MRD Evaluation in a Transplant-Eligible NDMM Study
Authors: Peng Yuhe , Fu Chengcheng , Jin Song , Shang Jingjing , Yao Weiqin , Yan Zhi , Zhai Yingying , Yao Li , Shen Hongmiao , Wu Xingyue , You Hongying , Huang Yue , Wang Jing , Lu Jiao , Wu Depei 
Published: December 2024

Background: Next-generation sequencing(NGS) assessment of minimal residual disease (MRD) at a sensitivity of 10−5 in multiple myeloma (MM) treatment response has just established in China recent years. MRD is one of the most powerful prognostic factors for progression-free survival and overall survival. It is adopted for evaluating therapy efficacy, tracking disease progression and making decision in MM trials. This retrospective study aims to investigate the role of MRD measured sequentially by the NGS in a real-world study.

Methods:164 newly diagnosed multiple myeloma patients who received 4 cycles of VRD prior to ASCT or tandem ASCT with 2 more VRD consolidations at the first affiliated hospital of Soochow University from August 2019 to August 2023 were enrolled in this NGS MRD study and retrospectively analyzed. The 3 time points of MRD evaluation were after induction, post-transplantation and consolidation and before maintenance. To evaluate whether factors other than MRD status could affect patient prognosis, we used a Cox proportional hazard model including MRD status ,age, β2-MG, LDH, Creatinine clearance rate（Ccr）,extramedullary disease, R-ISS stage, and high-risk cytogenetics including del(17p), t(4,14), t(14,16), t(14,20), 1q21 gain/amp to explore their effects on OS and PFS.

Results: The median age of patients at diagnosis was 58.5 (52-63) years. 12.8% patients were R-ISS III, 33% patients had high-risk cytogenetics. After induction, ORR was 91.8%, with 42.9% CR or better,37.8% VGPR,11.1% PR, 19.5% MRD negativity. After transplantation, ORR was 98.2%, with 59.6% CR or better, 30.5% VGPR, 8.1% PR, 44.5% MRD negativity. 76.3% patients with VGPR+ achieved MRD negativity. The proportion of MRD negative in CR patients increased significantly from induction to post-transplant (28 % vs 50%, p&lt;0.003).

With a median of follow-up of 29.3 months, 3-y PFS rate of patients achieving MRD - comparing to patients with MRD+ after induction was 100% vs 57.6% (p=0.014, HR=0.29, 95%CI 0.11-0.78). 3-y PFS rate was 79.9% vs 56.9%(p =0 .032, HR=0.43, 95%CI 0.20-0.93 ) for patients with MRD - versus MRD+ after transplantation. For Patients with MRD - vs MRD+ before maintenance , the respective 3-y PFS rate was 77.8% vs 51.3 % (p=0.046, HR=0.24, 95%CI 0.06-0.98). Three-year PFS rate was only 50.7% in patients with both MRD + after induction and transplantation. Median PFS was 37.3 months and only 23.4% patients are high cytogenetic risk. The time to progression was further divided into early-stage （&lt;=18m,n=11）and late-stage progression(&gt;=18m,n=16). There was a statistically significant difference in MRD + and cytogenetic risk between the two groups (91.9% vs 66.7%, 42.8% vs 18.1%, p=0.044).

We found that the following factors negatively affected PFS in the univariate Cox model: MRD consecutive positive (p=0.0002),MRD status changing from negative to positive(p=0.007), Ccr&lt;90 ml/min(p=0.035), extramedullary disease(p=0.046), R-ISS stage III (p=0.021)and high-risk cytogenetics(p&lt;0.001). But MRD negative after induction (HR=0.13, 95%CI0.02-0.97, p=0.045) and transplantation (HR=0.34, 95%CI0.14-0.87, p=0.039) was associated with prolonged PFS. MRD consecutive positive (p=0.0043),MRD status changing from negative to positive (p=0.024) and high-risk cytogenetics (p=0.012)also had significant adverse impacts on OS. In the multivariate analysis, MRD consecutive positive, MRD status changing from negative to positive and high-risk cytogenetics were significantly associated with an inferior PFS, whereas only high-risk cytogenetics predicted a worse OS.

Conclusion: This study demonstrates that patients achieved NGS MRD negativity before transplantation was associated with a prolonged PFS. But median PFS was only 37.3 months for those patients had sustained MRD positivity before and after transplantation regardless of cytogenetic abnormalities. High risk cytogenetics and MRD positive after transplantation resulted in earlier progression. These patients may need more aggressive intervention according to MRD monitoring.