The care of patients diagnosed with smoldering multiple myeloma (SMM) continues to evolve with the rapid release of new clinical evidence. Listen to this podcast with 2 experts discussing what healthcare professionals need to know about risk stratification, how to interpret evidence for early intervention, and how to decide between treatment and observation in an individualized manner. They will also discuss optimal treatment selection and sequencing considerations, proactive and mitigation approaches to ensure treatment safety, supportive care measures, optimization of shared decision-making and patient communication, and emerging therapies and key ongoing clinical trials for patients with high-risk SMM.
In this podcast episode, Natalie S. Callander, MD, and Tom Martin, MD, discuss the optimal approaches for the determination of whether a patient with high-risk SMM requires treatment or observation, including:
Presenters:
Natalie S. Callander, MD
Professor of Medicine
Director, Myeloma Clinical and
Cellular Therapy Program
University of Wisconsin Carbone
Cancer Center
Madison, Wisconsin
Tom Martin, MD
Professor of Medicine
Associate Chief, Hematology/Oncology
UCSF Medical Center
San Francisco, California
Link to full program:
https://bit.ly/4wqpYzU
This transcript was automatically generated from the audio recording and may contain inaccuracies, including errors or typographical mistakes.
Dr. Natalie Callander (University of Wisconsin): Welcome to our podcast, where we discuss topics in high-risk smoldering myeloma. My name is Natalie Callander. I am at the University of Wisconsin. I am so pleased to be joined by my colleague, Tom Martin.
Dr. Thomas Martin (University of California, San Francisco): Hi there. I am Dr. Thomas Martin from the University of California in San Francisco. I am very happy to join Natalie for our discussion on smoldering multiple myeloma.
Dr. Callander: I think everybody here is familiar with the fact that we define smoldering myeloma as this intermediate stage between MGUS and actual myeloma. In today's modern era of more sequencing of genetic profiling, what diagnostic approach, Tom, do you think should be applied to distinguish high-risk smoldering myeloma from active myeloma, particularly if we are going to think about treatment?
Dr. Martin: So, In my mind, when I think about somebody who has MGUS or smoldering myeloma, the first thing that puts them from MGUS to smoldering myeloma is the bone marrow biopsy showing more than 10% plasma cells, or the M protein, if it is more than three grams in the peripheral blood.
When I have somebody with smoldering myeloma, the first thing is really to do a risk assessment. I typically use the 2/20/20, where it is really looking at basically the bone marrow plasma cells, the involved/uninvolved free light chain ratio, and the number of plasma cells in the bone marrow. Greater than 20% plasma cells in the bone marrow is a high-risk feature. Having an M protein of two or greater is a high-risk feature, or having an involved/uninvolved free light chain ratio of greater than 20 is also a high-risk characterization.
If you have two out of three or three out of three of these, you are considered a patient who has high-risk smoldering myeloma. Using that 2/20/20 risk stratification, those high-risk patients have close to a 50% chance of progressing to active myeloma by the two-year time frame, which is pretty substantial. That is a 25% per year risk of developing active multiple myeloma. Those are the patients that we should consider, if it is time to intervene with some type of therapy?
Do you just use 2/20/20, or do you incorporate FISH?
Dr. Callander: There are a couple of things to make a point. One is that, at least in my mind right now, for patients who walk in the door, clearly with what appears to be MGUS, and those are typically patients who have under a gram of monoclonal protein. We know from old Mayo criteria that those patients who have an IgG monoclonal protein, it is less than 1.5 g their FLC ratio, if it is normal, we really do not want to advocate, in my mind right now, that every single person needs a bone marrow biopsy. We are really talking about people who do come in the door with, like you said, the criteria that is easy to see by just lab testing, like the greater than two grams per deciliter of monoclonal protein or a high FLC ratio. That is important now.
If I feel that the patient should go ahead and have a bone marrow biopsy, absolutely, I am very interested in their FISH results because it has now been documented in a number of different studies that certain abnormalities seem to be associated with a higher risk of progression. A little bit of variation from study to study, but it does look like the presence of 1q, either gain or amplification. The older cytogenetic change, 13q, either deletion of 13q or just monosomy 13, seems to be involved. Then there is t(4;14), and also translocation of t(14;16), and some people would even throw p53 in there if it is present or not. I do think knowing those, in addition to the other serum markers that you mentioned, as well as the bone marrow findings, really help you identify patients who probably need to be considered even now for treatment.
