James Armitage: Hello, I’m Jim Armitage from the University of Nebraska Medical Center. I want to welcome you to The ASCO Post Video Roundtable Series featuring the Appropriate Management of Challenging Cases in Myeloma and Lymphoma. This first installment will focus on the current treatment approach to patients with smoldering myeloma. Now today I am going to be joined by two of my friends and colleagues and experts in these areas, and I will let them introduce themselves.
Sarah Holstein: Hi! My name is Sarah Holstein, an associate professor here at University of Nebraska Medical Center. I specialize in multiple myeloma and related plasma cell dyscrasias.
Matthew Lunning: Hi, I’m Matthew Lunning, associate professor here at the University of Nebraska Medical Center. I specialize in lymphoma as well as cellular therapy.
Dr. Armitage: Alright. Now, the first case, as I just said, is going to be a patient with smoldering myeloma, and I am going to quickly present that case, and Sarah will be the person who will do most of the responding. Patient is a 65-year-old man who was referred because of a monoclonal protein being found in the blood. The patient was asymptomatic. He had a normal exam. He had an IgG kappa protein about 3.5 gm. There was no protein in the urine, and the bone marrow biopsy showed 17% clonal plasma cells. His renal function calcium and bone images were all normal. The patient had been told by another physician that no treatment was appropriate, and he came to you wanting another opinion, and so Sarah, what do you tell this person?
Dr. Holstein: So, I usually start out my discussion with patients who were referred for management of smoldering myeloma by saying that this is one of the murkiest discussions that I have these days in the field of myeloma, and it’s murky because although we do have some new data, these data really don’t tell us what to do with each individual patient who comes to our attention. Smoldering myeloma continues to change in terms of how we define it and the difficulty is that around the world, we still have not come to a consensus even as to what is high-risk smoldering myeloma versus low-risk versus intermediate-risk, and so it becomes difficult when you start to try to compare amongst studies, and it becomes difficult when you try to counsel patients because depending on which risk stratification model you use, you could tell them one number that might look pretty good to the patient—let’s say 10% risk over 10 years—or you could say while using a different stratification model you might have a 50% chance of turning into active myeloma, and obviously those numbers are very scary for patients to hear.
More recently, one of the models that seems to be gaining favor is that 20-2-20, and that is where there is a free light chain ratio of more than 20, an M spike more than 2, and more than 20% plasma cells. I don’t recall hearing what the free light chain ratio was in this particular case, but certainly this patient has less than 20% plasma cells and had an M spike that was more than 2, so at a minimum, this individual has at least one risk factor. When we look at the data, the most recent data comes from the ECOG study, but to understand the ECOG study, you have to understand that really this took all comers and this took people with completely normal free light chain ratios, and really as long as they had more than 10% plasma cells, they were counted as smoldering. In addition, the study really took anybody who had had smoldering myeloma for at least five years. The thing that I tell patients is that what gives me most comfort is knowing what the tempo of their disease is, and we cannot know that with just one data point. So when somebody has first been diagnosed with these numbers, yes, we might be able to use the risk factors a little bit to prognosticate, but ultimately if I have somebody who I have watched for a year or two and their M spike has done nothing, their light chains have done nothing, that is much more reassuring than just simply taking that one data point where I can’t draw a line and can’t predict the future.
And going back to the ECOG study again it was a mix of patients, some of whom had been watched for a while, and so it was known that really they probably had favorable disease as opposed to others who had just been diagnosed. And you really don’t know whether they are going to take off in the next six months and whether they were going to calmly smolder for the next two years. So I put that all in context and tell them that for me, unless somebody is really appearing with multiple high-risk factors, very high burden of disease, 60% plasma cells almost on the edge of what we now define as active myeloma, my initial impulse is to watch closely and try to understand the tempo of the disease.
Dr. Armitage: Is there anybody that you would say “you absolutely should be treated”?
Dr. Holstein: I think it comes down again to how closely you’ve really looked for myeloma-defining events, have you thoroughly imaged them? In some cases that includes not only doing things like a PET-CT but also whole-body MRI to really make sure you are not missing any lytic lesions or bone marrow lesions. There have been a few cases where it has not so much been the absolute numbers involved but perhaps things like recurrent pneumonias where to me that’s a myeloma-defining event if they have immunoparesis. So let’s say their IgG is 4000 and their IgA and IgM were very low. They have had two serious episodes of pneumonia in the last six months where they have been hospitalized. Regardless of what that bone marrow plasma cell percentage is, I am going to talk to them seriously about treating because I think at that point, there is evidence that the disease is truly harming them.
Dr. Armitage: When people are treated, most of the data of which I am aware—and you are the myeloma expert—but it has always included lenalidomide in whatever was done. Lenalidomide is not a nothing drug. In addition to the immediate side effects, there is always a concern about other cancers. What do you think about that?
