← The Fellow on Call: The Heme/Onc Podcast
The Fellow on Call: The Heme/Onc Podcast
Episode 142: Myeloma Series, Pt.3 - Management of Smoldering Multiple Myeloma (2025)
Ronak Mistry, Vivek Patel, Dan Hausrath
Loading summary
Transcript36 lines
- [00:00]
A
Hey, friends. This episode of the Fellow on Call is not meant to be used for medical advice and is intended for educational purposes only. Patient information has been modified to ensure privacy. The views expressed in this episode do not necessarily reflect the views of our employers. Enjoy. As a fellow, your network is your edge. With Primum, you can connect with over 100 leading oncologists. You can ask anonymously or by name and get answers in hours. And it's completely free. Sign up today at premum Co. Welcome to another episode of Fellow on Call, the hemonk podcast. We're coming at you from Rouleau University Medical Center. I'm Roanok.
- [00:38]
B
I'm Vivek.
- [00:39]
C
And I'm Dan.
- [00:40]
A
We've got a new addition to the team today. Please welcome Sean, one of our new malignant hematology attendings at Rouleau University Medical Center. Welcome, Shawn.
- [00:48]
D
Hey, everyone. Really excited to be here and really excited to talk about some very interesting and important cases in smoldering myeloma today.
- [00:56]
A
And Sean gave it away. We are going to talk all about smoldering myeloma today, and it's so fitting that today's the first day that we welcome Shawn onto the show since this is an area of interest for him and something that he treats in his clinic. So we're really excited to learn from him and see how he approaches this very heterogeneous disease. And, you know, I just want to say Sean is new to maybe many of our listeners, but Sean's actually not new to the show completely. He actually used to be a fellow here at Reload University Medical center and was really integral in helping us with the show behind the scenes. And now that he's a full seasoned attending, we decided to bring him on board especially for this topic, which is the area of expertise. So really, really excited to get into this one. So without further ado, let's roll that show, guys. Today we're talking all about smoldering myeloma as we continue this plasma cell dyscrasia myeloma series that we're currently on. The last couple of weeks, we sort of laid out the foundation for this discussion and I'm excited today to continue this, especially with a lot of that new data coming out about smoldering myeloma. I know we're going to get to that, but we have had a little bit of a hiatus lately, and so I think. Vivek, do you want to share what the big news is on your end?
- [02:12]
B
Yeah, yeah. I had a baby, so I have a son now. And so that really made us say, hey, we can't really record for the last three months roughly of the show, but we had this large catalog of all the shows we had done before. So, you know, I'm glad to be back. It's actually really fun to be back to do this. But really, really, really love being a dad, you know, love it so much. Couldn't recommend it more. Definitely lots of sleep deprivation and chips keeping me up at night. You know, the chips are the thing that gets you through the night. That's the fuel. But aside from that, I do want to say really excited to have Sean here. This is something that's going to be happening in our show where you'll see new guest speakers here, that we're going to have people who worked on our show as fellows who are now speaking as attending. Some other people are going to come on as guest hosts. And so, Sean, really, really excited to have you here.
- [02:58]
D
So, yeah, it's really exciting for me to be here. The Myeloma series that was originally put out a few years ago was actually one of the first set of episodes I listened to for the fellow on call. And so that really helped me to form my initial understanding of myeloma and really helped me to feel a lot more comfortable seeing those patients. And it's actually a big part of why I ultimately ended up specializing in the care of patients with multiple myeloma and other plasma cell dyscrasias. So me, this is really sort of a full circle moment and really excited to be here to be able to help share some of the updates that have happened in just the last three years since we released our original episodes.
- [03:33]
C
We're really glad to have you with us. And I also want to be clear that when Vivek said chips, he was referring to Lays, Pringles, Ruffles, you know, not clonal hematopoiesis. Indeterminate potential. Although it's something that keeps us up at night. He's talking about physical potato chips, am I correct?
- [03:48]
B
That's right. And remember, Lays, Pringles and Ruffles sponsorship, we always talk about that.
- [03:53]
C
Send them our way. Send us some free chips.
