Clinical characteristics and prognosis of central nervous system involvement in multiple myeloma: a multicenter retrospective analysis from China

Clinical characteristics and prognosis of central nervous system involvement in multiple myeloma: a multicenter retrospective analysis from China | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Clinical characteristics and prognosis of central nervous system involvement in multiple myeloma: a multicenter retrospective analysis from China Wenjing Li, Weiwei Tian, Jie Ma, Linyu Li, Zhihua Li, Jie Liu, and 10 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7484907/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Central nervous system (CNS) involvement is a rare and aggressive complication of multiple myeloma (MM), with limited data on its clinical characteristics and prognosis. This multicenter study characterizes the largest Chinese cohort of MM patients with CNS involvement (MM-CNS) to date. Methods We conducted a multicenter retrospective study across nine hematology centers in China (July 2017-June 2024), analyzing clinical records of MM-CNS patients. Data collection encompassed diagnostic parameters, treatment regimens, and survival outcomes. Results Among 35 identified MM-CNS cases (median age 55 years, range 40–83), CNS manifestations presented at initial MM diagnosis in 31.4% (11/35) versus relapse in 68.6% (24/35), with median latency of 22.8 months from MM diagnosis. Predominant features included IgG subtype (51.4%), λ light chain restriction (54.3%), and high-risk cytogenetics: 1q21 amplification (48.3%), t(4;14) translocation (13.8%), and complex karyotypes of chromosome (35.7%). Diagnostic confirmation combined CSF analysis (protein elevation, plasma cell detection) with neuroimaging (meningeal/parenchymal lesions). Treatments included systemic chemotherapy (88.6%), intrathecal therapy (51.4%), radiotherapy (17.1%), chimeric antigen receptor T-cell (CAR-T) therapy (11.4%), and autologous stem cell transplantation (ASCT) (14.3%). Despite 62.9% overall response rate (36.4% complete remission), 56% relapsed within median 3.1 (range 1.2–8.4) months. The median follow-up duration was 19.1 months (range: 0.1–46.8). Median overall survival (OS) at 13.0 months (range 0.1–43.1) with 60% mortality (21/35). Conclusions CNS involvement in MM is associated with aggressive disease and poor prognosis. Despite transient responses to multimodal therapies, rapid progression and high mortality persist. Novel strategies are urgently needed to improve outcomes in this high-risk population. Multiple myeloma Central nervous system involvement Characteristics Therapy Prognosis Figures Figure 1 Figure 2 Figure 3 Figure 4 INTRODUCTION Multiple myeloma (MM) is a malignant hematologic disease originating from plasma cells, characterized by clonal proliferation of abnormal plasma cells in the bone marrow and excessive production of abnormal immunoglobulins. The clinical manifestations of MM are diverse, including bone pain, anemia, renal insufficiency, and hypercalcemia [ 1 ]. Despite significant advances in MM treatment in recent years, such as novel agents including proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and monoclonal antibodies, which have improved patient survival, MM remains an incurable disease with a high propensity for relapse [ 2 ] . Central nervous system (CNS) involvement in MM (MM-CNS) is a severe complication of MM. Despite its low incidence (less than 1%) [ 3 ], MM-CNS is associated with poor prognosis once it occurs [ 4 ]. A large retrospective multicenter study (N = 172) reported a median overall survival (OS) of 6.7 months for MM-CNS patients, with untreated patients having a median survival of 2 months versus 8 months for treated patients [ 5 ]. Another study reviewing medical records of 31 MM-CNS patients found that patients receiving anti-MM therapy (n = 29) showed significantly shorter progression-free survival (PFS) and OS compared to the control group (MM without CNS involvement), and no survival advantage was observed with novel therapeutic agents [ 6 ] . The specific mechanisms underlying MM-CNS involvement remain incompletely understood, and there are currently no definitive biomarkers or clinical indicators to accurately predict its occurrence or prognosis. Although previous studies have attempted to identify