Curative Strategy (GEM-CESAR) for High-Risk Smoldering Myeloma (SMM): Post-Hoc Analysis of Sustained Undetectable Measurable Residual Disease (MRD)

Introduction: SMM is an asymptomatic plasma cell disorder with heterogeneous clinical behavior and once R-based regimens have shown to be effective in high-risk SMM patients, our next step was to perform this phase 2 trial, but aiming at abrogating the risk of progression through an intensive treatment regimen with the end point of achieving sustained MRD negativity (MRD-ve) at 3 and 5 years after ASCT. Patients and methods: Ninety SMM pts at high-risk of progression (>50% at 2 years), younger than 70 years and transplant candidates were included. Induction therapy consisted of six 4-weeks cycles of KRd in which carfilzomib (K) was given at dose of 36 mg/m2 twice per week plus lenalidomide (R) at dose of 25 mg on days 1-21 and dexamethasone (d) at dose of 40 mg weekly. Melphalan at dose of 200 mg/m2 followed by ASCT was given as intensification therapy followed by two KRd consolidation cycles and maintenance with R at dose of 10 mg plus dexamethasone at dose of 20 mg weekly for up to 2 years. The primary end-point was to evaluate the MRD-ve rate by next generation flow (NGF) after ASCT and MRD-ve rate maintained at 3 and 5 years after ASCT. Because of the COVID-19 pandemic, the MRD evaluation 3 years after ASCT was done in less patients than expected and we amended the protocol to evaluate sustained MRD-ve rate at 4 and 5 years. Patients experiencing biological progression (biochemical or MRD conversion from -ve to +ve) after stopping maintenance had the opportunity of receiving rescue therapy with daratumumab in combination with pomalidomide and dexamethasone (DPd). Results: Between June 2015 and June 2017, 90 high-risk SMM pts (31 with ultra high-risk) were recruited and 70 pts (78%) completed the scheduled treatment. After a median f/u of 65.8m, 94% of patients remain alive and progression-free: 6 pts progressed to MM and 7 pts died. Thirty-one patients biologically progressed (biochemical progression or conversion from MRD-ve to +ve) and the biological PFS at 5 years is 72%. In the ITT population, MRD-ve rates at 10-5 were observed in 40% of pts after induction, 63% after HDT-ASCT, 68% after consolidation and 52% after maintenance therapy. Forty-seven patients were in MRD-ve at the end of maintenance and 23 maintained it 2 years after stopping maintenance indicating that the sustained MRD-ve 2 years after stopping maintenance (4 years after ASCT) was 25.6%. The same analysis was done with the sensitivity threshold of 10-6 and the MRD-ve rates were 27%, 43%, 57%, 43% after induction, ASCT, consolidation and maintenance, respectively. Thirty-nine patients were in MRD-ve at the end of maintenance and the sustained MRD-ve 4 years after ASCT was 23% (21 patients). Conclusions: Twenty-three percent of high-risk SMM treated with this curative strategy maintained MRD-ve 4 years after ASCT and 2 years after finalizing the treatment protocol. Progression to MM as well as biochemical progression were driven by the persistence of MRD at the end of maintenance and by lack of sustained MRD-ve 4 years after ASCT (2 years after the end of maintenance).