Background: Quadruplet therapy increases the depth and duration of response in newly diagnosed multiple myeloma (NDMM) patients. In patients receiving same therapy in the context of clinical trials, the achievement of minimal residual disease (MRD) negativity is associated with improved outcomes, yet the use of MRD assessment to modulate therapy in NDMM remains elusive.
Aims: We performed a multi-center, phase 2 trial of MRD response-Adapted Sequential ThERapy (MASTER) in patient with NDMM to test the feasibility and demonstrate outcomes of MRD response-modulated duration of therapy and therapy cessation. This is the final trial analysis with median follow up of 42.2 months.
Methods: Recruitment included enrichment for patients with MM containing high-risk cytogenetic abnormalities (HRCA). Patients received induction therapy with daratumumab, carfilzomib, lenalidomide and dexamethasone (Dara-KRd, 4 cycles), followed by autologous stem cell transplantation (ASCT) followed by up to two blocks of consolidation with Dara-KRd (4 cycles each). MRD by next generation sequencing was assessed at each phase of therapy. Duration of therapy was determined by achievement of MRD negativity (<10-5) in two consecutive phases. Patients reaching confirmed MRD negativity transitioned to observation with MRD surveillance (MRD-SURE), otherwise patients received maintenance lenalidomide.
Results: MASTER accrued 123 patients. There were 53, 46 and 24 patients with 0, 1 and 2+ HRCA [t(4;14), t(14;16), del(17p), gain/amp 1q]. Of those, 20% had age ≥ 70, 20% R-ISS 3, and 118 (96%) had myeloma trackable by NGS-MRD. MRD negativity was reached in 78%, 86% and 79% (overall 81%) and sustained (>12 months) MRD negativity was reached in 64%, 73% and 46 % of patients with 0, 1 and 2+ HRCA respectively. MRD <10-6 was reached in 68%, 79% and 62% (71% overall) for patients with 0,1 and 2+ HRCA respectively. Overall 84 (71%) patients reached MRD-SURE with treatment cessation. Progression-free survival (PFS) at 3-years for the entire study population is 88.4 %, 78.9% and 50.0% and 3-year OS is 94%, 92% and 75% for patients with 0, 1 and 2+ HRCA respectively. The 3-year PFS was 82% for patients with sustained MRD negativity (N=75) compared to 55% for those without. For the 84 patients reaching MRD-SURE, median follow up from cessation of therapy is 32.7 months and the 2-year cumulative risk of progression is 9%, 9% and 47% for 0, 1 and 2+ HRCA. Twenty-three patients resumed therapy due to progression (N=16) or MRD resurgence without progression (N=7) with 100% OS 18 months after resuming therapy. Sixty-one patients (52% MRD evaluable patients; 73% MRD-SURE) remain free of therapy with sustained MRD negativity.
Summary/Conclusion: The use of Dara-KRd induction, ASCT and MRD-modulated post-ASCT consolidation and treatment cessation approach with MRD surveillance provides excellent outcomes and a path for treatment cessation in most patients with standard or high-risk NDMM. Management of ultra-high-risk MM (2+ HRCA) remains an unmet medical need even in the context of quadruplet therapy and these patients maybe candidates for early deployment of strategies including T-cell redirection.
Keywords: Monoclonal antibody, Myeloma, Minimal residual disease (MRD)