A Multicenter Retrospective Comparative Analysis of Therapeutic Outcomes in Multiple Myeloma Patients Receiving Varied Ixazomib Dosage Regimens.

Introduction

Multiple myeloma (MM) is a hematologic malignancy characterized by the clonal proliferation of plasma cells and excessive production of monoclonal immunoglobulins. Recent therapeutic advancements have significantly improved treatment outcomes, with proteasome inhibitors (PIs) remaining the cornerstone of MM management [ 1 , 2 ]. Currently approved PIs, including bortezomib, ixazomib, and carfilzomib, play pivotal roles in the comprehensive treatment of MM.

Ixazomib, the first oral PI, is frequently administered in combination with immunomodulatory drugs (IMiDs) and dexamethasone. This all‐oral regimen has demonstrated efficacy across various clinical settings, including relapsed/refractory MM (RRMM), newly diagnosed MM (NDMM), maintenance therapy, and in‐class transition (iCT) from other PIs. In RRMM, ixazomib‐based regimens significantly improved progression‐free survival (PFS) compared to placebo (20.6 vs. 14.7 months) [ 3 ]. Similarly, in the TOURMALINE‐MM2 trial, ixazomib, lenalidomide, and dexamethasone (IRD) extended PFS in NDMM patients (35.3 vs. 21.8 months; HR, 0.830) [ 4 ]. Ixazomib maintenance therapy has also shown PFS benefits without unexpected toxicity, both in patients undergoing autologous stem cell transplantation (ASCT) [ 5 ] and those not undergoing ASCT [ 6 ]. Real‐world data from the US MM‐6 study further support the efficacy of early transition from bortezomib‐based induction to IRD, demonstrating improved overall response rates (ORRs) and tolerability in transplant‐ineligible NDMM patients, with no decline in quality of life (QoL) [ 7 ].

Despite the emergence of novel immunotherapies, such as anti‐CD38 monoclonal antibodies, chimeric antigen receptor (CAR) T‐cell therapy, and bispecific antibodies [ 8 ], ixazomib‐based regimens remain a viable option for frontline therapy, iCT, and maintenance. In NDMM, ixazomib is particularly suitable for frail patients with comorbidities, offering the convenience of oral administration, reduced clinic visits, and lower risk of infectious disease exposure. iCT is an alternative for patients intolerant to other PI‐based combinations, particularly those experiencing severe peripheral neuropathy (PN) from bortezomib or cardiovascular adverse events (AEs) from carfilzomib. For maintenance therapy, ixazomib offers long‐term efficacy with minimal toxicity and no significant impact on QoL, making it a beneficial option for MM patients. Thus, ixazomib remains an essential therapeutic agent in the clinical management of MM.

While bortezomib and carfilzomib employ body surface area (BSA)‐based dosing in clinical practice, studies have demonstrated that fixed dosing of ixazomib exhibits minimal impact on pharmacokinetic (PK) characteristics [ 9 , 10 ]. Exposure–response analyses reveal that both 3 and 4 mg doses of ixazomib fall within the clinically effective range [ 9 ]. Additionally, covariates such as creatinine clearance and age have been shown to exert negligible influence on ixazomib PKs [ 11 ]. Consequently, the drug guidelines recommend a fixed dose of 4 mg per week within a 28‐day cycle, with a reduction to 3 mg per week in the event of adverse effects. Notably, empirical evidence from our center suggests that an initial dose of 3 mg also demonstrates efficacy and acceptable tolerability, potentially alleviating the economic burden on patients. However, it remains unclear whether the two dosing regimens yield differential therapeutic outcomes.

To address this question, we conducted a retrospective analysis of these two treatment strategies. By evaluating clinical data from 207 cases across six hematological centers, we systematically compared the efficacy and toxicity profiles of the 3 and 4 mg regimens in frontline, iCT, and maintenance therapy settings. This study provides critical insights into the optimization of ixazomib dosing across diverse clinical scenarios.