- [03:56]
A
Let's hope they do hear this. Listeners, if you guys have any connections, definitely forward our show over to them. Guys, why don't we start our discussion then about smoldering Myeloma? I know we're all itching to talk about this topic. Vivek, do you want to kick us off with a case?
- [04:10]
B
Yeah, let's do it. So we have a 63 year old female who has an M spike of 2, a Kappa light chain elevation at 70 with Lambda light chains of 7 and a ratio of 10. These were actually sent by our primary care provider because she had a normocytic anemia with a hemoglobin of 9.5. And actually on the CMP there was a small protein gap which prompted this further testing. There was no hypercalcemia and no elevation creatinine, so no evidence of any other CRAB features at that point. Remember to always get light chains with the spep. Often we see people order an S PEP without the light chains, but those are important to risk stratify your patients. As we've discussed previously on when do you get a 24 hour U PEP? Advanced Imaging Studies and a bone marrow biopsy. So for her with that M spike that was 2.2 and that light chain ratio, it was very clear that we needed to do further testing. The 24 hour UPEP showed monoclonal protein excretion and of 400mg over 24 hours. Recall that this is a synonym for the Bence Jones protein, which really just means there's an overwhelming amount of this monoclonal protein produced by plasma cells to the kidney, resulting in higher levels of detectable excretion. And that 24 hour UPEP is really the only useful number there. We also in her, because she had higher risk MGUS, got a bone marrow biopsy and that showed 20% clonal plasma cells. And she did get an ideal imaging modality with a whole body mri, which is the most sensitive. And remember you can do low do PET ct, whole body mri, MRI being the most sensitive, not a skeletal survey. And she didn't have any lytic lesions. So now we have a case of a patient with smoldering multiple myeloma that was high risk. So before we get into some details on smoldering multiple myeloma, Dan, can you tell us a little bit about the definitions of that when comparing it to mgus?
- [06:02]
C
Oh, for sure. And before I get into that real quick, did want to mention I was peeking at her chart earlier today. It turns out she was a little bit iron deficient, which is why she was anemic. So we're not going to count that as one of the CRAB criteria. But anyway, MGUs or monoclonal gammopathy of unknown significance or undetermined significance is defined by identifying an M spike on the SPEP in immunofixation or by having an abnormal free light chain ratio without an identifiable M Spike, but not meeting the criteria for smoldering myeloma or over multiple myeloma. Smoldering multiple myeloma or smoldering MM is defined by two criteria. The first criteria is bone marrow plasma cells taking up 10 to 60% of total cellularity in the bone marrow. An M spike greater than 3 or greater than 500mg monoclonal protein on a 24 hour urine protein electrophoresis. The second criteria is that there are no myeloma defining events as defined by the slim CRAB criteria. So that makes sense, right? We have a decent amount of plasma cells in the marrow or a pretty high amount of protein in circulation and no criteria that secure the diagnosis of myeloma. So it's kind of this middle ground. Multiple myeloma is also diagnosed by two criteria. The first criteria is that we have to have greater than 10% bone marrow plasma cells on bone marrow biopsy or a proven biopsy. Proven plasmacytoma. And criteria number two is a myeloma defining event by those slim CRAB criteria. And so remember, slim Crab greater than 60%. That's the S60% bone marrow plasma cells. The LI is for light chain, so 100 fold difference in light chains. That light chain ratio of 100 or 0.01 more than one focal MRI lesion. So that's the M and then the classic CRAB criteria. Remember, we have to keep the patient's other comorbidities in mind when we're thinking about alternative causes for those CRAB criteria. Like if they have some other obvious cause for being anemic, then maybe we don't consider anemia one of those defining criteria. That's kind of how we have to think about these disease states. MGUs being the lowest risk generally, smoldering myeloma being this intermediate category between MGUs and overt myeloma and myeloma typically defined by one of those slim CRAB criteria.
- [08:21]
D
Okay, great.
- [08:21]
A
And remember listeners, to check out our show notes for a visual representation of these entities. And in the last few weeks, we really broke down MGUs and smoldering myeloma in detail. But Vivek, can you give us a recap on the historical context of how these entities were defined? Before we get into our actual discussion on myeloma diagnostics and also on MRD.
