Elisabet Manasanch, MD, 
MD Anderson Cancer Center
Interview Date: October 27, 2021

Smoldering myeloma is evolving in thought and in treatment. In this comprehensive program, Elisabet Manasanch, MD of MD Anderson Cancer Center shares an update on the the treatment of smoldering myeloma in today's clinic. She shares treatment approaches to smoldering myeloma and shares her suggestions about protecting smoldering myeloma patients long-term with various treatment strategies. Dr. Manasanch shares two interesting clinical trials now open for smoldering myeloma patients - a customized vaccine to help prevent progression in smoldering myeloma and the use of BLENREP to prevent progression. Dr. Manasanch reviews the current thinking behind the precursor conditions and how they apply both in research and in practice. 

Thanks to our episode sponsor

Jenny: Welcome to today's episode of Myeloma Crowd Radio, a show that connects patients with myeloma researchers. I'm your host Jenny Ahlstrom. We'd like to thank our episode sponsor, Bristol Myers Squibb, for their support of this Myeloma Crowd Radio Show program. 

Now smoldering myeloma is a precursor condition that can become active myeloma. The term smoldering myeloma is actually one of debate right now, and we hope Dr. Manasanch will address that topic in today's show. Today, we'll be talking about smoldering myeloma, how it's defined, when patients should be treated and how they should be treated. 

Just before we get started, I'd like to make just a couple announcements. We are currently working on a genetics study inside of the HealthTree Cure Hub that I want to make sure that you're invited to join. Our goal in doing this study is to identify different treatment paths that might be potentially best for different types of genetic features in myeloma patients. That study can be found on healthtree.org. If you sign in and have an account, you can join that study. We're learning important things already about that. I know Dr. Manasanch will be talking about a few genetic features in this show.

I also wanted to highlight the fact that we have a smoldering myeloma Facebook group that you can join. If you just search on Facebook for smoldering myeloma, you can join that group. We also have quite an extensive smoldering myeloma class in HealthTree University. If you go to healthtree.org and log in, you'll see it in your sidebar. You'll also be able to find it outside of HealthTree, and it's available to everybody at university.healthtree.org. 

Let me introduce Dr. Manasanch. Dr. Manasanch, welcome to the program. 

Dr. Manasanch: Thank you, Jenny. 

Jenny: Let me introduce you before we get started. Dr. Manasanch is Associate Professor in the Department of Lymphoma and Myeloma at the University of Texas MD Anderson Cancer Center in Houston. She's a member of the Faculty Senate, Institutional Review Board and Continuing Medical Education Committee at MD Anderson. She's earned the High Impact Clinical Research Support Program Award at MD Anderson and the Clinical Innovator Award, also at MD Anderson, and the Brian D. Novis Research Award from the International Myeloma Foundation. 

She belongs to the Society for Immunotherapy of Cancer, the International Myeloma Working Group, European Hematology Association, and is a member of ASCO and ASH. Her research in myeloma focuses on the introduction of new therapies for newly diagnosed and relapsed/refractory patients, precursor conditions like smoldering myeloma, and immunotherapy in myeloma. 

We're so excited to have you on the program today. Let's get started with the definition of smoldering myeloma. Everybody used to think about smoldering myeloma as a stage in this progression. You go from this monoclonal gammopathy of undetermined significance or MGUS, to smoldering myeloma, and then you progress to active myeloma. Is it like that, or is it its own condition? 

Dr. Manasanch: Well, first of all, thank you so much for inviting me. I'm very happy to be here today, talking about something that is very important in my work/life, which is multiple myeloma. 

This is a very interesting question, the one you're asking. You're asking if it's a stage in the progression, or if its own condition. It's really a philosophical question. There's no right or wrong answer here, but if you asked me what I think, I think it's probably both. It definitely is a stage in the progression of a disease that starts as MGUS. We have patients that have MGUS that, after 10 years, 15 years, progress to multiple myeloma. Meaning, at that time, either they have so many of the cells in the body that they're not allowing some organs to do their operation, such as a bone marrow. When you have a lot of myeloma cells in the bone marrow, you don't make red cells, platelets, and so on. That's one of the things that happens. 

Now, the other thing is, when you have someone that you see in the clinic, and they have smoldering myeloma, meaning, they have more tumor burden than MGUS. That's one of the hallmarks of smoldering myeloma is that you have more tumor burden than MGUS. You don't yet have a lot of tumor burden like, maybe say, newly diagnosed myeloma, or you don't have any problems from that. Otherwise, you feel fine. That's kind of its own condition because the patient’s situation is very different from somebody who is very sick with a disease or somebody who is not sick at all, or they don't feel sick at all, even though there's some risk that they may become sick in the future from it. Clinically, these are very different patients, and they are treated very differently in the clinic. So, it is its own condition. 

However, if we look at smoldering myeloma, most smoldering myeloma patients have genetic abnormalities that we already see in multiple myeloma. So, it is similar. It is very similar. The one that is genetically less complex and a little bit more different is MGUS. In MGUS, usually most of the cells of the plasma cells in the bone marrow are normal. That usually does not happen in smoldering myeloma. By that time, we already see that most of the cells in the bone marrow are abnormal. Most of the patients that have smoldering myeloma eventually do progress. Whereas, these other patients with MGUS have never progressed. 

