Treating High-Risk Asymptomatic Myeloma

Transcript:Saad Usmani, MD: The high-risk patients, they tend to be a heterogeneous group. You want to have people, what the Spanish Myeloma Group folks call “ultra—high-risk,” that do need to be treated perhaps like real myeloma. We are going to get our answer with the ECOG study, Sagar, that you’re leading—lenalidomide/dexamethasone versus observation.

Keith Stewart, MB, CHB: Tell us about that, Sagar.

Sagar Lonial, MD: That’s a study that enrolls both the intermediate- and the high-risk group of patients, as defined by what I’ll call the “ECOG high-risk criteria,” which is greater than 10% plasma cells, free light chain ratio greater than 8 or less than 0.1, and M-protein greater than 3. And, I think, what we’re trying to do—what I think you’re hearing all of us talk about—is that smoldering patients are a pretty heterogeneous group. I think what we want to do is identify which smoldering patients actually have myeloma versus which smoldering patients are actually more like MGUS. I think, ultimately, smoldering will go away as a category. It will be replaced with either MGUS or myeloma, and how to get there I think is the real challenge.

Keith Stewart, MB, CHB: There have been some attempts to start treating these high-risk smolderers, from the Spanish group, as we mentioned a couple of times. Amrita, are you familiar with some of the Spanish studies? Would you like to comment on those?

Amrita Krishnan, MD: I think the Spanish studies certainly were very big landmarks, in regards that finally we had randomized trials.

Keith Stewart, MB, CHB: For the people who are watching might not know what they are, can you just explain what they are a little bit?

Amrita Krishnan, MD: The Spanish study that I was referring to was the trial looking at lenalidomide/dexamethasone for 2 years versus observation in patients “high-risk” by the various definitions. I think the challenge is the field moves so quickly, and when that study was developed, for example, imaging, as Sagar alluded to earlier, was not by MRI and PET. Now we look back at that study and say, “Perhaps there were a lot of patients who, in fact, had true myeloma, especially in the observation arm.” So, it makes that study a little bit more in question, which is why, in part, we’re waiting for the ECOG trial.

Keith Stewart, MB, CHB: Now, that study is being presented again at this ASH 2016 meeting. Does anybody want to expand on what they’re showing us at this meeting that’s an update? Having looked at it myself just recently, it seems that the advantage to treating early with lenalidomide/dexamethasone in that particular study persists with longer follow-up. And it shows a halving of the risk of developing active disease. In fact, there were less deaths on the group of patients who received the combination therapy. But, I think there were some questions about the number of deaths in the first place, Paul.

Paul Richardson, MD: My impression of the whole trial is that, clearly, survival benefit was demonstrated. If you looked at the control group, one of the most striking features was the frequency of skeletal events leading to mortality. I think that in that context, I agree with Amrita. We have to be a little careful how we interpret that data because I think with advanced imaging, many of those patients would have been considered active disease. And, obviously, we clearly know that you need to treat active disease, and survival benefit is well established with appropriate therapies. So, I think the principle of the trial is the point, isn’t it? Earlier intervention confers clinical benefit, and that’s how I interpret it.

Keith Stewart, MB, CHB: Saad?

Saad Usmani, MD: I agree with you. One of the critiques of the study had been that it was geared towards progression to active myeloma, and not really powered for survival benefit. And that’s where I think Sagar’s study will provide us with more information. The real debate between whether to treat or observe these patients I think will be settled, but then we’ll have to figure out what is the best approach to treating these patients.

Keith Stewart, MB, CHB: One of the debates that now comes up is if you’re going to treat them, shouldn’t you treat them as you treat an active myeloma patient? We have another abstract at this ASH 2016 meeting from Dr. Landgren and his colleagues. Sagar, do you want talk about that a little bit and what they did with the addition of carfilzomib to lenalidomide/dexamethasone in this high-risk smoldering population?