- [08:41]
B
Testing, MGUs is incredibly common. It's present in maybe 5 to 10% of the adult population. And the risk of progression for a true low risk, MGUS is in the ballpark of 1% per year. MGUS natural history was defined by Dr. Bob Kyle from the Mayo group and is very analogous to CLL reist stage 0, where many patients will remain asymptomatic and live normal lives, never eating treatment. So you can imagine this could have easily been named multiple myeloma stage zero, for example, and maybe smoldering could have been multiple myeloma stage one. And you can see how that can become very complicated and challenging when it comes to treatment and surveillance of these patients. So it's important to check out the very well done epidemiologic observational studies published in 2002 and 2007, which we'll summarize in our show notes for you. So please check out our website to check those things out. We risk stratify the MGUs as we mentioned earlier, to determine when we need to get a 24 hour UPEP bone marrow biopsy in imaging studies. And this is because some of these patients may already have smoldering myeloma or overt multiple myeloma. And so remember, check out our shownotes in the last episodes where we go into those details. But Sean, so we have this MGUS entity. So we have this patient who has this aberrant plasma cell population that was created. Why does it happen? We still don't know to this day. Is it chronic antigen stimulation? What is it? We don't know. Then they may have 10%. They started out with 5%, a small M spike, but that upticks over time. And then eventually they may get 10% bone marrow plasma cells and maybe their M spike then goes up to two and a half and we say wait a minute, this patient has smoldering myeloma. So can you tell us a little bit more about some facts on smoldering myeloma? Yeah.
- [10:20]
D
So smoldering myeloma is a little bit of an interesting diagnosis. Now just a word about how it was originally defined. This actually goes back to the 1980s when Dr. Bob Kyle defined this in a paper in the New England Journal. Now we've talked a little bit about what makes smoldering myeloma smoldering myeloma. But as a reminder, the original definition for myeloma was an M protein greater than 3 and plasma cells greater than 10%. Regardless of the classic CRAB criteria. They identified six patients who met the serologic criteria but did not have CRAB findings. None of these patients actually ended up developing symptoms after a follow up of 5 years. And one of them even managed to go 16 years without any symptoms. And so this is where the term smoldering Myeloma originally came from. And notably it does not mean that these patients are guaranteed to become active myeloma in every case. So some of these patients may never end up developing active myeloma. Smoldering myeloma itself is actually a very heterogeneous entity. And so some patients may actually behave more like mgus and again never develop active myeloma, while others have a very high risk of progressing to active myeloma imminently. We've discussed some of the ways that you can identify which patients are at high risk. And so, for example, there's the 2220 rule that we've talked about previously that is greater than 20% plasma cells on a bone marrow biopsy, M spike greater than 2 grams per deciliter, and then more than a ratio of greater than 20 for the involved to uninvolved light chains on serum free light chain assays. And so for patients who have two or more of these risk factors, those patients in particular are at very high risk for developing active myeloma in the short term. So as we alluded to, this is a very heterogeneous group of patients. And again, some behave more like MGUs. Some actually are more likely to be active myeloma in the very near future. And so for that reason, the risk of progression tends to actually be higher in the first few years after a patient is diagnosed with smoldering myeloma. And for that reason, we really want to watch these patients very closely. Once patients have gone about five years with a diagnosis of smoldering myeloma and have not progressed to active disease, their overall risk of progressing in the future actually goes down.