Methods

Study Design and Patients

This multicenter, retrospective cohort study was conducted across six medical centers (Xiangya Hospital, The Second Xiangya Hospital, General Hospital of Hunan University of Medicine, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central Hospital of Xiangtan, and Chenzhou First People's Hospital) in Hunan Province, China, and included patients aged ≥ 18 years diagnosed with MM between July 2018 and November 2024. MM diagnosis was established in accordance with the diagnostic criteria defined by the International Myeloma Working Group (IMWG). The study population comprised patients who received a minimum of two cycles of ixazomib‐based regimens. Exclusion criteria encompassed patients with irregular treatment patterns. A total of 207 patients were enrolled in the cohort. The cohort contains three subgroups based on the ixazomib‐based treatment phase: initial treatment (patients initiating ixazomib‐based regimens at diagnosis), iCT (patients transitioning from other PI‐based regimens to ixazomib‐based regimens), and maintenance/continuation therapy (posttransplant patients received standard reduced‐intensity ixazomib monotherapy or combination therapy as conventional maintenance. Nontransplant patients who maintained the original effective regimen without dose reduction for at least ninecycles were defined as continuation therapy. Both subgroups were combined into the maintenance/continuation therapy group). Because some patients start ixazomib‐based regimens at diagnosis or transitioning from other PI‐based regimens, they consistently maintain ixazomib‐based regimens to the maintenance phase, these patients were also grouped into the maintenance/continuation therapy cohort. Thus, the maintenance/continuation therapy cohort comprised 141 patients receiving ixazomib‐based regimens, including 26 from the initial treatment group and 58 from the iCT group. Additionally, patients were categorized into two groups according to ixazomib dosage: 3 or 4 mg. For most patients, the dose was defined as the initial and continuously maintained dose. Notably, 12 patients received both 3 and 4 mg ixazomib during treatment. These patients were assigned to the 3 or 4 mg group according to the dose accounting for more than 80% of the total medication duration. The distribution of patients across subgroups was as follows: initial treatment group ( n = 52; 3 mg: 35, 4 mg: 17), iCT group ( n = 95; 3 mg: 52, 4 mg: 43), and maintenance/continuation therapy group ( n = 141; 3 mg: 80, 4 mg: 61). The following Venn diagram of enrolled patients visualizes group compositions and the sources of overlapping pathways (Figure 1 ).

Outcomes and Assessments

Comprehensive data encompassing demographic profiles, clinical characteristics, diagnostic laboratory parameters, therapeutic interventions, treatment efficacy, AEs, and survival outcomes were systematically collected and analyzed for each participant. Survival outcomes were evaluated through two primary endpoints: PFS and overall survival (OS). PFS was calculated from the initiation of ixazomib‐based therapy until either the commencement of second‐line treatment or, in cases where second‐line therapy was not administered, until the date of mortality. OS was determined as the duration from the initial diagnosis of MM to the date of death. Treatment response and disease progression were rigorously assessed by clinical investigators in accordance with the IMWG Uniform Response Criteria for MM. The ORR was defined as the percentage of patients achieving at least a partial response (PR) based on IMWG criteria. AEs were classified and graded using the Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0.

Propensity Score Matching ( PSM )

PSM was applied in this study to eliminate baseline imbalances and reduce selection bias between study groups. All patients were matched at a 1:1 ratio using a nearest‐neighbor matching algorithm. Before matching, missing values were imputed using the median mode. Different sets of baseline covariates were adopted for matching according to the treatment group characteristics. Specifically, patients in the iCT group were matched for age and Eastern Cooperative Oncology Group (ECOG) performance status. Patients in the maintenance/continuation treatment group were matched for four baseline variables, including age, ECOG performance status (ECOG‐PS), body weight, and BSA. A fixed caliper width of 0.1 was specified for the PSM procedure to guarantee high‐quality matching and sufficient covariate balance between the paired cohorts. After matching, the baseline confounding factors were well balanced between groups.

