Multiple Myeloma Management in 2021 - Episode 5
Paul G. Richardson, MD: I’m going to touch briefly on 2 important updates, one of which was the early versus late transplant study conducted by our French partners. I thought Aurore Perrot, MD, PhD, did a wonderful job of summarizing and showing that with a median follow-up of 8 years, the overall survival [OS] was identical in both groups at approximately 60% in both arms. Regarding the late transplant group, about 70% had gone on to late transplant. We were thinking there might be a survival benefit in favor of earlier transplant, and we didn’t see it, suggesting that for a subset of patients we can think about reserving transplant, doing stem cell collection, but keeping transplant in reserve. Overall, that was a very important takeaway. Also, an important takeaway from Aurore’s presentation was that MRD [minimal residual disease] in the research setting clearly matters and is prognostically important regardless of whatever therapy you got.
There were also fascinating data from Mehmet Samur, PhD. Specifically, his work derived from the IFM trial data set where we looked at mutational change according to therapy. Specifically, be it RVd [lenalidomide, bortezomib, dexamethasone] followed by delayed transplant, or RVd [lenalidomide, bortezomib, dexamethasone], early transplant, and there was really striking information.
You recognize in whole-genome sequencing the enormous mutational burden that we have in our patients at diagnosis, with a median of around 7000 mutations in each group. When you saw relapse after RVd [lenalidomide, bortezomib, dexamethasone] with transplant kept in reserve, the mutational burden increased by about a median of 1500, whereas in the transplanted group receiving high-dose melphalan, that was substantially greater at about 5600, which was really striking. I think what jumped out at me from those data, was that even in the MRD-negative patients who received high-dose melphalan, when they relapsed, at whole-genome sequence analysis, that same mutational difference was seen.
I think it begs the question as we look to the future, recognizing the real value of high-dose melphalan where it stands right now, we need to think about ways of targeting this minimal residual disease state in terms of intensification that don’t allow this kind of mutational thrust to emerge at a later date, fully recognizing that these are subsets of patients. Therefore, you must be very careful. I did think that Mehmet’s presentation was fascinating because it certainly convinces me that we need to target stemness. The question is how? Do we do so with something that buys us a problem later, or do we do something, to David’s point of your work, Nina, looking at approaches that could target this earlier that could achieve that MRD-negative state without the late complication of mutational burden?
Overall, I thought that was an interesting analysis. I would caution everyone not to necessarily over-interpret it because the numbers were relatively small. I think that’s tremendously important because we want to be careful about making too much of a limited amount of data at this point. We’ll obviously have information from DETERMINATION and other studies to help us with that.
I want to turn now to David and say that post-transplant, recognizing its value and that it may not be for everyone, although it’s importance for a subset of younger patients is clearly beneficial. How do you think about consolidation? At ASH [the American Society of Hematology 2020 annual meeting], the Pieter Sonneveld, MD, PhD, abstract #550 was helpful. Moreover, we already touched on Jonathan Kaufman, MD’s data from GRIFFIN and Francesca Gay, MD’s information from FORTE. David, any thoughts on consolidation here?
David Siegel, MD, PhD: Clearly, that’s what we need to do, and we can talk about the specific trials. However, I think it is difficult to interpret these things because in the end it’s about OS and the progression-free survival [PFS], and even PFS2 [progression on next line of therapy], which has been addressed in some of these trials where there does seem to be a continued advantage. In the end, mutational burden and additional therapy carries some long-term ramifications that we don’t understand yet.
I would go back to some of those transplant data that you were speaking of. Heather Landau, MD, was also a first author on a similar kind of analysis of patients coming out of Memorial Sloan Kettering Cancer Center. However, what they’re looking at in these trials are the early relapsers, specifically the patients who don’t have long-term remissions, even long-term remissions with the support of maintenance therapy afterward. And these are melphalan-specific mutations that are seen, but we’re seeing them in a population that is maybe not high risk by the molecular definitions that we use, but are behaving as high risk, and those are, in fact, the ones that are most important.
