The Myeloma XI trial investigated the impact of post-autologous stem-cell transplant (ASCT) minimal residual disease (MRD) status on progression-free survival (PFS) and overall survival (OS) outcomes for myeloma patients. MRD negativity post-ASCT was associated with significantly longer PFS and OS, irrespective of the molecular risk status and the use of maintenance therapy. Serial MRD measurements might help to identify low-risk patients requiring only a limited period of maintenance.
The presence of minimal residual disease (MRD) after treatment predicts poor outcomes in multiple myeloma. Numerous studies have examined the prognostic impact of MRD status, particularly when assessed after autologous stem-cell transplantation (ASCT). A meta-analysis confirmed that MRD status is a significant predictor of progression-free survival (PFS) and overall survival (OS) in patients with myeloma. As a result, the use of MRD as a surrogate endpoint, quicker to read out than PFS or OS, has been debated. Enrolling 2,568 transplant-eligible patients, the Myeloma XI trial is one of the largest studies conducted to date in patients with multiple myeloma. Among other key results, the trial demonstrated that lenalidomide maintenance therapy, when given after induction therapy and ASCT, improved PFS from 30 to 57 months compared with observation in transplant-eligible patients (HR[95%CI]: 0.48[0.40-0.58]; p= 0.0001), and OS at 3 years from 80.2% to 87.5% (HR[95%CI]: 0.69[0.52-0.93]; p= 0.014). This analysis aims to assess the impact of MRD status on PFS and OS in patients receiving lenalidomide maintenance or observation in the Myeloma XI trial, the interaction with molecular risk, and the impact of sustained MRD negativity.
Myeloma XI was designed as an open-label, parallel-group, multi-arm, phase III, adaptive design trial that enrolled patients with newly diagnosed myeloma. At around 3 months (100 days) after ASCT, patients who had achieved at least a minimal response were eligible for the random assignment between maintenance with lenalidomide monotherapy, lenalidomide and vorinostat, or no further therapy. Maintenance therapy continued until progressive disease or unacceptable toxicity. Bone marrow aspirates were obtained before maintenance random assignment, which occurred at 100 days (around 3 months) after ASCT (ASCT+3) and 6 months after maintenance random assignment (ASCT+9). The presence of MRD was assessed using a validated flow cytometry assay (median sensitivity 0.004%). PFS and OS were estimated with summaries of time to event per MRD group using the Kaplan-Meier method landmarked from the date of ASCT+3/ASCT+9.
In the Myeloma XI trial, 1,248 transplant-eligible patients were randomly assigned to lenalidomide (N= 730) or observation (N= 518) at three months after ASCT. Median follow-up was 32.9 months. MRD-negative status was associated with improved PFS and OS at both ASCT+3 and +9. At ASCT+3, 475 of 750 (63.3%) patients were MRD-negative and 275 (36.7%) were MRD-positive. Patients who were MRD-negative at ASCT+3 had a significantly longer median PFS than MRD-positive patients (44 vs. 24 months; HR[95%CI]: 0.47[0.37-0.58; p= 0.0001). Although median OS was not reached (NR) in either group, 3-year OS rates were 86.5% and 78.7% in MRD-negative and positive patients. The difference between groups was statistically significant, favouring the MRD-negative group (HR[95%CI]: 0.59[0.40-0.85]; p= 0.0046). At ASCT+9, 214 of 326 (65.6%) were MRD-negative and 112 (34.4%) were MRD-positive. MRD-negative status was again associated with improved PFS (50 vs. 13 months; HR[95%CI]: 0.20[0.13-0.31]; p< 0.0001) and OS (NR vs. NR; HR[95%CI]:0.33[0.15-0.75]; p= 0.0077). OS at 3 years was 86.9 vs. 69.5%. The PFS and OS findings at ASCT+3 and +9 were very similar when restricted to patients with complete response/near complete response. Sustained MRD negativity from ASCT+3 to ASCT+9 or the conversion to MRD negativity by ASCT+9 was associated with the longest PFS/OS. Regardless of MRD status, lenalidomide maintenance was associated with a significant improvement in PFS at both ASCT+3 and +9 in comparison with observation. High-risk molecular features had an adverse effect on PFS and OS even for those patients achieving MRD-negative status. At ASCT+3, MRD-negative patients with one or more high-risk lesion had a shorter median PFS compared with MRD-negative standard-risk patients (33 vs. 63 months; HR[95%CI]: 2.57[1.55-4.26]; p= 0.0002). On multivariable analysis of MRD status, maintenance therapy with lenalidomide and molecular risk maintained prognostic impact for both PFS and OS at both ASCT+ 3 and ASCT+9.
Data from Myeloma XI suggest that MRD status at ASCT+3 and ASCT+9 predict PFS and OS in transplant-eligible patients with multiple myeloma. MRD negativity post-ASCT is associated with significantly longer PFS and OS, and serial MRD measurements might help to identify low-risk patients requiring only a limited period of maintenance. Regardless of MRD status, lenalidomide maintenance therapy and standard molecular risk were associated with improved PFS compared with no maintenance therapy.
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