prognostic factors associated with CNS involvement by analyzing clinical features, laboratory parameters, and imaging findings, most are limited by small sample sizes and inconsistent methodologies [ 6 – 8 ] . This study retrospectively analyzed multicenter clinical data with a larger sample size to summarize the clinical characteristics of MM-CNS and identify its prognostic factors, aiming to share our therapeutic experience and provide a foundation for further research. MATERIALS AND METHODS Patients Clinical data were retrospectively collected from MM-CNS patients across nine centers between July 1, 2017, and June 30, 2024. The dataset included: (1) demographics (age at MM diagnosis and CNS involvement, gender); (2) disease characteristics (immunoglobulin isotype, ISS stage); (3) cytogenetic abnormalities (assessed after CD138 magnetic bead sorting with a ≥ 20% positivity threshold); (4) clinical timeline (interval from MM diagnosis to CNS-MM diagnosis); (5) prior treatment history (number and types of therapies before CNS involvement); (6) neuroimaging findings; (7) cerebrospinal fluid (CSF) evaluations (cytology and flow cytometry); (8) CNS-directed therapies (number and types of interventions); and (9) survival outcomes (OS, PFS, causes of death). This comprehensive framework aimed to systematically characterize MM-CNS profiles and identify prognostic determinants. Criteria for central nervous system involvement The diagnostic criteria for MM-CNS were defined based on previously reported criteria[ 7 , 9 ] : the presence of plasma cells in CSF and/or imaging evidence of leptomeningeal, dural, or parenchymal brain involvement, confirmed by CSF analysis, magnetic resonance imaging (MRI), computed tomography (CT), and/or histopathological biopsy. Treatment Protocols and Response Criteria Treatment regimens included systemic chemotherapy, radiotherapy, and intrathecal therapy. Systemic chemotherapy comprised cytotoxic drugs, proteasome inhibitor (PI)-based regimens, immunomodulatory drug (IMiD)-based regimens, and CD38 monoclonal antibody-based regimens. Intrathecal therapy involved triple intrathecal injections (methotrexate/cytarabine/corticosteroids) or dexamethasone monotherapy. Autologous hematopoietic stem cell transplantation (ASCT) was administered as consolidation therapy post-remission, while chimeric antigen receptor T-cell (CAR-T) therapy served as salvage treatment. Treatment efficacy for systemic MM was evaluated according to the International Myeloma Working Group (IMWG) response criteria[ 10 ]. For MM-CNS, therapeutic response was defined based on previously reported studies[ 11 ] as follows: Complete response (CR) was defined as complete disappearance of the mass and complete disappearance of monoclonal plasma cells in the CSF; Very good partial remission (VGPR) was defined as a ≥ 75% reduction in the size of the mass; Partial response (PR) was defined as a ≥ 50% but < 75% reduction in the size of the mass; Nonresponse (NR) was defined as a reduction in the size of the mass of < 50%. Follow-up and Survival Definitions All patients were followed until October 2024. The median follow-up duration was 19.1 months (range: 0.1–46.8). OS was defined as the time from confirmed CNS involvement to death from any cause or the end of follow-up. PFS was defined as the time from confirmed CNS involvement to disease relapse/progression, death from any cause, or the end of follow-up. Statistical Analysis Statistical analyses were performed using SPSS 26.0, GraphPad Prism 8, and R 4.4.2. Continuous variables were expressed as median (range), and between-group comparisons were analyzed with the Mann-Whitney U test. Categorical variables were presented as frequency (percentage), and between-group differences were assessed using the chi-square test or Fisher’s exact test. Independent prognostic factors for MM-CNS were identified via Cox regression models for OS. Survival curves were generated using the Kaplan-Meier method. A two-sided P < 0.05 was considered statistically significant. RESULT Clinical characteristics of patients Over a seven-year multicenter study period, 35 consecutive cases of MM-CNS were identified across nine Chinese centers. Baseline demographic and clinical characteristics are summarized in Table 1 . The cohort included 16 males (45.7%) and 19 females (54.3%), with a median age of 