DR LOVE: I thought we could start out talking about smoldering myeloma.

So maybe to get into that, I thought we could actually, Rafael, start out with your 64-year-old lady. And maybe you can just summarize it for both of us and, again, maybe not so much all the details, but just think a little bit about the case and what it is that you think makes it a good teaching case.

DR FONSECA: Sure. Well, thank you for the opportunity. I think that the main teaching point I’d like to make with this case, I will share, is importance of the nuanced approach to the details for patients who are perceived to have a premalignant condition. I always say during my talks it’s a lot easier to teach CRAB than it is to practice CRAB or to explain the CRAB version now because we can see the extremes. Those are easy. But as you get into the nuances, you get into changes over time, it becomes really complicated.

So I’m going to show you a case where I saw this patient who was a 64-year-old woman who had been diagnosed with a monoclonal gammopathy since September of 2015. And the bottom line: She was referred to us because she had a very gradual progression of both her M spike as well as her immunoglobulins. IgG was rising, starting from the 2,600 range and going all the way up to 3,400 and, most recently, 3,700. Now, this is in the face of no evidence of end-organ damage, in the face to the cytogenetics and genetic markers that talk about standard-risk disease.

DR LOVE: When you say “no evidence of organ damage” — and I’ll ask you, Noopur, what do you do in terms of the bones? Do you do MRI, for example, in a situation like this?

DR RAJE: Typically, if the skeletal survey is negative, yes. The new recommendation now, with the new redefinition of what symptomatic myeloma should be, you don’t actually have to have symptoms, but you can have evidence of end-organ damage on more fine testing. So MRI is incorporated. And if you see a focal lesion on an MRI, that would be considered symptomatic multiple myeloma. You could also use a PET/CT scan instead, or a CT scan because CAT scans are pretty good at picking up bone disease. And if you have lesions on those kinds of tests, it would be considered symptomatic disease and not smoldering.

So we have incorporated all of these tests into the mix of now defining what we would call symptomatic multiple myeloma. And these are helpful.

I think you bring up an interesting point, though, Rafael. This is a person whose myeloma protein is rising gradually. I’m sure you’ve done the MRI and PET scan at the outset, but to constantly repeat these tests, they’re not the easiest to do.

DR LOVE: So what actually did you do in terms of imaging, special imaging on her?

DR FONSECA: The patient had a PET scan by the time we had seen the patient. And the PET scan was said to be negative. I’d like to make the point, back to your question about bone disease, that I personally have found the PET to be incredibly useful for a thorough evaluation of myeloma, particularly in the smoldering multiple myeloma stage. It’s worth remembering the blood tests just give you the average of the whole body. A PET scan will talk about focal problems, which may be diluted by the average.

What I mean by that: You can have a patient who could have a pretty large lesion, for instance, in a vertebral body. We look at the free light chain of 20 mg per deciliter, say — you might say that’s not very high. But if you don’t know what’s going on in the vertebral bodies, you’re missing an opportunity to intervene before the compression fracture.

DR LOVE: What about Noopur’s point about repeating imaging or PET, for example, as you follow the patient?

DR FONSECA: Of course there’re certain international guidelines, but they’re as arbitrary as anything else. I think it’s true that we cannot be repeating this on a very frequent basis. But for someone who it’s ultimately decided that they have a premalignant stage, I think repeating some of this thorough imaging, whether that’s through the MRI or through the PET scan, once every 2 years, at least, I would say, it’s a pertinent thing to do. And I would only omit that in patients who are truly very, very early MGUS patients. But in the smoldering, be more attentive to the imaging.

DR LOVE: Can you bring us up to date with this lady?

DR FONSECA: Sure. We saw the patient, and the referring physician was rightfully concerned. Bone marrows were done, showed 10% plasmacytosis. A repeat analysis of bone marrow showed that it was a little bit higher. The patient now, the most recent determination is 3,700 mg for her IgG. So there is this ongoing dialogue with the patient and with the referring doctor: It’s true. It fits criteria for smoldering, but should we start something?

