Реальная эффективность обслуживания бортезомиба после введения VMP в санитарную миелому: целевое экспериментальное исследование эмуляции.

Introduction

Multiple myeloma (MM) is a clonal plasma cell malignancy accounting for approximately 1% of all cancers and 10% of hematologic malignancies worldwide [ 1 , 2 ]. The median age at diagnosis is around 70 years, and a substantial proportion of patients are ineligible for autologous stem cell transplantation (ASCT) due to frailty, comorbidities, or organ dysfunction [ 1 – 3 ]. Despite therapeutic advances incorporating proteasome inhibitors (PIs), immunomodulatory drugs, and monoclonal antibodies, MM remains incurable, and relapse is inevitable for most patients [ 3 – 7 ]. Therefore, effective and well-tolerated long-term treatment strategies are essential for transplant-ineligible newly diagnosed MM (NDMM) patients.

For transplant-ineligible patients, bortezomib-melphalan-prednisone (VMP) is established as standard induction regimen based on the landmark VISTA trial, which demonstrated superior progression-free survival (PFS) and overall survival (OS) compared to melphalan-prednisone alone [ 8 ]. This trial showed that VMP significantly enhanced median time to progression (24.0 vs. 16.6 months; HR: 0.48, P < 0.001) and OS (56.4 vs. 43.1 months; HR: 0.65, P < 0.001) in NDMM patients ineligible for transplantation. However, despite these improvements, the optimal post-induction strategy following VMP remains to be determined.

Maintenance therapy (MT) has emerged as a cornerstone of MM management in transplant-eligible patients, with objectives of sustaining treatment responses, delaying disease progression, and ultimately improving PFS and OS [ 3 – 6 ]. However, the role of MT is less well-defined for transplant-ineligible patients lacking the benefit of high dose chemotherapy and ASCT. Nonetheless, unlike traditional intermittent treatments, MT provides continuous therapeutic pressure against residual disease, and thereby minimizes relapse risk and extends survival in this vulnerable population [ 8 – 12 ].

Among available MT agents, bortezomib, a first-in-class PI, has demonstrated significant efficacy in transplant-eligible and -ineligible patients with MM [ 3 ]. Clinical trials, such as the GEM2005MAS65 trial, have established the benefit of bortezomib-based maintenance regimens, demonstrating significant extensions in PFS and OS, particularly in high-risk cytogenetic subgroups [ 5 ]. Our previous study demonstrated the efficacy of bortezomib MT in transplant-ineligible MM patients, with median PFS of 27.2 months, median PFS2 of 49.2 months, and an unreached median OS [ 13 ]. However, real-world evidence regarding bortezomib maintenance following standard VMP induction in transplant-ineligible patients remains limited [ 14 ].

While bortezomib MT has demonstrated survival benefits, toxicity management remains a significant challenge. Peripheral neuropathy (PN), fatigue, and gastrointestinal (GI) symptoms are notable adverse events (AEs) that affect long-term compliance and quality-of-life (QoL) [ 3 – 6 ]. Subcutaneous administration has significantly reduced injection-related AEs, maintained efficacy, and improved feasibility of long-term treatment [ 14 ].

Despite the availability of contemporary regimens, VMP continues to be utilized in many healthcare systems, particularly in Asia, Eastern Europe, and Latin America, where access to newer agents is constrained by cost, reimbursement policies, or regulatory factors [ 15 ]. In Korea, VMP remained a standard option during our study period (2010–2021) and continues to be prescribed for selected patients, including those with renal impairment, thrombotic risk, or advanced age with comorbidities. Given the increasing prevalence of MM in the elderly population and the challenges facing transplant-ineligible patients, real-world evidence on the effectiveness of bortezomib maintenance following standard VMP induction is needed to guide post-induction treatment strategies in these settings. To address this gap, we conducted a multicenter retrospective study using a target trial emulation framework to evaluate the effectiveness of bortezomib maintenance in transplant-ineligible NDMM patients who achieved disease control after VMP induction, providing evidence to guide treatment decisions in real-world clinical practice where VMP-based regimens remain standard therapy.

Method

Study design

We conducted a comparative effectiveness analysis to evaluate bortezomib MT in transplant-ineligible patients with NDMM who completed 9 cycles of VMP induction. The intervention cohort comprised participants from a prospective single-arm clinical trial (Korean Multiple Myeloma Working Party; KMMWP-174). To address the limitations of single-arm design, we incorporated a control cohort using target trial emulation methodology applied to a multicenter registry database. The external control cohort was derived from the Catholic Research Network for Multiple Myeloma (CAREMM) registry, a multicenter database of university-affiliated hospitals. Control patients met all prospective trial eligibility criteria: completed 9 VMP cycles without progression, remained progression-free for at least 60 days post-VMP, and received no MT.

The primary aim of the study was to compare PFS between MT and control groups after 1:1 propensity score matching (PSM). To mitigate immortal time bias, we implemented a 60-day landmark analysis. The index date was defined as maintenance initiation for the intervention cohort and day 60 post-VMP for controls, reflecting the prospective trial’s actual enrollment window. Primary analyses employed matching based on sex, age, type of myeloma, International Staging System (ISS), estimated glomerular filtration rate (eGFR), cytogenetic profile, and VMP response. We performed 3 sensitivity analyses: (1) alternative landmark analyses at 30 and 90 days, (2) multivariable Cox regression using the entire unmatched cohort adjusting for all propensity score variables, and (3) E-value calculations to assess unmeasured confounding. The complete target trial emulation framework is detailed in Supplementary Table 1 .

Because the incidence of adverse events (AEs) in the two cohorts was collected during fundamentally different treatment phases (the control cohort received VMP induction therapy, while the case cohort received MT), a scientific comparison of AEs was not methodologically appropriate. Therefore, AEs were summarized descriptively, and frequency of grade ≥ 3 AEs in each cohort prior to PSM was reported.

The study protocol received approval from institutional review boards at all participating sites with waiver of informed consent for registry patients (lead IRB: XC23RIDI0066). Trial participants provided written informed consent. The study adhered to Declaration of Helsinki principles.

Study population

Between May 2017 and December 2021, the KMMWP-174 trial enrolled 78 patients, with 60 completing 9 VMP cycles and comprising the intervention cohort. From the CAREMM registry, we identified 644 transplant-ineligible NDMM patients treated between May 2010 and December 2024. Of 483 patients receiving first-line VMP, 118 met eligibility criteria for the control cohort after excluding: 327 who did not complete 9 VMP cycles, 7 who failed to achieve partial response (PR), 13 enrolled in KMMWP-174, and 18 who progressed or died within 60 days post-VMP. After 1:1 PSM, 54 patients from each cohort (total N = 108) were included in the primary analysis (Fig. 1 ). Baseline characteristics were well-balanced between matched cohorts. Fig. 1 Flowchart for study population selection. Abbreviations) NDMM, newly diagnosed multiple myeloma; PR, partial response

Treatment procedure with bortezomib

Bortezomib MT was administered subcutaneously at 1.3 mg/m² once weekly for 3 weeks (days 1, 8, 15) followed by a 1-week rest period in 28-day cycles [ 16 ]. Treatment continued until disease progression or completion of the planned 24-month protocol period.

