Decoding Smoldering Multiple Myeloma

Hematologist, Shahzad Raza, MD, joins the Cancer Advances Podcast to talk about the evolving understanding of smoldering multiple myeloma. Listen as Dr. Raza discusses the challenges in risk stratification, complexities of treatment decisions, and the need for close patient monitoring and education.

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Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals. Exploring the latest innovative research and clinical advances in the field of oncology.

Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale Shepard, a medical oncologist here at Cleveland Clinic directing the Taussig Early Cancer Therapeutics program and co-directing the Cleveland Clinic Sarcoma program. Today I'm very happy to be joined by Dr. Shahzad Raza, a hematologist specializing in plasma cell dyscrasias treating patients with stem cell transplants and cellular therapies. Dr. Raza was previously a guest on this podcast to discuss toxicities of the eye as a side effect of cancer treatment and this episode is still available for you to listen to. He's here today to talk to us about smoldering multiple myeloma. So welcome.

Shahzad Raza, MD: Thank you Dale. Thank you for having me here.

Dale Shepard, MD, PhD: Absolutely. So remind us a little bit about what you do here. We talked a little bit about what you see and treat, but fill us in.

Shahzad Raza, MD: Good question. So I'm a plasma cell expert here. So I see patients who have monoclonal retinopathies, smoldering myeloma, multiple myelomas, lichen amyloidosis and different types of disorders caused by plasma cells dyscrasias. I also do cellular therapies here and I also perform the stem cell transplants and we are very active in the clinical trial, so we have a very excellent and robust clinical program in multiple myeloma here.

Dale Shepard, MD, PhD: Excellent. Well, today we're going to talk about smoldering multiple myeloma and we have people who listen in a lot of different backgrounds. While I know multiple myeloma, what is smoldering multiple myeloma? So can you let us know what exactly we're talking about here?

Shahzad Raza, MD: I think this is a very good question and it just needs a little bit of insight what we are talking here. So first we talk about multiple myeloma. As we know that multiple myeloma means someone has abnormal plasma cells, clones in the bone marrow, which is damaging the bones, causing the anemia, kidney problems, and high calcium. So this is called the CRAB features and which is historically defined as multiple myeloma.

But what about those patients who have these abnormal plasma cells but they don't have any CRAB features like any other end organ damage? We call them historically as smoldering myelomas in the past. And there is a definite criteria like a monoclonal protein more than three, bone marrow plasma cells more than 10%. So this is how we were defining them, the smoldering myeloma. Now the question come up in the past, what do we do with that?

The historical data suggest that there is a risk of progression, so 10% per year for the first five years, but after five years the risk settles down and the 10-year overall progression from five to 10 years is only 3.5%. So there's a lot of interest why this is happening. So what we find out initially that those patients who were really progressing it in the first five years, they have either the light-chain ratios of more than a hundred or they have some asymptomatic spots on their bone, which we can only detect through MRIs or they have the bone marrow plasma cells more than 60%.

So we actually separated them from the smoldering myeloma and in 2014 we called them as asymptomatic multiple myeloma. So smoldering myeloma definition is already refined. After that whatever is left between 10% to 60% plasma cells and whatever the light-chain ratios less than a hundred we call them as an smoldering disease or a smoldering myeloma. And we define them in three risk categories like a high-risk, intermediate risk and low-risk. And right now there is no consensus who needs treatment, who needs to be watched and each institution has its own practice patterns that what they've been doing it. But I can tell you the general consensus is to watch them because we are not really sure who will truly benefit from the systemic treatment and if we do the systemic treatment, what is the right combination?

Dale Shepard, MD, PhD: And when we think about that systemic treatment, I guess the question would be, well there are patients who certainly say, "If there's any risk at all why I want to treat it." What's the downside of treatment, what do we treat with and what would be the hazards of that?

Shahzad Raza, MD: This is an excellent question, and this is a matter of debate right now that who needs treatment. So I give you two scenarios and two school of thoughts here. So the first is why somebody needs treatment when there is no end organ damage, what are you going to achieve that? So our physicians or colleagues who are really proponent to this thought that patients who have no end organ damage and they need treatment, they're basically talking about eradicating the plasma cell clone and then improving the quality of life. The counter-argument is we don't know the right standard definition of high-risk is smoldering. After separating those cases, which we did in 2014, that who are the right patients who will benefit from the treatment and if we treat the patients, what would be the optimal induction? And if they progress, what will affect after the second progression free survival?

