Prospective Trial Using Multimodal Measurable Residual Disease Negativity to Guide Discontinuation of Maintenance Therapy in Multiple Myeloma (MRD2STOP)

Introduction: Measurable residual disease (MRD) status is an important prognostic marker in multiple myeloma (MM). Despite an increase in MRD-adapted de-escalation and intensification strategies under investigation, the role of MRD in decision-making remains unproven. With an increasing number of patients experiencing durable and deep responses while on indefinite maintenance, MRD-negativity has emerged as a potential marker for the absence of any residual disease, which could be used for cessation of therapy in a subset of patients. The prospective MRD2STOP study (NCT04108624) is investigating sustained multimodal MRD-negativity in patients who discontinue maintenance therapy after meeting per-protocol eligibility criteria for the absence of residual disease.

Methods: Patients were required to have received at least one year of maintenance therapy and be in a complete response (CR) by IMWG criteria with MRD negativity by PET/CT, and by either flow cytometry or next generation sequencing (NGS) at a sensitivity of at least 10^-5 in the bone marrow (BM). Discontinuation of therapy was permitted for those MRD negative by PET/CT, flow cytometry (limit of detection [LOD] 10^-5), and NGS (LoD 10^-6) at screening. After discontinuation, patients underwent peripheral blood (PB) testing every 3 months, and bone marrow (BM) MRD testing and PET/CT assessments yearly for 3 years. MRD by NGS was assessed using the clonoSEQ Assay. In addition, assessing CD-138-enriched BM via clonoSEQ to achieve sensitivity of 10^-7 is being prospectively evaluated along with mass spectrometry (using automated MALDI-TOF and liquid chromatography) and cell free DNA (cfDNA) in PB at yearly and 6 months intervals, respectively. The co-primary endpoints are MRD resurgence rate (from negative to positive) at the 10^-6 threshold, and PFS and OS among those MRD-negative by the standard non-enriched NGS assay.

Results: 72 patients have been consented and screened of which 38 patients met protocol eligibility criteria and discontinued maintenance therapy at the data cutoff (July 13, 2022). The median age of enrolled patients is 66 (range 40-85) years; there are 7 (18%) Black and 4 (11%) Hispanic patients. Fifteen (39%) had high-risk disease at diagnosis (6 with 1q copy abnormalities, 5 with ISS stage 3, 2 with t(4;14), and 2 with del17p). The majority (36/38, 95%) had only one line of therapy; 21 (55%) received triplet, 14 (37%) quadruplet, and 1 (3%) doublet therapy. Prior autologous stem cell transplant was received by 26 (68%) and multi-drug consolidation in 30 (79%) prior to single-agent maintenance. Nearly all patients (95%) received lenalidomide as maintenance. The median duration of consolidation/maintenance therapy prior to discontinuation was 42 (range 12-90) months.

The median follow-up is 14 months. Of 38 enrolled patients, 34 (89%) pts remain on study; 2 (5%) have experienced disease progression and 2 (6%) withdrew from the study (1 due to relocation and 1 due to lack of insurance). The 2 patients who withdrew did so prior to their first MRD test and had no evidence of disease progression at the time. MRD resurgence at the 10^-6 threshold was identified in 5 (13%) patients, which included 2 patients with resurgence of an M-spike and disease progression. The rate of sustained MRD-negativity (10^-6) at 12 months is 21/25 (84%).

Among the 38 patients with baseline MRD assessments that were negative by the standard 10^-6 assay and who had a paired CD138-enriched sample analyzed, the CD138-enriched assay detected disease in 4 (11%) (figure 1). Among the 5 patients with MRD resurgence at the 10^-6 threshold using the standard assay, 4 (80%) had detectable MRD by the CD138-enriched MRD assay at baseline including the 2 patients who have experienced disease progression.

Out of 62 BM samples assessed thus far with the CD138-enriched assay, 2 (3%) failed quality control. Mass spectrometry and cfDNA evaluations will be completed at the study conclusion.

Conclusions: Discontinuation of maintenance therapy among patients with MM and multimodal MRD-negativity results in a high rate of sustained MRD-negativity and lack of disease progression 1 and 2 years later, with longer follow-up in progress. The results to date indicate that MRD assessed using the clonoSEQ assay with CD138-enrichment may help to identify patients who can discontinue therapy.

Derman:COTA Healthcare: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Sanofi: Consultancy. Wolfe:BMS: Speakers Bureau. Cooperrider:Abbvie: Other: Current employment by spouse. Jakubowiak:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.