Treatment Discontinuation After Achieving MRD Negativity in Multiple Myeloma in the Pre-BCMA Era: A Prospective, Single-Centre Study.

Introduction

Multiple myeloma (MM) is a haematologic malignancy that is generally considered incurable. Nonetheless, the introduction of high‐dose melphalan with autologous stem cell transplantation (HDM/ASCT) and three major classes of antimyeloma agents—proteasome inhibitors (PIs), immunomodulatory imide drugs (IMiDs), and anti‐CD38 antibodies—has significantly improved response rates and survival. In addition, novel immunotherapies targeting antigens such as the B‐cell maturation antigen (BCMA) have been introduced earlier in the treatment course for relapsed/refractory (RR) MM. These advances have markedly improved patient outcomes [ 1 , 2 , 3 ].

Conversely, the development of technologies to detect minimal/measurable residual disease (MRD) in the bone marrow (BM), such as next‐generation flow (NGF) cytometry and next‐generation sequencing (NGS), has enabled more sensitive treatment response assessments compared to conventional evaluations based on monoclonal protein detection or standard flow cytometry [ 4 ]. Notably, MRD negativity has been associated with significantly improved survival outcomes regardless of the treatment regimen, disease setting (newly diagnosed [ND] MM or RRMM), MRD sensitivity thresholds, cytogenetic risk, MRD assessment method, clinical response depth at MRD measurement, and MRD assessment timing [ 5 ]. Importantly, MRD negativity is widely accepted as a valid endpoint in clinical trials [ 6 ].

Currently, MM treatment is generally continued until disease progression, even after MRD negativity [ 1 ]. Although several prospective studies have evaluated treatment discontinuation after sustained MRD negativity, highlighting encouraging results [ 7 , 8 ], the current evidence remains insufficient to support changes to standard treatment strategies.

This prospective study aimed to evaluate the feasibility of discontinuing antimyeloma therapy in patients who achieved sustained MRD negativity in the pre‐BCMA‐targeting era and to determine whether this approach leads to durable, treatment‐free remission.

Methods

Patient Eligibility Criteria

The eligibility criteria for this study were as follows: patients aged 20 years or older with an MM diagnosis who had received continuous treatment, achieved MRD negativity at a sensitivity level of 10 −5 , and expressed a desire to discontinue treatment. The treatment regimen or line of therapy leading to MRD negativity was not predefined, and patients with a history of clinical trial participation were eligible for inclusion.

Study Design

Patients who met the eligibility criteria discontinued antimyeloma therapy and attended outpatient follow‐up visits every 1–3 months. At each visit, blood and urine tests, including quantification of M protein, measurement of serum‐free light chains, and serum and urine immunofixation electrophoresis, were performed to monitor disease progression. BM‐MRD status was assessed every 12 months using the Marrow Plasma 10c assay from BML Inc., which has a sensitivity comparable to that of the EuroFlow method [ 9 ]. Imaging (I)‐MRD status was evaluated using fluorine‐18 fluorodeoxyglucose (18F‐FDG) positron emission tomography (PET)/computed tomography (CT) scans every 12–24 months. When PET/CT imaging could not be performed, magnetic resonance imaging (MRI) or conventional CT was used as a substitute. Salvage therapy was initiated at confirmation of disease progression. In the event of BM‐MRD conversion without meeting the International Myeloma Working Group (IMWG) criteria for progressive disease (PD), treatment reinitiation was determined through discussion between the investigator and the patient.

This study was approved by the Ethics Committee of the Japanese Red Cross Medical Centre. Written informed consent was obtained from all patients in accordance with the Declaration of Helsinki.

Definitions of High‐Risk Cytogenetics, Treatment Response and MRD Negativity

High‐risk cytogenetic abnormalities (HRCAs) were defined according to the revised International Staging System (R‐ISS) and included t(4;14), t(14;16) and del(17p) [ 10 ]. Treatment response was assessed according to the IMWG criteria [ 11 ]. BM‐MRD negativity was defined as < 10 − 5 in accordance with the IMWG criteria.

