Transition to IRD maintenance after DRD induction significantly deepens response in transplant-ineligible NDMM: A prospective multicenter study

Abstract Background: The DRd regimen (daratumumab/lenalidomide/dexamethasone) has become a cornerstone of therapy for newly diagnosed multiple myeloma (NDMM). However, long-term DRd use is often limited by cumulative toxicities, infusion-related burdens, and socioeconomic constraints in real-world practice. We hypothesized that transitioning to an all-oral IRd regimen (ixazomib/lenalidomide/dexamethasone) after effective DRd induction could maintain efficacy while improving tolerability and quality of life (QoL) in transplant-ineligible NDMM patients. Methods In this prospective multicenter study (ChiCTR2400081601), we planned to enroll 60 transplant-ineligible NDMM patients from March 2024 to August 2026 as study subjects. We enrolled 53 transplant-ineligible NDMM patients (March 2024–August 2025), median age 72 [50-84], 22% high-risk cytogenetics, who achieved ≥minimal response after at least 6 months of DRd induction. Patients were switched to IRd maintenance (ixazomib 4mg days 1,8,15; lenalidomide 25mg days 1-14; dexamethasone 20mg days 1,8,15,22) until progression or intolerance. Primary endpoint was 2-year PFS; secondary endpoints included OS, response kinetics, safety, and QoL (EORTC QLQ-C30/ MY20). Results At median follow-up of 5.6 months (ongoing). Currently, three patients have withdrawn from the study: two due to Grade 3 adverse reactions (anaphylactic rash and diarrhea), and one for non-compliance with the treatment regimen:Efficacy: 50/53 patients completed ≥1 IRd cycle; 94% (50/53 evaluable) remained progression-free with deepening responses: CR/sCR rate increased from 47.5% to 60.4% (p=0.03)Safety: Hematologic: Grade ≥3 neutropenia (8%), thrombocytopenia (4%)Non-hematologic: Infections (20%, grade 3), gastro-intestinal AEs (10%), peripheral neuropathy (4% grade 3), anaphylactic rash (2% grade 3)QoL: Preliminary data showed stable or improved QoL scores in the patients, attributed to reduced infusion burden and incidence of infection compared to DRd. Conclusion Sequential IRd maintenance after DRd induction demonstrates promising efficacy, with deepened responses and excellent tolerability in transplant-ineligible NDMM patients. Early data suggest sustained disease control and potential survival benefits, while the oral regimen improves convenience and QoL. These findings support IRd as a viable maintenance strategy to prolong treatment duration and optimize outcomes in this vulnerable population. Given the relatively small sample size, further validation with a larger sample size is warranted.