- [12:31]
B
And Sean, I think that's really important. And these are very, very key things to understand. And so we can think about MGUs kind of like maybe this is like a polyp similar to in colon cancer, right? Some polyps are pretty benign. They have a very, very low risk of progression to an active colon cancer. That's like MGUs. So imagine you have a polyp, right? Not all polyps are going to be a bad thing. You don't need to pluck out all polyps actually, if they're not causing any problems. That's why you don't do a colonoscopy every year. We do a colonoscopy sometimes every 10 years in patients, right? It's not that every polyp is going to be bad. And this is the same concept here. And it's important then to identify who's at higher risk for developing this multiple myeloma. Because CRAB in its name is bone disease and potentially renal disease. And these are things that we definitely want to prevent. The other thing that I'll mention is the addition of SLIM to our definition of multiple myeloma. If you could imagine, there have been many patients then who were called MGUs, who were called smoldering myeloma, who then now have a diagnosis of active multiple myeloma. Because of slim, meaning just based on biochemical markers, they now have active multiple myeloma. This is an update that the IMWG did in 2014. And what that does, if we really think about it, we need to think about how many of those SLIM patients who had the SLIM criteria only progressed to have hypercalcemia, renal disease, anemia, or bone disease. And if you look at historical studies, about 80%. But if you look at modern studies, maybe it's a little bit lower than that. Maybe it's maybe 40 to 50%. So it's really complicated when you think about the landscape of myeloma. And that's why you'll hear a lot of chatter from both sides saying, don't treat any high risk smoldering myeloma. The SLIM criteria really changed everything. And this is why the controversy. So we're just bringing this up so people can understand a little bit better why there's controversy here. And when it comes to the SLIM criteria, remember, not every single patient with SLIM is definitely going to develop an active multiple myeloma per CRAB criteria. It's that they have a very high risk of doing that, 80 plus percent in historical studies.
- [14:38]
C
Yeah. And I think it's so important, like you said, to try and identify which of these are tubular adenomas, which of these are villous adenomas. Right. Like, we have a decent way of doing that in other tumors. And it's clear from your description of how heterogeneous this population is that there's gotta be some subset that's just so high risk that we have to treat it as morally equivalent to overactive multiple myeloma. And so state of the art 20, 25, which is when this is being recorded for all of our listeners in the distant future. How are we doing that now? How are we figuring out who we should submit for treatment in that smoldering category and who we just need to watch? I get that if they've had it for five years, great. We can kind of just watch them. But is there a way to know sooner than that?
- [15:19]
A
So for the longest time, as you guys were alluding to it, was a lot More simple. It was simply that we observed and didn't treat patients with smoldering myeloma. But now, as you guys have defined, we have some characteristic findings that we think about that may indicate who is at higher risk, like Dan was alluding to. So Sean just went through that 20 to 20 rule, which again is a bone marrow plasma cell population of more than 20%, an M spike of more than 2, or a free light chain ratio of involved to uninvolved of greater than 20. And if somebody has two or more of these, then they are by definition deemed a high risk smoldering myeloma. And these patients have approximately a 50 risk of progression at two years. We're also starting to integrate more cytogenetic and genomic risk factors into our calculations about who to treat. And so recall some of the other high risk factors that we had previously discussed. And this includes a translocation 14, 16, translocation 1420 and translocation 414. There's also deletion 17p. Remember that 17p is associated with that TP53 mutation and a gain 1q and a. Definitely go back, take a look at these numbers and these mutations. They are a favorite on the board. So just pay attention to those. And really, guys. The first studies to investigate the treatment of high risk smoldering myeloma was a trial known as the Qi Redex trial, which was a randomized control phase 3 study that looked at the role of lenalidomide and dexamethasone versus observation in these high risk moldering myeloma patients. So this study was actually published in the Lancet Oncology in July of 2016 and it took place at 22 centers in Spain and in Portugal where they randomized patients one to one to either the lenalidomide plus dexamethasone arm versus observation and then they were stratified from time of smoldering diagnosis to enrollment, which was either less than equal to six months or more than six months. The patients received nine four week induction cycles followed by maintenance lenalidomide for up to two years. And the primary endpoint that they were looking for was progression to symptomatic myoma and secondary endpoints for overall survival, response rates and safety. And what is interesting, I think here was that the median follow up at 75 months suggested that the time to progression wasn't reached in the treatment arm and it was 23 months in the observation arm. The median overall survival was also not reached in the treatment arm and was 117.6 months in the observation arm. And so what these data are suggesting is that perhaps in these higher risk patients there may be a role for treatment early on to try to prevent the disease from getting to overt signs of myeloma.
- [18:05]
C
Let's take a moment to learn more about the sponsor for today's episode.