Dr. Martin: I completely agree. The models can potentially be enhanced by incorporating some of the genetic information that we are currently receiving, and whether the presence of maybe a RAS mutation or that APOBEC genetic risk can potentially really enhance our ability to select out those patients, in my mind, with smoldering myeloma that actually have a cell genotype and phenotype that is more like active myeloma, they just do not have that bulky disease at that point.
Dr. Callander: That is an excellent point, Tom, because we all know that risk stratification continues to evolve. There have been people who have commented that the high-risk smoldering group of 15 years ago is actually a different group of patients, since now we do so much advanced imaging. We went through the change in 2014 with SLiM-CRAB. Those patients with the FLC ratio above 100 or higher plasma cell percentage above 60, they used to be included in our smoldering definition, and now they are out, so that grouping is a little bit tighter. I think we are going to see in the near future things like the inclusion of RAS mutations. That does seem to be important, MYC and the APOBEC, and then some combination of sequencing may end up happening on a routine basis as these tests become more available to us as practitioners.
Right now, I am not routinely sending sequencing. I do not know if you are, Tom.
Dr. Martin: Not really. Not for smoldering myeloma. For active myeloma, we have been doing a sequencing panel so that we can pick up those patients that have the new IMWG high-risk definition.
Dr. Callander: One of the most important things that we have all learned in the last 10 years or so is how important whole-body examination of some sort is. We have a lot of choices. You can do whole-body MRI, you could do a PET/CT, or a low-dose whole-body CT. Do you have a preference, if you see a patient with smoldering myeloma, which one of these you are going to use?
Dr. Martin: I actually do. I usually use a whole-body MRI. It is able to pick up these small focal bone marrow lesions better than any other modality. I do choose a whole-body MRI. Again, if they have two or more, then that actually fits the definition of SLiM-CRAB, and they would then be in the active myeloma category. I would start therapy on somebody like that. How about you?
Dr. Callander: We have an intervention in our institution where we have been studying PET/MR. We do those as well. A lot of the studies that are underway actually call for PET/CT. We usually do a combination of MRI and PET/CT, depending on how we are going to triage that particular patient, whether it is going to be for a study or whether it is going to be for maybe what we would explore later, standard-of-care treatment for high-risk smoldering.
The study that we do not do here is low-dose whole-body CT. There are some limitations, just like you said, you are not going to see the marrow lesions, potentially. You probably would see some extramedullary disease if it is big enough, but I think that we have been more in the same ballpark that you have been in terms of a whole-body MRI.
I know that we are all still trying to get used to the 2025 IMWG high-risk myeloma definition. This is not really something that is moved into smoldering myeloma at this point, although people are scrambling to go backwards and see if we can analyze patients using that high-risk definition. I have not seen any large data sets – I do not know if you have – looking at that re-evaluation.
Dr. Martin: No. I do think that all the smaller re-evaluations that they are doing with the new IMWG high-risk definition suggest that it actually does pull out a group of patients that are having lower progression-free and overall survival than those that do not have the high-risk features. Just to review, it now includes patients that have a chromosome 17 deletion or a TP53 mutation. It is typically in greater than 20% of the cancer cells. Patients can have the t(4;14), our typical t(4;14), t(14;16), or t(14;20) translocations, but they are only considered high-risk if they have a co-occurring chromosome 1 abnormality, either a 1q gain or a deletion of 1p. If you have both a 1q gain and a deletion of 1p, you are also considered high risk. In there is also elevated beta-2 microglobulin. Those people that have high beta-2 microglobulin are still considered high risk. We do send for p53 mutation these days. The rest you can pick up by FISH testing.
Dr. Callander: It is interesting, with just that beta-2 elevation, that we are still using that old definition, and even re-evaluations of older studies have shown that those ISS III or Revised ISS III patients still seem to do worse off than others based on that beta-2. Now we know that that needs to be interpreted in light of a normal creatinine, since, of course, that just gets pushed up by that.
