MRD-negative duration following latest line of therapy predicts long-term PFS in real-world patients with multiple myeloma

Minimal residual disease (MRD) is a highly sensitive measure of depth-of-response and a powerful predictor of progression-free survival (PFS) in multiple myeloma (MM).In the era of modern myeloma therapies, MRD status continues to be an independent predictor of long-term clinical outcome even in patients who have achieved a complete response (CR). 1,2Therefore, MRD negativity, defined as <1 clonal plasma cell in 100 000 cells in the bone marrow by next-generation flow (NGF) or nextgeneration sequencing (NGS), has been incorporated into the International Myeloma Working Group (IMWG) response criteria since 2016. 3Initial clinical trials evaluating MRD status typically assessed MRD at end of induction or ~3 months after autologous stem cell transplant and demonstrated improved PFS with a singular MRD-negative result. 1,2,[4][5]5][6][7][8] More recently, clinical trials have used serial MRD measurements to demonstrate the added prognostic benefit of sustained MRD negativity, including 6 months, 9 12 months, 10 and 24 months 11,12 from either the start of treatment or start of CR.However, few clinical trials report MRD data beyond a duration of 2 to 3 years, [11][12][13] and real-world data to corroborate clinical trial findings are lacking.Furthermore, the optimal duration of MRD negativity required to discontinue maintenance therapy is not yet known.A recent observational study reported a 10-year PFS of 88% for patients MRD negative for >3 years after total therapy, 14 highlighting the potentially excellent long-term prognosis associated with durable MRD negativity.Therefore, using our single-center real-world data, we estimate the long-term PFS of patients with MM patients with durable MRD-negative remission 5 years from the start of latest line of therapy and evaluate the prognostic impact of differing durations of MRD negativity.Routine MRD assessment was introduced for patients with MM in remission at Icahn School of Medicine at Mount Sinai in 2017.We systematically reviewed consecutive MRD results for patients in the Icahn School of Medicine at Mount Sinai (ISMMS) MM registry between July 2017 and May 2023 (Figure 1A).NGF was used to detect MRD from 2017 to 2021, with the addition of NGS from 2021 onward.Most patients (75%) had only NGF results available, in which MRD negativity was defined as <1 cells in 10 5 ; the remaining 25% of patients had additional NGS results available in which MRD negativity was defined as <1 cells in 10 6 .Patients were considered "MRD negative" for the calendar year if they had at least 1 negative and no positive MRD results.Missing MRD years in-between first and last MRD-negative results were allowed, providing patients remained in CR and had negative imaging throughout.Patients with 3 "MRD-negative years" were included in the study.These patients underwent detailed chart review.Patients with evidence of active myeloma by IMWG criteria during their MRD-negative period were excluded (n = 31).To mitigate potential bias from differing durations of CR before MRD negativity, we excluded patients who had started their latest line of therapy before January 2014, that is, >3 years before routinely available MRD testing.Whole-body positron emission tomography and magnetic resonance imaging were used to evaluate bone or extramedullary disease.PFS was evaluated using Kaplan-Meier curves and survival estimates.