MASTER trial updates: Dara-KRd induction, autologous transplantation and MRD response-adapted consolidation in NDMM

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Published: 9 Jul 2020
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Dr Luciano Costa - O'Neal Comprehensive Cancer Center at UAB, Birmingham, USA

Dr Luciano Costa speaks to ecancer in an online interview for the virtual EHA 2020 meeting.

He presents the updated results from the MASTER study, which investigated the combination of daratumumab, carlfizomib, lenalidomide and dexamethasone (Dara-KRd) to treat patients with newly-diagnosed multiple myeloma (NDMM), with the use of MRD-guided post autologous transplantation (AHCT) consolidation, and MRD surveillance.

Dr Costa outlines the study design, main findings and conclusions achieved with the use of this approach in this patient population. 

ecancer's filming has been kindly supported by Amgen through the ecancer Global Foundation. ecancer is editorially independent and there is no influence over content.

At the EHA 2020 we presented an update of the MASTER study. The MASTER study is a trial for patients with newly diagnosed multiple myeloma that combines the proteasome inhibitor carfilzomib, the immunomodulatory agent lenalidomide, the monoclonal antibody, anti-CD38, daratumumab and dexamethasone. What is unique about this trial is not only this quadruple combination including carfilzomib being used on a weekly schedule but also the fact that we use MRD assessment, not only as an endpoint but also to determine duration and intensity of therapy.

So all patients received four cycles of Dara-KRd induction. They have MRD assessed at the end of induction, they receive autologous stem cell transplant, they again have MRD assessed. Patients who have two consecutive MRD below 10-5, so at the end of induction and at the end of transplant, go on to observation, something that we call treatment-free observation and MRD surveillance, or TREPHONES for short.

The patients who do not meet that criteria yet go on to receive up to two blocks of four additional cycles of Dara-KRd, again with MRD assessed at each block and again at any time where the patient meets criteria for two cons ecutive MRD below 10-5 they transition to TREPHONES.

At the time of the data cut for the EHA abstract the study had accrued 101 patients. Of those patients 19% were ISS stage 3 and 29% of the patients had high risk chromosomal abnormality, including 17p, [4;14]  and [14;16]. We assessed MRD by clonoSEQ therefore we could report not only MRD to 10-5 but also could report MRD to 10-6. At the time of the data cut, of those 101 patients the vast majority of the patients had responded. 91% of the patients had reached VGPR or better after induction. Post-transplant 92% of the patients had a complete response or better using traditional response criteria.
In terms of MRD the rate of MRD below 10-5 was 42% post-induction, 73% post-transplant and 82% using MRD guided post-transplant consolidation. When you look at 10-6 those rates were 28%, 50% and 63% respectively.

The trial continues to accrue with some enrichment for high risk chromosome abnormalities which in the long run will allow us to have a better understanding of how this combination, how this approach, works for patients with high risk cytogenetics. For the time being, however, the rate and depth of response seems very different between the standard risk and high risk patients. For instance, the rate of 10-5 reached on the study was 83% for standard risk and 79% for high risk patients.

The study evidently has some toxicities, particularly considering that we enrol patients with a pretty liberal set of criteria compared with other transplant eligible trials, for instance, we didn’t have an age limit. Patients who present with a high disease burden were allowed to be included after, for example, one cycle of bridge therapy to overcome, for example, hypercalcaemia or renal failure. All in all we have had the most frequent adverse events have been cytopenias and infections, including one case of fatal metapneumovirus pneumonia.

Perhaps the most fascinating aspect of this study is we are essentially creating a cohort of patients who have a deep response with MRD negative, early and deep response, that are being observed off maintenance therapy and with MRD surveillance. At the time of the data cut we had had 40 patients who had transitioned to this, what we call TREPHONES phase. Of those 40 patients with a follow-up between less than a month and 15 months none of the patients had had a progression or had had resurgence of MRD. So we believe these preliminary results are very promising and, of course, we look forward to learning from a longer follow-up, particularly in what the kinetics would be of MRD resurgence among those patients who are off therapy.