Let us take a look at some of the evidence out there for early intervention. We had a number of studies going on years ago that were trying to look at the drugs of the day. That included things like thalidomide, there was an older study with melphalan and prednisone for smoldering myeloma, and none of them really showed any particular benefit – in some cases, maybe more of a detriment. Now that we have better choices for drugs, are you considering treatment in any particular interval that you think is appropriate? What do you pick?
Dr. Martin: That is just a hot topic in myeloma, isn't it?
Dr. Callander: Yes.
Dr. Martin: First things first is really to assess the risk status. For my patients that have low-risk smoldering myeloma, I will usually do their laboratory values every three to four months, routinely. I usually will not repeat a bone marrow biopsy. In terms of MRI, I may actually repeat an MRI, but if the labs are all completely flat, meaning they have non-proliferative disease, I typically will not even do that. I am just doing q3–4 months. Patients that have high-risk smoldering myeloma – I do like to follow them over time, versus take an individual assessment and say, "You have high risk. Let us start your therapy tomorrow."
For people that have truly high-risk by the 2/20/20 model and potentially high-risk FISH, I will follow their labs sometimes as frequently as every six to eight weeks, with bone marrow biopsies yearly, and potentially an MRI either yearly or potentially twice a year if they really have high-risk disease. How about you?
Dr. Callander: This is also interesting that there is a wide variation in practice that I have seen, talking to colleagues. We all agree that if people have what you want to call an evolving pattern, so let us say between the intervals, their M protein or their light chains are going up maybe 25% or more. That is an easy call to have those patients, maybe, as you said, every three to four months.
For patients who are originally deemed to be low risk, I tend to have them come back for another visit, maybe in a shorter interval of four months, just to see if they are evolving or not. Then, just as you said, to try to back them off, maybe to six months. Where I think it is controversial right now is just as you said, how much are you going to narrow these individuals? How much are you going to scan these individuals? I know some colleagues will do it yearly, just across the board. I do not know if we have enough evidence to recommend that routinely for patients. Certainly, if they have an evolving pattern, that makes sense. Just like you, I am not routinely repeating marrows on patients.
What is also very humbling in this particular group of patients, and I am sure you have seen this many times, is the smoldering person who actually, on their next visit, their M protein is lower. I have certainly seen that where you just feel maybe it was a good idea not to intervene or not to consider perhaps jumping the gun a little bit. That is where we mentioned the molecular profiling. They may help us tease out the patients who really do not need intervention in the long run.
For people who do not see many smoldering myeloma patients in their practice, do you think that at the time that they initially walk in the door that we would do that bone marrow biopsy, like we talked about, we would do some FISH and cytogenetics if you have molecular profiling potentially available? Let us say that they fall into a low-risk group. What would you then recommend? When should their next visit be?
Dr. Martin: I usually will do the labs again every three to four months initially. I will see them back in six months just so that I at least have a second or a third lab value to try to see, as you just discussed about the evolving phenotype. Those people, who their M protein is going up fast, they need to also remember that we have to follow the serum free light chains.
Those that have M proteins that are rising, you do have to wonder if that actually is going to be active myeloma in the short span within a year. You can consider therapy at that time, or at least make sure you are following them close enough so that you can intervene, hopefully, before they develop any SLiM-CRAB or severe complications of active multiple myeloma.
Dr. Callander: It is time now to think about patients who we think need treatment versus those that we can observe? It is helpful to just take a look at some of the older trials that laid the foundation.
Most people are very familiar now with the QuiRedex trial. A small study, 119 patients randomized to either lenalidomide with dexamethasone for up to two years. Dexamethasone could be restarted if there was evidence of progression versus observation. While this study had both progression-free and overall survival benefit for those receiving lenalidomide and dexamethasone, it really did not trigger a big tidal wave of moving to lenalidomide intervention. Probably that has to do with some concerns. Around the time that this study came out, there was more concern about secondary malignancy signals in the lenalidomide post-auto use. The other concern is that this study probably did contain some patients with actual myeloma based on the era that it was developed, and it did not require advanced imaging.
Along with that, then some years later, we had the ECOG study E3A06 that actually randomized patients to just lenalidomide alone versus observation. In this case, the lenalidomide was given until progression. This study did require advanced imaging, but because of concerns about the enrolment numbers, the entry criteria was changed halfway through the study or so, to include actually low-risk smoldering myeloma. The study did complete and the conclusions after about a median three-year follow-up, where the progression-free survival was significantly enhanced by the inclusion of lenalidomide, meaning that the hazard ratio was like 0.24. It was quite striking, but once again, lenalidomide was not really adapted in big numbers by the community. Do you have any thoughts about that? Why that occurred or why that did not occur?