MGUS, because they’re less clinically important in the sense that there is much less chance than, for example, a smoldering myeloma to progress to myeloma. There are some smoldering patients, however, that have features that are very similar to MGUS. So, this is all a spectrum. We all have to remind ourselves that these are arbitrary definitions that can change. 

Or we have here, we have patients that have a monoclonal gammopathy, means that they have plasma cells, immune cells that are producing these antibodies that are not a functional antibody. They don't target an infectious agent or anything. These patients can be in a spectrum of this, of this monoclonal gammopathy. We've named those so that it's easy for us to to give a diagnosis, but it's really a spectrum. Really, this question is both. It's a stage, and it's also its own condition because, clinically, it’s very different from the diagnosed myeloma. It’s also very different from MGUS. 

Of course, smoldering myeloma could be redefined. It could be, sometime in the future, we could decide that we don't want to do this anymore. We don’t like MGUS, smoldering and multiple myeloma. Now, we should do something different. This is an eternal question in the field. I don't think that there's enough support right now to change it. However, something may happen in the field in the future. 

Jenny: It’s so interesting because I've heard, and you may have answered this already, because I've heard some doctors say they want to redefine it. Maybe it's either MGUS or actual myeloma. You're saying it's sort of this spectrum. 

Dr. Manasanch: If we had MGUS, you would also have to redefine MGUS. If you want to have just MGUS and then you would have multiple myeloma, that is also interesting. The problem with that is that then you would have multiple myeloma patients that would have no symptoms at all, and some of those patients could have very low chance of progressing. Maybe they could progress in five to ten years. Then you could have patients who are in the hospitals, who are on dialysis from the myeloma. These are two very different patients, clinically. 

I think that if we have studies showing that certain patients with the smoldering myeloma, will certainly, 100%, progress, and we know that out of certainty. There are studies with clinical data and and with genomic data and so on, but if you get to the point where you know somebody will progress, if you know when, then you can discuss the risk and benefit of treatment early. The problem is that a lot of these things depend on the patient. How old is the patient? If you have a 75-year-old person who has smoldering myeloma that doesn't look very high risk, maybe you don't want to treat it. 

Clinically, there's a reason why it’s MGUS and smoldering and myeloma, because, clinically, it makes sense because the risk of progression is the risk that you see that, when are you going to have to intervene? You very rarely have to intervene in MGUS, unless it's related cause. Sometimes MGUS can cause kidney problems and other things, or you can have amyloidosis. Usually you don't have to intervene in MGUS. Smoldering myeloma, you see people progress much quicker, so you may have to intervene earlier. In myeloma, when you have newly diagnosed myeloma, you have to intervene right away. You cannot just wait six months or something like that.

Clinically, these stages make a lot of sense. However, whether you have something like MGUS which would probably not be called MGUS, you would just have myeloma, that we would have to know very clearly. Okay, these patients that have a monoclonal gammopathy that is benign. You could have a benign monoclonal gammopathy, and then you would have myeloma. The patients that have the benign, and I'm just making this up now, but the benign monoclonal gammopathy, then those patients, you could just tell them, you're never going to progress. We don't even need to see you in the clinic for this, potentially. Whereas, the myeloma patients, you would say, “Okay, we're just going to treat you, no matter what, because we know that this is going to progress.” 

This is probably too simplistic because each patient is different. You have to discuss it with them. You have to look at the situation and so on. That's my opinion with all these. I don't know that we will be able to come to a point where you can just say a benign monoclonal gammopathy and myeloma, because it is very difficult to predict precisely for every patient, who will and who won’t progress.

If you're telling someone, it’s a benign monoclonal gammopathy, nothing is going to happen, then you have to have a lot of certainty for that, and we don't have, that I know. I don't think we have studies right now that can tell us, 100%, what is going to happen in the future. All we can do is, with some certainty, it looks like this is what's going to happen, and it looks like this is what's not going to happen. We cannot know, 100%. That's why it would be very interesting if we could do that, but I don't know that we are there yet. 

Jenny: We’ll talk about the progress that's being made, right? Overall, can you share the rate of progression? If someone's diagnosed with smoldering myeloma, what's the likelihood that they will progress, just in terms of percentages? What percent of patients end up progressing? It slows down over time, right?

Dr. Manasanch: Yes. Something that has been published a long time ago at the Mayo Clinic, they said 1% per year for MGUS and about 10% per year for smoldering myeloma. If you don't progress in five or six years, it can be even less, maybe 5%. When we look at our studies and we look at our patients, we see that it keeps repeating the same thing. 

One thing we can say is it doesn't seem like people are progressing more now than they were before. Fifteen years ago or 40 years ago, you had a patient with MGUS, and you have a patient with MGUS now. They progress at the same rate. This is interesting because a lot of this data comes from older studies, but it's every time we look at our data, we look and see, oh, what are these people doing? They progress at about the same rate that was published before. So, this is still the same. 

What I can tell you is that people that have smoldering myeloma, when you start getting to the point that you have 20% plasma cells, 30% plasma cells in your bone marrow, of all your cells, and these are abnormal. These plasma cells are abnormal. They have something. They have abnormalities, or they have expressed markers in the surface of the cell that are not normal. We know very well which ones those are. If you live long enough, you will have myeloma. Most patients that have a smoldering myeloma, at some point, progress. There is a fraction of those that don't.