Statistics

Baseline characteristics were summarized using descriptive statistics appropriate for variable type, with continuous variables expressed as median (interquartile range, IQR) or mean (standard deviation, SD) and categorical variables presented as frequencies (percentages). Comparative analyses between the 3 and 4 mg groups were performed using the Mann–Whitney U test (Wilcoxon rank‐sum test) for nonnormally distributed continuous data, independent samples t ‐test for normally distributed continuous data, Pearson χ 2 test for categorical variables with expected frequencies ≥ 5, and Fisher's exact test (two‐sided) for categorical variables with expected frequencies < 5. Survival analysis was conducted using the Kaplan–Meier method to estimate PFS and OS, with intergroup differences assessed via the log‐rank test. Prognostic factor analysis was performed through univariate Cox proportional hazards regression to calculate hazard ratios (HRs) and 95% confidence intervals (CIs), followed by multivariate analysis incorporating variables with p < 0.2 (initial treatment group) or p < 0.1 (maintenance/continuation treatment group) from univariate analysis or established clinical prognostic factors (e.g., ISS stage, cytogenetic risk), with model optimization achieved through stepwise regression. Treatment response transitions were visualized using Sankey diagrams. Statistical significance was defined as a two‐tailed p ‐value < 0.05, and all analyses were conducted using SPSS (version 25; IBM Corp., Armonk, NY, USA).

Results

Initial Treatment Cohort

The study cohort comprised 52 patients who received ixazomib‐based therapy as initial treatment, stratified into 3 mg ( n = 35) and 4 mg ( n = 17) dosage groups. Notably, a higher proportion of elderly patients (≥ 70 years) were administered the 3 mg regimen, reflecting clinical preference for lower doses in older populations in real‐world practice. To ensure balanced clinical parameter analysis, the 3 mg cohort was further subdivided into < 70 years ( n = 15) and ≥ 70 years ( n = 20) subgroups. Baseline characteristics, including sex, ECOG‐PS, weight, BSA, and comorbidities, were comparable across groups (Table 1 ), with the exception of a higher prevalence of infectious diseases in the 4 mg cohort ( p = 0.037). Disease‐specific parameters, encompassing M protein subtypes, ISS stage, RISS stage, serum creatinine, calcium levels, albumin, LDH, and β2‐microglobulin, demonstrated no significant intergroup differences. However, hemoglobin levels exhibited a downward trend in the 3 mg (≥ 70 years) subgroup. Disease burden indicators, specifically M protein levels and bone marrow plasma cell percentages, showed no significant variation among groups. Genetic abnormalities and extramedullary disease rates were similarly distributed across cohorts (Table 1 ).

Therapeutic regimens predominantly consisted of IRD (58.8%) and ITD (33.3%) combinations, with a median of 6 induction therapy cycles administered. Postinduction ≥ VGPR rates were 83.3% in 3 mg (< 70 years), 43.8% in 3 mg (≥ 70 years), and 47.0% in 4 mg cohorts, indicating favorable treatment responses. The 4 mg cohort demonstrated higher ASCT rates ( p = 0.043), potentially attributable to its younger demographic composition. Maintenance therapy was administered to 75% of patients, with median treatment durations of 17, 9, and 13 cycles for 3 mg (< 70 years), 3 mg (≥ 70 years), and 4 mg cohorts, respectively. All 3 mg cohort patients maintained their initial dosage, while one patient in the 4 mg cohort transitioned to 3 mg during maintenance.