Study Endpoints

The primary endpoints were treatment‐free survival (TFS) and the MRD negativity rate 2 years after treatment discontinuation. The secondary endpoints included time to next treatment, overall survival (OS), and relapse‐free survival (RFS) among patients who resumed treatment, and the correlation between TFS and potential prognostic factors, as described below.

Statistical Analysis

TFS, RFS, and OS were analysed using the Kaplan–Meier method, and comparisons between groups were performed using a two‐tailed log‐rank test. Univariate and multivariate Cox proportional hazards models were used to assess potential covariates, including disease risk, treatment history, time to complete response (CR), the interval from confirmation of MRD negativity to treatment discontinuation, and the normal plasma cell ratio in the BM at treatment discontinuation. Quantitative factors were categorised into two groups based on the cut‐off value determined using receiver operating characteristic (ROC) curve analysis. Associations between categorical variables were evaluated using the χ 2 or Fisher's exact test. The Kruskal–Wallis test was used for comparisons involving three or more groups. p values of less than 0.05 were considered statistically significant, and 95% confidence intervals (CIs) were calculated for all analyses. All statistical analyses were performed using EZR software [ 12 ].

Results

Patient Characteristics

Between April 2020 and March 2025, eligibility was assessed in 51 patients when BM‐MRD negativity was confirmed during antimyeloma therapy; among these, 41 met the eligibility criteria. A subset of these patients was diagnosed at other referral institutions; however, all patients had a documented treatment history at our institution.

The baseline patient characteristics are presented in Table 1 . The median age at treatment discontinuation was 62 years (range, 39–80 years), and 56.1% of the patients were male. The ISS stage distribution was 46.3%, 41.5%, and 9.8% for Stages I, II and III, respectively; one patient was unevaluable. Regarding M‐protein type, IgG was the predominant type (58.5%), and κ light chain accounted for 68.3% of cases. HRCAs were detected in five patients (12.2%), with one patient exhibiting both t(4;14) and del(17p). At treatment discontinuation, 33 (80.5%) and four (9.8%) patients were on first‐line therapy and second‐ or third‐line therapy, respectively. The median time from treatment initiation to CR achievement and the median duration from CR to treatment discontinuation were 10 (range, 2–79) and 32 (range, 3–82) months, respectively.

The interval from MRD negativity confirmation to treatment discontinuation was < 12 (range, 2–11), 12–24 (range, 12–20), and >24 (range, 25–53) months in 12 (29.3%), 11 (26.8%), and 18 (43.9%) patients, respectively. Among the three groups, the ≤ 12‐month group included a higher proportion of patients with HRCAs. In contrast, all patients in the > 24‐month group were treated in the first‐line setting and had the longest exposure to PIs and IMiDs (Table S1 ).

The median proportion of normal plasma cells in the BM at the time of treatment discontinuation was 0.025647% (range, 0.000029–0.768090%). The median actual limit of detection (LOD) of the MRD was 0.000006% (range, 0.000006–0.000015%).

Treatment Characteristics

As this study did not impose restrictions on induction therapy regimens, the patients exhibited various treatment histories. A summary of treatment histories categorised by 65 years, the approximate age cut‐off for ASCT eligibility, is presented in Table S2 and Figure S1 .

The most common induction therapy was bortezomib (BTZ), with over 80% consisting of VRd (BTZ, lenalidomide [LEN] and dexamethasone [DEXA]); VCD (BTZ, cyclophosphamide and DEXA) and Vd regimens were also included. Daratumumab (DARA)‐containing regimens were administered to four (12.9%) and two (20%) patients aged < 65 years and 65 years or older, respectively; a four‐drug combination was administered to one patient in the ≥ 65‐year group. In some patients, a second induction regimen was administered to enhance the treatment response (Figure 1 ).

HDM/ASCT was performed in 25 (80.6%) and three patients (30.0%) aged < 65 years and ≥ 65 years during the course of treatment, respectively, leading to MRD negativity and treatment discontinuation.

Consolidation therapy was the first combination therapy with two or more agents or allogeneic transplantation, administered following the first‐line regimen, with or without ASCT. Consolidation therapy was administered to 80.6% and 20% of patients aged < 65 and ≥ 65 years, respectively.