Definitions

Disease staging followed the International Staging System (ISS) criteria [ 17 ]. High-risk cytogenetic abnormalities were defined as presence of del(17p), t(4;14), or t(14;16) detected by fluorescence in situ hybridization [ 18 ]. Renal function was evaluated using estimated glomerular filtration rate (eGFR) calculated with the Modification of Diet in Renal Disease (MDRD) formula [ 19 ]. Treatment responses were assessed according to International Myeloma Working Group (IMWG) 2016 consensus criteria [ 20 ]. OS was measured from the index date to death from any cause or last follow-up. PFS was measured from the index date to disease progression or death, whichever occurred first. The index date was defined as MT initiation for the intervention cohort and day 60 post-VMP completion for the control cohort, as specified in the study design. Severity of AEs was assessed with the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 [ 21 ].

Statistical analysis

Baseline characteristics were compared using Mann-Whitney U test for continuous variables and chi-square test for categorical variables. We performed 1:1 PSM using logistic regression incorporating sex, age, type of myeloma, ISS, eGFR, cytogenetic profile, and VMP response. A caliper width of 0.25 standard deviations of the logit-transformed propensity score was applied to optimize covariate balance. Standardized mean differences (SMD) assessed matching quality, with SMD < 0.2 indicating adequate balance. Survival outcomes were estimated using Kaplan-Meier methods and compared with log-rank tests. Cox proportional hazards models calculated hazard ratios (HR) with 95% confidence intervals. Variables with SMD > 0.2 after matching underwent additional adjustment in Cox models. Subgroup analyses examined treatment effects across all matching variables except eGFR. To evaluate robustness against unmeasured confounding, we calculated E-values for observed hazard ratios following VanderWeele’s methodology (PMID: 28693043). Statistical significance was set at two-sided P < 0.05. All analyses were performed using R version 4.4.0 (R Foundation for Statistical Computing, Vienna, Austria).

Result

Baseline characteristics

After 1:1 PSM, 54 patients in each cohort were analyzed. All covariates achieved adequate balance (Supplementary Fig. 1 ). Table 1 presents baseline characteristics of the matched cohorts. No significant differences were observed in sex, age, heavy- and light-chain isotypes, ISS stage, β2-microglobulin, albumin, neutrophil count, or platelet count between groups (all P > 0.05). The case cohort had higher mean hemoglobin levels (11.41 ± 1.18 vs. 9.50 ± 1.70 g/dL, P < 0.001) but lower absolute lymphocyte counts (0.96 ± 0.36 vs. 1.88 ± 0.82 × 10⁹/L, P < 0.001) compared to controls. Lactate dehydrogenase (LDH) levels exceeding the upper limit of normal were more frequent in the case cohort (55.6% vs. 29.6%, P = 0.018). Renal function was comparable between groups, with preserved eGFR (≥ 60 mL/min/1.73 m²) in 63.0% of case patients, compared to 57.4% of controls ( P = 0.808). Cytogenetic risk distribution showed no significant difference, though high-risk abnormalities were slightly more prevalent in the case cohort (25.9% vs. 22.2%, P = 0.834). Response to VMP induction was similar between groups: very good partial response (VGPR) rates were 44.4% versus 40.7%, and complete response (CR)/stringent CR (sCR) rates were identical at 25.9% ( P = 0.903). Among all eligible patients before matching, the case cohort ( N = 60) had a median follow-up of 51.5 months (95% CI: 44.8–61.5), while the control cohort ( N = 118) had 72.0 months (95% CI: 68.8-NA; Supplementary Table 2 ).

Table 1 Baseline characteristics of patients after propensity score matching Characteristic Overall ( N = 108) Control ( N = 54) Case ( N = 54) P -value Median follow up, months (95% CI) 60.7 (53.6, 66.9) 69.2 (62.7, NA) 53.6 (46.2, 62.5) < 0.001 Sex, n (%) 0.842 Male 68 (63.0%) 35 (64.8%) 33 (61.1%) Female 40 (37.0%) 19 (35.2%) 21 (38.9%) Age, n (%) 0.673 < 70 33 (30.6%) 16 (29.6%) 17 (31.5%) 70–74 47 (43.5%) 22 (40.7%) 25 (46.3%) \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\:\ge\:$$\end{document} 75 28 (25.9%) 16 (29.6%) 12 (22.2%) Heavy chain type, n (%) 1.000 IgG 61 (56.5%) 30 (55.6%) 31 (57.4%) Non-IgG 47 (43.5%) 24 (44.4%) 23 (42.6%) Light chain type, n (%) 0.601 Kappa 55 (50.9%) 27 (50.0%) 28 (51.9%) Lambda 52 (48.1%) 26 (48.1%) 26 (48.1%) Unknown 1 (0.9%) 1 (1.9%) 0 (0.0%) ISS stage, n (%) 0.659 I 30 (27.8%) 15 (27.8%) 15 (27.8%) II 34 (31.5%) 15 (27.8%) 19 (35.2%) III 44 (40.7%) 24 (44.4%) 20 (37.0%) \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\:{\beta\:}^{2}$$\end{document} -microglobulin, mg/L, mean (SD) 6.89 (6.29) 6.83 (6.39) 6.94 (6.27) 0.924 Albumin, g/dL, mean (SD) 3.53 (0.64) 3.42 (0.60) 3.63 (0.66) 0.081 Lactate dehydrogenase \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\:\ge\:\:$$\end{document} ULN, n (%) 46 (42.6%) 16 (29.6%) 30 (55.6%) 0.018 Hemoglobin, g/dL, mean (SD) 10.46 (1.75) 9.50 (1.70) 11.41 (1.18) < 0.001 Absolute neutrophil count, x 10 9 , mean (SD) 2.90 (1.11) 2.89 (1.17) 2.91 (1.05) 0.927 Absolute lymphocyte count, x 10 9 , mean (SD) 1.41 (0.78) 1.88 (0.82) 0.96 (0.36) < 0.001 Platelet count, x 10 9 /L, mean (SD) 188.67 (66.01) 197.34 (74.29) 180.17 (56.13) 0.180 eGFR, mL/min/1.73m 2 , n (%) 0.808 <30 16 (14.8%) 9 (16.7%) 7 (13.0%) <30–59 27 (25.0%) 14 (25.9%) 13 (24.1%) \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\:\ge\:$$\end{document} 60 65 (60.2%) 31 (57.4%) 34 (63.0%) Cytogenetic abnormalities, n (%) 0.834 Standard risk 31 (28.7%) 15 (27.8%) 16 (29.6%) High risk 26 (24.1%) 12 (22.2%) 14 (25.9%) Unknown 51 (47.2%) 27 (50.0%) 24 (44.4%) VMP induction response, n (%) 0.903 PR 34 (31.5%) 18 (33.3%) 16 (29.6%) VGPR 46 (42.6%) 22 (40.7%) 24 (44.4%) CR/sCR 28 (25.9%) 14 (25.9%) 14 (25.9%) CI confidence interval, Ig immunoglobulin, SD standard deviation, IU international unit, ULN upper limit of normal, eGFR estimated glomerular filtration rate, PR partial response, VGPR very good partial response, CR/sCR complete response/stringent complete response