Sagar Lonial, MD: I think Ola’s trial, that they are updating at this meeting, is a natural progression of if lenalidomide and dexamethasone don’t do harm and may actually offer benefit to these patients, what about giving more intensive therapy? And so, he did a small trial looking at carfilzomib in combination with lenalidomide/dexamethasone (KRd) for patients with high-risk smoldering myeloma. What I think he has nicely demonstrated is that almost all the patients achieved a response. A significant fraction after 2 years of therapy achieved stringent CR and achieved MRD-negative complete remission that was durable after discontinuation of therapy, at 2 years. What I think is really intriguing about this—and he’s presenting longer follow-up, and that benefit has been sustained in a number of patients—is the idea that he gave very intensive therapy and that he stopped at some point. Because, ultimately, if we’re going to treat these patients earlier, it’s not just about reducing risk of complications, but potentially offering curative therapy.

Keith Stewart, MB, CHB: I don’t know that it’s in the abstract, but do you think these patients will be cured?

Sagar Lonial, MD: I don’t know. I think it’s really early to know the answer to that question. But, certainly, there are subsets of patients that, with 3 years’ follow-up, now continue to be MRD-negative without being on therapy for over 1 year.

Keith Stewart, MB, CHB: Which is pretty exciting when you think about it. These are people who are pre-symptomatic. You treat them aggressively. Their disease is completely gone and staying gone. I guess the question is how long.

Sagar Lonial, MD: How long, right.

Paul Richardson, MD: Keith, if I may, I completely agree with Sagar. I think that the principle of earlier intervention to obtain durable clinical benefit is clearly established. The immunological approaches in that setting are very important, and, in our own group, we’re studying this very actively with antibody-based therapy, as well as vaccination strategies. The rationale, there, is to Sagar’s point, you can have real memory effects in terms of the immune system that lost for a prolonged period, and at the same time, you minimize toxicity.

Keith Stewart, MB, CHB: This might be a really good place to intervene with immune-based therapy, which we’ll get to later this morning. Just a little bit out in left field. There is a paper published this year about the use of statin therapy in myeloma patients that has generated some discussion. This was a VA study, a retrospective look at the people, who took statins or didn’t take statins, who got myeloma. What did that show, Paul?

Paul Richardson, MD: Well, it’s very interesting. It was a large trial, about 5000 patients in the analysis, so the database is quite robust. But, clearly, those patients who were on statins, either when their diagnosis was made or within 3 months of it, showed actually mortality benefit, which I think is fascinating. You might ask, “Why?”. Well, we do know the HMG-CoA reductase pathway has some overlap with the amino-bisphosphonate route. Interestingly, and this is what I found striking in that data, there was a reduction in skeletal events. I think that pans into what we’ve just been discussing. For example, in smoldering patients, if they have any evidence of bone loss, we have a low threshold for amino-bisphosphonate use. And, there’s some evidence that there’s an immunological effect from amino-bisphosphonates emerging. So, I think it’s intriguing.

Keith Stewart, MB, CHB: Are you going to put all your patients on a statin now?

Paul Richardson, MD: Well, no. I would say that, no, not necessarily.

Keith Stewart, MB, CHB: Why not then?

Paul Richardson, MD: I’m struck with the fact that statins aren’t without their price tag, too—proximal muscle weakness, LFT abnormalities—so one has to be a little careful. But, having said that, if it’s clinically indicated, why not?

Keith Stewart, MB, CHB: Anybody else going to use a statin routinely or not convinced?

Amrita Krishnan, MD: Generally, for most people who have hyperlipidemia, it tends to go along with type 2 diabetes. And, certainly, in that paper, based on that database, they weren’t able to sort it out. But, there are data, for example, in terms of metformin, and truly reducing myeloma progression and mortality. And so, I think it would be interesting to delve deeper into that. We’re doing some of that work at our institution. Obviously, we know that in terms of glucose, diabetes and IL-6 are also drivers of myeloma.

Keith Stewart, MB, CHB: So, watch this space.

Transcript Edited for Clarity