55 years (range: 40–83) at the time of MM-CNS diagnosis. Synchronous CNS involvement (diagnosed concurrently with initial MM) was observed in 11 patients (31.4%), while 24 cases (68.6%) developed CNS manifestations during disease progression after prior systemic therapy. Table 1 Baseline demographic and clinical characteristics (n = 35) Characteristics CNS involvement at initial MM diagnosis (n = 11) CNS involvement at MM relapse (n = 24) P Sex, male 7 (63.6%) 9 (37.5%) 0.273 Age, years, median, (range) 55 (46–66) 54 (40–83) 0.913 Immunoglobulin isotype 0.617 IgG 4 (36.4%) 14 (58.3%) IgA 4 (36.4%) 7 (29.2%) IgD 2 (18.2%) 2 (8.3%) light-chain 1 (9.1%) 1 (4.2%) ISS stage 0.186 I 3 (27.3%) 2 (8.3%) II 1 (9.1%) 7 (29.2%) III 7 (63.3%) 15 (62.5%) CSF abnormalities 2/7 (28.6%) 10/11(90.9%) 0.012 Anatomical involvement patterns imeningeal infiltration 0 8 (33.3%) 0.030 parenchymal lesions 11 (100%) 18 (75.0%) 0.146 Soft-tissue plasmacytomas 5 (45.5%) 4 (16.7%) 0.103 Pleural plasmacytomas 1 (9.1%) 2 (8.3%) 1.000 Plasma cell leukemia 0 1 (4.2%) Cytogenetic aberrations 6/9 (66.7%) 9/20 (45.0%) 0.427 Interval from MM diagnosis to CNS progression NA 22.8 (2.4 ~ 77.7) Preceding treatment lines NA 2 (1–8) Prior therapy PI-based NA 22 (91.7%) IMiD-based NA 12 (50.0%) CD38-targeted monoclonal antibodies NA 7 (29.2%) ASCT NA 6 (25.0%) MM, Multiple Myeloma; CNS, Central nervous system; IgG, Immunoglobulin G; IgA, Immunoglobulin A; IgD, Immunoglobulin D; PI, proteasome inhibitor; IMiD, immunomodulators; CD38, Cluster of differentiation 38; ASCT, autologous stem cell transplantation Immunoglobulin heavy-chain isotype analysis showed IgG dominance (n = 18/35, 51.4%), followed by IgA (n = 11/35, 31.4%) and IgD (n = 4/35, 11.4%), with light-chain-only disease observed in 5.7% (n = 2/35). Notably, λ light-chain restriction predominated across the cohort (n = 19/35, 54.3%). Concurrent extramedullary manifestations included soft-tissue plasmacytomas (25.7%, n = 9/35), pleural plasmacytomas (8.6%, n = 3/35), and secondary plasma cell leukemia (2.9%, n = 1/35). Disease staging by the International Staging System (ISS) revealed high-risk features predominance, with 62.9% (n = 22/35) classified as stage III, 22.9% (n = 8/35) as stage II, and 14.3% (n = 5/35) as stage I. Fluorescence in situ hybridization (FISH) analyses were successfully performed in 29 patients (82.9% of the cohort), identifying high-risk cytogenetic aberrations: 1q21 amplification (n = 14/29, 48.3%), TP53 deletions (n = 3/29, 10.3%), and immunoglobulin heavy chain (IgH) translocations—specifically t(4;14)(p16;q32) (n = 4/29, 13.8%), t(11;14)(q13;q32) (n = 1/29, 3.4%), and t(14;16)(q32;q23) (n = 1/29, 3.4%). Conventional karyotyping, available for 14 patients (40.0%), revealed complex karyotypes (≥ 3 chromosomal abnormalities) in 35.7% (n = 5/14) of evaluable cases. MM-CNS diagnosis was confirmed through multimodal approaches: histopathological verification via biopsy (n = 2/35, 5.7%), CSF analysis (n = 12/35, 51.4%), and neuroimaging (n = 21/35, 42.9%). Anatomical involvement patterns included isolated meningeal infiltration (n = 6/35, 17.1%), solitary parenchymal lesions (n = 27/35, 77.1%), and combined meningeal-parenchymal disease (n = 2/35, 5.7%). Among 18 patients undergoing CSF analysis, key findings comprised elevated protein levels in 66.7% (n = 12/18), morphology identified malignant plasma cells in 61.1% (n = 11/18), and clonal plasma cell confirmation by flow cytometric immunophenotyping (CD38+/CD138+/CD56 + with light-chain restriction) in 83.3% (n = 10/12) of tested cases. Among patients developing CNS involvement at MM relapse (n = 24, 68.6% of the cohort), the median number of preceding treatment lines was 2 (range: 1–8), with all patients exposed to multi-agent regimens. The median interval from initial MM diagnosis to CNS progression was 22.8 months (range: 2.4–77.7). Prior therapeutic exposures included PI-based combinations (n = 22/24, 91.7%), IMiD-based regimens (n = 12/24, 50.0%), CD38-targeted monoclonal antibodies (n = 7/24, 29.2%), and ASCT (n = 6/24, 25.0%). Compared to patients with CNS involvement at initial MM diagnosis (n = 11), those developing CNS relapse post-treatment exhibited significantly higher rates of meningeal infiltration (33.3% vs. 0%, P = 0.030) and CSF abnormalities, including elevated protein or clonal plasma cells (90.9% vs. 28.6%, P = 0.012). Treatment Regimens and Efficacy Therapeutic strategies for MM-CNS are summarized in Fig. 1 . Within the cohort, 33 patients (94.3%) received CNS-directed therapy, including multimodal approaches: systemic chemotherapy (n = 31/35, 88.6%), intrathecal therapy (n = 18/35, 51.4%), and radiotherapy (n = 6/35, 17.1%). One patient underwent surgical resection of a symptomatic parenchymal mass. Consolidation therapies included ASCT post-induction (n = 5/35, 14.3%) and CAR-T cell therapy as salvage treatment for refractory disease (n = 4/35, 11.4%). Systemic chemotherapy regimens universally employed combination strategies to address blood-brain barrier penetration challenges and therapeutic resistance. PIs formed the backbone of therapy in 82.9% of cases (n = 29/35). These were frequently combined with cytotoxic chemotherapy (n = 22/35, 62.9%). IMiDs were integrated into 42.9% of regimens (n = 15/35), while CD38-targeted monoclonal antibody therapy (daratumumab) demonstrated limited utilization (20.0%, n = 7/35). As shown in Fig. 2 , systemic therapeutic efficacy was categorized as follows: disease progression in 7 patients (20.0%), stable disease in 4 (11.4%), and partial or complete responses in the remaining 22 (62.9%). Among responders, 8 patients (36.4%) achieved complete remission (CR), 2 (9.1%) attained very good partial remission (VGPR), and 12 (54.5%) showed partial remission (PR) per IMWG criteria. Notably, 14 of the 22 responders (63.6%) experienced disease relapse within a median of 3.1 months (range: 1.2–8.4), underscoring the transient nature of therapeutic responses. For CNS-specific outcomes, objective responses were documented in 21 patients (60.0%), suggesting activity against CNS-infiltrating myeloma cells, though standardized criteria for CNS-MM response assessment remain lacking. Survival analysis With a median follow-up duration of 19.1 months (range: 0.1–46.8), the median OS from CNS involvement diagnosis was 13.0 months (range: 0.1–43.1), and the median PFS was 4.2 months (range: 0.1–19.3). Kaplan-Meier curves for OS and PFS are presented in Fig. 3 . Patients with CNS involvement at initial MM diagnosis exhibited significantly prolonged survival compared to those developing CNS relapse post-treatment (median OS: 34.0 months [95% CI: 18.6–49.4] vs. 12.8 months [95% CI: 7.1–18.5]; log-rank P = 0.01, Fig. 4 ). Prognostic factors for OS were evaluated using univariate and multivariate Cox proportional hazards models (Table 2 ). Univariate analysis identified post-treatment CNS involvement (HR = 4.735, 95% CI: 1.313–17.077, P = 0.018) as significant predictors of poor survival. This survival disparity persisted after adjusting for age, ISS stage and anatomical involvement patterns (adjusted HR = 4.825, 95% CI: 1.323–17.596, P = 0.017). Table 2 Univariate and Multivariate Cox Regression Analysis for Overall Survival Variable Univariate Analysis Multivariate Analysis HR (95% CI) P-value Adjusted HR (95% CI) P-value Age (≥ 60 years old) 1.717 (0.629–4.689) 0.292 2.188 (0.743–6.452) 0.155 Post-treatment CNS involvement 4.735 (1.313–17.077) 0.018 4.825(1.323–17.596) 0.017 Meningeal infiltration 1.151 (0.317–4.182) 0.831 1.580 (0.421–5.882) 0.496 ISS stage III 1.063 (0.416–2.720) 0.898 1.372(0.461–4.082) 0.570 CNS, Central nervous system; ISS International Staging System DISCUSSION This multicenter retrospective study systematically elucidated the clinical characteristics, treatment patterns, and prognostic trends of MM-CNS. As a rare complication of MM (with an incidence rate well under 1% overal[ 12 ] ), CNS involvement exhibits complex underlying mechanisms and is associated with extremely poor prognosis[ 13 ], demonstrating a median OS of 13.0 months based on our cohort analysis. Our findings describe the characteristics, treatment patterns, and prognosis of the MM-CNS population in China, providing baseline data and preliminary insights for understanding this clinical challenge. In our cohort, 68.6% of CNS involvement cases emerged after MM treatment (with a median time to onset of 22.8 months), suggesting that therapeutic pressures may drive tumor cell CNS infiltration through clonal selection. This observation aligns with previous reports: a multicenter retrospective study of 172 patients demonstrated CNS infiltration at relapse in 78% of cases[ 5 ], while