- [18:09]
B
Fellows, your network is everything. With Primum, you can expand yours instantly over 100 top oncologists ready to share their experience. Ask anonymously or by name about cases, data or careers. The smartest people ask questions and on premium you'll get answers in about two hours on average. It's mentorship you can trust completely free. Don't wait. Join today at Premum co. That's P R I M U M co. And as a little bit of a kicker to that, I'm actually on Premum as an expert. So find me and ask me a tough question. And one thing I want to highlight here is that as we go through these studies and Sean will go through the next study, the inclusion criteria for all these studies are all over the map. And the big question that I have is how many patients had a PET CT for did their staging imaging, was it appropriate? Meaning did people actually have active multiple myeloma by more sensitive imaging techniques? And we randomized them to observation. Right. So that's the flaw in many of these studies. And so this study here had a major flaw in it in that one, we're not truly including the high risk patients. And then two, you may have randomized patients to observation who actually had active myeloma. And number three, if you're in the control arm and you got observation, when you get active myeloma, you probably should get lenalidomide and the patients did not. And so when you look at overall survival in all of the studies we're going to talk about, that's the biggest flaw in many of these studies. So we have this original study, Sean, the Lendex versus Observation gave us some initial sort of information. It was a smaller study. They called it this randomized phase three, but it was a very small study. Can you tell us a little bit more about this ECOG study that was published after that?
- [19:49]
A
Yep.
- [19:50]
D
There was another study that looked at the benefit of lenalidomide alone in patients with higher risk smoldering myeloma. And so this is the ECOG E3AO6 trial and this was published in JCO in 2019. So this was a phase 3 trial in patients with intermediate and high risk smoldering myeloma as defined by the Mayo 2008 criteria, which was bone marrow plasma cells greater than or equal to 10% and an M protein greater than or equal to 3 or both. Randomized to lenalidomide versus observation the primary endpoint for this trial was PFS, and secondary endpoints were overall survival, response rate, and safety. PFS was significantly longer in the lenalidomide ARM 1, 2 and 3 year PFS was 98, 93, and 91% for lenalidomide versus 89, 76, and 66% for observation alone. That's a hazard ratio of 0.28 with a 95% confidence interval of 0.12 to 0.62. In terms of overall survival, there were two deaths in the lenolidomide group and four in the observation arm, and this was deemed not significant based off the 95% confidence interval. In terms of grade three and grade four adverse events, there were 28% noted in the lenolidomide arm, namely rash, fatigue and infection. And so what's important to realize is that the authors do note that the biggest effect was in the highest risk patients and that although they did include patients who were not high risk, they did not advocate for treatment of these patients outside of these trials. And so despite this data, these regimens were not approved for use and are listed as a category 2B recommendation by the NCCN.
- [21:27]
B
So here's an interesting thing. The FDA said no approval for lenalidomide for these patients in this randomized study because there's no overall survival benefit. So the idea was, if we're treating these patients who are asymptomatic and there's no OS benefit, what are we doing? And the big question and the big critique here is for those who progressed, are we preventing somebody from getting a bone fracture or renal failure? And the big, big criticism here is that that data was not reported. We didn't know how many patients actually had a symptomatic bone fracture or renal failure that was not reversible because those are the two big endpoints that we truly care about by treating somebody early versus later. If a third of them, you know, I'm doing a little bit higher number, there is 28%, but let's say roughly one in three patients are going to get a grade three, four adverse event, which is a pretty big deal, we think about the cost of treating these patients. But all this is kind of a little bit more irrelevant now because we have the most updated study and the Aquila trial that led to an FDA approval. So can one of you Go through the Aquila study, sure.