If you look over a period of ten to 15 years, patients that have smoldering myeloma almost always end up needing treatment for newly diagnosed myeloma. That's why I'm saying that it's very different to have someone who has MGUS to someone who has smoldering myeloma. Clinically, these are differentiated, and the risk of progression is both different.

Of course, you can have a smoldering patient with 10% plasma cells in one biopsy, and then you re-biopsy this patient, three years later, and it says 5%. Obviously this patients is still very early on. It's very different from a patient that they have 10% now. You do a biopsy in a couple of years, and now they're 20% or 30%. Things are not static. Things can change. That's why follow-up is important. That's why it's difficult to say, because of your characteristics, you may never progress. 

Ola Landgren has published a study saying that, if you have certain genomic signatures, in terms of mutations, if you have these signatures, then you don't progress until you’re MGUS. If you don't, then you progress. It's one study. Things have to be validated and so on. It seems like we may be getting to the point where we may be able to say, yes, you will, no, you won’t progress, but individually, it’s very difficult to predict. 

All we can say is that, usually, having more paraprotein that is larger in the blood, bigger paraprotein, having more abnormal plasma cells in the bone marrow, having higher light chain, abnormal light chains, those things tell us, okay, this is something that could progress in the future. Whereas, if you have very few of those abnormalities, then your risk is much less. Those are things that you don't need a lot of fancy tests to look at those things. Those are things that just doing blood work and urine studies, you can tell. When we want to go beyond that and look at genetic testing, then we have a lot of different tests that we can do. Most of them are research tests, though. 

Jenny: Yes, like the next generation sequencing or something like that, to see if you might have a high risk feature that -- because you're breaking patients into the standard risk smoldering myeloma stage and also high risk smoldering myeloma. Do you want to just explain the difference between those two? 

Dr. Manasanch: Yes. Physicians have tried, and researchers, for a very long time, to stratify patients with smoldering myeloma. Because I mentioned that if you follow patients with smoldering myeloma, most of them, do seem to end up progressing to myeloma, but there are some that don't. As physicians, what we want to know is who is going to progress. We want to know who is going to have problems from this disease because those are the ones we want to treat. The ones that are never going to have problems, we don't have to do anything. That's wonderful. You have a little bit different immune system from other people, and that's it. That's very important for us to know. 

Most of the time, when people have tried to stratify smoldering myeloma, they have used three tools, I would say. One is the clinical data. It's like the light chains, the paraprotein, how much myeloma you have in the bone marrow and so on. People have also used genetic features. Dr. Barlogie, he is retired now, but he used to work at the University of Arkansas where there's a Myeloma Center. He was there for many years. He developed a test called the gene expression profiling, GEP-70. This test was very useful at predicting or is very useful at predicting the patient's progress, and it is based on your genetic expression of your myeloma cells

You have a bone marrow biopsy, and you have your myeloma cells taken out of the bone marrow. Those myeloma cells are separated from the rest of the cells in the bone marrow, and then only those cells are analyzed in a machine that can look at RNA in the sample. Depending on what your RNA expression is in that sample, then that determines your risk. That test is a good test at telling us who will progress and who won’t, which means that the biology and the genetic abnormalities of patients in their myeloma cells can tell us a lot about who will progress and who won’t. Now that test was using an older technology to do gene expression. 

Right now, people do just RNA sequencing which is more advanced in terms of the technology, and you can get more information as well, instead of this profile, gene expression profile. Also people are starting to do the single cell RNA sequencing. These are very new technologies. This one, we don't know a lot, for example, how are we going to be able to do RNA sequencing, not just of all the cells that you can break down?

You can have a bone marrow, take a sample of cells. You can separate the myeloma cells from the sample, and then you can do bulk RNA sequencing, which means that you're looking at the expression, the genetic expression of all the cells together. You take all the cells, and you kind of mash them up together, and then you look at it. That's one technique to do it. Now, there's a technique in the single cell, which means that you don't smash the cells together. You can actually look at the sequencing of each different cells. That, again, is a very new technology. We’ve only decided to use it in the last few years, in myeloma.

The ability that that gives you is that it can tell you things like the different subgroups of plasma cells that you have, because it's looking at these different cells. Whereas, the ones about sequencing can tell you things, for example, you will know, if most of the cells are expressing a gene a lot that is very important for the cell, then that gene will be expressed a lot. You are not going to know how many of those cells have that. You're just going to know, overall, this gene is very expressed. Whereas, if you do the single cell sequencing, you're going to know things like, you have 5,000 cells, you're going to know, of those 5,000 cells, 200 have this gene, 300 have this one, 400. You're going to know the sub-populations.

Jenny: Yes, that will be very helpful. 

Dr. Manasanch: This is very new, and it is still to be determined how we can use that in the clinic. This is just part of research tests right now. Again, it is not determined to know how we're going to use this clinically, to know, for example, if someone can progress. The other thing that is very important, too, is that you can also do this single cell sequencing in the microenvironment. You can do it in the cells that, not normally the cancer cells or the pre-cancer cells, but you can do it in the cells that are around the cancer cells. Those also have changes that are different, potentially, if you progress, if you don’t progress and so on. These are areas of intensive research. Again, how can we do it in the future, clinically, is to be determined.

Jenny: That's fascinating. I think as the technology gets better, and these methods get used more and more, you'll have more information. 

