The MASTER study was conceived about four years ago as we foresaw the fact that the advent of monoclonal antibodies as well as the development of newer proteasome inhibitors was bringing to myeloma really a unique opportunity. There was the opportunity to drive the majority of patients into a deep remission. While continuous therapy had been the standard in myeloma for quite a few years, we believe that had to be re-appraised in a different setting where now most patients can achieve a deep response. At that point minimal residual disease, particularly by next generation sequencing, was becoming better understood. So we conceived this study in collaboration across five institutions, forming a consortium, to really deploy the best available myeloma therapy at the time, including autologous transplant, be able to tailor the duration of therapy to the achievement and confirmation of achievement of negativity of minimal residual disease and then have a path to cease therapy and follow those patients longitudinally without the burden of continuous maintenance therapy.
What was the methodology used in this study?
This was a prospective phase II single arm study where patients with newly diagnosed myeloma, including patients with an enrichment for patients for high risk cytogenetics, received quadruple therapy with daratumumab, carfilzomib, lenalidomide and dexamethasone. Those patients did not have an age limit – we had patients as old as 79 on this study. There were some eligibility details that allowed the inclusion of patients who often present as sick and are excluded from other newly diagnosed myeloma trials.
Patients received four cycles of induction, had MRD assessment, received an autologous transplant, had another MRD assessment and then they received zero, four or eight cycles of consolidation with dara-KRd. The duration of therapy was dictated by the MRD that was assessed at each of those blocks of therapy. Patients who had two consecutive MRD negatives read to less than 10-5 by NGS were then able to cease therapy after that last block that they received and go on to observation with MRD surveillance, something we call MRD-SURE. For patients who did not reach that milestone and proceed to receive the whole therapy, they then continued on standard of care maintenance single agent lenalidomide.
It is important to emphasise that MRD was assessed by next generation sequencing using the clonoSEQ platform and was performed and reported using the international harmonisation on performing reporting MRD in multiple myeloma trials.
What were your findings?
There were some important findings. One that is quite important but often overlooked is that this is doable. Even though we’re working with five different sites we are able to obtain trackable sequences; we’re able to implement MRD guidance in 96% of the patients. Despite the multiple MRD testing we had one single sample that was missed on the whole study. We always got results back on time to act for the next step. So that’s an important part, that is near real-time MRD response adapted therapy is feasible in a multi-institutional setting.
In terms of the safety of the regimen, it was safe. Of 123 patients we had three deaths, one sudden death on the second week of therapy and two during the recovery from autologous transplant. We had the usual neutropenia, thrombocytopenia, we had a few SAEs for pneumonia and deep venous thrombosis but no other new safety signals. The regimen, the programme, was highly active – overall we had 80% of the patients achieve MRD negativity of 10-5 which was the primary endpoint of the study. We also have 66% of the patients achieved MRD to 10-6 which was an exploratory endpoint. Overall 72% of the patients reached the milestone of having two consecutive MRD to 10-5 and were able to enter the MRD-SURE phase.
Importantly, we are reporting the results by subset according to cytogenetic risk. So we separated patients with zero cytogenetic high risk features or standard risk, patients with one high risk chromosomal abnormality or high risk, and patients with two or more that we call ultra-high risk. Their responses and their MRD responses between standard high risk were nearly identical; actually, in several circumstances they looked actually a little bit better for the high risk patients. When you look at the ultra-high risk you have a different story. They have the same likelihood of overall achieving MRD 10-5, but that tends to happen later, and they have a lower likelihood of achieving MRD to 10-6.
Among the patients with ultra-high risk disease we also had some early treatment failures, actually patients progressing on therapy while receiving quadruple therapy, and some other patients progressing shortly after discontinuation of quadruple therapy which speaks really to the bad behaviour of this small subset of patients that is often under-represented in clinical trials. In our trial they accounted for 20% because of the high risk enrichment.
Overall for patients who had zero high risk abnormality the two year progression free survival was 91% and for the patients with one high risk abnormality was 97%. The overall survival at two years was respectively 96% and 100%. However, for the patients who have two or more high risk abnormalities the two year PFS was 58% and the two year overall survival 76%.
We believe this speaks really to the need to adapt therapy, not only to the cytogenetic risk but to the depth of response. We have now the vast majority of patients with zero or one high risk abnormality doing well off therapy with reasonable follow-up but it’s pretty clear for the patients with ultra-high risk disease, particularly the ones who don’t reach a deep response, innovative therapy is going to be needed.
How can these results impact the future treatment of multiple myeloma?
We have to look at the study for what it is, which is a single arm phase II study. So it’s more of a precedent-setting, principle-proving, rather than definitive evidence. For one it shows the excellent activity of this combination, dara-KRd, along with autologous transplant. Perhaps more important it shows that we can instrumentalise MRD to enrich a subset of patients to then ask specific questions. So we believe in the very near future we will be employing quadruple therapy and then asking the de-escalation question for the patients who are early achievers of deep responses. But conversely for patients who do not reach those milestones, particularly the ones who have a high risk biology, we will need to experience with the introduction of agents with a different mechanism of action and at this moment that seems to be anti-BCMA agents.
What is next for this study?
We’re going to be learning from MASTER for a few years to come. It will be important to observe these patients, particularly the patients off therapy, for the following years to accurately report the risk of progression and the risk of MRD resurgence. I think it will be very interesting to see what happens to those MRD resurgences.
There are other things we want to learn, for example the immune reconstitution and the interplay of immune reconstitution with the MRD and with the risk of progression. However, in terms of clinical trials I believe this sets the stage to start asking different questions for different subsets of patients. We understand that early MRD, particularly after induction, is a good separator of disease with a better biology that is amenable to treatment de-escalation. I think in those patients we should explore in a randomised setting the omission of autologous transplant. But, conversely, for patients who remain MRD positive we need to explore new ways of consolidating that is not just repetition of additional cycles of quadruple therapy. That’s the direction we intend to go.