Survival analysis revealed no statistically significant differences in PFS or OS among the three cohorts. However, the 3 mg (≥ 70 years) subgroup exhibited a trend toward inferior PFS and OS outcomes (Figure 2A,B ), while 3 mg (< 70 years) and 4 mg groups demonstrated comparable survival rates. Subgroup analysis of clinical factors, including age, BSA, ECOG‐PS, sex, ISS stage, RISS stage, anemia, renal dysfunction, bone destruction, ASCT, maintenance therapy, and induction therapy efficacy, showed no significant impact on PFS or OS (Figure 3 ). To adjust for potential confounding factors, we performed multivariable regression analysis. Comorbidity with diabetes (PFS: HR = 4.794, p = 0.022; OS: HR = 7.890, p = 0.05) and concomitant other malignancies (PFS: HR = 10.440, p = 0.004; OS: HR = 44.664, p = 0.006) were identified as independent adverse prognostic factors for OS. Treatment dose, however, was not an independent prognostic factor (Table S1 ). These findings suggest equivalent therapeutic efficacy between 3 and 4 mg ixazomib‐based regimens in the initial treatment setting.

iCT Group

The iCT group comprised 95 patients, with 52 receiving a 3 mg ixazomib‐based regimen and 43 receiving a 4 mg regimen. Baseline demographic and clinical characteristics, including age, sex, ECOG‐PS, weight, BSA, and comorbidities, were comparable between the two cohorts (Table 2 ), except for a significantly higher prevalence of cardiovascular diseases, such as hypertension, in the 3 mg cohort ( p < 0.001). Disease‐specific baseline parameters, including M protein subtypes, ISS stage, RISS stage, serum creatinine, calcium levels, hemoglobin, albumin, LDH, β2‐microglobulin, M protein levels, bone marrow plasma cell infiltration, cytogenetic profiles, and extramedullary disease incidence, were also similar between the two cohorts (Table 2 ). Serum creatinine, calcium, hemoglobin, albumin, LDH, β2‐microglobulin, and M‐protein concentrations at diagnosis were comparable between groups (Table S2 ).

Both groups predominantly received bortezomib and IMiDs‐based induction therapy, with comparable rates of ASCT. Pre‐iCT therapeutic efficacy was similar, with very good partial response (≥ VGPR) rates of 44.2% and 50.0% in the 3 and 4 mg cohorts, respectively. All patients underwent first‐line transition, primarily due to treatment intolerance (75.6% in the 3 mg group, 71.4% in the 4 mg group), with bortezomib (83.9%) and lenalidomide (12.5%) being the most common intolerable agents. Intolerance manifestations, including PN (76.5% in the 3 mg group, 80.0% in the 4 mg group) and infections (11.8% vs. 10.0%), did not differ significantly between the cohorts. Ixazomib‐based regimens included IRD, ITD, IPD, DID, and ID. Post‐iCT therapeutic outcomes improved markedly (Figure 4A ), with comparable ≥ VGPR rates of 80.4% and 78.5% in the 3 and 4 mg groups, respectively (Table 2 ). PFS and OS were similar between the two groups (Figure 4B,C ), demonstrating the efficacy of ixazomib‐based regimens. Subgroup analysis revealed superior PFS in the 4 mg group for R‐ISS Stage 3 patients and improved OS in the 4 mg group for ECOG‐PS 1–2 patients. Other factors, including age, BSA, sex, ISS stage, anemia, renal dysfunction, bone lesions, induction therapy efficacy, ASCT, iCT efficacy, and cytogenetic abnormalities (1q+, 17p−, t(4;14), and t(11;14)), did not significantly influence PFS or OS (Figure 5 ).

PSM was implemented to balance baseline confounders across the two dosage groups. After PSM adjustment, baseline characteristics were not statistically different between the 3 and 4 mg cohorts, and no significant intergroup disparities in treatment efficacy or long‐term prognosis were observed (Table 2 and Figure 4 ). These findings suggest no significant difference in therapeutic outcomes between the 3 and 4 mg regimens in the iCT setting. Additionally, 81.0% of patients continued ixazomib‐based regimens as maintenance therapy, underscoring their favorable tolerability.