To reiterate what you were saying, these are small numbers, it’s early. But also, it’s the early relapsers that drove that analysis, and that’s a very interesting patient population that is not reflective of the more global population.
Paul G. Richardson, MD: That’s a very good point.
David Siegel, MD, PhD: We have a lot to learn. Consolidation is clearly a very important paper, and Nina began to speak about the FORTE trial, and I thought FORTE was one of the more interesting trials. I think what was important specifically was the topic of discussion. If people don’t understand FORTE, a very complicated trial, an initial 3-arm randomization to the combination of carfilzomib, cyclophosphamide, and dexamethasone, and then 2 KRd [carfilzomib, lenalidomide, dexamethasone] arms, 1 of which was with continuous KRd [carfilzomib, lenalidomide, dexamethasone] for 12 cycles. The other was KRd [carfilzomib, lenalidomide, dexamethasone], stop, go through a transplant, and then get more KRd [carfilzomib, lenalidomide, dexamethasone] as consolidation afterward. And then a randomization to Revlimid [lenalidomide] as maintenance therapy versus carfilzomib and Revlimid. I don’t know whether you want to call that maintenance or not?
What it showed is that the transplant-based regimen, the KRd [carfilzomib, lenalidomide, dexamethasone]/transplant as opposed to KCd [carfilzomib, cyclophosphamide, dexamethasone]/transplant—and I think that’s an important point because there are a lot of oncologists, both community oncologists and people who work in multiple myeloma centers, who still use cyclophosphamide-based regimens as their major induction regimen—and this clearly shows the inferiority of the cyclophosphamide-based regimen. Overall, the discussion is about KRd [carfilzomib, lenalidomide, dexamethasone] to transplant versus KRd [carfilzomib, lenalidomide, dexamethasone] to more KRd [carfilzomib, lenalidomide, dexamethasone] to more KRD [carfilzomib, lenalidomide, dexamethasone] again, which shows a substantial advantage to the transplanted arm.
The advantage is even more pronounced in terms of hazard reduction in high-risk patients than it is in the larger population. This is one of the more important trials for several reasons. It continues to support early transplant as a modality, and we’re fortunate that transplant is relatively easy, and it’s ubiquitously available. Also, it is very inexpensive relative to other modalities, and it seems to be preferentially effective in the high-risk patient population, which is the one that we have still to grapple with much more so than others. I think that if I was to pick out a single large trial from the 2020 ASH meeting, I thought that was the most important one.
Paul G. Richardson, MD: Yes. I think, David, though to be fair, we must be careful about the sample sizes in FORTE, just as we were cautious about those. You’ve got several randomizations, and you’ve got 150 patients per arm, and you’ve got 3 arms. I wholeheartedly agree with you that clearly KRd [carfilzomib, lenalidomide, dexamethasone]/transplant wins on the PFS signal in higher risk. Obviously, we don’t have survival data. I agree with you, KCd [carfilzomib, cyclophosphamide, dexamethasone] was clearly inferior on all counts compared to either KRd [carfilzomib, lenalidomide, dexamethasone] and delayed transplant, or KRd [carfilzomib, lenalidomide, dexamethasone] early, and I think that was an important message.
I think the message for clinicians is obviously chemotherapy plus proteasome inhibition only gets you so far. The synergy with immunomodulation is critical, and then this whole goal of targeting stemness is a very important one. I think you’re right, especially in health care systems that don’t have access to multiple new drugs, transplantation is a gold standard because if you don’t have access to salvage strategies, you’re getting the best benefit. But certainly in US practice, we’re blessed by 12 drugs as we stand with more to come in the next month or so, and especially the CAR [chimeric antigen receptor] T platform, which I’m excited about, plus the BiTEs [bispecific T-cell engagers].
Going forward, we can be powerful about that. There is important quality of life [QOL] data that was moved across by Aurore in our presentation somewhat quickly because it wasn’t quite as straightforward as was implied in the presentation as there was a substantial dip in QOL across transplant. We need to be careful about saying it’s straightforward. In expert hands like your own, you do an amazing job. I think the patient perspective is a little bit more varied. That aside, I totally agree with everything you said.
Transcript Edited for Clarity