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EHA 2022 | DETERMINATION: RVD vs high-dose melphalan conditioning with autoHSCT in NDMM

Paul Richardson, MD, Dana-Farber Cancer Institute, Boston, MA, discusses the key results of the Phase III DETERMINATION study (NCT01208662) evaluating the use of lenalidomide, bortezomib, and dexamethasone (RVD) versus high-dose melphalan-based conditioning with autologous hematopoietic stem cell transplantation (autoHSCT) in patients with newly diagnosed multiple myeloma (NDMM). Dr Richardson explains that whilst the trial demonstrated a statistically significant benefit in progression-free survival (PFS) for patients receiving autoHSCT, the trial did not show a difference in overall survival (OS). In addition, there were more toxicities observed in transplanted patients. Moving forward, Dr Richardson discusses the conclusions from this trial in the context of novel effective quadruplet therapies as well as future directions. This interview took place at the European Hematology Association (EHA) Congress 2022 held in Vienna, Austria.

Transcript (edited for clarity)

Well, obviously, the DETERMINATION study has finally been able to be reported. We’re at 12 years into the journey with DETERMINATION, which says a lot in itself. In the old days, you could be reporting on a newly diagnosed study in multiple myeloma in three to five years. Now, you have to wait 12 and I think that speaks volumes. Suffice to say, an incredible team effort across 56 centers in the United States supported and sponsored by the Clinical Trials Network, the BMT CTN, and also endorsed and supported by The Alliance, but actually led at Dana-Farber...

Well, obviously, the DETERMINATION study has finally been able to be reported. We’re at 12 years into the journey with DETERMINATION, which says a lot in itself. In the old days, you could be reporting on a newly diagnosed study in multiple myeloma in three to five years. Now, you have to wait 12 and I think that speaks volumes. Suffice to say, an incredible team effort across 56 centers in the United States supported and sponsored by the Clinical Trials Network, the BMT CTN, and also endorsed and supported by The Alliance, but actually led at Dana-Farber. What we were able to show is a striking progression-free survival benefit to the addition of transplant to the RVd platform. But interestingly, when using transplant or keeping transplant in reserve, we showed no overall survival difference. You could use RVd alone, collect stem cells, and use continuous maintenance, and actually achieve the best results we’ve seen today around a 46-month progression-free survival overall and with high response rates.

But with transplant that PFS jumps dramatically to 67 months or a 21-month median gain. Fascinatingly, despite that degree of clinical benefit though, overall survival was identical. And with five year [inaudible] estimate of 80% for both arms. And so, that I think tells us a lot. It tells us that on the one hand transplant clearly is a standard of care in the younger patient, that PFS gain is the biggest we’ve seen. It points to the power of maintenance, because this was continuous maintenance and that’s why our French partners would use it for just one year. The degree of benefit that they showed, which was about one year’s difference. Ours was substantially bigger for both arms, so clearly maintenance until progression makes a big difference. The other aspect of the study that’s so important though, is that melphalan matters. I mean, it’s driving that deeper response and that results in a PFS gain.

The fascinating question is why was there no overall survival benefit? And that’s where I think our study really does offer some intriguing insights. Number one, in salvage, transplant was used in just 28% of the patients because patients and providers chose to use other novel therapies in 72% of the patients versus 28%. And yet the survival was the same. So it tells us that whilst you may lose PFS benefit by not going to transplant early, keeping transplant in reserve, doesn’t penalize you for survival. That’s really important because what we did identify in the early transplant group was significant toxicity differences, which we expected. But they were manageable, which is very important. We also showed a significant drop in quality of life across the transplant process. But the really good news is that it recovered with maintenance over time. But then something a little more concerning, the second primary malignancy signal, the same in both arms overall.

But critically in the high-dose melphalan arm, we saw 10 cases of AML/MDS versus zero in the non-melphalan containing arm. Now, small numbers fortunately. So this remains a very rare phenomenon, but that is a very real difference. And that was a statistically significant difference. And at the EHA meeting we’re presenting outcome in these hem malignancies and whilst we have just a couple of deaths in the RVd alone arm, we have more in the transplant arm. So, clearly there’s this difference that may be emerging from this second primary phenomenon that may be important. I want to stress though, it’s early data and its very small numbers. So I wouldn’t suggest for a minute that this means, “My goodness, we shouldn’t be transplanting because there’s too much AML/MDS.” That’s not what I’m saying at all. What I really believe though, is we need to be better able to identify who these patients are and protect them from this potential complication in the longer term, because clearly high-dose melphalan is making a big difference in terms of quality of response, MRD negativity, and progression-free survival.

The question is how can we improve on that? How can we make that translate potentially in the future into a survival benefit? And that’s a key question as we go forward. So, I think the other point about DETERMINATION that’s so critical is that we obviously tested this in the setting of just a triplet RVd. And we designed the trial in 2008-2009. We’re now in 2022, quadruplets are here. We have RVd-Dara. We have RVd isatuximab. We have KRd-Dara. We have KRd isatuximab. So we’ve got these fantastic quads, which are generating tremendous quality responses and very deep responses and MRD negativity with or without transplant. So the question is where do we go from here? And my sense is over time, this field will continue to dramatically evolve. And I think we’ll see higher quality of responses, better outcomes, hopefully much less toxicity, and a more targeted approach, especially when it comes to targeting what I call stemness, which is this core of disease that melphalan clearly targets. But the question is, can we do better than that? Will cellular therapies help us? Will there be better forms of targeted melphalan that we can use to deliver that key hit that’s required to generate those best responses? So lots of exciting new directions to go in.

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