Maintenance/Continuation Therapy Cohort

The maintenance/continuation therapy cohort comprised 141 patients receiving ixazomib‐based regimens, including 26 from the initial treatment group and 58 from the iCT group. Patients were stratified into 3 mg ( n = 80) and 4 mg ( n = 61) dosage groups. Demographic analysis revealed significant differences between groups: the 4 mg cohort demonstrated a younger median age (58.0 years, IQR 50.0–67.0) compared to the 3 mg cohort (66.0 years, IQR 58.5–71.0; p < 0.001). The 3 mg cohort exhibited a higher proportion of patients with ECOG‐PS 3–4 (26.0% vs. 11.9% for ECOG‐PS 3; 11.0% vs. 0.0% for ECOG‐PS 4; p = 0.003). Additionally, the 4 mg cohort showed significantly greater body weight and BSA ( p < 0.001), while sex distribution and comorbidity profiles were comparable between groups. Disease characteristics, including M protein types, ISS stage, RISS stage, serum biomarkers (creatinine, calcium, hemoglobin, albumin, β2‐microglobulin), M protein level, bone marrow plasma cell infiltration, cytogenetic profiles, and extramedullary disease incidence were well‐balanced between groups. At the initiation of maintenance therapy, LDH levels were slightly lower in the 3 mg group than in the 4 mg group (179 vs. 207, p = 0.01), while both values fell within the normal range (Table 3 ). No statistically significant between‐group differences were found in baseline serum creatinine, corrected calcium, hemoglobin, albumin, LDH, β 2 ‐microglobulin, and M‐protein at diagnosis (Table S3 ). Therapeutic patterns differed significantly between cohorts: the 4 mg group demonstrated higher utilization of bortezomib‐based induction therapy (83.3% vs. 67.5%; p = 0.034) and ASCT ( p = 0.034), consistent with their younger age and favorable performance status. Pre‐maintenance treatment response rates were comparable, with ≥ VGPR achieved by 84.0% and 76.7% of patients in the 3 and 4 mg cohorts, respectively ( p = 0.627). The median duration of induction therapy was longer in the 3 mg cohort (7 vs. 5 cycles; p = 0.037), primarily attributable to higher ASCT rates in the 4 mg group. The median interval from transplantation to maintenance initiation was 2.5 and 3 months for the 3 and 4 mg groups, respectively ( p = 0.354) (Table 3 ).

Maintenance therapy regimens predominantly included ixazomib‐based combinations (IR, I, IT, DI) with or without dexamethasone. Both cohorts received a median of 10 maintenance cycles, with comparable postmaintenance response rates (≥ VGPR: 89.7% vs. 87.9%; p = 0.951) (Table 3 ). Given baseline characteristic disparities, univariate and multivariate analyses were conducted to identify prognostic factors. For PFS, univariate analysis identified ECOG‐PS, cardiovascular disease, and maintenance therapy response as significant factors, with multivariate analysis confirming independent associations for age ≥ 70 ( p = 0.030), ECOG‐PS of 4 ( p = 0.001) and cardiovascular disease ( p = 0.046). OS analysis revealed potential influences from comorbidities (infection, respiratory diseases), ASCT, and ixazomib dosage. However, multivariate analysis demonstrated independent prognostic significance only for ASCT and comorbidities (infection, respiratory diseases). Notably, ixazomib dosage did not independently influence either PFS or OS outcomes (Table S4 ). In addition, PSM was performed to balance baseline patient characteristics. After matching, no statistically significant differences in clinical features during the maintenance therapy phase were identified between the 3 and 4 mg cohorts (Table 3 ). The findings indicate that under maintenance therapy conditions, treatment regimens incorporating 3 and 4 mg doses of ixazomib demonstrated no statistically significant differences in therapeutic efficacy or OS rates.

