Dr Costa on the Clinical Implications of the MASTER Trial in Multiple Myeloma

Luciano J. Costa, MD, PhD, associate director, clinical research, O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham (UAB), discusses clinical implications derived from a final analysis of the phase 2 MASTER trial (NCT03224507) which evaluated quadruplet induction therapy in multiple myeloma.

The MASTER trial assessed the efficacy of induction therapy with daratumumab (Darzalex), carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone (Dara-KRd) followed by autologous stem cell transplantation (ASCT) and consolidation with the quadruplet. Findings from the final analysis of the trial demonstrated that this regimen was highly effective for both high-risk and standard-risk patient populations. Moreover, a post induction landmark analysis showed that minimal residual disease (MRD)-adapted therapy reduced the effect of MRD positivity on progression-free survival and overall survival by the cessation of induction. This underscores the potential for achieving long-lasting remission through this approach.

Lastly, results from MASTER indicate that the regimen holds significant promise for guiding treatment cessation strategies, particularly for patients without ultra-high-risk disease. This adds to the growing body of evidence strengthening the notion that induction therapy alone can provide patients with an extended period of remission. For example, the phase 3 CASSIOPEIA trial (NCT02541383), which incorporated daratumumab, bortezomib (Velcade), thalidomide (Thalomid), and dexamethasone induction/consolidation without maintenance, revealed that patients who achieved MRD negativity experienced good outcomes without subsequent or ongoing treatment.

Approximately 10-15% of patients with multiple myeloma are considered ultra-high risk. Despite deliberate enrichment of this subgroup in the MASTER trial, patient outcomes were less favorable compared to other cohorts, even with quadruplet therapy. This trend was consistent with observations in the phase 2 GRIFFIN trial (NCT02874742), in which the continuation of daratumumab and lenalidomide produced a similar trajectory. Furthermore, data presented at the 2023 ASCO Meeting regarding the use of carfilzomib/pomalidomide (Pomalyst) maintenance therapy in high-risk patients also exhibited a similar pattern, with high rates of progression in the first few years.

These findings suggest that the optimal strategy for improving the treatment of this patient subset lies beyond existing combinations or treatment continuation strategies. Instead, research should pursue the integration of innovative practices that have revolutionized myeloma care in later stages. This includes CAR T-cell therapy and bispecific antibodies, which hold promise in challenging the high-risk prognostic paradigm.