In the case cohort, median treatment duration was 9 cycles (range: 1–26). Fifteen patients (25.0%) completed the planned 24-month protocol. Treatment discontinuation occurred in 45 patients (75.0%), primarily due to disease progression ( N = 37, 61.7%) or withdrawal of consent ( N = 7, 11.7%). One additional patient discontinued for other reasons. These findings reflect real-world treatment patterns in transplant-ineligible MM patients receiving MT.

Primary analysis: matched cohort outcomes

Bortezomib maintenance significantly improved PFS compared to observation. Median PFS was 26.5 months (95% CI: 21.9–32.2) in the case cohort versus 8.8 months (95% CI: 3.7–16.5) in the control cohort (HR 0.437, 95% CI: 0.292–0.653, P < 0.001; Fig. 2 B). This benefit persisted over extended follow-up, with 3-year PFS rates of 33.2% versus 13.4% ( P < 0.001) and 6-year PFS rates of 17.0% versus 5.4% ( P < 0.001), respectively. Overall survival showed favorable trends without reaching statistical significance. Median OS was not reached in the case cohort (HR 0.703, 95% CI: 0.385–1.284, P = 0.252; Fig. 2 A). The 3-year OS rates were 81.9% (95% CI: 71.8–93.4%) for case versus 70.8% (95% CI: 59.4–84.4%) for control ( P = 0.195), with 6-year rates of 54.6% (95% CI: 39.0-76.5%) versus 44.5% (95% CI: 31.4–63.1%), respectively ( P = 0.118).

Fig. 2 Comparative survival analysis of matched cases (red line) and matched controls (blue line) ( A ) overall survival and ( B ) progression-free survival. Abbreviations) HR, Hazard ratio; CI, Confidence interval

Subgroup analyses revealed consistent PFS benefits across all patient subsets (Fig. 3 ). Significant improvements occurred regardless of sex (males: HR 0.333, 95% CI: 0.177–0.627; females: HR 0.071, 95% CI: 0.020–0.248), age ≥ 70 years (HR 0.321, 95% CI: 0.191–0.539), immunoglobulin type (IgG: HR 0.420, 95% CI: 0.232–0.761; non-IgG: HR 0.410, 95% CI: 0.197–0.854), ISS stage 2–3 (HR 0.352, 95% CI: 0.206–0.603), cytogenetic risk (standard: HR 0.228, 95% CI: 0.062–0.839; high-risk: HR 0.260, 95% CI: 0.091–0.742), and depth of response (PR/VGPR: HR 0.437, 95% CI: 0.269–0.708; CR/sCR: HR 0.159, 95% CI: 0.049–0.512). Overall survival benefits were limited to female patients (HR 0.123, 95% CI: 0.018–0.864) and ISS stage 1 (HR 0.001, 95% CI: 0.000-0.292; Supplementary Fig. 2 ).

Fig. 3 Forest plot comparing progression-free survival of each cohort. Abbreviations) HR, hazard ratio; CI, confidence interval

Adverse events prior to PSM

Grade ≥ 3 AEs occurred in 37 patients (31.4%) in the control and 11 patients (18.7%) in the case cohorts, respectively, prior to PSM (Table 3 ). The most common grade ≥ 3 AEs were fever/neutropenic fever (9.3%) and anorexia (5.9%) in controls, while enterocolitis (5.1%) was most frequently observed in cases. No grade ≥ 3 PN was observed in either cohort.

Table 2 Frequency of grade 3 or 4 adverse events prior to propensity score matching Variables Control cohort ( N = 118) Case cohort ( N = 60) Total events, n (%) 37 (31.4%) 11 (18.7%) Hematologic toxicities Neutropenia - - Lymphopenia - - Thrombocytopenia - 1 (1.7%) Anemia - 1 (1.7%) Gastrointestinal toxicities Anorexia 7 (5.9%) - GERD - 1 (1.7%) Nausea and vomiting - 1 (1.7%) Infectious complications Chilling 2 (1.6%) - Pneumonia 2 (1.6%) 1 (1.7%) Enterocolitis 2 (1.6%) 3 (5.1%) Herpes zoster 1 (0.8%) - Septic shock 1 (0.8%) - Acute pyelonephritis 1 (0.8%) - Fever / Neutropenic fever 11 (9.3%) - Neurologic toxicities Anxiety 1 (0.8%) - Dizziness 2 (1.6%) - Headache 1 (0.8%) - Peripheral neuropathy - - Other toxicities Pain 2 (1.6%) - Rash - 1 (1.7%) Fatigue 2 (1.6%) 1 (1.7%) Hypoglycemia 1 (0.8%) - Hyperglycemia 1 (0.8%) - Operation due to trigger finger - 1 (1.7%) GERD gastro-esophageal reflux disease

Sensitivity and supplementary analyses

Unmatched cohort analysis

To validate our findings in the broader eligible population, multivariable Cox regression was performed using all 178 patients (Table 2 ). After adjusting for baseline covariates, bortezomib maintenance remained significantly associated with improved PFS (HR 0.400, 95% CI: 0.268–0.596, P < 0.001), consistent with the matched analysis. No significant association with OS was observed (HR 0.735, 95% CI: 0.409–1.324, P = 0.306). Among other covariates, depth of response to VMP induction emerged as an independent prognostic factor, with VGPR (HR 0.557, 95% CI: 0.360–0.862, P = 0.009) and CR/sCR (HR 0.363, 95% CI: 0.224–0.588, P < 0.001) associated with significantly reduced PFS risk compared to PR. Other baseline characteristics including sex, age, heavy chain type, ISS stage, and cytogenetic risk were not independently associated with survival outcomes.