Well, let's talk about the genetic features of smoldering myeloma because you mentioned that at the beginning that patients who have smoldering myeloma might already have whatever genetic features they might have if they progressed to active myeloma. What are the more typical or more common genetic features in smoldering myeloma versus active myeloma? Just for patients, just so patients know, you can have a gene deletion where you have, so two copies, you can have one or none. You can have a gain or an addition of chromosomes, or you can have a translocation where the genes are swapping, the chromosomes are swapping places. 

Dr. Manasanch: It really depends what is the genetic abnormality. As you mentioned, this was a very nice summary, that you can have a translocation, and you can have additions. You can have genes that are deleted. In myeloma, there are usually three types of abnormalities. One is called hyperdiploidy, which means that you have extra chromosomes or extra parts of chromosomes, and that's very common in myeloma. Then you have hypodiploidy, which means that you are missing some chromosomes.

When the myeloma cells or the plasma cells are dividing, they have to basically redo their genetic material every time they create a new cell. They can create abnormalities in there. The genetic material is not immune to abnormalities. These abnormalities usually are those where you can have a missing part of a chromosome, or you can have extra copies, or you can have translocations. Translocation is exactly what you said, when you exchange genetic information between chromosomes. The most common ones in smoldering myeloma are also the most common ones in myeloma. 

You have a translocation (11;14), which is very common in myeloma, newly diagnosed myeloma and myeloma, in general. It’s also very common in smoldering myeloma. You can also see it in MGUS. It's really one of the most common translocations that we see in myeloma. Basically, what it does is it puts something called the promoter of chromosome 14, which is a gene that has an immunoglobulin that is telling the cell to produce immunoglobulins or proteins. That is what cells do. They produce antibodies which are just immunoglobulins. 

They have this promoter very active in the cell because that's the job of the plasma cell is to produce antibodies. This gets swapped to chromosome 1 where there's a protein called Cyclin D1, which is a protein that tells the cell to divide. When you have that, you have cells that have this translocation, a protein called cyclin D1, and also express something called Bcl-2. That's just a very common and very early abnormality that we've seen in myeloma. 

Then you have other abnormalities such as deletion 17p, which is usually a marker. It’s not a good marker for having myeloma. However, it depends how many copies of the chromosome was deleted. That's something that you can do with sequencing, but you cannot see with a test that we do that is called FISH. We have really few patients with bad abnormalities in smoldering myeloma and MGUS, such as translocation (14;16), (14;20). Those, we don't see very much in smoldering myeloma. 

The other thing that we see a lot in smoldering myeloma, you can certainly see, especially in what we call more high-risk smoldering myeloma, is there’s mutation because those are the abnormalities. We see mutations. The mutations are in genes called KRAS, NRAS. Those are very common in myeloma, and you can see those in smoldering myeloma as well. There have been publications Dr. Ghobrial has published on this mutation, saying, if you have them, your risk of progression may be higher. 

All these things seem to correlate a little bit, all the clinical abnormalities. The higher you have your M spike, your paraprotein, all these things correlate sometimes with the mutations you have, the genetic abnormalities you have, if you have hyperdiploidy, hypodiploidy, if you have translocations and things like that. Those are the common things that we can see in smoldering myeloma. 

Jenny: Okay, great. There's also, I've heard about this mutation. I guess it's labeled the  mutation of MYC. I was reading some information that just said there's a higher incidence of this MYC in smoldering myeloma. What does MYC do, and why do you think there's more of it in smoldering myeloma patients?

Dr. Manasanch: MYC is just a gene. There are different types of that gene that create different types of proteins, but what it does is called as an oncogene. It's very common in cancer. It's not just in myeloma. In myeloma, we see it. We don't see it very much. When we see it, it’s usually not a good thing. We don't see that a lot in smoldering myeloma. It's mostly in people who have newly diagnosed myeloma or who have relapsed myeloma. It's really a gene that when you have a high expression of it, it just promotes survival of the cells. 

It can be an abnormality. It’s an abnormality that you don't want to have. It usually makes cancers aggressive, more difficult to treat. It's not very common, I would say, in smoldering myeloma. If you have smoldering myeloma, and you have high levels of MYC expression, then that's probably not a good thing. Again, just one thing, sometimes, that doesn't determine the whole story. I don't want to say, because someone has a MYC, maybe they’re doing really well. Overall, that's what happens. There could be cases where things are not like that, but usually MYC is not a good thing to have in any cancer, an abnormality in this gene. 

Jenny: Okay, great. You talked earlier about the microenvironment, that you can see genetic changes in the microenvironment. I think a lot of patients are wondering, especially with immunotherapy playing such a big role in myeloma now, what role does our immune system play? Because we hear that, okay, everybody's probably had some kind of initial cancer cell, and most of the time your immune system will go and knock it down, and it doesn't develop into something like myeloma. How do you test for good versus bad immune system function, and can that predict progression? Is there any test that that patients can go run, to say, oh, I have a strong immune system or don't have a strong immune system? I know there are a lot of factors. That may be too broad of a question, but just wanted to get your perspective. 

Dr. Manasanch: We can start by saying that myeloma is a cancer of the immune system. People that have myeloma are prone to infections. People that have myeloma usually have something called hypogammaglobulinemia. That's just a fancy name to say that you don't have normal levels of antibodies that you're supposed to have. That's because, again, your plasma cells, they’re abnormal. They’re not producing the normal antibodies. They’re producing some antibody that is nonfunctional, and that's the paraprotein. That antibody is not helping you fight infections. It’s just there. You have a lot of cases when you can get in trouble with the kidneys and things like that. 

