AFFILIATIONS
1 Department of Haematology, Cork University Hospital, Cork, Ireland, School Of Medicine, University College Cork, Cork, Ireland
2 Cancer Research @ UCC, College of Medicine and Health, University College Cork, Cork, Ireland, Department of Haematology, Cork University Hospital, Cork, Ireland, School Of Medicine, University College Cork, Cork, Ireland
3 Cancer Research @ UCC, College of Medicine and Health, University College Cork, Cork, Ireland, School Of Medicine, University College Cork, Cork, Ireland
4 Cancer Research @ UCC, College of Medicine and Health, University College Cork, Cork, Ireland, School Of Medicine, University College Cork, Cork, Ireland
5 Cancer Research @ UCC, College of Medicine and Health, University College Cork, Cork, Ireland, School Of Medicine, University College Cork, Cork, Ireland
6 Cancer Research @ UCC, College of Medicine and Health, University College Cork, Cork, Ireland, School Of Medicine, University College Cork, Cork, Ireland
7 Department of Haematology, Cork University Hospital, Cork, Ireland, School Of Medicine, University College Cork, Cork, Ireland
8 Department of Haematology, Cork University Hospital, Cork, Ireland, School Of Medicine, University College Cork, Cork, Ireland
9 Cancer Research @ UCC, College of Medicine and Health, University College Cork, Cork, Ireland, School Of Medicine, University College Cork, Cork, Ireland
10 Cancer Research @ UCC, College of Medicine and Health, University College Cork, Cork, Ireland, Department of Haematology, Cork University Hospital, Cork, Ireland, School Of Medicine, University College Cork, Cork, Ireland
ABSTRACT
Background: Continuous maintenance therapy is a standard practice for many physicians treating multiple myeloma (MM). Lenalidomide maintenance treatment has been shown to improve progression-free survival (PFS) and, in some studies, overall survival (Richardson et. al. NEJM 2022, Jackson et. al. Lancet 2019). Recent phase 3 clinical trials have demonstrated non-inferiority of fixed-duration to indefinite maintenance therapy in patients that have not received autologous stem cell transplantation, thus avoiding adverse effects of treatment (Kumar et. Al. NEJM 2026). However, the benefit of continuing maintenance therapy in patients who attain Minimal Residual Disease (MRD) negativity remains unclear. Evidence from prospective clinical trials would help instruct future therapeutic decisions in this context.
Aims: The primary aim of this discontinuation trial (NCT05866757) is to determine if patients diagnosed with standard risk MM, who have completed at least two years of maintenance therapy and achieved MRD negativity, can safely discontinue maintenance treatment for a prolonged period of time without losing their MRD negativity, regardless of the induction therapy they have received in the past. Additionally, we will compare Quality of Life (QoL) in patients on and off maintenance.
Methods: Patients over 18 years of age diagnosed with multiple myeloma with standard-risk cytogenetics were included in this trial if they had received one line of standard-of-care therapy and a minimum of 24 months maintenance therapy. Patients who received less than 24 months maintenance due to treatment side effects were included if they achieved MRD negative remission. Patients were non-randomly divided into two arms (A) discontinued (B) continued on maintenance with three monthly blood test monitoring and bone marrow MRD by next generation flow (NGF) every 12 months. Patient QoL was assessed at baseline and 3,6 and 12 months of the study using the European Organisation for Research and Treatment of Cancer Quality of Life Multiple Myeloma questionnaire (EORTC QLQ-MY20). An additional subgroup of patients with biochemically detectable disease were continued on maintenance therapy for the purpose of evaluating the QoL on maintenance therapy and clinical importance of MRD in our patient subset. Ethical approval has been attained by the Clinical Research Ethics Committee of Cork Teaching Hospitals for this study.
Results: All 50 enrolled patients were monitored to 12 months, with 36 patients completing 24 months follow up. Groups were divided into (A) MRD negative with maintenance discontinuation (n=26), (B) MRD negative continuing maintenance (n=9) and (C) MRD-positive and continued maintenance (n=15). 68% of participants (n=34) were male and the mean age was 69 ±11.8 years. Study participants were predominantly IgG multiple myeloma (n=34), R-ISS Stage 1 (n=23) and ECOG 0 (n=42) at screening. Approximately two-thirds of patients (n=32) had received prior autologous stem cell transplantation. The median duration of maintenance therapy before commencement of the study was 33 months (Group A), 32 months (Group B) and 46 months (Group C- MRD positive arm) respectively. Detectable MRD was found in four of nineteen patients who discontinued treatment after 24 months (78.9% MRD-negativity, 95% confidence interval (CI), 56.7-91.5%), which was not statistically significant compared to initially MRD-negative patients who continued on maintenance at 24 months (n=6, 83.3% MRD-negativity, 95% CI 43.6-97%). Of note, any changes to MRD status occurred within the first 12 months for both groups. Two of the eleven initially MRD-positive patients demonstrated disease progression at 12 months and one mortality due to cardiovascular disease was observed. Of the five patients that lost MRD negativity, just one required further treatment beyond restarting maintenance. There were no associations among patient gender, age, disease stage or induction/consolidation regimens on outcome effects.
Conclusion: Our data demonstrates 78.9% sustained MRD negativity in patients after discontinuation of maintenance therapy at 24 months, which was not statistically significant compared to those that continued on maintenance. Any patients who became MRD-positive did so within the first year off maintenance. MRD-directed maintenance discontinuation appears to be safe and may spare unnecessary treatment toxicity in standard-risk multiple myeloma.
DISCLOSURES
Sam Holt, M.B., B.Ch., B.A.O, MRCPI: No relevant conflicts of interest to declare.