Table 3 Multivariate analysis of factors associated with survival outcomes Variables Overall survival (OS) Progression-free survival (PFS) Hazard ratio (95% CI) p -value Hazard ratio (95% CI) p -value Cohort Control ( N = 118) 1 1 Case ( N = 60) 0.735 (0.409, 1.324) 0.306 0.400 (0.268, 0.596) < 0.001 Sex Male 1 1 Female 0.907 (0.533, 1.546) 0.720 1.113 (0.777, 1.593) 0.561 Age < 70 1 1 70–74 1.317 (0.725, 2.394) 0.366 1.339 (0.891, 2.013) 0.160 \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\:\ge\:$$\end{document} 75 1.234 (0.632, 2.411) 0.537 0.892 (0.563, 1.413) 0.627 Heavy chain type Non-IgG 1 1 IgG 0.935 (0.542, 1.614) 0.809 0.921 (0.630, 1.347) 0.671 ISS stage I 1 1 II 1.111 (0.551, 2.240) 0.768 0.753 (0.475, 1.193) 0.227 III 1.165 (0.512, 2.651) 0.716 0.875 (0.528, 1.452) 0.606 eGFR, mL/min/1.73m 2 <30 1 1 <30–59 1.064 (0.474, 2.389) 0.880 2.043 (1.144, 3.648) 0.016 \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\:\ge\:$$\end{document} 60 0.897 (0.383, 2.104) 0.803 1.463 (0.826, 2.589) 0.192 Cytogenetic abnormalities Standard risk 1 1 High risk 1.729 (0.883, 3.383) 0.110 1.280 (0.781, 2.096) 0.327 Unknown 0.900 (0.493, 1.642) 0.731 0.965 (0.648, 1.439) 0.863 VMP induction response PR 1 1 VGPR 0.771 (0.389, 1.527) 0.456 0.557 (0.360, 0.862) 0.009 CR/sCR 0.845 (0.415, 1.724) 0.644 0.363 (0.224, 0.588) < 0.001 Abbreviations) CI confidence interval, Ig immunoglobulin, SD standard deviation, eGFR estimated glomerular filtration rate, PR partial response, VGPR very good partial response, CR/sCR complete response/stringent complete response

Robustness checks

The PFS benefit remained consistent across different follow-up periods and alternative eligibility criteria (Supplementary Table 3 ). E-value analysis for unmeasured confounding yielded a value of 2.93 for the observed HR of 0.437, indicating that an unmeasured confounder would require risk ratio associations of at least 2.93 with both treatment assignment and PFS to nullify our findings. Even at the upper confidence limit (HR 0.653), the E-value remained substantial at 2.02, suggesting that only relatively strong unmeasured confounders—not modest confounding—could explain away the observed treatment effect. These sensitivity analyses provide robust evidence supporting the protective effect of bortezomib maintenance on PFS in transplant-ineligible NDMM patients.

Discussion

This multicenter study employing target trial emulation framework demonstrates that bortezomib maintenance following VMP induction significantly prolongs PFS in transplant-ineligible NDMM patients. The magnitude of PFS benefit (HR 0.437) and its consistency across clinically relevant subgroups—including elderly patients, those with ISS stage II-III disease, and those with high-risk cytogenetic abnormalities—establish the clinical value of PI-based maintenance. While lenalidomide-based or monoclonal antibody-containing regimens have emerged as preferred options for transplant-ineligible patients [ 22 – 26 ], substantial variability in drug availability, reimbursement policies, and patient comorbidities continues to shape treatment selection across diverse healthcare settings. In Korea, VMP continues to be frequently used, particularly for elderly patients and those with renal impairment or elevated thrombotic risk, for whom lenalidomide-based triplets may be contraindicated or less feasible. Our study provides outcome benchmarks relevant to such populations, offering practical evidence for bortezomib maintenance as an accessible post-induction strategy in resource-constrained settings.

Our findings align with landmark trials investigating bortezomib-containing maintenance regimens. The GEM2005MAS65 [ 5 ] and GIMEMA-MM-03-05 [ 27 ] studies demonstrated significant survival benefits with ongoing proteasome inhibition (median PFS: 35.3 vs. 24.8 months, HR 0.58; 5-year OS: 61% vs. 51%, HR 0.70). The 18-month PFS improvement observed in our predominantly elderly cohort (65.8% ≥ 70 years) is particularly noteworthy given limited therapeutic options and poorer outcomes in this vulnerable population. Age-stratified analyses revealed differential benefits (Supplementary Tables 4 , 5 ): while patients ≥ 70 years derived clear benefit from maintenance, treatment effects appeared less pronounced in younger patients (< 70 years, N = 33), likely reflecting biological heterogeneity, small sample size, and limited statistical power. These findings emphasize tailoring maintenance strategies to patient characteristics and clinical context.

The unmatched multivariable analysis further validates the robustness of our findings, demonstrating consistent treatment effects (HR 0.400, 95% CI: 0.268–0.596) when evaluated within the broader eligible population. Notably, depth of response to VMP induction emerged as a strong independent prognostic factor, with CR/sCR patients showing superior PFS compared to PR (HR 0.363, 95% CI: 0.224–0.588). This reinforces that MT may be particularly valuable in sustaining and potentially deepening remissions achieved during induction, thereby delaying relapse and preserving organ function.

The observed median PFS of 8.8 months in our control cohort requires careful interpretation within our study design context. Our stringent eligibility criteria—completion of all 9 VMP cycles, achievement of at least PR, and 60-day progression-free status—selected a specific subpopulation distinct from intention-to-treat populations in randomized trials. This selection process excludes patients who progressed early, potentially enriching for a cohort at higher risk once active therapy ceased. Additionally, the 60-day landmark analysis, while essential for eliminating immortal time bias, creates a distinct analytical timeframe compared to trials measuring PFS from treatment initiation. Real-world registry data also capture greater clinical heterogeneity than controlled trials, with our cohort including 30% with renal impairment and 66% aged ≥ 70 years—populations often underrepresented in prospective trials. The decision to discontinue therapy after VMP may itself reflect unmeasured clinical factors such as treatment tolerance or physician assessment. However, our comprehensive sensitivity analyses support treatment effect robustness. The E-value of 2.93 indicates that an unmeasured confounder would need to be associated with both treatment assignment and PFS by nearly 3-fold to fully explain our observed HR of 0.437. Furthermore, consistent treatment effects across alternative landmark definitions (30, 60, and 90 days) and multivariable regression in the full cohort (HR 0.400, P < 0.001) validate our findings. Clinically, what matters most is the relative treatment effect—the 18-month PFS improvement—rather than absolute values, with this substantial benefit consistent across high-risk subgroups.

Beyond addressing methodological concerns, our study demonstrates the value of target trial emulation in hematologic malignancy research. This causal inference framework, increasingly recognized in cardiology and infectious diseases, remains underutilized in myeloma despite its potential to generate robust evidence when randomized trials are infeasible. The convergence of results across multiple analytical approaches—PSM, landmark analyses, multivariable regression, and E-value assessment—strengthens confidence beyond what any single analysis could provide, offering a replicable template for future comparative effectiveness studies.