- [22:25]
C
So this is a phase 3 open label multicenter randomized trial. So all the buzzwords in NEJM in 2025 and this is a study where patients had to have a confirmed diagnosis of smoldering myeloma within the past five years with measurable disease, an ECOCHG performance status of 0 to 1. So pretty good, pretty fit and high risk features. And that's talking about a bone marrow clonal plasma cell percentage greater than 10% with at least one of the following criteria A serum M protein greater than 30 grams per deciliter greater than 3, an IGA class, a free light chain ratio of 8 to below 100. Again remember greater than 100 we're talking about myeloma, so between 8 and overt myeloma or bone marrow clonal plasma cells between 50 and 60%. So just barely not meeting criteria for active myeloma. And that was the population that was included. So one of those extremely high risk features plus greater than 10% bone neuroplasma cells. We'll have that all listed in our show notes too, so don't worry about trying to jot that all down while you're like driving to work listening to this. And all patients were also very importantly required to have a PET CT and MRI to make sure that they didn't actually have active myeloma. Patients in the trial were randomized to active monitoring versus single agent daratumumab which after the initial loading period was continued every four weeks for up to 36 months or until progression to active myeloma. The primary endpoint was progression free survival defined as the time to progression to active myeloma according to the International Myeloma Working Group. The IMWG criteria. Secondary endpoints included overall response, looking for a partial response or better and complete response, disease progression to myeloma, initiation of first line treatment for active multiple myeloma and death from any cause. So a lot of secondary endpoints in there too. Looking at that first endpoint, the primary endpoint, the five year progression free survival was 63.1% in the Daratumumab arm versus 40.8% in the monitoring arm. The hazard ratio of 0.49. That was a statistically significant hazard ratio as well with a confidence interval between 0.36 and 0.67. A total of 15 patients, about 7.5% in the daratumumab group and 26 patients or 13.3% in the active monitoring group died during the trial period. The hazard ratio of 0.52, also statistically significant. The overall survival at 5 years was 93% with Daratumumab versus 86.9% with active monitoring. Based on this data, the NCCN does now list daratumumab as level 1 indication for smoldering myeloma. But additional clinical trials were still recommended for additional information.
- [25:07]
B
So I want to point out a couple things as we get into the discussion of this for the treatment of smoldering myeloma. So one thing dan said is 10% plasma cells plus one of these really high risk features. And we include that on purpose, saying that on purpose because technically these aren't really the true high risk features that we talked about with the two 2020 criteria from the Mayo group. That's really been adopted as the high risk smoldering patient. If anyone had IgA smoldering myeloma, they could be in the trial that's not necessarily a high risk patient. So you can see here the inclusion criteria is still quite heterogeneous and broad. Keep in mind this trial was designed before the 2018 update for these Mayo criteria were really adopted. So you can't blame the authors for doing this. But that's something that's really important to think about. The second thing that we had mentioned here was clearly there's a PFS benefit that is obvious. Something is always better than nothing. There's no doubt about it, right? But the interesting thing to me is that there were many patients, you know, over 40% of patients at five years in the observation arm that still didn't need treatment. That means we're over treating the rest of those people, right? That 40% of patients, we over treat it. If we treat everybody with daratumumab. The third thing that I think is really important is when we said overall survival, when I think about overall survival, I think about what did the patient get at progression. We talked about the Lendex trial, the Spanish trial, from way back, and we knew that's what the criticism of that was. They didn't get linamidic progression. So at progression, are these patients getting modern myeloma regimens? Only about a quarter of patients got VRD treatment with bortezomib, lenalidomide and dexamethasone, a triplet, which would have been reasonable standard of care. And only 18% of patients got daratumumab. So when I think about overall survival, I don't know if that's fair. The other thing is many of these patients cause of death in the supplementary Appendix was unknown. So I've had unknown causes of death and many times death was very, very shortly after they progressed to myeloma. It makes me question exactly who these patients were. Why were they actually dying from multiple myeloma or did they get substandard treatment? So this is why it's very, very important to know that today this remains an unanswered question. So, Sean, when you have these patients, can you talk a little bit about how often you're going to get imaging and labs? What did they do in this study that you might implement as an active surveillance arm? And who would you treat if you had a patient in front of you in clinic with daratumumab?