Patients with multiple myeloma usually do not have a normal immune system. That doesn't mean that everybody that has myeloma is going to get into very severe infections, but it is something that is common. When you have MGUS and smoldering myeloma, you have usually some abnormalities of your immune system, and that's the most common one. It's very easy to see because it's just blood work. Everybody can check immunoglobulins because they’re very easy to do. 

If you have lower levels of immunoglobulins, that means that's not normal. Usually you have to have very, very low levels for you to run into trouble, to run into infection. Most patients, for example, with a smoldering myeloma, they will have lower levels of immunoglobulin. That doesn't mean that they're going to get tons of infections. It just means it’s a little bit lower. If the levels are very severely low, that's when you can get into more trouble. If they're not, if they're just a little bit lower than normal, then that's usually okay. A lot of patients with smoldering myeloma have low immunoglobulins. Different studies have shown that that's something that signals that you could progress to myeloma is if you have lowering in immunoglobulin. So, that's the number one thing that is very important to discuss. 

The other thing is, you can do fancy tests. You can look at something called flow cytometry where you can look at this, usually in the bone marrow. Usually, due to changes in the bone marrow, you look at the bone marrow, and you look at the cells that are in the bone marrow. You can see that they express certain markers in a cell surface, that make the immune system to be a little bit toned down, so it doesn't hide the myeloma. You see that the myeloma cells have markers in the surface that send signals saying, oh, I'm really good, you cannot kill me things, like that. So, you see those abnormalities. 

That's why immunotherapy has been so important in myeloma and in other cancers because in certain cancers, we have been able to overcome this limitation of the immune system. In myeloma, we're still trying to figure out how to do that. However, we can definitely use, at least there’s the CAR T-cell therapies and everything, so we can definitely use the immune system to stop and kill the myeloma, and we do with several antibodies that we have.

In smoldering myeloma, there's really not a way that you can do a test in the clinic and say, okay, these are your results, this is your immune system, these are the markers in your cells and all that. This is, again, an area of research where we can do flow cytometry. Or you can also do sequencing to sequence the cells, and then you will be able to tell how high or low the expression is, of certain markers. Some of these markers are the markers that, say, attack or don't attack the myeloma cells. You can see how high they are. If you see that there is a marker that is very high, that is a marker that is suppressing the immune system. You can overcome that marker by making a therapy. Those are the things that you would look for, to do treatments in the future.

There's not a test, apart from the immunoglobulin, there's not really a lot of other tests that you can do. You can look in the blood as to the number -- you can look at the numbers of T cells, B cells. You can look at the different populations of cells of the immune system in the blood also, but most of the things, to do like immune profiling, this would be more research, not something that you would just do and get results from your doctor

Jenny: Yes, there’s not just like a normal lab you would run. 

Dr. Manasanch: Right.

Jenny: Let's talk about treatment because I know patients with smoldering myeloma sometimes have a really tough time, emotionally, because they're like, well, do I get treated? Do I wait? When do I get treated? Is it now? Is it now? 

In clinical trials, it seems like there are two different types of treatment strategies. There's this, let's try to cure it by treating it like active myeloma and just seeing if we can get longer responses or even cure you. Or let's delay progression and use something that doesn't have as many side effects or is more like an immunotherapy or something like that. Maybe you just want to first review the difference in the strategies about treating smoldering myeloma and then we'll talk about the individual clinical trials. 

Dr. Manasanch: I think that is a very interesting question. There are different types of strategies. I think that we have made a very big step in the myeloma field in the last ten years, and that big step is that most people believe that we have to treat myeloma earlier than when we have been treating it. That's a huge step because it's hard to change things in medicine. Once you're used to doing something, it’s hard to change, but this is a huge step. I think it's a very good step in the right direction. We have to treat it earlier.

Really the question now is, it’s not whether we have to do it earlier. The thing most people you would talk to that are in the field would say, yes, we have to treat it earlier. The question is, what are we going to treat it with? That's the real question now. What are we going to treat it with? We have so many different drugs for myeloma that would treat myeloma with. Which ones will be the best to treat patients earlier? 

People are trying out different strategies. What we’re doing is, get all the data from all the studies and decide which one seems to be the best. That can be done. However, studies in smoldering myeloma sometimes take a long time. You have to realize also for accrual. Smoldering myeloma is only a subset of all the myeloma patients. When you do a study for smoldering myeloma, accrual can be challenging sometimes because you don't have as many patients with smoldering myeloma. You may not have as many as with active myeloma. That could be something that can take a long time to have study done and read. 

That being said, yes, there are people that are doing studies where they're giving, basically, the best treatment that you have that you would give to a newly diagnosed patient, you apply that to smoldering myeloma. You do the same treatments that you have for the newly diagnosed patient. Now you give it to the smoldering myeloma patient, and you see what happens. 

Once people have done that, what we see is that the patients with smoldering myeloma have less tumor burden, so it's easier to get them to a remission. Because, generally, it is easier to get from two to zero, than it is to get from four to zero. If you have a paraprotein of two, it's usually easier to get to zero. If it’s four, it's harder to get to zero. So smoldering myeloma patients have less tumor burden. That's one of the observations that we see when you apply this treatment. Usually these are combinations of three or four drugs, with or without a transplant, and you have smoldering myeloma. What we're seeing is that these patients, it's easier to get to complete remission, and it's also easier to maintain the complete remission. These are good things. What we're seeing are good things.