The safety profile requires careful interpretation given that AEs were collected during different treatment phases. Distinct toxicity patterns emerged: the control cohort predominantly experienced infectious events during intensive VMP induction, whereas the case cohort showed primarily GI toxicity with lower rates of infections. Notably, no grade ≥ 3 PN was observed in either cohort. While bortezomib-associated PN remains a concern in MT, the absence of severe neuropathy may reflect strict eligibility criteria (baseline PN grade ≤ 1), weekly subcutaneous administration [ 14 , 28 ], and proactive dose modifications [ 29 – 31 ]. These findings support feasibility of bortezomib maintenance in elderly, transplant-ineligible patients with appropriate patient selection and monitoring.

The clinical relevance extends beyond settings where VMP remains first-line due to economic constraints. Patient-specific factors mandate VMP-based approaches even in resource-rich environments. Renal impairment, present in approximately 50% of newly diagnosed patients, contraindicates or requires significant lenalidomide dose reduction due to renal excretion and toxicity risk [ 32 , 33 ]. Elderly patients with comorbidities may be unsuitable for intensive triplet regimens. Our study addresses whether proteasome inhibitor continuation after VMP provides benefit over observation—a question remaining relevant independent of whether VMP represents optimal initial therapy. This applies to healthcare systems globally where VMP continues as standard practice due to economic disparities (lifetime costs differing by over $300,000 between VMP and contemporary regimens), regulatory timelines, or patient-specific contraindications [ 34 ]. The substantial treatment effect establishes comparative benchmarks for evaluating emerging maintenance strategies across diverse contexts.

This study has several limitations inherent to its retrospective design. First, despite rigorous PSM and comprehensive sensitivity analyses, our retrospective design cannot completely eliminate the possibility of unmeasured confounding. Second, the study population comprised patients who successfully completed 9 VMP cycles and remained progression-free for 60 days, potentially limiting generalizability to less selected or intention-to-treat populations. Third, the control group’s shorter median PFS, while reflecting real-world practice patterns and our specific eligibility criteria including the 60-day landmark analysis, may limit direct comparisons with published trial data that measure outcomes from treatment initiation. Fourth, data collection predated widespread adoption of contemporary lenalidomide- or daratumumab-based triplet regimens; however, this does not diminish the relevance of our findings for settings where VMP remains standard therapy due to economic, regulatory, or patient-specific factors. Fifth, AEs assessment based on retrospective chart review rather than standardized prospective scales may have underestimated toxicity severity, particularly for subjective symptoms such as PN or fatigue. Finally, we lacked systematic assessments of minimal residual disease and QoL outcomes, which are increasingly recognized as important endpoints for evaluating maintenance therapy benefits beyond survival metrics.

In conclusion, this multicenter study demonstrates that bortezomib maintenance following VMP induction significantly prolongs progression-free survival in transplant-ineligible NDMM patients, with benefits consistent across elderly and high-risk subgroups. The convergence of findings across propensity score matching, alternative landmark analyses, and E-value assessment strengthens confidence in these results despite the observational design. Weekly subcutaneous bortezomib administration demonstrated acceptable tolerability, supporting the feasibility of proteasome inhibitor-based maintenance in real-world practice. These findings provide actionable evidence for healthcare settings where VMP remains standard therapy due to economic constraints, regulatory factors, or patient-specific contraindications such as renal impairment. This study also demonstrates the value of target trial emulation in generating robust comparative effectiveness evidence from observational data. Future research should incorporate minimal residual disease monitoring, QoL assessments, and direct comparisons with contemporary maintenance approaches to optimize treatment strategies for this vulnerable population.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary Material 1

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Jung Yeon Lee and Suein Choi contributed equally to this work.

Acknowledgements

The authors thank Hyo Jin Seo and Min Ji Lee for their co-ordination in data collection.

Author contributions

J.Y.L. conceptualized and designed the study. J.Y.L., S.C., and S.J. curated the data. S.C. and S.J. performed the statistical analysis. J.Y.L., S.S.P., J.S.K., S.H.S., Y.W.J., S.A.Y., J.J.L., H.J.K., G.W.L., H.S.E., M.K.K., Y.K., J.K., and C.K.M. conducted the investigation and collected clinical data. J.Y.L. and S.C. wrote the original draft. J.Y.L., S.C., and C.K.M. reviewed and edited the manuscript. S.C. and S.S.P. acquired funding. C.K.M. supervised the study and administered the project. All authors read and approved the final manuscript.

Funding

This research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HE23C002800). This research was supported by a grant (RS-2023-00216446) from Ministry of Food and Drug Safety in 2023.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Competing interests

The authors declare no competing interests.

References

1. Palumbo A Anderson K Multiple myeloma N Engl J Med 2011 364 1046 1060 10.1056/NEJMra1011442 21410373 Palumbo A, Anderson K (2011) Multiple myeloma. N Engl J Med 364:1046–1060. 10.1056/NEJMra1011442 21410373 10.1056/NEJMra1011442

2. Howlader N Noone AM Krapcho M Neyman N Aminou R Altekruse SF SEER cancer statistics Review, 1975–2009 (Vintage 2009 Populations) 2012 Bethesda, MD National Cancer Institute Howlader N, Noone AM, Krapcho M, Neyman N, Aminou R, Altekruse SF et al (2012) SEER cancer statistics Review, 1975–2009 (Vintage 2009 Populations). National Cancer Institute, Bethesda, MD

3. Palumbo A Bringhen S Larocca A Rossi D Di Raimondo F Magarotto V Bortezomib-melphalan-prednisone-thalidomide followed by maintenance with bortezomib-thalidomide compared with bortezomib-melphalan-prednisone for initial treatment of multiple myeloma: updated follow-up and improved survival J Clin Oncol 2014 32 634 640 10.1200/JCO.2013.52.0586 24449241 Palumbo A, Bringhen S, Larocca A, Rossi D, Di Raimondo F, Magarotto V et al (2014) Bortezomib-melphalan-prednisone-thalidomide followed by maintenance with bortezomib-thalidomide compared with bortezomib-melphalan-prednisone for initial treatment of multiple myeloma: updated follow-up and improved survival. J Clin Oncol 32:634–640. 10.1200/JCO.2013.52.0586 24449241 10.1200/JCO.2013.52.0023

