many times, patients would consider doing a new bone marrow and maybe PET CT or MRI after such an interval. And if that is confirmed again, sometimes the interval gets extended a little bit. So three, four, or even six months sometimes. If that's being done another year or two, sometimes additional workup is done with biopsies or PET CTs or MRI. And usually after five years or so of follow up, patients will say, I feel confident. The guidelines would support that this does not look like a changing, progressing disease. Usually a five year window is going to predict the future. The history is usually a good predictor of the future. And that's what the guideline also suggests. Many times, patients would do a biopsy and imaging workup after that five year window and maybe do six or 12, even eventually month intervals for blood testing. I think with more sophisticated technologies with sequencing that I did mention before, patient could be profiled up front. You don't have to do all these workups and do all the blood work. You could much sooner identify if the disease is programmed to stay stable or if this is a disease that is programmed to progress. And you don't have to go through all these different steps. But there is more work to be done before this will become the clinical standard of care. And who should consider clinical trials? And then that's the small group should really not go with the standard of care, but think about some of these treatment trials. So for individuals that have the high risk or sometimes also the intermediate risk, investigators have developed clinical trials for these patients. So depending on how these protocols have been written, different criteria have been set up to define eligible patients. So if a patient meets the literality criteria for a particular protocol, if that patient is interested in enrolling on that protocol and meets the criteria, the patient could go on. These are clinical trials. Most of these trials have as the primary endpoint to delay progression or ultimately prevent progression. And usually they study the progression in relation to historical control. If there's a delayed progression, they are trying to improve based on just monitoring. The criticism against these types of protocols is, for example, that we don't know if this is going to make a difference long term. Because if the disease will happen anyway, it's just a matter of delaying it. If it comes back later and it turns into multiple myeloma, you will have to treat it anyway. And if you have stayed on therapy for a long time on the protocol, this would be years that you maybe didn't have to do therapy if you just chose to be monitored. But on the other hand, if the therapy is successful, if the protocol really is doing a good job, maybe the patient would not develop multiple myeloma. So these are, of course, very important questions. But we currently don't know the answer, which of these scenarios is the right answer. Also there are toxicities associated with these therapies. And there are like a lot of practical things that come into play, all the inconvenience and things like that. Again, there are not yet any FDA approved drugs. It's hard to counsel each and every patient. But I think individuals have a different appetite for doing things early versus not. And I think there are some patients who really look to go on trials and they want to really take the opportunity. The last criticism I address also is that with more emerging data from genomic sequencing and other types of technologies, I think although an individual could be high risk with these retrospective models, if the disease is truly not biologically going to progress, another criticism against these trials is that you would treat the person that would not have progressed anyway. And the trial would then show that there is superior outcome with the intervention. But the reality is that the disease would not have progressed anyway. So these are very difficult questions. And I don't have the full answer for every person. I think it is an individual decision whether it's the right thing or not to go on the trial.