Safety Profiles

The toxicity profiles are summarized in Table 4 . The incidence of hematological AEs, including anemia, neutropenia, and thrombocytopenia, was comparable between the 3 and 4 mg groups, with the incidence of Grades 3–4 AEs ≤ 5%. We further analyzed nonhematological AEs, namely diarrhea, constipation, nausea, vomiting, PN, upper respiratory tract infection, pneumonia, herpes zoster, and edema. During the initial treatment phase, the 4 mg dose group demonstrated significantly higher incidence rates of Grades 1–2 vomiting (0% vs. 23.5%, p = 0.016). In the iCT setting, the 4 mg group exhibited a trend toward increased rates of diarrhea (9.6% vs. 16.3%, p = 0.069, predominantly Grades 3–4) and Grades 1–2 constipation (0% vs. 7.0%, p = 0.089). No statistically significant differences ( p > 0.05) were observed between the treatment arms for all other safety endpoints, as detailed in Table 4 .

Discussion

Previous studies have established the optimal dosing range for ixazomib, identifying 5.5 mg as the maximum tolerated dose (MTD). Clinical investigations have demonstrated that doses of 3 mg (55% of MTD) and 4 mg (73% of MTD) offer a favorable benefit/risk profile. Specifically, a starting dose of 3 mg weekly yields clinical benefit (≥ stable disease) in 37% of patients, while 4 mg increases this proportion to approximately 44%. However, the 4 mg dose is associated with a slightly higher incidence of AEs [ 9 ]. Notably, there is a paucity of data regarding the impact of ixazomib dosage on therapeutic outcomes, particularly in Asian populations characterized by relatively lower BSA. This study presents evidence that in Chinese patients, ixazomib‐based regimens at doses of 3 or 4 mg demonstrate comparable efficacy and toxicity profiles across various clinical settings, including initial treatment, in‐class transition, and maintenance/continuation therapy.

Ethnic differences in physical characteristics are an indispensable consideration for individualized medication. The 4 mg starting dose of ixazomib was primarily established based on data from Western populations [ 3 , 9 ]. In contrast, Chinese patients generally have a smaller body size, with lower overall body weight and BSA compared with their Western counterparts. Such anthropometric differences may explain why comparable efficacy was observed between the 3 and 4 mg doses in our study. This ethnicity‐adjusted dose strategy also helps maintain a favorable therapeutic window and improves treatment tolerability in Chinese patients. Further prospective clinical trials are warranted to validate this conclusion in the future.

In the context of initial treatment, the IRD regimen (ixazomib, lenalidomide, and dexamethasone) represents a viable option for elderly patients, those declining hospitalization, or individuals with frailty [ 12 ]. The Tourmaline‐MM2 study demonstrated that the all‐oral IRD regimen significantly improved PFS compared to the RD regimen in transplant‐ineligible patients with NDMM, utilizing ixazomib at 4 mg as frontline therapy [ 4 ]. In clinical practice, however, a 3 mg dose of ixazomib is often preferred for elderly and frail patients. Our cohort analysis revealed inferior prognosis in patients aged over 70 years, whereas those under 70 years receiving 3 mg ixazomib exhibited comparable efficacy and prognosis to the 4 mg group. The regimen's favorable tolerability and convenience enabled 82.1% of patients to continue maintenance therapy. With the current recommendation of quadruplet therapies as frontline treatment for high‐risk patients [ 13 ], the potential for increased toxicity necessitates careful dose optimization. Lowering individual drug dosages, such as using 3 mg ixazomib, may mitigate toxicity in these combination regimens. Nevertheless, further comparative studies are required to establish definitive evidence regarding ixazomib dosing in quadruplet therapy settings.