Dr. Martin: You spoke to the issues that are important when we think about treating smoldering myeloma. These are asymptomatic patients. With every patient, you have to think about risks and benefits. What are the risks? What are the side effects? What are the benefits? None of these studies have actually shown curative potential for treatment for smoldering myeloma. That is important. With the QuiRedex and the ECOG study, both using lenalidomide, lenalidomide has side effects. It has some significant side effects. Fatigue, especially taken over time, GI toxicity. They have problems with cytopenias, and even some patients in those trials, when they did develop myeloma, they had difficulty with collecting stem cells.
I am not a big fan, of using lenalidomide-based therapy in general, especially until progression in patients that have smoldering multiple myeloma. I think most of the community feels the same way about that.
The AQUILA trial is a big difference. I am curious what you think about the AQUILA trial, observation versus the anti-CD38 antibody daratumumab for a time-limited period for three years. Daratumumab is actually pretty well tolerated. In terms of the risks, the biggest risks with daratumumab are the risk for an infection. Perhaps there is a little bit higher risk of grade 3 or 4 pneumonias in patients receiving daratumumab than patients in the observation arm.
At 60 months of follow-up, the median progression-free survival was 63% in the daratumumab arm, and it was 41% in the observation arm. That led to a 50% reduction in basically the progression to SLiM-CRAB, which I thought was pretty substantial. What did you think about the AQUILA trial?
Dr. Callander: The AQUILA trial is the largest phase III trial to date conducted in smoldering myeloma; 400 patients, which is pretty impressive. Then, as you said, the fact that this is time-limited therapy. The other thing is, sometimes timing is so, so critical here because since daratumumab was introduced in 2015, most people who treat myeloma patients are quite familiar with it and quite comfortable with it. Of course, the other advantage here is that this was the subcutaneous formulation, and so the toxicity – you did not have all the infusion-related side effects that we know used to happen when we were using IV.
For those reasons, this kind of therapy, particularly going to month eight, everybody is pretty comfortable with that. This has really been a game changer. One of the things that is pretty clear, at least in the first couple of analyses that have come out, including the update that just occurred at ASH by Pete Voorhees, it still looks like maybe this therapy should be confined to higher-risk individuals. The definition of high risk in this study varies from other studies, but nonetheless, those patients who met that high-risk 2/20/20 definition, it was analyzed really seemed to benefit the most. Even those who had the intermediate also did benefit in terms of their PFS.
The other really striking thing about this study, you alluded to this before, is they have the overall survival statistically significant result, which QuiRedex did, but in this study, this was really seen as, just as you mentioned, a game changer.
Dr. Martin: I was really impressed also by, in the daratumumab arm, 20% of patients progressed to active myeloma and required therapy over 24 months, whereas it was 40% that progressed to active myeloma in the active monitoring arm. That is a big difference when we talk about smoldering multiple myeloma.
Who is your candidate to receive daratumumab for high-risk multiple myeloma? What risk factors do you see this person should get daratumumab?
Dr. Callander: We are still trying to put people on trials. The more rigorous we can do interventions, the better off everybody will be. Having said that, what I see more and more is maybe you have noticed this in your practice, but people in the community are embracing this. They are not even necessarily sending the patients for us to weigh in as to whether they think using daratumumab is a good idea or not. There are a lot of people, like I said, they are just so comfortable with daratumumab. They just feel like this is something that they know, they understand, they can explain it well to patients. They are very comfortable with it.
In terms of my own practice, we have seen a few individuals who have been sent in to say, do we agree with the plan to start them on daratumumab? I try to make sure that the practitioners pay some attention to the hypogammaglobulinemia you are going to get from daratumumab. You do need to make sure that patients, at least in my opinion, get some prophylaxis for zoster. We tend to put people on Bactrim as well. I do think that is something that people need to understand that that is probably going to happen as a result of the treatment that they will have, perhaps even more immunoparesis than they started off with at the time of their original diagnosis of smoldering.
