Background Multiple myeloma (MM) remains incurable, and maintenance therapy is critical for sustaining remission and improving survival. While lenalidomide is the standard maintenance therapy for newly diagnosed MM (NDMM), its efficacy in high-risk patients remains suboptimal. Furthermore, cumulative toxicity and secondary resistance progressively curtail its long-term use. Proteasome inhibitor (PI)-based maintenance therapy offers a mechanistically complementary approach, though real-world evidence for oral PIs like ixazomib (Ixa) in NDMM is scarce, particularly in Asian populations. This study evaluates the efficacy and safety of Ixa-containing regimens in Chinese NDMM patients.

Methods We conducted a retrospective analysis of 54 NDMM patients receiving Ixa-based maintenance therapy at Guangxi Medical University Affiliated Hospital between December 2020 and April 2025. Patients achieving a minimal response (MR) or deeper remission, regardless of prior induction therapy regimen or autologous stem cell transplantation status, were eligible for maintenance therapy with Ixa -based regimens. These regimens included Ixa monotherapy (I), Ixa-lenalidomide (IR), or daratumumab-Ixa-lenalidomide (DIR). Maintenance therapy was administered until disease progression or discontinuation due to unacceptable toxicity. The primary endpoint was progression-free survival (PFS), defined as the time from initiation of maintenance therapy to documented disease progression or death from any cause. Secondary endpoints encompassed overall survival (OS), tumor response assessment per IMWG criteria, and safety.

Results Among 54 enrolled patients (median age 57.5 years [range 34–74], 57% male), 50.0% had ISS stage III, 31.5% R-ISS stage III, and 74.1% mSMART 3.0 (version 2018) high-risk disease， with 40.7% had double/triple hit; 59.3% had ECOG PS ≥2, and 55.6% presented with comorbidities, primarily hypertension (25.9%). Induction regimens included VRd (bortezomib-lenalidomide-dexamethasone, 57.4%), DVRd (daratumumab-bortezomib-lenalidomide-dexamethasone, 22.2%), and DVd (daratumumab-lenalidomide-dexamethasone, 9.3%). Autologous stem cell transplantation (ASCT) was performed in 59.3% of patients. Maintenance therapies comprised IR (81.5%), DIR (11.1%), and I (7.4%), with a median duration of 13.0 months (range, 0.5–48.5).The best overall response rate (ORR) pre-maintenance was 100%, including stringent complete response (sCR) in 18.5%, complete response (CR) in 9.3%, very good partial response (VGPR) in 61.1%, and partial response (PR) in 11.1%. During maintenance, the best responses were sCR (18.5%), CR (11.1%), VGPR (59.3%), and PR (11.1%). One patient (1.9%) achieved response deepening (from VGPR to CR) with IR maintenance.With a median follow-up of 14 months (range, 0.5–48.5), 5 patients progressed and 2 died. Median progression-free survival (PFS) was not reached, with estimated 12-month and 24-month PFS rates of 97.2% and 80.3%, respectively. More importantly, according to the mSMART3.0 criteria, there was no difference in PFS regardless of the presence of high-risk factors or double/triple hit status among patients, indicating that the Ixa-containing regimen can effectively overcome high-risk factors. Similarly, achieving VGPR or better before maintenance therapy does not significantly affect PFS outcomes during maintenance.Safety analysis revealed that any-grade adverse events (AEs) predominantly included diarrhea (44.4%), nausea (38.9%), myelosuppression (16.7%), and peripheral neuropathy (3.7%), while grade 3 or higher AEs were primarily thrombocytopenia (5.6%). The overall safety profile was well-tolerated. Conclusion The Ixa-containing maintenance regimen demonstrates favorable efficacy and a manageable safety profile in patients with NDMM. Notably, it effectively mitigates the adverse impact of high-risk genetic factors, positioning it as an emerging therapeutic option for high-risk NDMM maintenance therapy. Longer follow-up is warranted to confirm sustained survival benefits.

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2025
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