another retrospective study identified CNS involvement at initial diagnosis versus relapse in 24% and 76% of 76 evaluated cases, respectively[ 9 ]. Notably, the post-treatment CNS involvement group exhibited significantly higher rates of leptomeningeal involvement (53.3% vs. 0%) and cerebrospinal fluid (CSF) abnormalities (83.3% vs. 33.3%) compared to the diagnosis-time CNS involvement group (p < 0.05). This temporal association suggests that prolonged therapeutic exposure may select for aggressive subclones with enhanced neurotropic potential. Molecularly, the high prevalence of high-risk cytogenetic aberrations (51.7%) and complex karyotypes (35.7%) in our cohort is consistent with the genetic profiles associated with high risk of CNS invasion reported before[ 3 , 8 ]. These genetic aberrations likely promote CNS metastasis by upregulating homing receptors and driving extracellular matrix remodeling [ 12 ] . While neuroimaging findings demonstrated substantial diagnostic utility in detecting CNS involvement, CSF confirmation rates remained suboptimal, highlighting persistent challenges in diagnostic standardization. Notably, discordant results between conventional cytomorphological assessments and flow cytometric analyses were observed in a subset of cases, emphasizing the critical need for integrating advanced detection modalities, such as high-sensitivity immunophenotyping or molecular profiling techniques, to overcome limitations inherent to single-method diagnostic paradigms. Our study demonstrates a significant survival advantage in MM-CNS at initial diagnosis (n = 9, median OS 34.0 months) compared to those developing CNS involvement post-treatment (n = 26, median OS 12.8 months; p = 0.01), a finding consistent with prior observations from a Japanese nationwide multicenter study of 77 patients (48.5 vs. 2.7 months for diagnosis-time vs. relapsed CNS involvement)[ 7 ]. This discrepancy may be attributed to the diagnosis-time group having received fewer prior therapy and thus exhibiting greater sensitivity to systemic treatment and the post-treatment group having accumulated high-risk genetic abnormalities due to multiple relapses. Regarding therapeutic strategies, current literature supports multimodal approaches for MM-CNS management, including IT, radiotherapy, and systemic regimens such as IMiDs, PIs, cytotoxic chemotherapy, CD38-targeted monoclonal antibody, high-dose dexamethasone, ASCT, and CAR-T cell therapy[ 9 , 14 ]. Recent evidence highlights the promise of CAR-T therapy, with one study reporting comparable outcomes in 17 MM-CNS patients receiving idecabtagene vicleucel (ide-cel) versus non-CNS myeloma (mPFS 10.5 vs 8.5 mo, p = 0.59; mOS 13 vs 10.6 mo, p = 0.92; ORR 82% vs 80%)[ 15 ]. Another study of 10 MM-CNS patients treated with ide-cel (n = 6) or ciltacabtagene autoleucel (n = 4) demonstrated an 80% best overall response rate (≥ VGPR) and 100% CNS response rate, with median OS and PFS of 13.3 and 6.3 months at median 381-day follow-up[ 16 ]. Given that most patients develop CNS involvement after multiple prior lines of therapy and exhibit short remission durations (3.1 months in this cohort), combination therapies are often necessary[ 17 ]. However, significant heterogeneity in treatment protocols (e.g., 51.4% receiving IT therapy, 17.1% combined with radiotherapy) and limited sample size (n = 35) preclude comparative efficacy analysis across modalities, a limitation also observed in other retrospective studies[ 6 , 8 , 13 ] . The retrospective design and sample size limitations of this study suggest that our conclusions warrant further validation in prospective trials. While our findings reveal critical associations between treatment timing and survival outcomes, deeper exploration of molecular mechanisms and microenvironmental interactions remains necessary. Future research should prioritize the establishment of standardized diagnostic frameworks, the development of dynamic monitoring tools to track disease progression, and the integration of systemic and localized interventions through innovative therapeutic paradigms. Strengthening interdisciplinary collaboration, constructing risk stratification models, and deepening molecular subtyping studies will be pivotal in advancing breakthroughs for this clinical challenge. Declarations Acknowledgments: The authors acknowledge all