None of these answers are truly understandable at this point and we really struggle to find out who will truly benefit from them. Now there is another thought about unnecessarily exposure to the patients and then there is a financial toxicity, blood clots, pneumonia, heart failure because these are chemotherapies and these they have their own side effects. So if we say, okay, you have a two-year progression free survival around 70% because you have a high-risk disease, what about those 30% who do not have that particular risk? So we are exposing a lot of people to these types of therapies without knowing that there is an actual benefit to the whole population. That is why it's still a matter of debate like who will benefit? So our approach is watchful observation because there is a possibility patients won't progress from here. We'll keep an eye, we watch their numbers every couple of months and then make sure that if they're increasing in their numbers and they reach to the point and they need treatment, then we treat them at this point.

Dale Shepard, MD, PhD: And that treatment, is that still lenalidomide being one of the common treatments if people chose to treat?

Shahzad Raza, MD: So for a small ring myeloma, this is based on our 2013 line study when initially we did the study about lenalidomide and dexamethasone as a backbone that was two drug optimum induction. As you know in multiple myeloma, now the optimum induction is three drugs, so there is always a concern giving the two drugs is will be an under treatment if we really have to treat. And if they become resistant and they progress, are they going to do the same response to the traditional multiple myeloma treatment? I think those answers are not been addressed. There's only a study which really show the small ring myeloma has overall survival benefit.

Unfortunately, in that study there were a lot of patients who have asymptomatic myeloma and now we call them as an asymptomatic disease and we treat them like multiple myeloma. I think there is a lot of heterogeneity here, understanding who will truly benefit from the three drugs combinations. There's several clinical trials going on from two drugs to three drugs to four drugs and most of these trials do not have a very clear endpoint. That one is eradicating the plasma cells clones. Overall survival, we have to wait for many, many years to really clarify. But the three-year PFS, five years PFS is in surrogate endpoints that people have been looking for, but I still feel that there is because of a lot of heterogeneity, there is no clear consensus who will truly benefit from these type of therapies.

Dale Shepard, MD, PhD: It seems like a really difficult spot to be in considering you might have a patient, you say, "Look, I can do nothing, or I can give you four drugs." I mean it seems like a tough sell.

Shahzad Raza, MD: Well, this is a very good question, but for those who are listening this podcast, I can tell you we have a very good way of telling the patients so that they can understand and I can give you that example that helps. So one is called the cancer. Cancer word itself is considered a death sentence as somebody we use it. But you know, and a lot of patients and our physicians also know there are chronic leukemias. You watch them, you keep an eye, they may not progress and they're there. You just need education, constant meeting and talking to the patients.

Now think about the high blood pressure, hypertension. The person has hypertension but it's not necessarily they are on the treatment. They may be home monitoring blood pressure, just keep an eye on the blood pressure. Again, it is incurable. At some point they need treatment, but at this point they just need monitoring.

I think it is the similar context. We talk about the small ring disease. Look, you have the clone, but we don't know it's going to truly progress to multiple myeloma or not. There is a highly likelihood and if we treat you early, there is a potential risk of toxicities and complications and why not, we can wait and keep an eye on that. So many times if you wait them very every three months and keep an eye, I think we can capture those cases and treat them, if we see the pattern is more consistent like multiple myeloma. That's why we have this asymptomatic multiple myeloma definition from 2014 and they're being treated so if they progress based on their biochemical markers, we can treat. Now end organ damage can happen at any time with any numbers of the plasma cells clones in the bone marrow.

That is why you have to see the patients keep an eye. If they're having any new symptoms, check the labs. I think that's still the best way of monitoring these patients, but sometimes we may end up with patients who have a high level of anxiety, concerns, and worries. So we do offer some of these patients clinical trial when we think that they can benefit from the clinical trial evaluation because anything right now, any drug we recommend it has to be through the clinical trial because we just don't have an optimum induction protocol at this point for those three categories of a small ring myeloma, which after 2014, we are defining them.

And the way we define them is based on 2018 Mayo criteria which includes a 2 20 20, means monoclonal protein of 2, plasma cells percentage in the bone marrow, 20% or above and the free light-chain ratios of more than 20. So we are actually evolving trying to define what is truly small ring diseases are, and then if we know that somebody is in higher risk small ring, we watch them very carefully, educate them and if there is a clinical trial we try to enroll them into the clinical study.