However, we realized that these patients, as I mentioned before, these patients usually don't have any symptoms. Meaning, they could have the anxiety of what to do and all that, but they’re not sick like they have these infusions or they have the re-infections that they could die from the infection, or they have kidney problems. It's not like that. It's another set of problems, but it’s not the problem of newly diagnosed smoldering myeloma patients. So, some people look at this and believe that giving so much treatment to these patients earlier on, maybe there could be a different approach that is more suited for these patients. 

Also we have a lot of new treatments, a lot of new immunotherapy treatments. We have a lot of new antibodies. We have, for example, something called bispecific antibodies. These are new medicines in myeloma. We have a lot of different treatments. One strategy is to treat with immunotherapy, so, deal with antibodies. These are treatments that not all the patients are going to go through a complete remission, but they have very few side effects of treatments. The patients are doing really well. They don't usually get hospitalized because of side effects and things like that. They can have maybe a little bit better quality of life. They don't have to come into the center all the time. These are the advantages of each treatment. 

The jury is still out on what to do. For example, giving high dose chemotherapy to smoldering patients, high dose chemotherapy has a lot of risks. Smoldering patients are usually younger than patients that have newly diagnosed myeloma, and so they're going to live with this for a longer time. When you do transfer, you're giving really high dose alkylating chemotherapy, which basically can create a little bit of a dysfunction in the bone marrow. If you're going to live another 20, 30 years, having had these very high dose chemotherapy, then that could create problems in the future, with precursors of leukemia and things like that. 

In my view, that's certainly not something that I would like to do, to give high dose chemotherapy to smoldering patients. There are other methods instead that you can give that are not so harsh, for example, for smoldering myeloma. That’s where the field is right now, and this is okay. We will figure it out. We just need to see the studies and see the data. 

Right now, in terms of treatment, there are two studies that are comparing the antibodies, the CD38 antibodies, daratumumab and isatuximab, with lenalidomide and dexamethasone, compared to lenalidomide and dexamethasone. These are combinations that are usually better tolerated than chemotherapy drugs and so on. This could be the first treatment that we have for smoldering myeloma that we will compare other newer treatments to, in the future. That's where we are right now, in terms of treatments. Nothing is approved yet, but there could be an approval coming up in the future, especially with the CD38 antibodies.

Jenny: So interesting. I know people are looking at using those anti-CD38 antibodies in regular myeloma as well. They're bringing them up to the front line. That's what, sounds like, those studies are doing, even earlier in the smoldering myeloma setting. I also know that at MD Anderson, you have a smoldering myeloma vaccine trial. Can you talk a little bit about that trial and how it works and just the rationale for that study also? 

Dr. Manasanch: This vaccine study, it is a study that is funded through a grant, through a foundation, through the Dr. Miriam and Sheldon Adelson Foundation. We are doing the study with 30 study patients. We've already accrued about 20-something patients, so we're almost to the point where we’ve accrued all the patients. What we do is we do a bone marrow biopsy, and we take the myeloma cells from the bone marrow. We do DNA and RNA sequencing of those cells. We do also single cell sequencing for researchers to know what changes in the cells, within, before and after the vaccine. 

We mostly do this bio RNA and DNA sequencing, where we're looking at mutations. We look at what mutations the myeloma cells have. We look in the normal DNA of the person, the DNA that you pass to your children, and we make sure that those mutations are only in the myeloma cells. Because we all have mutations that are just normal mutations, like variations in the DNA. We just want to make sure they’re not these normal variations in the DNA. We make sure these are really something that is very specific to the concept. Then we look to see in the gene expression, okay, there's a mutation in this gene. Will it express or not express? 

The ones that are expressed, we take those and then you can actually make, from the DNA and RNA, you can know what type of peptide, which is just very short protein, that you can have that is expressing in that cancer. You can make those peptides, and you can put them in a vaccine. For each patient, we're doing ten peptides. We put ten of them, and it depends on where the mutations are and things like that. Each patient gets his own vaccine. We use eight vaccines over a period of six months, where the first four vaccines are given every two weeks, and then there are four vaccines given once a month.

For the first ten patients, we just gave the vaccine. I think the goal of the study was to see whether this could even be done because we didn't know, first of all, if you're going to have enough material. Because some of these patients with smoldering myeloma, they have lower risk of smoldering myeloma, so their bone marrow doesn't have a lot of myeloma cells. We didn't even know if we would be able to even collect the cells and take the genetic material. We were able to do that. We're able to do that. We know that we can make the vaccine. 

On the second stage of the study, we added lenalidomide because lenalidomide is a medicine that there's a lot of track record for use in smoldering myeloma. We have larger studies showing that it actually can delay the onset of multiple myeloma. We're only giving it for six months, so it's not very long-term treatment. The idea to give lenalidomide is to stimulate the immune system to recognize the materials in the vaccine and create an immune response. That's where we are right now. That's really what we're doing in this study. 

Jenny: I think that's just fascinating. Good for you for putting that together. That's just so amazing that you could potentially use a vaccine to prevent progression. 

Dr. Manasanch: It will be amazing.