patients who participated in this study and their families. Funding Declaration : This study was supported by National Natural Science Foundation of China (82470198), and Clinical Research Incubation Project (Beijing Chao-Yang Hospital, Capital Medical University, CYFH202208). Human Ethics and Consent to Participate declarations: The study protocol was conducted in accordance with the principles of the Declaration of Helsinki and approved by the Health Human Research Ethics Committee of Beijing Chaoyang Hospital, Affiliated to Capital Medical University. Written informed consent was obtained from the participates. Data Availability declaration: The data that support the results of this study are available from the corresponding authors upon reasonable request. Conflict-of-interest disclosure: The authors declare no competing financial interests. Author Contribution: Contribution: W.G. designed the study, interpreted the data, and reviewed the manuscript; W.-J.L.interpreted the data and wrote the manuscript. W.-J.L., T.-W.W., J.M., L.-Y.L., Z.-H.L., J.L., G.-R. G., Z.-F.X., L.Z., W.-H.Z., L.-X.D., H.G., J.M., H.-H.Z., and W.-M.C. recruited patients and collected the data; and all authors reviewed and approved the final version of the manuscript. 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Blood Abbr 144:4759–4759. https://doi.org/10.1182/blood-2024-202467 Gaballa MR, Puglianini OC, Cohen A, Vogl D, Chung A, Ferreri CJ, Voorhees P, Hansen DK, Patel KK (2025) BCMA-directed CAR T-cell therapy in patients with multiple myeloma and CNS involvement. Blood Adv Abbr 9:1171–1180. https://doi.org/10.1182/bloodadvances.2024014345 Gangatharan SA, Carney DA, Prince HM, Wolf MM, Januszewicz EH, Ritchie DS, Harrison SJ (2012) Emergence of central nervous system myeloma in the era of novel agents. Hematol Oncol Abbr 30:170–174. https://doi.org/10.1002/hon.1021 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7484907","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":513498558,"identity":"9e45fc31-46bf-4fa2-9c9c-76ab8df35866","order_by":0,"name":"Wenjing Li","email":"","orcid":"","institution":"Beijing Chao-Yang Hospital","correspondingAuthor":false,"prefix":"","firstName":"Wenjing","middleName":"","lastName":"Li","suffix":""},{"id":513498559,"identity":"6e10970a-0e14-4b90-98ff-1cd0f9754bf2","order_by":1,"name":"Weiwei Tian","email":"","orcid":"","institution":"Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Weiwei","middleName":"","lastName":"Tian","suffix":""},{"id":513498560,"identity":"2e791c5c-da09-415e-8282-f4e01d9ce9a4","order_by":2,"name":"Jie Ma","email":"","orcid":"","institution":"The First Affiliated Hospital of Zhengzhou University","correspondingAuthor":false,"prefix":"","firstName":"Jie","middleName":"","lastName":"Ma","suffix":""},{"id":513498561,"identity":"4028a99c-8642-4f09-ba62-fa2e0f870199","order_by":3,"name":"Linyu Li","email":"","orcid":"","institution":"Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Linyu","middleName":"","lastName":"Li","suffix":""},{"id":513498562,"identity":"618d8ca4-a19b-4b46-b28c-ceb0e7fa71c5","order_by":4,"name":"Zhihua Li","email":"","orcid":"","institution":"Sinopharm Tongmei General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Zhihua","middleName":"","lastName":"Li","suffix":""},{"id":513498563,"identity":"934f0e61-6899-4354-b188-7bbf62380949","order_by":5,"name":"Jie Liu","email":"","orcid":"","institution":"Sinopharm Tongmei General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jie","middleName":"","lastName":"Liu","suffix":""},{"id":513498564,"identity":"b16d8481-b8d2-4b43-9a98-2501479535f6","order_by":6,"name":"Guorong Gao","email":"","orcid":"","institution":"Linfen People's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Guorong","middleName":"","lastName":"Gao","suffix":""},{"id":513498565,"identity":"c54621dc-a3d8-40a4-b046-5ec6a044a64d","order_by":7,"name":"Zhenfang Xi","email":"","orcid":"","institution":"Linfen People's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Zhenfang","middleName":"","lastName":"Xi","suffix":""},{"id":513498566,"identity":"e7d51588-e2da-4ef8-a8ab-d2a242b4cb37","order_by":8,"name":"Lan Zhang","email":"","orcid":"","institution":"First Hospital of Shanxi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Lan","middleName":"","lastName":"Zhang","suffix":""},{"id":513498567,"identity":"b2ccafe5-7643-42f4-b739-7a68f1fc70c9","order_by":9,"name":"Weihua