Dale Shepard, MD, PhD: When we think about the patients that you choose to watch, is it fairly uniform how most people do surveillance? So what should people be testing? How often should they test? If people might be listening, what kind of guidance do you give for surveillance to make sure that if surveillance is the route you go, you don't miss things?

Shahzad Raza, MD: I think one of the most important thing is comprehensive testing. A comprehensive testing includes blood work, the urine testing, sometimes imaging like PET scan and MRIs because that's how you can say because you are excluding the disease. If somebody, we say you have a small ring disease, so we want to make sure they don't have asymptomatic multiple myeloma. So this is how you do the imaging, but you do one-time imaging and then after three months you bring the patients back again, see if there is anything change, clinical status change, no. Then you bring them in the next three months.

I think the first two years are so important that many of these risk predictions models, they have a risk of progression in the first two years, which based on the high-risk protocol, which they can progress 60% of the time, 60 to 70% of the time in the first two years. So we watch them very closely in the first couple of years and if they do good and they do not progress, then you have an answer. Then you just keep an eye every couple of months and watching them. And all of us physicians have patients like that. They have a small ring for a long period of time and they were just keeping an eye and keep monitoring it. And if you see they're progressing, you just go ahead and treat them and I still think this is the best way to pursue for these small ring cases.

Dale Shepard, MD, PhD: Since technically they don't have multiple myeloma, are there cases where insurance companies push back on some of the monitoring, some of the imaging saying, "The patient doesn't have cancer. Why are you doing all these tests?" Is this a barrier at times?

Shahzad Raza, MD: Yes, it does happen, but here's the thing. Things are called multiple myeloma unless you can prove this is a small ring. I will just counter-argue, many times we say small ring, the question come how can you say it's a small ring? Have we done the MRI? Have we done the PET scan? If you don't have it and you are fitting the criteria of myeloma in the marrow, so it's myeloma until you prove it. So once you prove them and okay, this is a small ring disease, you keep an eye and keep watching them. We are not seeing much problem at this point getting this approved, getting those testing approved because you have plasma cells more than 10% in the marrow, at least you're calling them as a myeloma. It's not multiple myeloma but it is a myeloma.

But then you have a small ring myeloma or a small ring, multiple myeloma. Actually here at Cleveland we are not seeing of pushback on this, but a lot of things has to do with the cost and expenses. For example, PET scan is expensive, but the simple skeletal survey can help as well. Low dose whole body CT scans can help as well to see what the bones look like. It's the same thing when we use very primitive phones in 1980s and now we have iPhones and the smartphones, same thing. You have an MRI, you have much sophisticated imaging testing that can help. I think most of the time we are able to get these testing done if we need proper surveillance and monitoring. And the first two years is the one that I really think they need to be closely watched.

Dale Shepard, MD, PhD: We talked about what surveillance looks like. Treatment, if someone goes on treatment, you talked about clinical trials. In general, you said the risk is greatest the first couple of years, you don't have end organ damage. You're trying to minimize risk. What are the decisions going from a trial standpoint or sort of how you think about the world? How long do you treat people? I mean you have people who don't have an active disease, because they don't have the end organ damage. You're giving them things that are potentially harmful. How long do you treat someone to try to minimize that risk?

Shahzad Raza, MD: This is again a complex question because there is no consensus on that. Multiple myeloma treatment is lifelong and if you're treating in small ring disease, they don't progress. So there are therapy, there are protocols you treat for fixed duration of treatment for two years and then what do you do if the things comes back again, you want to treat, you're going to watch until they progress. I think these are the questions that we are trying to address. What is the right way of optimum induction? Then another question come up, do they need stem cell transplants in an upfront setting? Do we treat these patients like a multiple myeloma? There are different clinical trials with different endpoints and different way of assessing it. I personally feel the most important thing is PFS-2, which we have never addressed that. If you give them somebody lenalidomide in small ring disease and let's say that patient progresses to multiple myeloma in three years.

Yes, therapy works. It delays the progression of the disease from that aspect. But what about the PFS-2 because you already consume your first line of the treatment. Now your second line PFS will be very, very different, like a progression free survival. So we really do not have these answers yet, but we have learned quite a lot lesson from the asymptomatic multiple myeloma. If somebody has just a numbers, more than 60% plasma cells, we are treating like a multiple myeloma now. Somebody who has light-chains ratio of more than a hundred, we are treating like multiple myeloma, these patients. They're offered optimum induction therapy. Now what we don't know that other small ring myeloma risk categories, which are called now low risk, intermediate risks and high risk and knowing in a clinical practice that the high risk patients have a high risk of progression in the first couple of months.