Maintenance therapy consisted of either monotherapy or a second combination therapy (i.e., combination therapy incorporating second or subsequent agents) with two or three agents following ASCT or consolidation therapy. In maintenance therapy, conventional single‐agent regimens, including LEN or ixazomib (IXZ), were uncommon (< 65 years: 22.6% or 12.9%; ≥ 65 years: 10% each), with most patients receiving combination therapy. In some patients, a second or subsequent maintenance regimen was administered to maintain or further enhance the achieved response (Figure 1 ).

Primary Endpoint

The observation period of this study spanned from treatment discontinuation to death from any cause or last follow‐up, with a median of 34.7 months (range, 6.1–70.0).

Regarding the primary endpoint, the 2‐year TFS rate was 71.2% (95% CI, 54.0–83.0), with the median not reached (Figure 2 ); the 3‐year TFS rate was 67.9% (95% CI, 50.1–80.4). The MRD negativity rate 2 years after treatment discontinuation was analysed in 34 of 41 patients because only these patients had > 2 years of follow‐up (Table 2 ); 19 (55.9%) showed sustained MRD negativity. In two patients, MRD negativity was demonstrated by only one modality (BM or imaging), whereas in two patients, only BM‐MRD was positive. Maintenance therapy was resumed in one patient after discussion between the patient and the treating physician. In another patient, follow‐up PET/CT detected FDG uptake in the para‐aortic lymph nodes; despite no other findings indicative of myeloma progression, treatment was restarted per patient preference. Nine patients (22.0%) experienced clinical or paraprotein relapse within 2 years.

OS and Treatment Interventions

The 3‐year OS rate was 97.3% (95% CI, 82.3–99.6), and the median OS was not reached. During the observation period, 12 patients required retreatment (Figure 1 and Table S3 ). The median time to events prompting retreatment was 11.6 months (range, 3.0–28.7), whereas the median time to treatment initiation was 16.7 months (range, 5.4–37.6). Among these 12 patients, paraprotein relapse, localised bone lesions and testicular plasmacytoma occurred in six, three and one patient, respectively; the testicular plasmacytoma appeared and enlarged 3 months after treatment discontinuation. Two patients restarted treatment without meeting the IMWG criteria for PD (BM‐MRD positivity alone or suspicious FDG uptake on PET/CT). Except for one patient, retreatment comprised combination therapy with three or more agents, most commonly isatuximab, carfilzomib and DEXA (IsaKd), followed by IXZ, LEN and DEXA (IRd). No patient received chimeric antigen receptor‐T cell (CAR‐T) therapy or bispecific antibodies in this treatment line.

The post‐treatment RFS was 40.0% at a median observation period of 15.9 months, with a median RFS of 13.1 months (Figure 3 ). Of the 12 patients, one experienced disease progression 8.4 months after retreatment, elected to transition to best supportive care at 9.5 months, and died of MM at 11.8 months. In this patient, FISH revealed t(4;14) at diagnosis and 1q amplification (seven copies) at relapse.

Factors Associated With TFS

Among the factors identified by univariate analyses as potential predictors, HRCAs, HDM/ASCT status, and the normal plasma cell proportion in the BM at treatment discontinuation were simultaneously entered into the Cox regression model (Table 3 ). Owing to the limited number of events, multivariate Cox analysis was restricted to these three clinically relevant covariates, and the results should be interpreted as exploratory. Of these three factors, HRCAs were associated with a poorer prognosis (hazard ratio [HR] 8.520, 95% CI 1.989–36.50, p = 0.0039), whereas a normal plasma cell proportion in the BM of ≥ 0.003% at treatment discontinuation was associated with a favourable prognosis (HR 0.130, 95% CI 0.030–0.565, p = 0.0066). These findings were also statistically significant in the Kaplan–Meier analysis (Figure 4a,b ). The interval from the confirmation of MRD negativity to treatment discontinuation was not associated with TFS (Figure 4c ).

