Sustained MRD Negativity for Three Years Can Guide Discontinuation of Lenalidomide Maintenance after ASCT in Multiple Myeloma: Results from a Prospective Cohort Study
Authors: Malandrakis Panagiotis , Ntanasis-Stathopoulos Ioannis , Kostopoulos Ioannis V , Spiliopoulou Vasiliki , Fotiou Despina , Theodorakakou Foteini , Migkou Magdalini , Kanellias Nikolaos , Eleutherakis-Papaiakovou Evangelos , Kastritis Efstathios , Gavriatopoulou Maria , Tsitsilonis Ourania , Dimopoulos Meletios , Terpos Evangelos 
Published: December 2024

Introduction
Autologous stem cell transplantation (ASCT) followed by lenalidomide maintenance continues to be the standard of care for eligible patients with newly diagnosed multiple myeloma (NDMM). Maintenance treatment is currently administered until disease progression, whereas the optimal duration of maintenance is yet to be defined. More sensitive methods are currently used to detect residual disease and early relapse, such as next generation flow (NGF) cytometry and PET/CT, which are used to determine minimal residual disease (MRD) status. Sustained marrow and imaging MRD correlate with prolonged progression-free survival (PFS) and overall survival (OS).
Methods
In this prospective study, we included patients with NDMM from January 1st, 2016 to December 31st, 2021, who underwent ASCT followed by lenalidomide maintenance. MRD status was assessed in patients who had achieved stringent complete remission (sCR) and then at 6, 12, 24, and 36 months after the initiation of lenalidomide maintenance. MRD samples were evaluated by NGF, according to the EuroFlow protocol. Patients, who had at least 3 consecutive MRD negative results and had received at least 36 months of maintenance, underwent a PET/CT scan. If patients had also achieved imaging MRD negativity, they discontinued lenalidomide maintenance and MRD was performed every 6 months thereafter. If a patient converted from MRD negative to positive or if the patient relapsed from sCR, lenalidomide maintenance was restarted at the same dose level.
Results
Overall, 194 patients received induction with proteasome inhibitor-based regimens (VCD, VRD or VTD) and underwent ASCT. During a median follow-up of 63.5 months (range 6-104 months) from diagnosis, 49 (25.2%) patients had disease progression and 20 (10.3%) patients died. During the follow-up period, 51 (26.3%) patients achieved sustained bone marrow MRD negativity and imaging MRD negativity at 3 years after maintenance initiation. Thus, they discontinued lenalidomide maintenance, according to study schedule. Their median age at MM diagnosis was 56 years (range 39-66). Twenty-seven (53%) patients were males, whereas 53% had IgG, 25.5% had IgA and 21.5% had light chain MM. The patient distribution per ISS was ISS-1 66.6%, ISS-2 19.6% and ISS-3 13.8%, whereas per R-ISS was RISS-1 60.8%, RISS-2 33.3% and RISS-3 5.9%. In this subgroup of the patients, 31% had at least one high risk cytogenetic risk factor (1q21 addition or amplification, t(4;14), t(14;16) and p53 loss).
The median follow-up time from maintenance discontinuation was 32 months (range 4-52 months). Percentage of patients who continued to be MRD negative after discontinuation of maintenance was 96% (48/50 pts), 95.1% (39/41 pts), 97% (37/38 pts), 94.4% (34/36 pts) and 92% (23/25 pts) at 6, 12, 18, 24 and 30 months post lenalidomide discontinuation, respectively. Three years after discontinuation of lenalidomide maintenance, 12 out of 14 patients (86%) were MRD negative, whereas at 42 and 48 months post lenalidomide discontinuation all evaluable patients (N=8 and N=4, respectively), were MRD negative. Overall, 11 patients restarted treatment with lenalidomide monotherapy after converting from MRD negative to MRD positive following the initial completion of maintenance;, four of them progressed and received second-line treatment. For these patients, the median follow-up from the re-initiation of lenalidomide was 7 months (range: 0-35 months), and the median time to progression for those who progressed was 9.5 months (range 1-26 months). The median PFS is 74 months (CI: 38-104 months). Only one patient who discontinued maintenance died for reasons not related to MM (breast cancer), less than 6 months after lenalidomide discontinuation.
Conclusion
Sustained MRD negativity after ASCT and a completion of 3 years of lenalidomide maintenance may guide the safe discontinuation of maintenance, although this has to be proven in prospective randomized clinical trials. Close follow-up with consecutive MRD testing can trace an early myeloma relapse and the reinitiation of lenalidomide in relapsed patients could possibly delay disease progression.