- [27:28]
D
Yeah, so typically with our smoldering myeloma patients, we'll want to reCheck Labs. So CBC, CMP, Spep and Serum Free Light chains about once every three to four months, as well as see these patients in clinic to help reassess for any symptoms that might indicate progression to active disease. This is really most important in the first five years. If patients have been stable for that time period, it might be reasonable to space that out a little bit further. Beyond that, one thing that this study did do was implement more routine imaging to reevaluate for any neolytic lesions that may not have been otherwise detected. While this is not necessarily standard of care at the moment, it is something that you could potentially consider for your patients that you are particularly worried about that are at high risk for progression. Otherwise, the main reason to reimage patients is if they have an area that's causing particular pain or that you're otherwise worried may represent a new lytic lesion. The question now is who would we treat with single agent daratumumab for smoldering myeloma? And this actually was very recently approved at the start of November 2025 by the FDA for regular use. And so this, I think is going to raise a lot of questions for what we should do for these patients. Since historically our paradigm has been primarily to monitor. Right now I'm not sure that there's a 100% clear answer. On one hand, I think it is hard to argue against an overall survival benefit generally, but as Vivek pointed out, there are certain limitations with the design of this trial that really raise the question of are we potentially exposing a lot of patients to over treatment and do these patients truly represent what we would expect in modern day practice, particularly when they progress and what types of regimens they're getting? To be honest, one of the main Areas where I think that this approval may be particularly helpful is as part of a shared decision making. So if I have a patient who comes to me with smoldering myeloma and is really, really concerned about their risk for progression and strongly feels like they would want to do something for treatment, we now have an FDA approved option. And so even if there's not a clinical trial available for enrollment, this is something that we can offer to those patients who meet the high risk criteria.
- [29:35]
C
I think that's great. And you know, it's such an important question, right? Who are we going to treat? Because on the one hand, you know, especially by the classic CRAB criteria, active myeloma is defined by organ damage happening. Be great if we could prevent organ damage from happening to people, you know, by treating in an earlier stage of their disease. On the other hand, we still consider myeloma something that can't really be cured. We kind of just have to treat it indefinitely with different types of treatment. Probably some population is going to be in long term remission without treatment, but we still haven't gotten there for the vast majority of folks that we treat. And so exposing someone to a treatment early on, maybe we're taking that treatment out of being used in a later line. So it's a tough balance. You're right. Maybe there's shared decision making here. Somebody's already CKD4 before they had smoldering myeloma. They really don't want to progress to esrd. Maybe you're a little more aggressive with them up front. So that was a lot of stuff. Good discussion. I think maybe we can break here and pick up again next week. Does that sound reasonable to everyone?
- [30:33]
B
Yeah, it sounds good to me. And the last thing I do want to say because I'm going to have one more thing to say here is that when you think, when you hear about the buzz and you look at nccn, it's easy to just give everybody daratumumab. It's fixed duration treatment, right? It's like why not give everybody daratumumab? But remember, 40% of patients didn't need that treatment. So that 85 year old patient do. All 85 year old patients need to get daratumumab because it does come with infection risk. We didn't talk about the adverse events in the study, but there were infections. Remember that. That's definitely a risk here for these patients. And don't hang your hat always on an overall survival benefit that wasn't powered for it. We talked about post protocol treatment, which is really important to understand when putting these trials in context that there was not adequate post protocol treatment in these patients. And the last thing is, if you may have the theory that, well, for those high risk smoldering myeloma patients, they basically have active myeloma, you're just waiting for a ticking time bomb. Why aren't we just going to treat them now? Well, that type of patient, we need to have better inclusion criteria for them in future clinical trials to really identify that patient who truly has active myeloma. Genomics in the future is going to be really interesting and really excited to see where the field is heading and when it comes to the nitty gritty information on this Aquila trial. When it came down to how many of these patients actually had bone disease, how many of these patients progressed from anemia, it was only about 9% of patients in the active surveillance arm progressed with bone disease and none of them were symptomatic fractures. So it's an important thing to consider that if you have them on active surveillance, as Shawn talked about, the annual imaging whole body MRIs are the most sensitive technique. With modern surveillance strategies, it's very reasonable to defer treatment in some of these patients.
- [32:14]
A
A really exciting time for plasma cell dyscrasias for sure, and a lot of information that's coming out constantly. So guys, I think this really is a great place for us to break this time. Listeners go back, digest this information. It was a lot and a lot of new updated data since the last time we talked about myeloma a couple of years ago. So until next time, we'll see you all later.
- [32:35]
B
See you later.
- [32:36]
C
Peace.
- [32:37]
D
See you later.
- [32:39]
C
Sa.