Dr. Martin: Yes. There is certainly very strong evidence for delaying progression to active myeloma in the AQUILA study. Personally, I am like you; I would rather treat patients at the current time on a clinical trial if we have one open and they fit the high-risk criteria. The trials that you discussed did not really have a uniform high-risk definition. None of those were really, truly all the 2/20/20 high-risk patients. However, if you just take those 2/20/20 high-risk patients, they all benefited from treatment versus observation. That is, I think, an important part.
It is pretty easy for me, in a high-risk smoldering patient, to think about and to discuss daratumumab. I probably do it more commonly in an older, perhaps less fit patient that I think daratumumab is a great treatment that they can tolerate without many side effects. I still am a little nervous in the younger high-risk patient, especially someone that might have abnormal FISH or abnormal genetics. Is daratumumab by itself enough? Should I wait and give them the four-drug combination? I am curious what your practice is.
Dr. Callander: There has been this tension in the treatment of smoldering myeloma if you decide to treat between what we hope is resetting to maybe an MGUS-like state versus really taking more of a curative approach or elimination of the clone approach. The studies that have had the more aggressive treatments, just to mention a few, like GEM-CESAR, where they were using induction with KRd, with carfilzomib, lenalidomide, dexamethasone, and a stem cell transplant, followed by some consolidation, and then lenalidomide and dexamethasone maintenance, they were able to show some very exceptional MRD negativity when they have done longer term follow up. There has been a price to pay. In those individuals, there were some early deaths from toxicity. We are going to continue to see that approach evolve.
Shaji Kumar recently updated his ASCENT trial, which was carfilzomib, lenalidomide, dexamethasone, and daratumumab. Pretty intensive two-year program. This is a phase II trial. They showed a progression-free survival that is impressive. We may need to see more time go by for that approach as well to say whether that should be considered standard of care, particularly in a younger individual. It did not contain the stem cell transplant, which probably people would be in many ways more comfortable omitting at this point.
Dr. Martin: In smoldering myeloma, even in high-risk smoldering myeloma, there are some patients that it would be years before they progress. Are we overtreating some patients? Then with daratumumab, are we undertreating them without giving them a triplet or a quad-based therapy? It is a big decision between the physician and the patient on when to move forward, and also what therapy to use when moving forward.
There is, out there, too many other studies. There is doublets of lenalidomide-dexamethasone versus the triplets of the CD38 antibodies with lenalidomide-dexamethasone; we have daratumumab + lenalidomide-dexamethasone, we have isatuximab + lenalidomide-dexamethasone. Then, like you said, there is other immunotherapies that are really showing quite a lot of promise in this domain.
Dr. Callander: The dynamic right now is really trying to figure out is there really the opportunity here to completely prevent myeloma progression and not cause any long-term side effects or maybe an immune alteration, if you want to put it that way, that would, in the long run, be detrimental.
No one should take away from this discussion that we are advocating across-the-board intervention for every smoldering patient. There are definitely people who are going to benefit from sitting on the fence or sitting on their hands, we do not want to imply that every single smoldering patient needs to go right into therapy right now. I have many patients that I continue to follow who have maybe zero or maybe one of those 2/20/20 features that I think right now that we still should just observe them.
Dr. Callander: Tom, I have a question for you, and this has happened with a couple of patients. Let us say you have a person who is getting maybe daratumumab off protocol or perhaps even lenalidomide, although you said you do not use that very much. If they start to show some signs of progression, meaning their monoclonal protein goes up, what is your strategy for handling that situation? Let us say they still have no myeloma-defining events at that time.
Dr. Martin: In the IMWG, we discuss a couple important things. One is, when you start somebody with smoldering myeloma on therapy, they have not really reached the definition of active myeloma. The worry is that you are going to limit the options, especially options for clinical trials down the road? We discussed that we want to make sure we include patients in clinical trials that have been treated - with smoldering myeloma - and that we should all try to define eligibility that allows enrolment. We can actually answer the question that you just asked.
