We know that currently patients with high risk myeloma unfortunately mostly become apparent when they are relapsing. They’re normally getting very similar treatment up front but an early relapse identifies patients with aggressive disease and that means that in hindsight the management has to be changed which does not only mean that there is a strain on resources and stressful for patients but we also know these patients have reduced response in the second line of their therapy and subsequent lines. So the aim of our study was really a) to identify these patients with high risk disease earlier but then also to use improved biological risk prediction to alter their management already early on and to test a new treatment regimen with dara-CVRd before and after transplant to improve outcomes for patients with ultra-high risk disease or plasma cell leukaemia.
What was the methodology used in this study?
We took really all the evidence in that we and others have generated over the past years and identified patients that were really at high risk of relapse with ultra-high risk disease based on genetics, either double-hit genetics or gene expression profiling, or if they had features of plasma cell leukaemia. We screened a newly diagnosed patient population up front centrally for these features. We then included them into the trial with the specific treatment if they showed such ultra-high risk features and treated them with dara-CVRd up front. They then received a single transplant and then dara-VRd consolidation over a prolonged time of 18 cycles then followed by dara-R maintenance.
The real novelty of the trial is that we felt it was really difficult to tell these patients in the first place that they have ultra-high risk disease and then randomise them to standard of care therapy which is actually our preferred way of running trials in the UK because we need to really generate high level evidence to make a good case for a new treatment. We came to a novel solution which we termed a digital comparator trial. So we used the data that we have generated in a very recent phase III randomised trial and we used the winning arms of this trial to select a group of about 500 patients that we also screened for presence of these high risk markers. All of this was done centrally in a central laboratory using the same tests and we identified about the same proportion of patients with ultra-high risk features. So we were able then to define a novel, as we call it, Bayesian framework to compare the outcomes of the patients enrolled in the new study prospectively with those that had just been treated with very up-to-date therapy that we consider standard of care – KCRd induction or CRd induction, a transplant and Revlimid maintenance without the need to really randomising the patients that went into the study in the first place.
What were your findings?
The data that we are presenting at this year’s ASH are the primary endpoint analyses which is a comparison of progression free survival at 18 months from start of treatment of the patients treated in the OPTIMUM MUKnine trial - ultra-high risk patients undergoing dara-CVRd transplant and dara-VRd consolidation – against patients with ultra-high risk disease that were treated in Myeloma XI with KCRd or CRd transplant and Revlimid maintenance. Our finding was that progression free survival at 18 months was significantly better for those patients in the OPTIMUM MUKnine trial treated with daraCVRd before and after transplant.
How can these results impact the future treatment of myeloma?
Two really important outcomes from this trial already for standard of care treatment of patients at the moment. First is the identification of patients with ultra-high risk disease. We have generated, really, a vast amount of evidence, and others as well, in large meta-analyses that show that the double-hit, so co-occurrence of two cytogenetic high risk markers, and/or gene expression profiling identifies patients at very high risk of early relapse and for plasma cell leukaemia this has been shown as well. So defining ultra-high risk that way, and really our readouts support that this is done, actually, in standard of care as well, does identify about the 20-25% of patients that we know are tending to relapse early. That in itself is an important finding.
But, of course, in terms of improvements of outcomes for patients we are showing, to our knowledge for the first time, comparative evidence that intensified treatment, both before the transplant but, more importantly, in contrast to current standard of care, also after transplant with dara-VRd for a year at least, if not longer, does really improve outcomes for these patients. Because all of these drugs are on their own used in this setting of first-line patients, we feel that this is a particularly relevant finding for patients. It is also quite a patient-centric finding because this is a regimen that can be delivered as an oral or a subcutaneous regimen only.