4. Zhuang Z Tian Y Shi L Zou D Feng R Tian WW Lenalidomide or bortezomib as maintenance treatment remedy the inferior impact of high-risk cytogenetic abnormalities in non-transplant patients with newly diagnosed multiple myeloma: a real-world multi-centered study in China Front Oncol 2023 13 1028571 10.3389/fonc.2023.1028571 37152063 PMC10157094 Zhuang Z, Tian Y, Shi L, Zou D, Feng R, Tian WW et al (2023) Lenalidomide or bortezomib as maintenance treatment remedy the inferior impact of high-risk cytogenetic abnormalities in non-transplant patients with newly diagnosed multiple myeloma: a real-world multi-centered study in China. Front Oncol 13:1028571. 10.3389/fonc.2023.1028571 37152063 10.3389/fonc.2023.1028571 PMC10157094

5. Mateos MV Oriol A Martinez-Lopez J Gutierrez N Teruel AI Lopez de la Guia A Maintenance therapy with bortezomib plus thalidomide or bortezomib plus prednisone in elderly multiple myeloma patients included in the GEM2005MAS65 trial Blood 2012 120 2581 2588 10.1182/blood-2012-05-427815 22889759 Mateos MV, Oriol A, Martinez-Lopez J, Gutierrez N, Teruel AI, Lopez de la Guia A et al (2012) Maintenance therapy with bortezomib plus thalidomide or bortezomib plus prednisone in elderly multiple myeloma patients included in the GEM2005MAS65 trial. Blood 120:2581–2588. 10.1182/blood-2012-05-427815 22889759 10.1182/blood-2012-05-427815

6. de la Rosiñol L de la Oriol A Teruel AI Guía AL Blanchard M Rubia J Bortezomib and thalidomide maintenance after stem cell transplantation for multiple myeloma: a PETHEMA/GEM trial Leukemia 2017 31 1922 1927 10.1038/leu.2017.35 28111466 Rosiñol L, Oriol A, Teruel AI, de la Guía AL, Blanchard M, de la Rubia J et al (2017) Bortezomib and thalidomide maintenance after stem cell transplantation for multiple myeloma: a PETHEMA/GEM trial. Leukemia 31:1922–1927. 10.1038/leu.2017.35 28111466 10.1038/leu.2017.35

7. Moreau P Hulin C Perrot A Arnulf B Belhadj K Benboubker L Maintenance with daratumumab or observation following treatment with bortezomib, thalidomide, and dexamethasone with or without daratumumab and autologous stem-cell transplant in patients with newly diagnosed multiple myeloma (CASSIOPEIA): an open-label, randomised, phase 3 trial Lancet Oncol 2021 22 1378 1390 10.1016/S1470-2045(21)00428-9 34529931 Moreau P, Hulin C, Perrot A, Arnulf B, Belhadj K, Benboubker L et al (2021) Maintenance with daratumumab or observation following treatment with bortezomib, thalidomide, and dexamethasone with or without daratumumab and autologous stem-cell transplant in patients with newly diagnosed multiple myeloma (CASSIOPEIA): an open-label, randomised, phase 3 trial. Lancet Oncol 22:1378–1390. 10.1016/S1470-2045(21)00428-9 34529931 10.1016/S1470-2045(21)00428-9

8. Mateos MV Richardson PG Schlag R Khuageva NK Dimopoulos MA Shpilberg O Bortezomib plus Melphalan and prednisone compared with Melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial J Clin Oncol 2010 28 2259 2266 10.1200/JCO.2009.26.0638 20368561 Mateos MV, Richardson PG, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O et al (2010) Bortezomib plus Melphalan and prednisone compared with Melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial. J Clin Oncol 28:2259–2266. 10.1200/JCO.2009.26.0638 20368561 10.1200/JCO.2009.26.0638

9. Proskorovsky I Lewis P Williams CD Jordan K Kyriakou C Ishak J Mapping EORTC QLQ-C30 and QLQ-MY20 to EQ-5D in patients with multiple myeloma Health Qual Life Outcomes 2014 12 35 10.1186/1477-7525-12-35 24618388 PMC4007827 Proskorovsky I, Lewis P, Williams CD, Jordan K, Kyriakou C, Ishak J et al (2014) Mapping EORTC QLQ-C30 and QLQ-MY20 to EQ-5D in patients with multiple myeloma. Health Qual Life Outcomes 12:35. 10.1186/1477-7525-12-35 24618388 10.1186/1477-7525-12-35 PMC4007827

10. Jordan K Proskorovsky I Lewis P Ishak J Payne K Lordan N Effect of general symptom level, specific adverse events, treatment patterns, and patient characteristics on health-related quality of life in patients with multiple myeloma: results of a European, multicenter cohort study Support Care Cancer 2014 22 417 426 10.1007/s00520-013-1991-4 24122403 PMC3882558 Jordan K, Proskorovsky I, Lewis P, Ishak J, Payne K, Lordan N et al (2014) Effect of general symptom level, specific adverse events, treatment patterns, and patient characteristics on health-related quality of life in patients with multiple myeloma: results of a European, multicenter cohort study. Support Care Cancer 22:417–426. 10.1007/s00520-013-1991-4 24122403 10.1007/s00520-013-1991-4 PMC3882558

11. Forde K Cocks K Wells JR McMillan I Kyriakou C EORTC Quality of Life Group Use of the European organisation for research and treatment of cancer multiple myeloma module (EORTC QLQ-MY20): a review of the literature 25 years after development Blood Cancer J 2023 13 79 10.1038/s41408-023-00849-8 37193682 PMC10188493 Forde K, Cocks K, Wells JR, McMillan I, Kyriakou C, EORTC Quality of Life Group (2023) Use of the European organisation for research and treatment of cancer multiple myeloma module (EORTC QLQ-MY20): a review of the literature 25 years after development. Blood Cancer J 13:79. 10.1038/s41408-023-00849-8 37193682 10.1038/s41408-023-00815-9 PMC10188493

12. Cocks K Cohen D Wisloff F Sezer O Lee S Hippe E An international field study of the reliability and validity of a disease-specific questionnaire module (the QLQ-MY20) in assessing the quality of life of patients with multiple myeloma Eur J Cancer 2007 43 1670 1678 10.1016/j.ejca.2007.04.022 17574838 Cocks K, Cohen D, Wisloff F, Sezer O, Lee S, Hippe E et al (2007) An international field study of the reliability and validity of a disease-specific questionnaire module (the QLQ-MY20) in assessing the quality of life of patients with multiple myeloma. Eur J Cancer 43:1670–1678. 10.1016/j.ejca.2007.04.022 17574838 10.1016/j.ejca.2007.04.022

13. LeeJY, Jung S Choi S Park SS Kim JS Lee JJ Efficacy, safety, and health-related quality of life in transplant-ineligible newly diagnosed multiple myeloma patients receiving bortezomib maintenance therapy: a study of the Korean Multiple Myeloma Working Party KMMWP-174 study Haematologica 2026 111 379 384 10.3324/haematol.2025.287889 40820811 PMC12775751 Lee JY, Jung S, Choi S, Park SS, Kim JS, Lee JJ et al (2026) Efficacy, safety, and health-related quality of life in transplant-ineligible newly diagnosed multiple myeloma patients receiving bortezomib maintenance therapy: a study of the Korean Multiple Myeloma Working Party KMMWP-174 study. Haematologica 111:379–384. 10.3324/haematol.2025.287889 40820811 10.3324/haematol.2025.287889 PMC12775751

