OAB-015: Minimal residual disease following autologous stem cell transplant for myeloma patients in the Myeloma XI trial: prognostic significance and the impact of lenalidomide maintenance and molecular risk

Abstract

<h3>Background</h3> Minimal residual disease (MRD) status after autologous stem cell transplant (ASCT) predicts progression-free and overall survival outcomes in patients with multiple myeloma. The prognostic impact of MRD when assessed at serial time points in the context of maintenance therapy and the interaction between MRD and molecular risk are less well defined. <h3>Methods</h3> In the phase III Myeloma XI trial eligible patients were randomly assigned to lenalidomide maintenance or no maintenance at 3 months following ASCT. MRD status was assessed by flow cytometry prior to maintenance randomization (ASCT+3) and 6 months after maintenance randomization (ASCT+9). The relationship between MRD status and progression-free survival (PFS) and overall survival (OS) was examined. PFS is landmarked as the time from the date of ASCT+3/ASCT+9 to the date of progression or death from any cause. OS is landmarked as the time from the date of ASCT+3/ASCT+9 to the date of death from any cause. Participants who had not met the endpoint were censored at the date last known to have not met the endpoint. Adverse molecular risk abnormalities were defined as gain(1q), del(17p), t(4;14), t(14;16) or t(14;20). <h3>Results</h3> At ASCT+3, of 750 patients with informative samples, 475 (63.3%) were MRD negative and 275 (36.6%) were MRD positive. MRD negative status at ASCT+3 was associated with a 57% reduction in PFS events (HR=0.43, 95% CI 0.34-0.55; P<0.001) and a 47% reduction in the risk of death (HR=0.53, 95% CI 0.36-0.78; P=0.0011). At ASCT+9, of 326 patients with informative samples, 214 (65.6%) were MRD negative and 112 (34.4%) were MRD positive. MRD negative status was associated with a 79% reduction in PFS events (HR=0.21, 95% CI 0.13-0.34; P<0.0001) and a 67% reduction in the risk of death (HR=0.33, 95% CI 0.15–0.75; P=0.0077). Regardless of MRD status, at both time points, maintenance lenalidomide was associated with a significant improvement in PFS compared with observation. Sustained MRD negativity from ASCT+3 to ASCT+9 or the conversion to MRD negativity by ASCT+9 were associated with the longest PFS and OS. Patients randomized to lenalidomide maintenance were more likely to convert from being MRD-positive before maintenance randomization to MRD-negative 6 months later (lenalidomide 30%, observation 17%). High-risk molecular features had an adverse effect on PFS and OS for patients both MRD-negative and MRD-positive at both ASCT+3 and ASCT+9. On multivariable analysis MRD status, maintenance therapy and molecular risk maintained prognostic impact at both ASCT+3 and ASCT+9. <h3>Conclusions</h3> In patients with multiple myeloma, MRD status at both ASCT+3 and ASCT+9 is a powerful predictor of PFS and OS. At both time points, regardless of MRD status, lenalidomide maintenance was associated with improved PFS and OS, whilst high-risk molecular features were associated with adverse outcomes.