Discussion

Here, we evaluated the feasibility of antimyeloma therapy discontinuation in patients who achieved MRD negativity, irrespective of disease status (ND or relapsed), treatment history, ASCT status, sustained CR duration or MRD negativity duration. BM‐MRD was assessed by multiparameter flow cytometry, which is widely used in routine clinical practice, with a cut‐off value of 10 −5 . The estimated 2‐ and 3‐year TFS rates were 71.2% and 67.9%, respectively, and the median TFS was not reached. The MRD negativity rate at 2 years after treatment discontinuation was 55.9% in the analysed cohort. At a median follow‐up of 34.7 months, retreatment was initiated in 29.3% of patients. Median time from treatment discontinuation to retreatment was 16.7 months, and RFS after retreatment was 40% at a median follow‐up of 15.9 months. HRCAs correlated with shorter TFS, whereas a BM normal plasma cell proportion of ≥ 0.003% at treatment discontinuation was associated with prolonged TFS.

Recently, several prospective trials have reported treatment discontinuation after sustained MRD negativity. In the IFM2009 trial, among patients who were MRD‐negative at the 10 −6 level by NGS, the 36‐month progression‐free survival (PFS) after maintenance completion was approximately 75% [ 13 ]. In the GEM2014MAIN trial, the 4‐year PFS of patients who sustained MRD negativity at a sensitivity of 2 × 10 −6 after 24 cycles of maintenance therapy was 82.8%, including those with high‐risk features [ 14 ]. In the MRD2STOP study, MRD was evaluated at the 10 −7 level using combined CD138‐positive cell sorting and NGS, and 80.9% of patients had MRD < 10 −7 at treatment discontinuation. The estimated 3‐year PFS was 92% for patients with MRD < 10 −7 and 49% for those with MRD ≥ 10 −7 [ 7 ]. In addition, Terpos et al. conducted a prospective trial evaluating the discontinuation of LEN maintenance therapy after BTZ‐based triplet or quadruplet (including DARA) induction therapy followed by ASCT. Treatment was subsequently discontinued upon confirmation of sustained BM‐MRD negativity at the 2 × 10 −6 level using NGF and I‐MRD negativity using PET. The 2‐ and 3‐year TFS rates were 91.6% and 75.8%, respectively. No statistically significant associations were observed between disease risk, treatment history and TFS [ 8 ]. Here, using a cut‐off of 10 −5 for MRD negativity, the TFS rates at 2 and 3 years were 71.2% and 67.9%, respectively. Considering both our results and those of previous studies, maintaining deep MRD negativity for a prolonged period appears to be essential for enabling safe therapy discontinuation. Our analysis demonstrated no significant TFS differences based on the duration between MRD confirmation and treatment discontinuation, likely due to patient heterogeneity resulting from the protocol, which enrolled individuals upon MRD negativity confirmation. Therefore, because MRD assessment timing varies, the period may not accurately reflect the time from treatment initiation to MRD negativity.

Notably, both our study and previous reports observed no significant treatment history differences, including ASCT, underscoring that achieving and sustaining MRD negativity may be feasible with individualised treatment strategies tailored to each patient's tolerability.

In our analysis, HRCAs were significantly associated with shorter TFS, in contrast to previous findings suggesting that MM risk does not affect TFS. This discrepancy may reflect the MRD negativity threshold, as we used 10 −5 compared with < 10 −6 in earlier studies. Thus, a 10 −5 threshold may be insufficient to mitigate high‐risk cytogenetics impact, and deeper response levels (e.g., < 10 −6 ) may be required in these patients. Indeed, the MASTER trial, which also used a cutoff of 10 −5 for MRD negativity, reported inferior PFS in patients with HRCA, particularly those with two or more abnormalities [ 15 ]. Furthermore, whereas prior studies focused on NDMM, our analysis included patients who achieved MRD negativity after second‐line or later therapy, which may have influenced the results. A retrospective analysis of 39 patients with MM, including RRMM, who discontinued treatment using a 10 −5 MRD cut‐off reported shorter TFS in the high‐risk group, which included patients with HRCAs [ 16 ].