14. Sonneveld P Schmidt-Wolf IG van der Holt B El Jarari L Bertsch U Salwender H Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/GMMG-HD4 trial J Clin Oncol 2012 30 2946 2955 10.1200/JCO.2011.39.6820 22802322 Sonneveld P, Schmidt-Wolf IG, van der Holt B, El Jarari L, Bertsch U, Salwender H et al (2012) Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/GMMG-HD4 trial. J Clin Oncol 30:2946–2955. 10.1200/JCO.2011.39.6820 22802322 10.1200/JCO.2011.39.6820

15. Mateos MV Cavo M Blade J Dimopoulos MA Suzuki K Jakubowiak A Overall survival with daratumumab, bortezomib, melphalan, and prednisone in newly diagnosed multiple myeloma (ALCYONE): a randomised, open-label, phase 3 trial Lancet 2020 395 132 141 10.1016/S0140-6736(19)32956-3 31836199 Mateos MV, Cavo M, Blade J, Dimopoulos MA, Suzuki K, Jakubowiak A et al (2020) Overall survival with daratumumab, bortezomib, melphalan, and prednisone in newly diagnosed multiple myeloma (ALCYONE): a randomised, open-label, phase 3 trial. Lancet 395:132–141. 10.1016/S0140-6736(19)32956-3 31836199 10.1016/S0140-6736(19)32956-3

16. Berdeja JG Bauer T Arrowsmith E Essell J Murphy P Reeves JA Jr Phase II study of bendamustine, bortezomib and dexamethasone (BBD) in the first-line treatment of patients with multiple myeloma who are not candidates for high dose chemotherapy Br J Haematol 2017 177 254 262 10.1111/bjh.14532 28169430 Berdeja JG, Bauer T, Arrowsmith E, Essell J, Murphy P, Reeves JA Jr et al (2017) Phase II study of bendamustine, bortezomib and dexamethasone (BBD) in the first-line treatment of patients with multiple myeloma who are not candidates for high dose chemotherapy. Br J Haematol 177:254–262. 10.1111/bjh.14532 28169430 10.1111/bjh.14536

17. Greipp PR San Miguel J Durie BG Crowley JJ Barlogie B Blade J International staging system for multiple myeloma J Clin Oncol 2005 23 3412 3420 10.1200/JCO.2005.04.242 15809451 Greipp PR, San Miguel J, Durie BG, Crowley JJ, Barlogie B, Blade J et al (2005) International staging system for multiple myeloma. J Clin Oncol 23:3412–3420. 10.1200/JCO.2005.04.242 15809451 10.1200/JCO.2005.04.242

18. Palumbo A Avet-Loiseau H Oliva S Lokhorst HM Goldschmidt H Rosinol L Revised international staging system for multiple myeloma: A report from international myeloma working group J Clin Oncol 2015 33 2863 2869 10.1200/JCO.2015.61.2267 26240224 PMC4846284 Palumbo A, Avet-Loiseau H, Oliva S, Lokhorst HM, Goldschmidt H, Rosinol L et al (2015) Revised international staging system for multiple myeloma: A report from international myeloma working group. J Clin Oncol 33:2863–2869. 10.1200/JCO.2015.61.2267 26240224 10.1200/JCO.2015.61.2267 PMC4846284

19. Levey AS Bosch JP Lewis JB Greene T Rogers N Roth D A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of diet in renal disease study group Ann Intern Med 1999 130 461 470 10.7326/0003-4819-130-6-199903160-00002 10075613 Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D (1999) A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of diet in renal disease study group. Ann Intern Med 130:461–470. 10.7326/0003-4819-130-6-199903160-00002 10075613 10.7326/0003-4819-130-6-199903160-00002

20. Kumar S Paiva B Anderson KC Durie B Landgren O Moreau P International myeloma working group consensus criteria for response and minimal residual disease assessment in multiple myeloma Lancet Oncol 2016 17 e328 e346 10.1016/S1470-2045(16)30206-6 27511158 Kumar S, Paiva B, Anderson KC, Durie B, Landgren O, Moreau P et al (2016) International myeloma working group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol 17:e328–e346. 10.1016/S1470-2045(16)30206-6 27511158 10.1016/S1470-2045(16)30206-6

21. National Cancer Institute Common terminology criteria for adverse events v4.03 2009 Bethesda, MD National Cancer Institute National Cancer Institute (2009) Common terminology criteria for adverse events v4.03. National Cancer Institute, Bethesda, MD

22. Shank BR Brown VT Schwartz RN Multiple myeloma maintenance therapy: a review of the Pharmacologic treatment J Oncol Pharm Pract 2015 21 36 51 10.1177/1078155213510359 24395544 Shank BR, Brown VT, Schwartz RN (2015) Multiple myeloma maintenance therapy: a review of the Pharmacologic treatment. J Oncol Pharm Pract 21:36–51. 10.1177/1078155213510359 24395544 10.1177/1078155213514468

23. Sivaraj D Green MM Li Z Sung AD Sarantopoulos S Kang Y Outcomes of maintenance therapy with bortezomib after autologous stem cell transplantation for patients with multiple myeloma Biol Blood Marrow Transpl 2017 23 262 268 10.1016/j.bbmt.2016.11.013 PMC11099879 27856369 Sivaraj D, Green MM, Li Z, Sung AD, Sarantopoulos S, Kang Y et al (2017) Outcomes of maintenance therapy with bortezomib after autologous stem cell transplantation for patients with multiple myeloma. Biol Blood Marrow Transpl 23:262–268. 10.1016/j.bbmt.2016.11.013 10.1016/j.bbmt.2016.11.010 PMC11099879 27856369

24. Baertsch MA Mai EK Hielscher T Bertsch U Salwender HJ Munder M Lenalidomide versus bortezomib maintenance after frontline autologous stem cell transplantation for multiple myeloma Blood Cancer J 2021 11 1 10.1038/s41408-020-00397-y 33414374 PMC7791127 Baertsch MA, Mai EK, Hielscher T, Bertsch U, Salwender HJ, Munder M et al (2021) Lenalidomide versus bortezomib maintenance after frontline autologous stem cell transplantation for multiple myeloma. Blood Cancer J 11:1. 10.1038/s41408-020-00397-y 33414374 10.1038/s41408-020-00390-3 PMC7791127

