COSTEM 2021 | The efficacy of double ASCT for multiple myeloma

Hello, today- my name is Pieter Sonneveld- today we will discuss the role of double autologous transplant in multiple myeloma, in particular in patients with high-risk cytogenetics, which, as you know, is a poor prognostic factor in these patients. So, some studies have been performed in the past that looks at the role of autologous transplantation, single versus double in particular, with the aim of improving the poor prognostic outcome of these patients with high-risk cytogenetics. One of the studies, one of the first studies, I would say, that’s looked at this was a French study. Which demonstrated that in particular patients that have, let’s say a less optimal response to the first transplantation, would benefit from a second autologous transplant.

But in a randomized fashion the next studies that I want to report are mainly in upfront multiple myeloma in the younger group of patients that are eligible for transplantation. One study has been a co-creation between the HOVON group from the Netherlands, with the German GMG group coordinated by Professor Goldschmidt that studied the role of bortezomib for induction and also for continuous treatment or maintenance during two years, with a single or with a double autologous transplants. And the results of this study have been published already almost 10 years ago, but they demonstrated very clearly that patients with deletion 17p, but also other prognostic abnormal cytogenetics, like additional q and a 4;14 translocation, that in these groups, the progression-free survival was better with bortezomib continuous treatment for two years, but also that the double autologous transplant in combination with this regimen was very effective.

Another trial is the EMN02 trial that was performed five to six years ago in the European Myeloma Network, comparing standards, melphalan dosing with high-dose melphalan and autologous transplant, and the high dose could be administered once or twice. Without going in many details, it was very clear from the evaluation that a 20% or so patients with high-risk cytogenetics clearly benefited from the double autologous transplants, with a hazard ratio of 0.42 in those high-risk cytogenetics for the PFS and also a benefit for overall survival, if a hazard ratio of 0.52. So, this clearly indicated that there may be a benefit from a second autologous transplant in the subgroup of patients with high-risk cytogenetics and the same was true for patients with ISS3. Did we observe any other effects? The answer is yes, because with the second autologous transplant, we could also see that there was a clear upgrade for patients to a complete response with autologous transplants from 3-14%. And so this is a real increase and that was translating a better progression-free survival and overall survival.

Other studies have also looked at, for example, the effects of MRD-negativity in long-term treatment, in this EMN02 trial. And recently we published the results in the Journal of Clinical Oncology indicating that the achievement of MRD-negativity, in fact overrules the other effects of consolidation, and was also observed in all patients with single or double autologous transplants, indicating that within the subgroups of patients, there is a group that achieves MRD-negativity, and this is the most, I would say the strongest prognostic factor for PFS and possibly also OS.

Other trials, for example, one from the US the STaMINA trial as indicated by a long-term follow-up, that there is a benefit of the second autologous transplant, so double auto-auto in the high-risk group, with 43% PFS at five years, which is not observed in two other groups in this trial, single autologous followed by consolidation or a single autologous followed by maintenance only. Again, although there were many comments to the study, the clear outcome is that double autologous transplant is better.

And in an attempt to get more information from large numbers of patients, the EMN and in particular, Professor Cavo from Bologna have done a meta-analysis with three trials, including 900 patients with single or double autologous transplants. There approximately 18 to 20% of the patients had a high-risk cytogenetics. And also there, the benefit of autologous transplant was clearly indicated both for PFS and for OS if hazard ratio of 0.76 and 0.69, both significant. So again, this is an argument in favour of using double autologous transplant. However, if we construct a risk score based on this, on this meta-analysis, you can find prognostic subgroups where the PFS and OS which, especially PFS range from 8%-44% at 10 years.

So, this is clinically very useful, and it can be used to identify patients that may benefit from the double autologous transplants. However, all of this was done before the era of the novel agents, especially the introduction of anti-CD38 antibodies and novel therapies, anti-BCMA, and other T-cell engagers in CAR T-cell programs.

So, with the recent publication of the CASSIOPEIA trial that included VTd with, or without daratumumab, it was decided not to include a second autologous transplant and the results of this prolonged treatment with daratumumab clearly indicates that also high-risk patients benefit from this addition, making the question whether we really need a second autologous transplant, an important one, and we will discuss this further at this COSTEM meeting. I thank you for your attention.