To identify additional factors guiding treatment discontinuation in MRD‐negative patients, we evaluated immune‐related marker associations with TFS. The association between normal plasma cell proportion and MM prognosis has long been reported. Paiva et al. showed that, in a cohort receiving standardised therapy including ASCT, patients with > 5% normal plasma cells among BM plasma cells at diagnosis had significantly improved PFS and OS compared to those with ≤ 5% [ 17 ]. San Miguel et al. reported that, after treatment, patients with > 30% normal BM plasma cells had favourable PFS [ 18 ]. Although these studies used conventional flow cytometry, NGF allows more sensitive identification of both normal plasma cells and malignant myeloma cells [ 19 ]. The Marrow Plasma 10c assay used in our study also quantifies BM normal plasma cells [ 9 ]. Therefore, we assessed whether the normal plasma cell proportion at treatment discontinuation was associated with TFS. A normal plasma cell ratio of ≥ 0.003% correlated significantly with improved TFS in univariate and multivariate analyses. As noted above, deeper MRD negativity appears essential for favourable TFS; however, treatment strategies that also consider the preservation and recovery of normal immune function may represent an additional key factor.

Since the introduction of three major drug classes, cost‐effectiveness‐oriented treatment strategies have become increasingly important for MM management [ 20 , 21 , 22 ]. With improved MM prognosis, prolonged continuous therapy has created a substantial economic burden for patients and the healthcare system. In rapidly ageing and declining populations, appropriate healthcare resource allocation is urgent, particularly in countries with universal health insurance, such as Japan. Beyond implementing therapies that achieve deep MRD negativity early, identifying patient populations for whom treatment discontinuation may be feasible after MRD negativity is essential.

This study had some limitations. This was a single‐centre, single‐arm trial, and the sample size and follow‐up period were insufficient to draw definitive conclusions. Selection bias was also present, as patients without HRCAs tended to be more inclined to discontinue treatment. Furthermore, HRCAs were not comprehensively assessed in all cases, and some variables required to fully evaluate the current definition of high‐risk MM were not available in this study. In addition, only one patient in this cohort received a four‐drug combination regimen as first‐line therapy, which is currently regarded as the standard of care. Although no relationship was observed between TFS and the interval from treatment initiation to MRD negativity confirmation, MRD assessment timing varied among patients. Consequently, the sustained MRD‐negativity duration required to justify treatment discontinuation remains unclear. To guide decisions on treatment discontinuation, clarifying whether the duration of sustained MRD negativity or the balance between MRD and normal plasma cells is the critical factor is essential. Further investigations with larger cohorts and standardised assessment schedules are required.

In conclusion, treatment discontinuation may be feasible for some patients with MM who achieve and sustain MRD negativity, particularly those without HRCAs or with normal plasma cells in the BM. This approach may also help minimise treatment‐related toxicities and reduce the healthcare and economic burdens associated with therapy. Future studies with longer follow‐up and larger patient cohorts are warranted to establish clear criteria for identifying patients eligible for treatment discontinuation.

Author Contributions

All authors contributed to the study conception and design. Sample collection was performed by K. Sato, M.O., T.K., T.I. and N.T. K. Sato wrote the first draft of the manuscript, and all authors commented on earlier versions. All the authors have read and approved the final manuscript.

Funding

The authors have nothing to report.

Ethics Statement

This study was approved by the Ethics Committee of the Japanese Red Cross Medical Centre (Approval No. 1095; approved on March 18, 2020).

Consent

Written informed consent was obtained from all the patients in accordance with the Declaration of Helsinki.

Conflicts of Interest

The authors declare no conflicts of interest.

Supporting information

Supplemental Figure 1 : jha270281‐sup‐0001‐figureS1.pdf

Supporting File 2 : jha270281‐sup‐0002‐SuppMat.docx

Acknowledgements

The authors thank all participants, physicians and staff involved in this study. We thank Editage (www.editage.com) for English‐language editing.

Data Availability Statement

Data are available upon request.

