Maintenance therapy discontinuation for patients diagnosed with multiple myeloma without high-risk features in minimal residual disease (MRD) negative remission: An interim analysis

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). However, side effects from maintenance treatments such as lenalidomide include skin rashes, debilitating fatigue, unpredictable gastrointestinal disturbances, bone pain and others that frequently lead to premature discontinuation of treatment. At present, the benefit of continuing maintenance therapy in patients who attain Minimal Residual Disease (MRD) negativity is unclear. MRD-based discontinuation has already become established practice by MM specialists due to emerging data from recent studies (Costa L et. al. Lancet 2023). Evidence from prospective randomized 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 without high-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 achieved MRD negative remission. Patients were non-randomly divided into two arms (A) continued (B) discontinued 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: The study enrolled 50 patients with 25 patients completing 12 months follow up to date. Groups were divided into (A) MRD negative with maintenance discontinuation (n=15), (B) MRD negative continuing maintenance (n=3) and (C) MRD-positive and continued maintenance (n=7). 68% of participants (n=17) were male and the mean age was 67.9±13.6 years. Study participants were predominantly IgG multiple myeloma (n=19), R-ISS Stage 1 (n=13) and ECOG 0 (n=21) at screening. Fifteen patients had undergone autologous stem cell transplantation. The median duration of maintenance therapy before commencement of the study was 40 months (Group A), 44 months (Group B) and 52 months (Group C- MRD positive arm) respectively. Three of the fifteen patients who discontinued treatment had detectable MRD after 12 months (80% PFS, 95% confidence interval, 50-93). Only those with newly detectable MRD at 12 months had changes in International Myeloma Working Group (IMWG) response criteria for this group. Two of the seven MRD-positive patients demonstrated disease progression at 12 months and one mortality due to cardiovascular disease was observed. All three patients who continued maintenance remained in MRD-negative remission, maintaining at least a complete response. Global log-rank regression did not show statistical significance between groups (p=0.31). There were no associations among patient gender, age, disease stage or induction/consolidation regimens on outcome effects. Conclusion: Preliminary data has shown 80% 12 month PFS in MRD negative patients after discontinuation of maintenance therapy. Corresponding changes to IMWG response criteria were found only in patients who became MRD positive in this group. The patients are continuing follow up and this trial is still opened to recruitment.