Phase 2 Study Using Minimal Residual Disease-Driven Adaptive Strategy in Newly Diagnosed Multiple Myeloma with Upfront Daratumumab-Based Therapy – First Report from the Maestro Trial

Introduction: Minimal residual disease (MRD) negativity has emerged as an important prognostic marker in multiple myeloma (MM), correlating with improved overall survival (OS). This study aims to optimize therapeutic outcomes and minimize treatment-related toxicity in newly diagnosed multiple myeloma (NDMM) patients (pts) by investigating an MRD-driven adaptive approach utilizing daratumumab (Dara)-based induction and consolidation regimens.

Methods: This is a Phase 2, single-arm, multi-center trial designed for NDMM, including both transplant-eligible (TE) and transplant-not-eligible (TNE) pts. Key inclusion criteria included the following: >=18 years of age, NDMM diagnosis as per IMWG criteria, and an ECOG status of <=2. MRD response evaluations included bone marrow (BM) MRD (10^-6 sensitivity) and imaging (PET/CT) MRD. Induction included cycles(C)1-6 (28-day cycle) with Dara 16 mg/kg IV or SC (q1wk in C1-2 and q2wks in C3-6), lenalidomide (Len) 25mg PO days(D)1-21, and dexamethasone (Dex) 40mg PO or IV weekly. TE pts underwent stem cell collection at C4-6. After 6 cycles of induction, pts achieving VGPR or better underwent MRD1 assessment. If MRD1 was positive, pt proceeded to consolidation for C7-9 by adding bortezomib (1.5 mg/m² SC on D1, 8, 15, 22) to the prior induction regimen (changing Dara frequency to q4wks in C7+), before proceeded to maintenance therapy (Dara-Len for 1 year followed by Len). If MRD1 was negative, pt proceeded directly to maintenance therapy. Pts underwent MRD2 and MRD3 evaluations at the end of consolidation, and 1-year maintenance, respectively. TE-eligible pts who were MRD2-positive had the option of proceeding to Autologous Stem Cell Transplantation (ASCT). Pts who became MRD2-negative proceeded to maintenance as described above. The primary endpoint was MRD negativity after induction and consolidation therapy (if applicable). Secondary endpoints included overall survival (OS), progression free survival (PFS), and safety. Patient reported outcomes included peripheral neuropathy and Quality of Life (QoL) assessments.

Results: Of 57 enrolled pts, 50 were evaluable for efficacy and 56 for safety/tolerability at data cut (31 May 2024). Patient characteristics included the following: median age of 65 years (range 44-85); 45.6% females; 77.2% White, 19.3% Black, 1.8% Asian, and 1.7% of unknown ancestral descent; 15.7% high risk pts (1 del17p, 3 t[4;14], 3 t[14;16], and 2 t[14;20]); and 56.1%, 29.8%, and 10.5% had R-ISS I, II, and III respectively. Of the 50 pts assessed for efficacy, 42 were TE, 8 were TNE, and 9 pts received ASCT after consolidation. 47 pts had MRD1/MRD2 evaluation; 5 pts achieved MRD1 negativity, and 14 pts converted from MRD1 positivity to MRD2 negativity. The trial met the primary objective as 38% pts achieved post-induction/consolidation MRD-negativity (n=19; 95% CI 25.9%, 51.8%). All pts who achieved negative BM MRD also had negative PET/CT results. VGPR or better was observed in 88% (n=44) of pts at the last follow-up. The median follow-up time was 20.2 months (min, max: 5.2, 38.9; IQR: 13.2 to 27.9). The median PFS and OS were not reached. The estimated two-year probability was 86.1% (95% CI: 76, 97.4) for PFS, and 94.2% (95% CI: 86.4, 100) for OS. The most frequent (>=5%) >=Grade 3 treatment-related adverse events (TRAE) were as follows: hematologic AEs included neutropenia (n=10, 17.9%) and lymphopenia (n=4, 7.1%); non-hematologic AEs included diarrhea (n=4; 7.1%). Grade 4 Treatment-related Serious AEs included neutropenia (n=5; 8.9%) and lymphopenia (n=4; 7.1%); 1 pt developed acute myeloid leukemia (without ASCT). No pts discontinued therapy due to TRAEs. There were 4 treatment-unrelated deaths (all over 3 mo after end of treatment on study). Per received surveys in 43/50 patients, no statistically significant patient reported peripheral neuropathy was noted at the end of consolidation. Both TE and TNE pts demonstrated encouraging QoL: the Mean (SD) QoL overall health score at baseline (screening) was 69.15 (21.47), and at post-consolidation was 82.29 (14.81), demonstrating a 19% improvement (P <0.001).

Conclusions: An MRD-driven therapeutic strategy is effective in converting positive MRD to negative MRD at 10^-6 in both TE and TNE NDMM pts, with promising 2-year PFS and OS rates. Daratumumab-based induction and consolidation therapies were well-tolerated and highly effective, also offering improvements in patient-reported QoL.