We've watched them very carefully and if they progress, we offer them as multiple myeloma treatments. But what I would say there are patients who have a very low risk disease, a small ring disease, they may have a presentation like MGUS, monoclonal gammopathy of unknown significance. They may not progress. So question is do we really have to treat this particular population? I think almost all the hematologists agree that's the population nobody wants to treat. But the high risk population, that's the one high risk small ring which is now evolving. I think we're trying to understand the better way, the risk category and optimum induction. Once it's been defined, there's a very likely possibility they will be in the asymptomatic multiple myeloma cases at that time and we will be offering the treatments to that. So I think still we are way behind knowing exactly when to use those terminologies, but until we don't have a clear consensus, watch and wait is a very optimum approach.

Dale Shepard, MD, PhD: And it sounds like maybe the intermediate risk will be the gray zone because low risk will be sort of like MGUS? Which I'll hit on in a second.

Shahzad Raza, MD: Right.

Dale Shepard, MD, PhD: High risk, more like asymptomatic disease. What do you do with the intermediates? But just to make sure everybody's kind of on the same page again from a terminology standpoint, you just mentioned MGUS. How does MGUS vary from smolder and myeloma? Yeah,

Shahzad Raza, MD: Very good question. So it's called the monoclonal gammopathy of unknown significance or undetermined significance. So these unknown and undetermined words are very important that you just don't know about these abnormal monoclonal proteins. 1% of the common population can have these abnormal proteins. Bone marrow, if you do in these patients, they have less than 10% plasma cells in the bone marrow. In the blood, their monoclonal proteins are less than 3. So biologically, this is how we define them. But from the patient's perspective, these are the conditions that you just watch and keep an eye. The risk of progression from the MGUS to the disease is only 1 to 3% per year, but if you look at in Blacks for example, they have very high rates of MGUS in that population and Dr. Vallen has a study here. He's been trying to investigate why the risk of MGUS is much higher in them.

Now, the MGUS, somebody has a COVID infection, viral infections, autoimmune conditions, our monoclonal proteins can be seen falsely positive in those cases and we have to really watch them and keep an eye until we have a clarity on that. I think it's all about education, understanding the risk and then knowing how you will monitor them. As long as the patient and the doctors understand this whole process like what is MGUS and how the doctor will watch. I do see that this thing worked out really well, but I think we have to also keep an eye that anxiety, concerns, worries are always there with that and many times we do very comprehensive testing because comprehensive testing is the only way the patient understand their fully risk and you can watch it from there.

Dale Shepard, MD, PhD: You mentioned the anxiety component, which is really understandable and maybe even more so with the uncertainty. You can tell someone they have multiple myeloma, they get it, they understand it. These smoldering things may be even more anxiety-provoking, even though maybe not as harmful. How do we work with our social workers, our psychologists, our psychiatrists? How do we work with those folks?

Shahzad Raza, MD: I think the most important person in that one is the physician. Physician has to spend time with the patient. That is one of those areas. I mean you really physician have to sit down, educate the patient, and I think I disagree with that, that when we say patients come back in six months, I think in six months a lot of things can be a problem for the patients. First initial meetings, I do recommend patients should come frequently to the doctors every couple of two months or three months and go back to the same questions. I think the best way to educate and get an eye and how we will monitor those conditions, and it is not a cancer, it is an entity, it's a disorder. You really have to keep an eye and keep monitoring it.

Same applies to smoldering disease and understandably high-risk smoldering understand, "Well, okay, I have that can progress. Doctor is watching me very closely, which I progress, I will get treated." But if you have a low-risk, smoldering disease or intermediate that you're keeping an eye and keep monitoring it, I think it's a trust. If the doctors achieve the trust of the patient that look, we are going to work as a team, get things, watch it closely and you're checking the labs. This will help to ease out the anxiety in these patients. But there are patients who have a pre-existing anxiety issue, a lot of stress. I do recommend their psychology appointments and psychiatrists to see how best we can help them, but many times our experience is patients do get better if we continue to monitor them and win their trust.

Dale Shepard, MD, PhD: Excellent. So great to see we have such great work going here at the Cleveland Clinic, not only in people with multiple myeloma, but really all of these shades beforehand, so fantastic. Awesome.

Shahzad Raza, MD: Very good.

Dale Shepard, MD, PhD: Appreciate your insights.

Shahzad Raza, MD: Thank you, sir. Thanks a lot. It's been nice to be here.

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