Zhang","email":"","orcid":"","institution":"First Hospital of Shanxi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Weihua","middleName":"","lastName":"Zhang","suffix":""},{"id":513498568,"identity":"ac69d24a-796c-41d3-9d26-163878896703","order_by":10,"name":"Lixiang Duan","email":"","orcid":"","institution":"Yuncheng Central Hospital affiliated to Shanxi Medical University","correspondingAuthor":false,"prefix":"","firstName":"Lixiang","middleName":"","lastName":"Duan","suffix":""},{"id":513498569,"identity":"22ffe064-dc8c-4413-8548-85f9d6dfa62a","order_by":11,"name":"Hui Geng","email":"","orcid":"","institution":"Qinghai University Affiliated Hospital","correspondingAuthor":false,"prefix":"","firstName":"Hui","middleName":"","lastName":"Geng","suffix":""},{"id":513498570,"identity":"59b88e6f-e086-4b66-9fe8-678d6fe578d6","order_by":12,"name":"Jie Meng","email":"","orcid":"","institution":"The Second Affiliated Hospital of Hainan Medical University","correspondingAuthor":false,"prefix":"","firstName":"Jie","middleName":"","lastName":"Meng","suffix":""},{"id":513498571,"identity":"e95a97c9-54a8-49f4-8668-5418c6faebae","order_by":13,"name":"Honghu Zhu","email":"","orcid":"","institution":"Beijing Chao-Yang Hospital","correspondingAuthor":false,"prefix":"","firstName":"Honghu","middleName":"","lastName":"Zhu","suffix":""},{"id":513498572,"identity":"cc0fd1cf-ff79-45b3-b2aa-ecac6f0a3080","order_by":14,"name":"Wenming Chen","email":"","orcid":"","institution":"Beijing Chao-Yang Hospital","correspondingAuthor":false,"prefix":"","firstName":"Wenming","middleName":"","lastName":"Chen","suffix":""},{"id":513498573,"identity":"7fc53467-4717-47c1-8b38-a65204d7b338","order_by":15,"name":"Wen Gao","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA+ElEQVRIiWNgGAWjYBADHhBxgIHBhoefv4E0LWkykjMOkGbbYRuDhgT8SuTdDx+T+Ljjjow5/9qDhwt+necxYDjA+OFjDm4thmfS0iRnnnnGYznjXcLhmX23ecyZG5glZ27Do6Uhx+w2b9thHoMbZwwO8/bc5rFsOMDGzItPS/8bs9t/EVrO8RgcSMCvRV4CaAsjSMv5HoPDPD8OENZiIPEs/Wdv2zOgLXwJh3kbknkkZxxsxusX+f7kwwY/2+7YG5w/e/gzzx87e37+5oMfPuKz5QCYApISwHBlbANxGBtwqwfZ0gDTwn8GSP/Bq3gUjIJRMApGKAAAQB1cm0AHUJsAAAAASUVORK5CYII=","orcid":"","institution":"Beijing Chao-Yang Hospital","correspondingAuthor":true,"prefix":"","firstName":"Wen","middleName":"","lastName":"Gao","suffix":""}],"badges":[],"createdAt":"2025-08-29 04:53:29","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7484907/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7484907/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":91198138,"identity":"9d7327dd-48db-4c97-b9b9-db6f01645372","added_by":"auto","created_at":"2025-09-12 15:13:45","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":34480,"visible":true,"origin":"","legend":"\u003cp\u003eTherapeutic strategies for patients with central nervous system (CNS) involvement in multiple myeloma (MM). RT, radiotherapy; ASCT, autologous stem cell transplantation; CAR-T,chimeric antigen receptor T-cell; CD38, Cluster of differentiation 38; IMIDs, immunomodulators; IT, intrathecal therapy; PI, proteasome inhibitor\u003c/p\u003e","description":"","filename":"image1.png","url":"https://assets-eu.researchsquare.com/files/rs-7484907/v1/ea68e6baadc8492911cb7355.png"},{"id":91199629,"identity":"78e8065f-c23d-4839-b61c-6f586a6f747e","added_by":"auto","created_at":"2025-09-12 15:21:45","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":50147,"visible":true,"origin":"","legend":"\u003cp\u003eTherapeutic efficacy for patients with central nervous system (CNS) involvement in multiple myeloma (MM). (a) Systemic therapeutic efficacy. (b) CNS-specific therapeutic efficacy. CR, complete remission; VGPR, very good partial remission; PR, partial remission; SD, stable disease; PD, progression disease; NR, nonresponse.\u003c/p\u003e","description":"","filename":"image2.png","url":"https://assets-eu.researchsquare.com/files/rs-7484907/v1/fd5e1e5fb8ef3c704a7666e1.png"},{"id":91198139,"identity":"8b20f1a7-5e02-4810-8679-b4ae4f8a358b","added_by":"auto","created_at":"2025-09-12 15:13:45","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":43360,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier survival curves for OS (a) and PFS (b) in patients with central nervous system (CNS) involvement in multiple myeloma (MM).