Should HRSMM be treated? Why is there a focus on HRSMM in trials?

[Music] should high risk smoldering myeloma be treated should high risk smoldering multiple myeloma patients receive therapy in my opinion this should not occur outside a well-designed clinical trial there have been two trials that have been completed in patients with high-risk smoldering multiple myeloma but they suffer from a number of defects in the first trial which is now quite old patients who are admitted to the trial did not have the studies that are usually done today such as a PET scan or an MRI as a consequence some patients in the trial may have had actual active myeloma and so now we're comparing treatment versus no treatment in a patient population that includes active myeloma in addition trials have demonstrated that their survival benefit but one of the issues is that patients who were elected not to be treated with high-risk smoldering multiple myeloma were observed even in the face of a rising protein and that doesn't conform to current practice the second trial has shown an improved time without myeloma but has not demonstrated a survival benefit I think understanding the biology of high-risk smoldering multiple myeloma is important and by that I mean patients who are destined to develop multiple myeloma with at least a 50% risk within two years but in order to be treated I believe they should go on to a well-designed clinical trial I'm also concerned that less intensive treatments for smoldering myeloma patients may select out more aggressive multiple myeloma populations that could put them at risk and so in the context of a well-designed clinical trial I think it's completely appropriate to participate but I think outside of a clinical trial high-risk smoldering myeloma requires a expert in multiple myeloma to assess whether it would be appropriate to intervene but my general answer would be no so the think 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 and these were the lenalidomide and dexamethasone studied by the Spanish group as well as the lenalidomide alone versus observation by the ACOG study by cigar L'Oreal those two were wonderful because if 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 small drink 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 gonna 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 as standard of care the treatment of high-risk smoldering myeloma that that is I will tell you that in every single conference that you go to 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 when 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 percent 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 taking 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 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 why treat high-risk smoldering myeloma and not watching wait the idea of watching wait until people fall apart is wrong and I really try to think if I have a cancer why would I want it to cause fractures in my bones until I get treated it doesn't make sense in any other cancer why are we doing it in myeloma we did this in myeloma in two old days when we had no treatment now we have amazing treatment options however having said that I don't think we should treat high-risk smoldering myeloma off clinical trials until we have a good understanding of what is high-risk and we don't know that yet and until we have good therapeutic options that are truly making a difference in progression-free survival and overall survival of our patients and truly changing the way we think I think we have a good first step but I'm not recommending to patients to go and get lenalidomide or lend X alone until we have better options of therapy for those patients what are the different approaches being taken by high-risk smaller myeloma clinical trials in general if you look at smoldering myeloma there are different clinical trials that are ongoing there are some that are on one spectrum let's treat it as overt myeloma so let's use three drugs further drugs car fills may blend X transplant is one of the option there to MU map car fills and of length X is another option these are on the extreme end of let's treated as overt myeloma and we will get to know the answers from this we have data from it M rz- disease looks very exciting the question is is there an opportunity for us not to use all of those drugs of myeloma in a patient who does not have all of the symptoms and the tumor burden of myeloma the other extreme are things like a single agent antibody there to map single agent and I think that's interesting or lenalidomide single agent it's interesting it's good but is it the right thing to use a single agent in those patients and I think both are correct there is no wrong answer but maybe there is no right answer in both of them I think we need something called precision intervention we're not all smoldering myeloma are the same not all of them should be treated either with this or that let's redefine them correctly and certain patients should get three for drugs should be treated like overt myeloma to prevent clonal selection certain patients learn alone or an antibody alone would be perfect for them it will delay progression it will give them an amazing response and progression free survival without making them exposed to all those drugs and then what we're trying to think now is can we develop immunotherapy true immunotherapy for certain groups of patients that we can make a difference in their survival without exposing them to all of the drugs of myeloma why is there such a focus on high-risk smoldering myeloma in clinical trials I think from an immuno serpent of view the benefit of high-risk smoldering myeloma is that it's a clean experiment in other words clinically you can argue that those patients almost have myeloma I think it depends on where you're divided you put that line the standard of care is nothing and so n because of the disease isn't that advanced their immune system is not as beat up as somebody that has more advanced disease and so you have a very you have a clinical need with a relatively intact immune system in a situation which you can apply only the experimental therapy without any other extraneous things because there is no standard of care so I think it makes it a very clean setting in which to study vaccine therapy and other types of immunotherapy [Music] you