MRD Testing in Multiple Myeloma: Modeling the Potential Clinical and Economic Outcomes Based on the Master Trial

Introduction Developments in therapeutics over the last decade have called into question the ubiquitous use of lenalidomide maintenance therapy until disease progression in all patients with newly diagnosed Multiple Myeloma (MM), particularly those who are amenable to more intense initial therapy. Minimal Residual Disease (MRD) testing is part of the response evaluation criteria for MM and patients who reach MRD negativity (MRD-) after triplet or quadruplet therapy and autologous hematopoietic stem cell transplant (HSCT) have excellent outcomes even without indefinite maintenance therapy. Deep MRD negativity (malignant cells <10-5) correlates with improved health outcomes for MM patients, decreased benefit from drug treatments, and can inform treatment discontinuation decisions. The MASTER trial evaluated MRD status in 123 patients with newly diagnosed MM using next-generation sequencing (NGS) at the end of daratumumab, carfilzomib, lenalidomide and dexamethasone (Dara-KRd) induction, post autologous HSCT, and every 4 cycles of Dara-KRd consolidation, with a maximum of 8 cycles. Patients who achieved deep MRD negativity for two consecutive phases stopped treatment and began observation with MRD surveillance (MRD-SURE), others received lenalidomide maintenance. Induction therapy with Dara-KRd, followed by autologous HSCT, MRD-guided post-transplantation consolidation and treatment discontinuation resulted in most patients reaching an MRD-free, treatment-free state with a low risk of disease progression in MRD-SURE. Our objective was to quantify the long-term clinical and economic impact of MRD directed treatment decisions and identify key data uncertainties. Methods We developed a Semi-Markov model with health states tracking MRD status, treatments received, and progression to compare NGS MRD directed treatment to no MRD testing over a lifetime horizon. In line with the MASTER trial, treatment stopped after two consecutive MRD- results during consolidation treatment; otherwise, treatment continued through consolidation and maintenance until discontinuation, disease progression, or death. MRD- patients restarted treatment after MRD resurgence. Progression-free survival and overall survival data for MRD- and MRD+ patients were applied based on the MASTER trial. As the MASTER trial was single armed, we simulated outcomes for patients who would have received full consolidation and maintenance therapy (MTX) using literature-based hazard ratios (HR). Due to uncertainty in the treatment effect in MRD- patients, we explored a range of HRs during consolidation and maintenance. The upper bound of effects were based on estimates from studies that included both MRD+ and MRD- patients (consolidation HR of 0.72 (Straka et. al. 2019), MTX survival: 0.87 [Jackson et. al. 2019]), or studies not powered to differentiate effects between MRD+ and MRD- patients (MTX progression: 0.62 [de Tute et. al. 2022]). The lower bound was no treatment effect. Health state utilities and costs were based on peer-reviewed literature. We used a US health system perspective and a 3% discount rate. Outcomes included life years, quality adjusted life years, costs, and incremental net monetary benefit (iNMB) calculated using $150,000/QALY. Outcomes were reported across plausible ranges for progression and death during maintenance treatment of MRD- patients, with uncertainty quantified using probabilistic and one-way sensitivity analysis (OWSA). Results MRD directed treatment yielded substantial costs savings in all scenarios, with greater savings at the upper bound of treatment effects ($1,064,773) versus the lower bound ($797,490). These costs savings were associated with substantial iNMBs of $919,998 and $818,696, respectively. MRD directed treatment led to incremental QALYs ranging from -0.97 to 0.14. Probabilistic analysis yielded iNMBs between $907,428 and $811,725, while OWSA identified the cost and duration of lenalidomide, utility values, survival inputs after consolidation, and MRD resurgence rate as key model drivers. Conclusions Our analysis demonstrates that MRD directed treatment may yield between small losses to small gains in clinical outcomes accompanied by large decreases in costs. These results are driven by the substantial uncertainty in the consolidation and maintenance treatment effects in patients who achieve deep MRD- disease early in treatment.