References

1 S. V. Rajkumar , “ Multiple Myeloma: 2024 Update on Diagnosis, Risk‐Stratification, and Management ,” American Journal of Hematology 99 , no. 9 ( 2024 ): 1802 – 1824 , 10.1002/ajh.27422 . 38943315 PMC11404783

2 S. K. Kumar , N. S. Callander , K. Adekola , et al., “ Multiple Myeloma, Version 2.2024, NCCN Clinical Practice Guidelines in Oncology ,” Journal of the National Comprehensive Cancer Network 21 , no. 12 ( 2023 ): 1281 – 1301 , 10.6004/jnccn.2023.0061 . 38081133

3 S. K. Kumar , N. S. Callander , K. Adekola , et al., “ NCCN Guidelines Insights: Multiple Myeloma, Version 1.2025 ,” Journal of the National Comprehensive Cancer Network 23 , no. 5 ( 2025 ): 132 – 140 , 10.6004/jnccn.2025.0023 . 40340857

4 B. Chen , Q. Pan , and Y. Dong , “ Advancing MRD Detection in Multiple Myeloma ,” American Journal of Clinical Oncology 48 , no. 7 ( 2025 ): 376 – 380 , 10.1097/COC.0000000000001197 . 40214184 PMC12180695

5 N. C. Munshi , H. Avet‐Loiseau , K. C. Anderson , et al., “ A Large Meta‐Analysis Establishes the Role of MRD Negativity in Long‐Term Survival Outcomes in Patients With Multiple Myeloma ,” Blood Advances 4 , no. 23 ( 2020 ): 5988 – 5999 , 10.1182/bloodadvances.2020002827 . 33284948 PMC7724898

6 I. Ntanasis‐Stathopoulos , C. Filippatos , A. Ntanasis‐Stathopoulos , et al., “ Evaluating Minimal Residual Disease Negativity as a Surrogate Endpoint for Treatment Efficacy in Multiple Myeloma: A Meta‐Analysis of Randomized Controlled Trials ,” American Journal of Hematology 100 , no. 3 ( 2025 ): 427 – 438 , 10.1002/ajh.27582 . 39784302 PMC11803549

7 B. A. Derman , A. Major , J. Cooperrider , et al., “ Discontinuation of Maintenance Therapy in Multiple Myeloma Guided by Multimodal Measurable Residual Disease Negativity (MRD2STOP) ,” Blood Cancer Journal 14 , no. 1 ( 2024 ): 170 , 10.1038/s41408-024-01156-x . 39375362 PMC11458825

8 E. Terpos , P. Malandrakis , I. Ntanasis‐Stathopoulos , et al., “ Sustained Bone Marrow and Imaging MRD Negativity for 3 Years Drives Discontinuation of Maintenance Post‐ASCT in Myeloma ,” Blood 145 , no. 20 ( 2025 ): 2353 – 2360 , 10.1182/blood.2024027686 . 40009496

9 K. Sato , K. Okazuka , T. Ishida , et al., “ Minimal Residual Disease Detection in Multiple Myeloma: Comparison Between BML Single‐Tube 10‐Color Multiparameter Flow Cytometry and EuroFlow Multiparameter Flow Cytometry ,” Annals of Hematology 100 , no. 12 ( 2021 ): 2989 – 2995 , 10.1007/s00277-021-04634-5 . 34430990

10 A. Palumbo , H. Avet‐Loiseau , S. Oliva , et al., “ Revised International Staging System for Multiple Myeloma: A Report From International Myeloma Working Group ,” Journal of Clinical Oncology 33 , no. 26 ( 2015 ): 2863 – 2869 , 10.1200/JCO.2015.61.2267 . 26240224 PMC4846284

11 S. Kumar , B. Paiva , K. C. Anderson , et al., “ International Myeloma Working Group Consensus Criteria for Response and Minimal Residual Disease Assessment in Multiple Myeloma ,” Lancet Oncology 17 , no. 8 ( 2016 ): e328 – e346 , 10.1016/S1470-2045(16)30206-6 . 27511158