Jenny: I just think it's so exciting that you're looking at approaches like that because wouldn't that be unbelievable if that works? Very exciting. 

You mentioned lenalidomide because it kind of boosts the immune system. A lot of these combinations, like there are trials in smoldering myeloma that have elotuzumab and lenalidomide and dex, and then, like you said, isatuximab-len-dex and daratumumab-len-dex. Is it just the the factor that it boosts the immune system is why it's always included? My follow-up question would be, these CELMoDs that are coming out like iberdomide and things like that, those are also in smoldering myeloma clinical trials. Will those eventually replace REVLIMID? Do they do the same thing as REVLIMID? 

Dr. Manasanch: They're not exactly like REVLIMID or lenalidomide. They could, and it all depends on what studies you do. If you do a study with smoldering myeloma where, let's say, iberdomide alone is better than the CD38 antibody with lenalidomide, then why not? Or if you you do a study where you do iberdomide with the antibody, compared to the antibody with lenalidomide, and it’s better. It all depends on the studies that you do. If you can prove that it is a better drug, that it works better, that has maybe fewer side effects; sure. A lot of this depends on the drug development, on what studies we do with the medications. 

It is a possibility. It certainly is a medication that has been very successful in clinical trials for late relapse in myeloma. It can decrease the blood count a little bit, but it usually seems to be well-tolerated. I think that when we talk about smoldering myeloma, in my opinion, we usually try to do medications that we think are going to be, overall, well-tolerated, and we try to minimize toxicity. We always try to do that. That's why the CD38 antibodies have been chosen, and that type of treatment is moving forward, because those antibodies are usually very well-tolerated by myeloma patients. That's why that’s with smoldering.

We're also doing a study with, for example, belantamab mafodotin, which is an antibody-drug conjugate, and a single agent without steroids, in smoldering myeloma. This study is going to start in the next few months at MD Anderson. It’s a medication that is, overall, very well-tolerated. It is conjugated to something called mAbs, which is a microtubule-destabilizer. Basically goes in the cells, and it can kill the myeloma cells on one side on its own, the medicine. It can also attach to the myeloma cells, and your own immune system can kill the myeloma cells. It has those two modes of action, two or three different modes of action, so a smoldering patient’s immune system is not as compromised as a newly diagnosed patient or relapsed patient. 

This is a medicine that is approved for relapsed myeloma. In the patients that it works, it works really, really well. There are patients with relapsed myeloma who had ten different lines of therapy, have had myeloma for ten years. You put them on this drug, and they can have a response on this drug alone, without any combination. So it's a medication that has a good level of efficacy. The only problem with this medication is that it can give blurry vision. The mAb is this part that is toxic to the myeloma cells. Or the mAb, this part can be deposited in the cornea, and it can give blurry vision, for example.

The difference in our study is that it’s a phase one study. Basically, we're going to be trying to see what is the dose that we can give with smoldering patients. This is what you were saying about, oh, is this smoldering its own thing, or is it different? In a way, it is it’s own thing because, for example, within the study, we already know what dose we can give in myeloma patients and not just somebody with a different cancer. We're still doing a phase one study which means we're going to be looking at what is the dose for smoldering myeloma, not just for myeloma, for smoldering myeloma, and we're giving 15 to 25% of the dose that is given to relapsed patients. So we're giving a lot less dose, overall. We're giving a lot less dose, overall. 

We're also doing a lot of studies to see how this drug is metabolized, how smoldering patients metabolize. So, this is a study that is really focused on smoldering myeloma. It is designed to minimize the toxicity that the drug has, which can give blurry vision, which is reversible; can also give dry eyes, but these are reversible. There's no blindness or anything like that. I've heard some people say that, but it's not true.

Jenny: No, there’s no blindness.

Dr. Manasanch: We give it one infusion, 30-minute infusion, every two months. 

Jenny: Every two months, wow. 

Dr. Manasanch: Yes. Someone who has smoldering myeloma, who is working, you don't necessarily want to give steroid to this patient. You don't want to give a lot of fatigue. This medicine doesn't give a lot of fatigue. The main things are you can have blurry vision, and you can have a little bit of decreased platelets. Patients with smoldering myeloma usually have really good numbers of platelets, so we're not expecting it to be a big thing. With the toxicity, you can really modulate the toxicity of the drug in the eyes with the dosing and the schedule. We have really modified the dosing and the schedule to see if we will have efficacy with a decrease of the dose. This could be something that, if it has a lot of efficacy, could be very important, and so I just wanted to mention it here as well.

Jenny: Oh, that's so important. Patients might know that drug by the name of BLENREP. Our last radio program was actually on keratopathy. If you have patients who are interested in that, I just barely posted that on the website, you can go read about that. What you're saying in terms of dosing and frequency is really important because when the doses were reduced, there was less of that, and that was given every three weeks. You're giving it every two months. I'm so excited to see what we're going to learn about that. 

Dr. Manasanch: That's right. The study has been made to see if we can have a lot of efficacy while really reducing the dosing and the schedule. Really, when you calculate the doses that you give, the minimum, the lowest dose is 15%, and the highest dose that we give in the study is 25% of what was given on those relapsed studies that you mentioned on your prior podcast. 

Jenny: Oh, wow. Some of the patients didn't really notice much about their eye side effects, so that will be really interesting to see what happens.

Dr. Manasanch: We'll see what happens. We'll see. 

