Should Every Patient With Newly Diagnosed MM Receive a Transplant?
In light of recent clinical trial data, key opinion leaders reflect on the appropriate selection of transplant for patients with newly diagnosed multiple myeloma.
Transcript:
Sagar Lonial, MD: I think the other elephant in the room is about the role of high-dose therapy in the context of these highly effective triplets or quad-based therapy. I think every patient who comes in to see me somehow has read or heard about [the] DETERMINATION [trial; NCT01208662], and usually they interpret it in a way different than I do. I’m curious how you all address that.
Caitlin Costello, MD: Disclaimer, I believe in the transplant. The reality of it is that every trial that we keep asking in the modern era of myeloma is, do we still need the transplant? With this hope and theory somewhere out there that we can just get rid of transplant as an effective therapy that’s cheaper probably [better] than much of what we have to offer. If we keep asking the right questions, do we need to get this or can we get rid of it? I think the answer we keep seeing is that they complement each other. All the transplant studies, whether it’s the IFM09 followed up by DETERMINATION, are showing us the same answer. It is continuing to be an effective strategy that we still should continue to offer our transplant-eligible patients. Now, we’ve had a lot of discussions about well, it didn’t show an overall survival benefit, and that is really what my patients walk in. They’re very well-informed patients who come in and say that the study showed there was no overall survival benefit, which they heard the argument is that [that] wasn’t the primary end point. It wasn’t statistically designed to do that. The statistical design was to show progression-free survival benefit, and it did that by almost 2 years. How do we argue with that? If that is when compared to someone who didn’t get [a] transplant [surviving] 2 years shorter, that PFS [progression-free survival] matters.
Samuel M. Rubinstein, MD: I think the counterargument to that is that in our practice, it becomes an individualized discussion. How much does a patient value that 2 extra years of progression-free survival versus the tail risks of an autologous transplant [of] nonzero transplant-related mortality up to 1 in 30 rates of secondary hematologic malignancy.
Sagar Lonial, MD: Which was similar in both arms.
Samuel M. Rubinstein, MD: Similar in both arms but more therapy-related myeloid disease, which is more challenging to treat in general in the transplant arm. Then, of course, excellent quality of life analysis on that study shows that the typical patient returns to their pretransplant quality of life, but it takes 3 months or even longer, and not every patient will recover their status from prior to a transplant. It’s an individualized discussion. How much an individual patient values those things is very important in whether we choose to proceed with high-dose therapy or not.
Caitlin Costello, MD: That discussion very much has to be transparent. I say to some of my patients, yes, there is a very small risk of dying from a transplant. It is very small. There is a reasonably small risk of getting secondary malignancies. There’s an extremely high, almost close to a 100% risk, of your myeloma coming back. When you’re weighing those discussions, and yes, the quality of life is going to take a hit for a short while, but then I think we’ve all seen our patients at the 3-month mark and feel fine. That short-term struggle for long-term benefit in my mind is worth it.
Timothy Schmidt, MD: I think that not only that, you’re also seeing much higher rates of MRD [minimal residual disease] negativity and these long durable responses after transplant, and you’re giving your patients a better chance at having that deep and durable response. I would argue we don’t yet have all the data to show that MRD is the end all, be all of myeloma therapy in terms of choosing our treatments, the duration, everything like that, but we’re very heavily exploring MRD-adapted treatment durations and treatment strategies. If these end up panning out, these patients are more likely to benefit from some of these potential strategies where we could de-escalate therapy or other things like that as well. I think that not only are we looking at what are we [seeing] in the data today, but what’s coming down the road and how are we giving our patients the best chance to not only achieve MRD negativity, and all those questions, but [we’re] also pushing the bar down the road farther for the [advancement] of some of these more exciting therapies. I think there really is a lot, too, [regarding] that duration of response and the depth of response.
Samuel M. Rubinstein, MD: Tim, you raised an interesting point of response-adapted therapy and because this is coming out of DETERMINATION, I have to ask: How do you think about the outcomes in the patients who are MRD negative prior to their transplant? They did not seem to derive much progression-free survival advantage. [The trial was not] powered to that group of patients, and I’m not yet intentionally deferring transplant in patients who get MRD negative beforehand, but it’s a tempting thought in light of that analysis.
Sagar Lonial, MD: I think that analysis was at 1 year. It was not pretransplant. I think the analysis was done at 1 year and showed that if at 1 year you were MRD negative, it didn’t matter which arm you were on in terms of PFS. The problem is, at 1 year you’ve already made the decision on transplant versus no transplant. The fraction of patients who are MRD negative at 1 year is double in the transplant group compared to the nontransplant.
Timothy Schmidt, MD: I think that the other point there is that in the IFM 2009 trial [NCT01191060], in a really great analysis that they did looking at MRD results, even among MRD-negative patients, you still saw a benefit for the transplant. I think that there’s certainly plenty of nuance there and I think that we’re all excited to see where this heads but I think overwhelmingly more evidence to suggest that transplant is a great option for our patients.
Sandy Wong, MD: I would also add that just because a patient reaches MRD negativity, I think underlying risk is still a major factor. Someone who’s standard risk and MRD negative, I think I feel better about those patients than someone who is high risk and MRD negative because I think if you look at some of the subset analyses from IFM [and] DETERMINATION, you can see that those high-risk patients, even if they achieve MRD negativity, they still don’t do that well. I’m reticent especially about those patients. I’m going to throw a little bit of a monkey wrench in this conversation. This comes up all the time with my patients when they come to clinic. They’re not as savvy so they don’t ask the survival questions, but they know a lot about CAR-Ts. I have a lot of patients that say, I’m going to save myself. I don’t want to do stem cell transplant. I’m going to save myself for CAR-Ts. How do you respond to that? I’m curious.
Caitlin Costello, MD: I don’t think they’re mutually exclusive. I think these patients are going to get all of these therapies. If our goal is to kick the can down the road to keep these patients in remission as long as possible, that will give them the opportunity for the CAR-T once we have it at earlier lines of therapy.
Sagar Lonial, MD: From my perspective, you never get a shot at the most sensitive disease like you do at the time of initial diagnosis. Prolonging that first PFS is a major goal, at least, in the way I present this to patients when they are hesitant about a transplant, your disease is never as sensitive as it is now. If you lose that shot, and remember in DETERMINATION, only 30% of patients got a salvage transplant, whereas in the French study it’s 80%. I worry a little bit about losing a really important tool. Maybe it’s not a great tool for everybody, but certainly, for the majority in a population it does offer benefit.
Samuel M. Rubinstein, MD: I suppose I’m the least still pro-transplant. What I tell patients at the end of the day is, if I as a younger man were to develop myeloma tomorrow, I would definitely still want upfront autologous transplant. You have to weigh the pros and cons. I do wonder if someday sustained MRD negativity may enable us to defer an increasing number of patients and still derive benefit.
Transcript edited for clarity.