Clinical studies have demonstrated that iCT from bortezomib to ixazomib significantly enhances the ≥ VGPR rate while reducing the incidence of PN [ 7 , 14 , 15 ]. Consequently, iCT represents a viable therapeutic strategy for MM patients exhibiting bortezomib intolerance, particularly due to parenteral administration‐related complications and PN. Our findings align with previous reports, indicating that MM patients experiencing bortezomib‐induced intolerable PN and infections may benefit from transitioning to ixazomib‐based therapy, which facilitates deeper disease remission and alleviates AEs. Notably, our analysis revealed comparable therapeutic efficacy between 3 and 4 mg ixazomib dosages in the iCT setting. Subgroup analysis demonstrated that RISS Stage 3 patients exhibited improved PFS with 4 mg ixazomib, while ECOG‐PS 1–2 patients achieved superior OS with the 4 mg regimen, suggesting a potential preference for higher dosage in high‐risk patients. However, no significant correlation was observed between ixazomib dosage and high‐risk genetic alterations (1q+, 17p−, and t(4;14)), potentially attributable to the limited sample size of patients with these genetic events. Furthermore, patients with favorable ECOG‐PS, characterized by better physical condition and treatment tolerance, may benefit from the 4 mg dosage to optimize OS outcomes.

In the context of maintenance/continuation therapy, there is a critical need for agents that demonstrate efficacy while minimizing toxicity and enhancing convenience. Lenalidomide, a standard maintenance therapy, frequently necessitates dose reductions, with a discontinuation rate of approximately 50% at 2 years [ 16 ]. The utility of bortezomib as a maintenance agent is constrained by its parenteral administration and elevated risk of PN. In contrast, ixazomib maintenance therapy exhibits significantly lower rates of dose reduction or discontinuation compared to lenalidomide (9% vs. 24%, respectively) [ 17 ]. For patients who are intolerant to lenalidomide, the TOURMALINE‐MM3 trial demonstrated a PFS benefit with ixazomib maintenance versus placebo, suggesting its viability as an alternative [ 5 ]. Additionally, double or triple combination regimens are recommended for high‐risk MM patients undergoing maintenance therapy. Ixazomib is particularly well‐suited for maintenance due to its once‐weekly oral administration, robust efficacy, and favorable toxicity profile, particularly with respect to PN. Our data indicate comparable efficacy between 3 and 4 mg doses in the maintenance setting, with a median of 10 maintenance cycles, reflecting good tolerability among MM patients.

The integration of immunotherapy into maintenance therapy has shown promising potential. Recent studies have demonstrated superior PFS outcomes with daratumumab in the maintenance phase [ 18 ], and the combination of daratumumab with ixazomib is currently under investigation. However, data reveal that 37% of patients receiving 4 mg ixazomib require dose modifications, primarily due to low‐grade PN [ 19 ], with frail and elderly patients exhibiting higher rates of dose reduction and discontinuation [ 20 ]. Dose escalation strategies, such as initiating with 3 mg ixazomib to assess efficacy and tolerability before transitioning to 4 mg, have been employed in the TOURMALINE‐MM3 [ 5 ] and TOURMALINE‐MM4 [ 6 ] studies. Nonetheless, in real‐world settings, patients who achieve satisfactory efficacy and tolerability with 3 mg often decline escalation to 4 mg, perceiving it as unnecessary and economically burdensome. Consequently, 3 mg ixazomib is preferred for maintenance therapy in frail and elderly patients, particularly in multidrug regimens, to enhance long‐term treatment adherence and reduce early discontinuation.

Regarding safety profiles, both 4 and 3 mg doses of ixazomib demonstrated favorable tolerability in real‐world clinical settings. In the initial treatment cohort, the 4 mg group exhibited significantly higher incidence rates of Grades 1–2 vomiting ( p = 0.016). During the iCT cohort, the 4 mg group showed a trend toward increased rates of diarrhea ( p = 0.069, predominantly Grades 3–4) and Grades 1–2 constipation ( p = 0.089). All other safety endpoints were comparable between the two treatment arms. The observed AE rates in our study were notably lower than those reported in multiple clinical trials, including the Tourmaline 1–4 series, potentially attributable to our comprehensive prophylactic medication protocol. Our institution maintains a full‐course disease management system that enables timely reporting of adverse reactions and prompt therapeutic interventions. Specifically, antiemetic agents are co‐administered with ixazomib, while probiotics and antidiarrheal medications are prescribed for patients predisposed to diarrhea. All patients receive antiviral prophylaxis (e.g., Valacyclovir or Acyclovir) to prevent herpes zoster virus infection, and neuroprotective agents are recommended for those at risk of PN. This systematic approach to symptom management effectively controlled AEs in the majority of cases.

