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Background: Early therapeutic intervention in high-risk SMM (HR-SMM) has demonstrated benefit in previous studies of lenalidomide with or without dexamethasone. Triplets and quadruplet studies have been examined in this same population. However, to date, none of these studies examined the impact of depth of response on long-term outcomes of participants treated with lenalidomide-based therapy, and whether the use of the 20/2/20 model or the addition of genomic alterations can further define the population that would benefit the most from early therapeutic intervention. Here, we present the results of the phase II study of the combination of ixazomib, lenalidomide, and dexamethasone in patients with HR-SMM with long-term follow-up and baseline single-cell tumor and immune sequencing that help refine the population to be treated for early intervention studies., Methods: This is a phase II trial of ixazomib, lenalidomide, and dexamethasone (IRD) in HR-SMM. Patients received 9 cycles of induction therapy with ixazomib 4mg on days 1, 8, and 15; lenalidomide 25mg on days 1-21; and dexamethasone 40mg on days 1, 8, 15, and 22. The induction phase was followed by maintenance with ixazomib 4mg on days 1, 8, and 15; and lenalidomide 15mg d1-21 for 15 cycles for 24 months of treatment. The primary endpoint was progression-free survival after 2 years of therapy. Secondary endpoints included depth of response, biochemical progression, and correlative studies included single-cell RNA sequencing and/or whole-genome sequencing of the tumor and single-cell sequencing of immune cells at baseline., Results: Fifty-five patients, with a median age of 64, were enrolled in the study. The overall response rate was 93%, with 31% of patients achieving a complete response and 45% achieving a very good partial response or better. The most common grade 3 or greater treatment-related hematologic toxicities were neutropenia (16 patients; 29%), leukopenia (10 patients; 18%), lymphocytopenia (8 patients; 15%), and thrombocytopenia (4 patients; 7%). Non-hematologic grade 3 or greater toxicities included hypophosphatemia (7 patients; 13%), rash (5 patients; 9%), and hypokalemia (4 patients; 7%). After a median follow-up of 50 months, the median progression-free survival (PFS) was 48.6 months (95% CI: 39.9 - not reached; NR) and median overall survival has not been reached. Patients achieving VGPR or better had a significantly better progression-free survival (p<0.001) compared to those who did not achieve VGPR (median PFS 58.2 months vs. 31.3 months). Biochemical progression preceded or was concurrent with the development of SLiM-CRAB criteria in eight patients during follow-up, indicating that biochemical progression is a meaningful endpoint that correlates with the development of end-organ damage. High-risk 20/2/20 participants had the worst PFS compared to low- and intermediate-risk participants. The use of whole genome or single-cell sequencing of tumor cells identified high-risk aberrations that were not identified by FISH alone and aided in the identification of participants at risk of progression. scRNA-seq analysis revealed a positive correlation between MHC class I expression and response to proteasome inhibition and at the same time a decreased proportion of GZMB+ T cells within the clonally expanded CD8+ T cell population correlated with suboptimal response., Conclusions: Ixazomib, lenalidomide and dexamethasone in HR-SMM demonstrates significant clinical activity with an overall favorable safety profile. Achievement of VGPR or greater led to significant improvement in time to progression, suggesting that achieving deep response is beneficial in HR-SMM. Biochemical progression correlates with end-organ damage. Patients with high-risk FISH and lack of deep response had poor outcomes. ClinicalTrials.gov identifier: (NCT02916771)., Competing Interests: Declaration of Interests ON: Research support from Takeda and Janssen; Advisory board participation: Bristol Myers Squibb, Janssen, Sanofi, Takeda, GPCR therapeutics. Honorarium:Pfizer M.P.A: No conflicts of interest exist. R.A.R.: No conflicts of interest exist. M.T: No conflicts of interest exist. S.M.: No conflicts of interest exist. J.B.A. No conflicts of interest exist. L.B.: No conflicts of interest exist. A.K.D. No conflicts of interest exist. H.E.: No conflicts of interest exist. M.B.: Consultancy with Janssen, BMS, Takeda, Epizyme, Karyopharm, Menarini Biosystems, and Adaptive. E.D.L.: No conflicts of interest exist. J.P.L.: No conflicts of interest exist. G.B.: Consultancy: Prothena E.O.: Advisory Board/Honoraria: Janssen, BMS, Sanofi, Pfizer, Exact Consulting—Takeda Steering Committee: Natera T.W.: No conflicts of interest exist. J.T.: No conflicts of interest exist. K.A.: Consultant: AstraZeneca, Janssen, Pfizer, Board/ Stock Options: Dynamic Cell Therapies, C4 Therapeutics, Next RNA, Oncopep, Starton, Window G.G.: No conflicts of interest exist. L.T.: No conflicts of interest exist. P.G.R.: Advisory Boards/Consulting: Celgene/BMS, GSK, Karyopharm, Oncopeptides, Regeneron, Sanofi, Takeda. Research Grants: Oncopeptides, Karyopharm R.S.P.: Co-founder, equity holder, and consultant on pre-seed stage startup. I.M.G.: Consulting/Advisory role: AbbVie, Adaptive, Amgen, Aptitude Health, Bristol Myers Squibb, GlaxoSmithKline, Huron Consulting, Janssen, Menarini Silicon Biosystems, Oncopeptides, Pfizer, Sanofi, Sognef, Takeda, The Binding Site, and Window Therapeutics; Speaker fees: Vor Biopharma, Veeva Systems, Inc.; I.M.G.’s spouse is CMO and an equity holder of Disc Medicine.