That said, if somebody progresses on daratumumab or progresses on a CD38 antibody, then probably I will not use the CD38 antibody potentially for the next induction therapy for multiple myeloma. I actually would choose the triplet. Probably, I would give them the triplet, our standard triplet of lenalidomide, bortezomib, and dexamethasone, or VRd. I would start there. If they are transplant-eligible, I would take them to transplant. Then I potentially would consider lenalidomide maintenance, or if they were high risk, I would consider a two-drug maintenance. That could be lenalidomide plus daratumumab or a CD38 antibody. It could be lenalidomide plus bortezomib. It could be bortezomib plus daratumumab, depending on what they have tolerated with their regimen.
I do try to limit re-exposure right away if they have progressed on that therapy. How about you?
Dr. Callander: I think that approach makes sense. This is something I really struggle with. I think it is an easy call if you see a person who is ratcheting up and maybe their hemoglobin is not quite less than 10, but it is clearly going down, you can say, "That person should be moved over to real myeloma-type therapy."
I am paying close attention to the trials that are allowing retreatment of a smoldering patient who is still smoldering with a different intervention, because I am very interested to see how those patients ultimately do. As we know, the treatment for active myeloma is changing so quickly. In the long run, does it benefit those patients to not, I guess, if you want to use the analogy, 'pull the trigger,' so to speak, for myeloma treatment, and whether they are just better off in the long run, going through maybe another iteration of smoldering treatment, whether that is with a trial or off trial? I have to say that I am in favor of that, but I absolutely understand for those patients who look like they are really ramping up their protein levels to take them and say, "This is close enough to myeloma that I am going to treat them that way."
Dr. Martin: If we further dig into treatment selection and sequencing considerations, we think about what are the important factors to consider to appropriately select the right patient in the right sequence of treatment. These will include disease-associated factors like we have talked about. Do they have the genetic profile of somebody that has high-risk as well as high-risk smoldering myeloma? Also, patient-related factors: are they frail or are they young? Are they fit or are they not fit? Logistics plays a vital role in it, like distance to the treatment center, and obviously, comorbidities. In some patients, you want to avoid dexamethasone because they have bad hypertension or they have hyperglycemia, difficult-to-control sugars.
The daratumumab regimen is a pretty good regimen because it is very limited steroids. It is just steroids in my mind for the first couple of doses, and it is done.
Then there are treatment-related factors. I am curious what your approach is, Natalie, with somebody that has the high-risk FISH, and they have high-risk smoldering myeloma by the 2/20/20. That makes me nervous to give them daratumumab as a single agent. How do you treat that patient?
Dr. Callander: Our bias is we are trying to get everybody on the ECOG study. You mentioned triplets, which is lenalidomide, daratumumab, and dexamethasone versus lenalidomide-dexamethasone. I do think that the steroid for a limited amount of time, that the trial includes, can be helpful. However, I would agree, I would be a little concerned about daratumumab just on its own. If you dig into the protocol for AQUILA, they did recommend a dose of steroid going through the entire three years. With daratumumab, I have not seen a breakdown about how many of those patients actually got that for each of the doses over the 36 months, but that is an interesting question.
I would agree with you that that may not be enough. Having said that, I certainly have had the experience, and I know this is not perhaps your favorite intervention that I have treated some individuals off protocol with lenalidomide. In several cases that I have done this, these are individuals who just cannot get to our center or really anybody's center because of some family considerations. I have actually found the lenalidomide pretty easy to do at lower doses. I still have that in my back pocket as a consideration for patients who just cannot get to clinic and do it on a time-limited basis. I have had what I would consider some very good results again, not necessarily putting them in remission, but controlling them and putting them back to an MGUS-like state.
Dr. Martin: You said time-limited. Do you do it until they achieve a plateau?
Dr. Callander: I started doing this, I guess, in my own practice when QuiRedex came out, so I have copied that, I guess I would say. I usually try to limit it to two years. I have certainly appreciated for the E3A06 trial. The median time that people were able to stay on lenalidomide was about two years anyways, so I just feel like that is the realistic approach. That is what I have done. I have not really treated to maximum response as you are suggesting, but that has been my practice to try to adhere to the studies that are out there.
Dr. Martin: Great. Let us talk a little bit more about safety and supportive care that you use for the smoldering myeloma patients. You had talked about earlier, that daratumumab single agent is associated with a higher risk of pneumonia. You had mentioned IVIG. I am curious, do you use a level in the blood lower than a certain level that you give them supportive IVIG, or will you only do it in patients that had pneumonia or had a bacterial infection or recurrent bacterial infections?