Dr. Holstein: So, it’s also a very difficult question even if you decide that you want to treat somebody as smoldering myeloma, do you treat them as smoldering or do you treat them as active myeloma? There is a big difference there. Again the most recent ECOG study was single-agent lenalidomide. We would never use single-agent lenalidomide if you had a 65 year old who came in with two bone lesions and anemia. These days you would use a three-drug or even four-drug regimen. With respect to the long-term consequences of lenalidomide, for me, looking at the data, the most convincing data for increased risk of second primary malignancies is really in the context of post high-dose melphalan associated with autologous stem cell transplant. There really has not been appreciable signal from the smoldering studies conducted to date that there is a significant increased risk of SPMs and associated with just lenalidomide in the smoldering setting. So, from an SPM perspective, it doesn’t concern me but you’re absolutely correct, Jim: there are other side effects. Again when you look at the ECOG study, a fairly large number of patients discontinued treatment who are on the lenalidomide arm not because their myeloma or their smoldering myeloma was progressing but because of side effects. And whether that is because of fatigue or diarrhea or other issues, it does give one pause when you are talking about treating a patient population who by definition is asymptomatic.
Dr. Armitage: Okay, you see this person, you decide not to treat them. How often do you see them?
Dr. Holstein: If I’m really concerned, so an M spike of 3.5 to me is pretty high, so that is somebody who we’re pretty uncomfortable, so I might see them back in a month. If somebody is coming in with an M spike of 2 and no other alarming factors, I generally see patients every three months for at least a couple of years to try to understand the tempo of their disease.
Dr. Armitage: Does it matter to you what the protein is? With the light chains only, [whether] there’s an [Ig]A
or a [Ig]G. Does it matter to you?
Dr. Holstein: That’s an excellent question. Personally IgA does give me much more pause in terms of really feeling comfortable about simply monitoring versus pulling the trigger and initiating treatment much more so than IgG or free light chain.
Dr. Armitage: So Sarah, does it make any difference to you if the patient is IgG or an IgA or a light chain only or a kappa or lambda light chain? What matters to you about that?
Dr. Holstein: It does. So, I typically get much more nervous about an IgA smoldering myeloma and actually an IgA myeloma as well, more so than I do IgG or a free light chain myeloma. Again the data are difficult to piece apart. There is at least one stratification system that does incorporate IgA as an additional risk factor, but at least with the 20-2-20 that does not take into account the type of paraprotein.
Dr. Armitage: Alright. Well, I appreciate your comments, but before we end this I want to see if there is anything else that the people watching would benefit from thinking about when they encounter a patient who fits into this new disease category—which didn’t used to exist when I learned it—smoldering myeloma.
Dr. Holstein: Yeah. I think there is so much still we do not know about smoldering myeloma, and I think a large part of that is what the immune system is doing. So we like numbers as physicians, and so we like the catchy things like the 20-2-20 system, but really that’s not taking into account what the immune system is doing, and I think most of us appreciate that for many of the patients who smolder for 10 to 20 years, that they are probably doing so because their immune system is keeping the plasma cell dyscrasia in check whereas those whose disease takes off in a very rapid period of time, there’s probably more dysregulation in the immune system, and knowing more about that I think will help us predict which patients will progress to active myeloma in a shorter period.
In addition, it gets back to the ultimate question of what our goal of treatment is. Do we think in smoldering myeloma that if we just give one drug, for example, like lenalidomide, that we are doing something to the immune system that therefore will reset it in some ways so that we are curing the disease permanently? Or are we just giving kind of mid-level therapy, meaning one drug instead of three drugs so that we can delay the inevitable but the inevitable is still going to happen meaning progressing to active myeloma? And I think that’s really a philosophical divide right now amongst myeloma specialists in terms of clinical trial designs. You have the study like len vs. nothing, and in contrast you have a study that’s going on in Europe, which is throwing everything in the kitchen sink to smoldering myeloma patients in the attempt to cure it, so in that case they are getting daratumumab plus carfilzomib and lenalidomide-dex plus transplant plus consolidation plus maintenance and asking the question well if you give all the best drugs when it’s smoldering, can you cure it that way? I don’t know what the answer is going to be, but I admit to being somewhat skeptical that we can cure smoldering myeloma with just a single drug.
Dr. Armitage: Alright. Well, thank you very much.
Dr. Holstein: Thank you.
Dr. Armitage: Matt and I certainly enjoyed this, and I hope you all watching us today did too. Stay tuned for more installments of The ASCO Post Video Roundtable Series. I will be talking about a couple of types of lymphoma and another problem with myeloma in upcoming presentations. You will see this on ascopost.com and they’ll be up soon. Thank you.