The economic burden represents a significant determinant of patient prognosis [ 21 ]. Despite advancements in immunotherapy, MM remains incurable, necessitating continuous treatment for most patients. The prolonged treatment duration and high costs of novel therapeutic agents impose substantial financial strain on patients [ 22 ]. Our findings indicate that 3 and 4 mg ixazomib demonstrate comparable efficacy in the Chinese population, with the 3 mg dose offering potential cost‐saving benefits. Therefore, the 3 mg regimen may represent a more favorable therapeutic option for MM patients.

Several limitations of this observational study warrant consideration. As a retrospective analysis, the study exhibits some baseline imbalances between the 3 and 4 mg cohorts. Future prospective cohort studies are required to validate these findings. Additionally, the sample size in the initial treatment group was relatively limited. Furthermore, the study population received varied combinations of ixazomib‐based therapies. Despite these limitations, this study represents the first comparative analysis of 3 versus 4 mg ixazomib‐based regimens in MM treatment.

Conclusions

This retrospective multicenter study investigated the efficacy and safety of ixazomib at doses of 3 and 4 mg in combination therapy for initial treatment, iCT, and maintenance/continuation therapy among Chinese MM patients. The results demonstrated comparable efficacy and toxicity profiles between the two dosage regimens across most clinical scenarios. Subgroup analysis within the iCT cohort revealed that patients with RISS Stage 3 disease exhibited superior PFS in the 4 mg group. Additionally, patients with ECOG‐PS of 1–2 achieved improved OS with the 4 mg dose. These findings suggest that initiating treatment with 3 mg ixazomib, rather than employing dose de‐escalation strategies, represents a viable approach in real‐world clinical practice.

Author Contributions

Liang Zhao: formal analysis, visualization, writing – original draft, writing – review and editing, funding acquisition. Xiao He: data curation, formal analysis. Mingyang Deng: data curation. Yun Yuan: data curation. Zhiyu Su: data curation. Zhongqi Ding: data curation. Youping Liao: data curation. Chanjuan Shen: data curation. Zhongjun Huo: data curation. Zimian Luo: data curation. Zhiqin Li: data curation. Limei Fu: data curation. Ping Zhu: data curation. Xiangling Feng: formal analysis. Shuping Chen: data curation. Yanjuan He: conceptualization, supervision, writing – review and editing. Yan Zhu: writing – review and editing, supervision.

Funding

This project was supported by grants from the Natural Science Foundation of Hunan Province, China (Grants 2026JJ50581 and 2021JJ41056).

Ethics Statement

This multicenter retrospective study was approved by the Ethics Committee of Xiangya Hospital (approval no. 2025071087), the lead participating center. All participating sites completed institutional ethical filing based on this lead‐center approval.

Consent

The requirement for written informed consent was waived by the lead ethics committee given the retrospective study design.

Conflicts of Interest

The authors declare no conflicts of interest.

Supporting information

Table S1: Univariate and multivariate Cox regression analyses for prognostic factors in the initial treatment cohort.

Table S2: Baseline clinical characteristics of the iCT cohort at diagnosis.

Table S3: Baseline clinical characteristics of the maintenance/continuation cohort at diagnosis.

Table S4: Univariate and multivariate Cox proportional hazards regression analyses were conducted to evaluate the prognostic significance of various indicators within the maintenance group.

Acknowledgments

The authors have nothing to report.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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