Jenny: We’re excited to see what you learn. Okay, I have another question. Oh, I just realized we're running out of time. I have so many more questions for you. If more patients with smoldering myeloma have the (11;14) translocation and that drug, Venetoclax, is good for patients with that, I know it's not approved yet in myeloma, and it's in a lot of different clinical trials; but is that something that should be considered in smoldering myeloma, if somebody has that genetic mutation?

Dr. Manasanch: Yes, I think so. I think that we can do a study and prove that it is safe in smoldering myeloma patients, that it doesn't have side effects that we were not expecting. I think that we could see really good responses, just with Venetoclax. That drug, it could be given also without steroids, just direct, and it's usually just a few tablets a day that you take every day. I do think, potentially, a study would be better just to know if there's anything else that we have not picked up because smoldering myeloma can be a little bit of its own beast, but yes, I think it should work well in smoldering myeloma patients that have that translocation.

Jenny: Do you know of any clinical trials that are planned for that or no? 

Dr. Manasanch: I don't know of any trials. I haven't heard of any trials, but certainly something that could be worth doing. I know that there are other physicians that think the same. I think that because there was a little bit of trouble, remember, Venetoclax, they did the lineage study, and there were a lot of infections in that study. Still, we give Venetoclax a lot in myeloma with translocation (11;14), and we usually have very good responses. It works really well. I'm very happy with it. 

When there was a big clinical trial with this drug, all comers, not just the ones with translocation (11;14), they ran into some safety issues. Maybe that was something that precluded doing other things, maybe, in smoldering myeloma. I don't know the whole story, but it could be. 

Jenny: Yes, so interesting. Okay, well, we only have just a few minutes left. I have several other questions about smoldering myeloma, just tracking and maintenance and things like that? One more question about the treatment strategies. If you treat early in the smoldering myeloma stage, will that affect the overall survival once you progress to myeloma? I think I saw a study that the answer was no, but just wanted to confirm that with you. 

Dr. Manasanch: Yes. This was something that people were worried about when we started to do studies involving myeloma. The answer, based on the data that we have, is no. In fact, it seems that if you're treated earlier, in fact, you live longer. That’s what it’s seeming to be. That's what it seems to be right now. Of course, with science, there could be a study tomorrow contradicting this. As it stands today, it seems if you treat earlier with medicines that have very high efficacy, and you get rid of the myeloma, that seems to be the best, to do it earlier rather than later.

Jenny: Okay, perfect. On assessment, how often should a smoldering myeloma patient be assessed, and what's the role of imaging in that assessment, as you have myeloma? I know that's one of the most common questions that patients have. 

Dr. Manasanch: Usually patients should do, with smoldering myeloma, blood work or urine every three to six months. If you've been on follow-up for ten years and nothing has changed, you could probably do once a year. It depends how long you've been on follow-up. Usually it's every three to six months, you have some monitoring blood work done. You can do 24-hour urine. With imaging, it depends. You could do every year or every couple of years, depending on your risk. Of course, if you have pain or something, you should have some imaging done of that area as well. 

Jenny: Okay, great. Oh, you've given us some new things to think about. I had no idea about the BLENREP study and your vaccine study. I'm just delighted to hear about that. Just to mention too, before we end, I know we're out of time. You mentioned Dr. Ghobrial's study. For smoldering myeloma patients, there is a study that you can join as an MGUS or smoldering myeloma patient. It’s called the PCROWD study. You can go to enroll.pcrowd.org. That's a study that's just an observational study. You don't even have to go anywhere or do anything, that you can send in samples. 

Our show today, Dr. Manasanch, just reminds me of the importance of seeing a myeloma specialist like you and going to centers like MD Anderson, because you have so many studies open and available. If I were a smoldering myeloma patient, I would be looking for a clinical trial to join because, to me, I think I've heard the experts say you should only get treated inside of the context of a clinical trial. This just reminds me that it's amazing that you have these studies running, and that your research is just so dedicated to learning more about this subset. 

Dr. Manasanch: Yes, I agree. I think that, especially for smoldering myeloma, you definitely want to go to a center of reference where there's somebody who has some experience. Because I think that if you don't do a lot of multiple myeloma, you may miss things. You really want to go to someone who really knows the disease. We know that that could improve outcomes as well. Now with the trials, there are so many trials in smoldering myeloma. Again, the vaccine, you can do different types of antibodies. We have a lot of options for patients right now. 

Jenny: Yeah, so I would just encourage patients to meet with a myeloma specialist like yourself, and look for centers that do have a lot of clinical trials open for smoldering myeloma because that may be your very best strategy. Just a reminder. I just think clinical trials are the way that we do this research and figure these things out that are so important for, not only ourselves, the people that are joining them, but for everybody that comes after us. 

Dr. Manasanch: I agree. It’s extremely important. Thank you so much for the invitation to be here today. This has been a lovely discussion.

Jenny: Oh, I had so many more things to ask you, but we'll have to end. I just thank you so much for joining us today. Thank you for sharing your expertise. Thank you for caring for myeloma patients every day. I'm just so impressed all the time at the dedication that you have to your work. As a patient, I'm just so very grateful. 

Dr. Manasanch: Thank you so much, Jenny. 

Jenny: Thank you for joining us today and thank you for listening to Myeloma Crowd Radio. We invite you to join us next time to learn more about what's happening in myeloma research and what it means for you.