12 Y. Kanda , “ Investigation of the Freely Available Easy‐to‐Use Software ‘EZR’ for Medical Statistics ,” Bone Marrow Transplantation 48 , no. 3 ( 2013 ): 452 – 458 , 10.1038/bmt.2012.244 . 23208313 PMC3590441

13 A. Perrot , V. Lauwers‐Cances , J. Corre , et al., “ Minimal Residual Disease Negativity Using Deep Sequencing is a Major Prognostic Factor in Multiple Myeloma ,” Blood 132 , no. 23 ( 2018 ): 2456 – 2464 , 10.1182/blood-2018-06-858613 . 30249784 PMC6284215

14 L. Rosiñol , A. Oriol , R. Ríos , et al., “ Lenalidomide and Dexamethasone Maintenance With or Without Ixazomib, Tailored by Residual Disease Status in Myeloma ,” Blood 142 , no. 18 ( 2023 ): 1518 – 1528 , 10.1182/blood.2022019531 . 37506339

15 L. J. Costa , S. Chhabra , E. Medvedova , et al., “ Minimal Residual Disease Response‐Adapted Therapy in Newly Diagnosed Multiple Myeloma (MASTER): Final Report of the Multicentre, Single‐Arm, Phase 2 Trial ,” Lancet Haematology 10 , no. 11 ( 2023 ): e890 – e901 , 10.1016/S2352-3026(23)00236-3 . 37776872 PMC10836587

16 S. Sato , E. Sawazaki , S. Tsunoda , W. Kamata , T. Togano , and Y. Tamai , “ Retrospective Analysis of Treatment Discontinuation in Minimal Residual Disease Negative Multiple Myeloma ,” International Journal of Hematology 122 , no. 2 ( 2025 ): 217 – 223 , 10.1007/s12185-025-03966-6 . 40057936

17 B. Paiva , M.‐B. Vidriales , G. Mateo , et al., “ The Persistence of Immunophenotypically Normal Residual Bone Marrow Plasma Cells at Diagnosis Identifies a Good Prognostic Subgroup of Symptomatic Multiple Myeloma Patients ,” Blood 114 , no. 20 ( 2009 ): 4369 – 4372 , 10.1182/blood-2009-05-221689 . 19755674

18 J. F. San Miguel , J. Almeida , G. Mateo , et al., “ Immunophenotypic Evaluation of the Plasma Cell Compartment in Multiple Myeloma: A Tool for Comparing the Efficacy of Different Treatment Strategies and Predicting Outcome ,” Blood 99 , no. 5 ( 2002 ): 1853 – 1856 , 10.1182/blood.v99.5.1853 . 11861305

19 J. Flores‐Montero , R. de Tute , B. Paiva , et al., “ Immunophenotype of Normal vs. Myeloma Plasma Cells: Toward Antibody Panel Specifications for MRD Detection in Multiple Myeloma ,” Cytometry Part B: Clinical Cytometry 90 , no. 1 ( 2016 ): 61 – 72 , 10.1002/cyto.b.21265 . 26100534

20 M. R. Seefat , D. G. Cucchi , S. Dirven , K. Groen , S. Zweegman , and H. M. Blommestein , “ A Systematic Review of Cost‐Effectiveness Analyses of Novel Agents in the Treatment of Multiple Myeloma ,” Cancers 13 , no. 22 ( 2021 ): 5606 , 10.3390/cancers13225606 . 34830761 PMC8615675

21 C. Yamamoto , D. Minakata , S. Koyama , et al., “ Daratumumab in First‐Line Therapy is Cost‐Effective in Transplant‐Eligible Patients With Newly Diagnosed Myeloma ,” Blood 140 , no. 6 ( 2022 ): 594 – 607 , 10.1182/blood.2021015220 . 35580269 PMC9373013

22 C. Yamamoto , D. Minakata , D. Yokoyama , et al., “ Cost‐Effectiveness of Anti‐BCMA Chimeric Antigen Receptor T Cell Therapy in Relapsed/Refractory Multiple Myeloma ,” Transplantation and Cellular Therapy 30 , no. 1 ( 2024 ): 118.e1 – 118.e15 , 10.1016/j.jtct.2023.10.001 . 37802181