Dr. Callander: We all started using daratumumab either singly or in combination, going back to the first studies that came out. I do not believe, unless I was late to this party, that people were saying initially everybody should get IVIG, even though we all were impressed that the immunoglobulin levels were pretty low.
For the smoldering individuals, I am not routinely prescribing IVIG if they are getting daratumumab unless they are having a grade 3/4 event and their IgG level is falling below 400. IVIG is a wonderful option to have. It is not a perfect intervention, as I am sure you are aware; it does not prevent all infections by any means, but for a person who has had a hospitalization for a respiratory event or another infection, I would certainly consider it.
Dr. Martin: You had mentioned prophylaxis – acyclovir and VZV prophylaxis. I usually use VZV prophylaxis when they are on steroids. Otherwise, probably, I will not use a PJP prophylaxis. There was data in the first couple of cycles of using an antibacterial oral regimen like Levaquin for the first couple of cycles to prevent bacterial infections. Do you ever do that in smoldering myeloma?
Dr. Callander: No, I have not. The way our ECOG trial is set up, you have an option to consider it if you want, but it is not mandatory. We actually have done that now much more aggressively than we used to because we have had a few situations where we had, within the first couple of cycles, some early, really serious, life-threatening infections in people who are not getting it. I would say Levaquin prophylaxis or something similar to that, we are doing an active myeloma, particularly if they are on quad therapy. In the smoldering space, we are not routinely doing it outside of a clinical trial unless it is mandatory.
Dr. Martin: What about bone-targeted agents?
Dr. Callander: Yes, I am very influenced by older studies that really did not show any benefit for that. I know that there is, some Scandinavian data that has suggested that there is some bone disease in people – in particular, they were looking at individuals with MGUS. While that is interesting research, we have not routinely done it. There are some reasons why I am not sure that everybody should be on bisphosphonates. How about you?
Dr. Martin: For us, we do check the bone density. It is reasonable to check the bone density. If they do have osteoporosis, then I will start a bone-targeted agent. If they have osteopenia, then pretty much we recommend vitamin D and calcium replacement. I try to do as much exercise as possible, and then we will repeat it in two years and see if that has made any improvement in their bone density. At least it is not getting worse.
Any other recommendations for community practices to operationalize this risk stratification with imaging, cytogenetics, and specialty care, etc?
Dr. Callander: We want to take home the message here that the simple tools that we have are very useful. The 2/20/20, people feel like it is too simplistic, but it is really stood up pretty well in these re-evaluations. That is a way to risk stratify that is available essentially to everyone. You can start with that. If you do do the bone marrow biopsy, absolutely pay attention to the FISH and cytogenetics to further refine the risk stratification. I feel like those are very easy tools, along with the advanced imaging. If you weed out those patients who clearly have active myeloma, you are doing a real service to your patients.
If you find a patient who just is purely high risk, I would still want to try to get them on a trial if at all possible. I do think that there is sufficient data now to consider daratumumab for those high-risk individuals. Again, I would say based on the older data, I would not take lenalidomide off the table either.
Dr. Martin: It is very difficult with the high-risk smoldering myeloma population in that you can follow them as closely as possible with 6-, 8-, or 12-week M proteins with bone marrows and X-rays, but they can come in with a fracture, or they can come in with renal insufficiency or hypercalcemia, where they really feel bad. That is a hard nut to swallow when you knew, "Man, if I just had started that agent, they might have done better." It is hard to watch people actually progress. It is really getting the experience of seeing more and more patients to try to decide what you are going to do and when you are going to do it.
Dr. Callander: I think along those lines, about whether we can now apply our more potent interventions that we have for treating myeloma to smoldering. There have been a couple of very interesting studies that have been presented. We have got now, I believe, three different trials that have looked at bispecific engagers in smoldering myeloma. There was the initial Immuno-PRISM that I think was about 19 patients coming out of Dana-Farber. We now have the LINKER‑SMM1 smoldering trial also looking at patients with high risk, either by 2/20/20 or the PETHEMA high-risk, and then, of course, there was the very recent ERASMM study presented at ASCO and also updated just a little bit at EHA. That is now the largest bispecific trial that has 50 patients in it.
