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Abstract Long-term proteasome inhibitor (PI) treatment can improve multiple myeloma (MM) outcomes, but this can be difficult to achieve in clinical practice due to toxicity, comorbidities, and the burden of repeated parenteral administration. US MM-6 (NCT03173092) enrolled transplant-ineligible patients with newly diagnosed MM to receive all-oral ixazomib-lenalidomide-dexamethasone (IRd; ≤39 cycles or until progression or toxicity) following three cycles of bortezomib-based induction. Primary endpoint: 2-year progression-free survival (PFS). Key secondary/exploratory endpoints included overall response rate (ORR), overall survival (OS), safety, quality of life (QoL), treatment satisfaction, and actigraphy. At datacut, in the fully accrued cohort of 140 patients, median age was 73 years with 42% aged ≥75 and 61% deemed frail; 10% of patients were ongoing on treatment. After a median follow-up of 27 months, the 2-year PFS rate was 71% (95% confidence interval: 61–78). ORR increased from 62% at the end of induction to 80% following in-class transition (iCT) to IRd for a median of 11 months. The 2-year OS rate was 86%. The overall safety profile/actigraphy levels were consistent with previous reports; QoL/treatment satisfaction scores were stable with ongoing therapy. iCT to IRd may allow prolonged PI-based therapy with promising efficacy and a tolerable safety profile, while maintaining QoL.