And then we’re going to talk a little bit more about this with the Mateos study on the long-term outcomes with lenalidomide. Should this patient be considering a clinical trial, maybe participating in a clinical trial? Is this enough that it warrants early initiation of therapy? And that’s the dialogue that we currently have going on with the patient. She has not started treatment yet.

DR LOVE: Just out of curiosity in terms of trials, for example, do you have any trials right now open at your place?

DR RAJE: We do. This is a space which has a lot of interest, a lot of research going on. And obviously we’ve done well in the myeloma space. And the next question, Neil, is can you act early? So the smoldering myeloma, specifically the high-risk smoldering myeloma space, is a space where I do think, if there are patients around, you should be seeking out a clinical trial.

We have quite a few clinical trials in the Boston area. The one which I’m particularly interested and involved with is we’re using a vaccination approach. And the vaccination approach is we’ve created a tripeptide vaccine, recognizing certain markers on tumor cells. And, in this case, it’s the PVX-410 vaccine. It recognizes some of the proteins we already know about in the myeloma world. One is SLAMF7, which is the same target for elotuzumab. Then there’s CD138, which is how we recognize myeloma. And XBP1 is a protein which is pretty much expressed on myeloma cells. So it’s XBP1, the total form as well as the splice form.

And for the first time we’ve been able to create a vaccine which can recognize all 3 proteins. We’ve done quite a lot of work with the vaccine as a single agent, vaccine with lenalidomide and, right now, we’re going to be doing vaccine with the IMiD as well as checkpoint blockade. So that’s the trial which is just about to happen. That’s one trial. There are others. There’s the elotuzumab/len/dex trial. And nationally, also, there are trials through ECOG, where we’ve compared len versus observation in patients with smoldering myeloma.

DR LOVE: I’m curious if you can talk a little bit about your interactions with this woman and what her thoughts are about what’s going on. And I was also really curious about the note that you wrote on this patient. I thought that was really interesting. I want to ask you about how you see patients and do this. But can you talk a little bit more about her and her reaction to this situation? And are there any trials that you presented to her?

DR FONSECA: Well, I think one of the greatest things of modern medicine is we have a much more informed patient because of the access to information, the Internet and particularly in cases like this where it’s someone who is intellectually very sophisticated. I think that allows for a very high-level dialogue. I know that’s not the case always, but I feel very rewarded when I have a patient where we can have this nuanced dialogue about what are the things that we should be talking about.

DR LOVE: What was her background?

DR FONSECA: This is an individual with a doctorate-level degree who’s very interested in options for treatment and is thinking, “Is there anything I can do to improve my health?” So I go through the description of what the diagnosis is and what are the historic aspects of that. We talked about options for clinical trials, which is very important. I always talk about hygiene. Now, what I mean by that is I want to make sure that patients who have a premalignant condition, such as smoldering myeloma, are aware of what are the symptoms that prompt us to think more about myeloma bone disease. I want them to have concern about renal hygiene.

So I always talk about the proper hydration, the importance of the free light chain as a marker for renal damage, the avoidance of nonsteroidal medications, avoidance of contrast dye for x-ray procedures. So we go through that discussion because I think that is as important as just merely the provision of a diagnosis and some statistics about what to do. And with that in mind, I think this is a person that we anticipate will be very engaged within her care.

DR LOVE: From a statistical point of view, Noopur, what would you see in terms of future for her?

DR RAJE: Over the last few years, we’ve been fortunate to identify, within the smoldering myeloma, who are the ones who can actually progress. And there’s about 10% of smoldering myeloma patients who will progress within the first 5 years, 50% of those. And we have some data to suggest, depending on the presence of the monoclonal protein or how high that monoclonal protein is, bone marrow plasmacytosis as well as the serum free light chains. But once we get all that information on this individual, you can predict. It’s not the best prediction, having said all of this, but you can say whether she has the likelihood of progressing to symptomatic myeloma in the first 5 years. And those are the ones which I think we would talk more about trying to consider putting on a trial and trying to learn from the trial, and trying to prevent symptomatic multiple myeloma.

Diagnosis and management of smoldering myeloma

Induction, consolidation and maintenance therapy for MM

Treatment of relapsed/refractory MM

Novel approaches under investigation for MM