Those results are very interesting. The MRD rates are very, very high. The response rates are very, very high. However, I think you would agree that what we really need to see is longer-term follow-up to see not only is that something that sticks, is that intervention helping, but is it also not, we hope, creating any long-term problems for patients who end up becoming more resistant.
Dr. Martin: I am quite impressed by some of these bispecific trials, especially at ASCO, hearing about the EMN34 trial. The one thing that we need to better address is time-limited therapy. I know it was 24 months for the study. The overall response rate was over 90%. More than 70% of the patients are in complete response, and 90% of patients are MRD-negative. Those responses are going to deepen over time, which is amazing. I actually do think they are much better tolerated than a lenalidomide combination, but there is that signal of infection that we have to worry about. I am very curious on where bispecifics are going to go. Do we just need three months? Do we need six months? Do we need 12 months? What is going to be the best time?
The other study that I did want to mention is the Boston group. Dr. Nadeem and Dr. Ghobrial just published a study using ciltacabtagene or cilta-cel, a CAR T cell therapy, in those patients at high-risk of smoldering myeloma. This trial showed an MRD negativity rate of 100%. The majority of patients have achieved a CR and are MRD-negative. However, there were side effects. Seven of the patients developed these late neurologic toxicities. Four, they were cranial neuropathies. Those cranial neuropathies get better, typically with steroids and IVIG therapy. There were three patients that developed Parkinson-like symptoms. Only one required intervention more than steroids and IVIG, actually got cyclophosphamide, got intrathecal therapy to try to prevent further progression. The people that had the Parkinsonian-like symptoms still have those symptoms. Again, this was an asymptomatic patient population. What do you think about CAR T cell therapy?
Dr. Callander: Again, there is a lot of different things to look at in the trial. You have underscored the neurotoxicity. What I was also impressed about is they had tried to deliberately select patients who they thought were going to have less toxicity. They tried to limit the amount of plasma cells in the bone marrow. They did not pretreat them at all. There may be some take-home lessons in the future if this is explored, which it probably will be. What would you do to prepare patients better to try to eliminate that neurotoxicity? I do think that this is not ready for prime time. I certainly would not recommend anybody consider CAR T for smoldering myeloma at this point. I think the neurotoxicities, particularly the Parkinson's, were sobering. I suspect it is going to continue to be explored, particularly as we have other ways to deliver CAR T coming up in the near future.
Dr. Martin: Well, Natalie, this has been a wonderful discussion. So your final thoughts on, to treat or not to treat: assessing risk and treatment options in high-risk smoldering myeloma.
Dr. Callander: Sure. We just have to get in the practice, to the best of our ability, trying to stratify these patients. It does not take that long with the 2/20/20. The bone marrow FISH and cytogenetics is helping. Hopefully, sequencing is going to be added in the near future. We want to really watch those patients first before we just uniformly recommend treatment for all of those individuals. I do not know what your opinion is about that.
Dr. Martin: It is the same thing. You and I do things very similarly. To treat or not to treat? That is really the main question in smoldering myeloma. It ends up being a long discussion with the patient. It is so important that we take each individual patient with smoldering myeloma, watch their movie, in my mind, rather than taking an individual time point and saying, "You have high-risk, let us get going." I do think that the 2/20/20 plus FISH is a great way to differentiate those people that truly have high-risk smoldering myeloma. A 50% chance within two years of progressing to active myeloma. Those are the patients that I do think you can think about initiating therapy. When you are considering therapy, really the best tolerated one so far has been daratumumab. It is approved in high-risk smoldering myeloma: three years of time-limited therapy, and you just have to watch them closely with supportive care measures, antibiotics for infections. IVIG, I would say, only if they have infections or if their level goes real low, less than 200, I would generally give it to them. We are all waiting for the immunotherapies. These immunotherapies may actually end up being a way that we can really reset the clock on smoldering myeloma, hopefully back to even a pre-MGUS stage. Last thoughts, Natalie?
Dr. Callander: I would agree with that. One area that we still need to explore is not just the plasma cells that are the problem in smoldering. It is probably the microenvironment, too, that we have to understand a little bit better. Lots and lots for us to continue to work on here. I share your optimism that in the near future, we are going to take these patients and keep them from ever developing myeloma, which is, of course, the goal.
Dr. Martin: Awesome.