25. Jackson GH Davies FE Pawlyn C Cairns DA Striha A Collett C Lenalidomide maintenance versus observation for patients with newly diagnosed multiple myeloma (Myeloma XI): a multicentre, open-label, randomised, phase 3 trial Lancet Oncol 2019 20 57 73 10.1016/S1470-2045(18)30687-9 30559051 PMC6318225 Jackson GH, Davies FE, Pawlyn C, Cairns DA, Striha A, Collett C et al (2019) Lenalidomide maintenance versus observation for patients with newly diagnosed multiple myeloma (Myeloma XI): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol 20:57–73. 10.1016/S1470-2045(18)30687-9 30559051 10.1016/S1470-2045(18)30687-9 PMC6318225

26. Facon T Dimopoulos MA Dispenzieri A Catalano JV Belch A Cavo M Final analysis of survival outcomes in the phase 3 FIRST trial of up-front treatment for multiple myeloma Blood 2018 131 301 310 10.1182/blood-2017-07-795047 29150421 PMC5774211 Facon T, Dimopoulos MA, Dispenzieri A, Catalano JV, Belch A, Cavo M et al (2018) Final analysis of survival outcomes in the phase 3 FIRST trial of up-front treatment for multiple myeloma. Blood 131:301–310. 10.1182/blood-2017-07-795047 29150421 10.1182/blood-2017-07-795047 PMC5774211

27. Palumbo A Bringhen S Rossi D Cavalli M Larocca A Ria R Bortezomib-melphalan-prednisone-thalidomide followed by maintenance with bortezomib-thalidomide compared with bortezomib-melphalan-prednisone for initial treatment of multiple myeloma: a randomized controlled trial J Clin Oncol 2010 28 5101 5109 10.1200/JCO.2010.29.8216 20940200 Palumbo A, Bringhen S, Rossi D, Cavalli M, Larocca A, Ria R et al (2010) Bortezomib-melphalan-prednisone-thalidomide followed by maintenance with bortezomib-thalidomide compared with bortezomib-melphalan-prednisone for initial treatment of multiple myeloma: a randomized controlled trial. J Clin Oncol 28:5101–5109. 10.1200/JCO.2010.29.8216 20940200 10.1200/JCO.2010.29.8216

28. Bringhen S Larocca A Rossi D Cavalli M Genuardi M Ria R Efficacy and safety of once-weekly bortezomib in multiple myeloma patients Blood 2010 116 4745 4753 10.1182/blood-2010-07-294983 20807892 Bringhen S, Larocca A, Rossi D, Cavalli M, Genuardi M, Ria R et al (2010) Efficacy and safety of once-weekly bortezomib in multiple myeloma patients. Blood 116:4745–4753. 10.1182/blood-2010-07-294983 20807892 10.1182/blood-2010-07-294983

29. Sun CY Li JY Chu ZB Zhang L Chen L Hu Y Efficacy and safety of bortezomib maintenance in patients with newly diagnosed multiple myeloma: a meta-analysis Biosci Rep 2017 37 BSR20170304 10.1042/BSR20170304 28706008 PMC5529203 Sun CY, Li JY, Chu ZB, Zhang L, Chen L, Hu Y (2017) Efficacy and safety of bortezomib maintenance in patients with newly diagnosed multiple myeloma: a meta-analysis. Biosci Rep 37:BSR20170304. 10.1042/BSR20170304 28706008 10.1042/BSR20170304 PMC5529203

30. Noguchi Y Iriyama N Takahashi H Uchino Y Nakagawa M Hamada T Maintenance therapy with bortezomib and dexamethasone for Transplant-ineligible patients with multiple myeloma Cancer Diagn Progn 2021 1 35 42 10.21873/cdp.10006 35403126 PMC8962762 Noguchi Y, Iriyama N, Takahashi H, Uchino Y, Nakagawa M, Hamada T et al (2021) Maintenance therapy with bortezomib and dexamethasone for Transplant-ineligible patients with multiple myeloma. Cancer Diagn Progn 1:35–42. 10.21873/cdp.10006 35403126 10.21873/cdp.10006 PMC8962762

31. Gay F Jackson G Rosiñol L Holstein SA Moreau P Spada S Maintenance treatment and survival in patients with myeloma: A systematic review and network Meta-analysis JAMA Oncol 2018 4 1389 1397 10.1001/jamaoncol.2018.2961 30098165 PMC6233774 Gay F, Jackson G, Rosiñol L, Holstein SA, Moreau P, Spada S et al (2018) Maintenance treatment and survival in patients with myeloma: A systematic review and network Meta-analysis. JAMA Oncol 4:1389–1397. 10.1001/jamaoncol.2018.2961 30098165 10.1001/jamaoncol.2018.2961 PMC6233774

32. Dimopoulos MA Mikhael J Terpos E Leleu X Moreau P Bladé J Management of multiple myeloma-related renal impairment: recommendations from the international myeloma working group Lancet Oncol 2023 24 e293 311 10.1016/S1470-2045(23)00223-1 37414019 Dimopoulos MA, Mikhael J, Terpos E, Leleu X, Moreau P, Bladé J et al (2023) Management of multiple myeloma-related renal impairment: recommendations from the international myeloma working group. Lancet Oncol 24:e293–311. 10.1016/S1470-2045(23)00223-1 37414019 10.1016/S1470-2045(23)00223-1

33. Dimopoulos MA Sonneveld P Leung N Merlini G Ludwig H Kastritis E Impact of renal impairment on outcomes with Lenalidomide and dexamethasone treatment in the FIRST trial, a randomized, open-label phase 3 study in transplant-ineligible patients with multiple myeloma Haematologica 2016 101 363 369 10.3324/haematol.2015.133629 26659916 PMC4815728 Dimopoulos MA, Sonneveld P, Leung N, Merlini G, Ludwig H, Kastritis E et al (2016) Impact of renal impairment on outcomes with Lenalidomide and dexamethasone treatment in the FIRST trial, a randomized, open-label phase 3 study in transplant-ineligible patients with multiple myeloma. Haematologica 101:363–369. 10.3324/haematol.2015.133629 26659916 10.3324/haematol.2015.133629 PMC4815728

34. Patel KK Giri S Parker TL Bar N Neparidze N Huntington SF Cost-Effectiveness of First-Line versus Second-Line use of daratumumab in Older, Transplant-Ineligible patients with multiple myeloma J Clin Oncol 2021 39 1119 1128 10.1200/JCO.20.01849 33411586 Patel KK, Giri S, Parker TL, Bar N, Neparidze N, Huntington SF (2021) Cost-Effectiveness of First-Line versus Second-Line use of daratumumab in Older, Transplant-Ineligible patients with multiple myeloma. J Clin Oncol 39:1119–1128. 10.1200/JCO.20.01849 33411586 10.1200/JCO.20.01849