Luciano Costa, MD, PhD, Discusses Final Results of the MASTER Trial of Daratumumab Plus KRd in Multiple Myeloma

At the 2021 American Society of Hematology Annual Meeting, Luciano Costa, MD, PhD, associate director for Clinical Research at O’Neal Comprehensive Cancer Center, discussed the results of the phase 2 MASTER trial (NCT03224507), which examined daratumumab (Darzalex), carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone (DARA-KRd) in patients with multiple myeloma.

Transcript:

At ASH, we are [giving] an update of the MASTER trial and reporting the final primary end point analysis. This study enrolled patients with newly diagnosed multiple myeloma, but with a deliberate enrichment for patients who have a higher proportion of high-risk cytogenetics. The treatment plan consisted of 4 cycles of induction therapy with daratumumab, carfilzomib, lenalidomide, and dexamethasone [DARA-KRd], followed by an autologous transplant, followed by anywhere from 0 to 8 cycles of DARA-KRd. The duration of therapy was determined by achievement of minimal residual disease [MRD] end points. The patients proceed on this path, with MRD at each block of therapy: at induction, post-transplant, and after each 4 cycles of consolidation. If at any point they have 2 consecutive read-outs with MRD less than 10-5, they exit therapy. [Patients] entered a phase that we call MRD-SURE, which is essentially surveillance including MRD, but without maintenance therapy. The primary end point was achievement of MRD negative at 10-5, and that was achieved in 80% of the patients. We also reported that two-thirds of the patients, or 66%, achieved MRD at 10-6. [A total of] 72% of the patients were able to achieve 2 consecutive MRD negative rates and proceed to treatment cessation and monitoring for MRD resurgence.

This trial was a bit different population wise than any other trial because [we] included patients without limit of age. We had several patient’s way into their 70s and had a bunch of high-risk patients. That allowed us to analyze patients by the presence of 0, 1, or 2 or more high-risk chromosomal abnormalities that we now call ultra–high-risk myeloma. There’s really no difference between how patients with standard risk and 1 high-risk abnormality behave. There are very high chances of MRD negativity, and most of them go on to discontinue therapy, and we have seen a very low risk of recurrence or resurgence of MRD. Those ultra–high-risk patients remain problematic.

We had 24 of those patients, and we saw about 6 patients progress on therapy [or] while receiving DARA-KRd. [Other patients progressed] shortly after finishing therapy. The way we read this trial is there’s clearly a path in myeloma to treat patients intensively upfront, obtain a deep response, cease therapy, and just monitor with MRD. I think that’s going to be feasible for the majority of patients and needs to be confirmed in a randomized trial. There’s also a subgroup of patients that have been underrepresented in clinical trials that behave very poorly, even with quadruple therapy, and those patients are going to need innovation, including perhaps the early introduction of novel agents, such as the anti–B-cell maturation antigen [BCMA] agents.

Reference

Costa L, Chhabra S, Medvedova E, et al. Daratumumab, Carfilzomib, Lenalidomide and Dexamethasone (Dara-KRd), autologous transplantation and MRD response-adapted treatment cessation. Final primary end point analysis of the Master Trial. Presented at: 63rd American Society of Hematology Annual Conference. December 11-14. Abstract 481. Accessed December 7, 2021. https://bit.ly/3GozUPK