Assistant Professor of Medicine University of Alabama at Birmingham, United States
Introduction: Minimal residual disease (MRD) is the most important dynamic prognostic marker of progression free (PFS) and overall survival (OS) in newly diagnosed multiple myeloma (NDMM). While autologous stem cell transplantation (ASCT) increases the proportion of patients (pts) reaching MRD negativity (< 10-5), it has short- and long-term toxicities. Quadruplets lead to high rates of MRD negativity creating the opportunity of MRD-adapted transplantation deferral. In the MILESTONE trial, we prospectively study the feasibility of using post induction MRD to defer ASCT in pts with NDMM.
Methods: MILESTONE (NCT04991103) is a phase II clinical trial for ASCT eligible NDMM and AL amyloid pts. In cohort A (NDMM), treatment consists of daratumumab 1800 mg SC (typical schedule), weekly bortezomib 1.3 mg/m2 SC, lenalidomide 25 mg PO days 1-21 and weekly dexamethasone 40 mg PO/IV (DaraVRd) every 28 days for 6 cycles followed by assessment of MRD by next-generation sequencing (clonoSEQ). Pts with MRD< 10-5 defer ASCT and continue with consolidation DaraVRd x3 cycles, pts with MRD³10-5 proceed with ASCT. After consolidation, all pts continue with maintenance (daratumumab on D1 and lenalidomide 10 mg D1-21 every 28 days; DaraR). Pts achieving sustained MRD< 10-5 (2 consecutive assessments 1 year apart) discontinue maintenance and proceed with MRD surveillance (MRD-SURE). The primary endpoint is the rate of ASCT deferral. Secondary endpoints included MRD conversion with ASCT, complete response (CR) by IMWG criteria at end of induction and consolidation, PFS and OS.
Results: We accrued 20 pts between 11/2021 and 5/2023. The median age is 69 years (37-78), 50% male, 45% racial and ethnic minorities, 40% with ISS stage III disease, 15% with high risk FISH abnormalities [t(4;14), t(14;16) and del17p]. All pts successfully collected sufficient stem cells for ASCT ( >2 × 106 CD34+ cells/kg), 5/20 (25%) achieved MRD < 10-5 post induction leading to ASCT deferral and one additional pt deferred ASCT by choice. One pt withdrew from participation before the end of induction. Thirteen pts completed ASCT and 6 (46%) converted to MRD < 10-5. With a median follow up of 18.4 months, there are no progressions or deaths, 4 pts have transitioned to MRD-SURE and 15 remain on maintenance and cumulative MRD negative rate 60% (12/20). The overall response rate 100%, best response ≥CR 80% (16/20).
Conclusions: Quadruplet induction results in deep responses allowing an opportunity to defer ASCT based on individual treatment response in NDMM. This study provides the initial feasibility of utilization of post induction MRD in guiding next steps in treatment. This approach is being further explored in the larger ongoing, randomized phase II MASTER-2 clinical trial to see if comparable clinical outcomes are possible without ASCT in those achieving deep response to induction therapy. Additionally, cohort B is accruing for pts with AL amyloidosis to defer transplantation based on MRD status.