\u003c/p\u003e","description":"","filename":"image3.png","url":"https://assets-eu.researchsquare.com/files/rs-7484907/v1/50db9904d33dac240e5cd3df.png"},{"id":91198143,"identity":"5dc5a270-b4d4-4d13-a0d1-15ebe485348e","added_by":"auto","created_at":"2025-09-12 15:13:45","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":47931,"visible":true,"origin":"","legend":"\u003cp\u003eSurvival comparison based on central nervous system (CNS) involvement timing. CNS involvement at multiple myeloma diagnosis was associated with superior OS compared to post-treatment CNS relapse (34.0 vs. 12.8 months, log-rank \u003cem\u003eP\u003c/em\u003e = 0.01).\u003c/p\u003e","description":"","filename":"image4.png","url":"https://assets-eu.researchsquare.com/files/rs-7484907/v1/2523fcd398f8395ac6261a5d.png"},{"id":91720720,"identity":"4d03effe-b876-4292-8c73-19f4cb0fb555","added_by":"auto","created_at":"2025-09-19 14:08:55","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":899434,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7484907/v1/2b5854b5-b965-4e52-8f4d-ca9ff2ac4286.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Clinical characteristics and prognosis of central nervous system involvement in multiple myeloma: a multicenter retrospective analysis from China","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eMultiple myeloma (MM) is a malignant hematologic disease originating from plasma cells, characterized by clonal proliferation of abnormal plasma cells in the bone marrow and excessive production of abnormal immunoglobulins. The clinical manifestations of MM are diverse, including bone pain, anemia, renal insufficiency, and hypercalcemia [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Despite significant advances in MM treatment in recent years, such as novel agents including proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and monoclonal antibodies, which have improved patient survival, MM remains an incurable disease with a high propensity for relapse [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] .\u003c/p\u003e\u003cp\u003eCentral nervous system (CNS) involvement in MM (MM-CNS) is a severe complication of MM. Despite its low incidence (less than 1%) [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e], MM-CNS is associated with poor prognosis once it occurs [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. A large retrospective multicenter study (N\u0026thinsp;=\u0026thinsp;172) reported a median overall survival (OS) of 6.7 months for MM-CNS patients, with untreated patients having a median survival of 2 months versus 8 months for treated patients [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Another study reviewing medical records of 31 MM-CNS patients found that patients receiving anti-MM therapy (n\u0026thinsp;=\u0026thinsp;29) showed significantly shorter progression-free survival (PFS) and OS compared to the control group (MM without CNS involvement), and no survival advantage was observed with novel therapeutic agents [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] .\u003c/p\u003e\u003cp\u003eThe specific mechanisms underlying MM-CNS involvement remain incompletely understood, and there are currently no definitive biomarkers or clinical indicators to accurately predict its occurrence or prognosis. Although previous studies have attempted to identify prognostic factors associated with CNS involvement by analyzing clinical features, laboratory parameters, and imaging findings, most are limited by small sample sizes and inconsistent methodologies [\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] .\u003c/p\u003e\u003cp\u003eThis study retrospectively analyzed multicenter clinical data with a larger sample size to summarize the clinical characteristics of MM-CNS and identify its prognostic factors, aiming to share our therapeutic experience and provide a foundation for further research.\u003c/p\u003e"},{"header":"MATERIALS AND METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003ePatients\u003c/h2\u003e\u003cp\u003eClinical data were retrospectively collected from MM-CNS patients across nine centers between July 1, 2017, and June 30, 2024. The dataset included: (1) demographics (age at MM diagnosis and CNS involvement, gender); (2) disease characteristics (immunoglobulin isotype, ISS stage); (3) cytogenetic abnormalities (assessed after CD138 magnetic bead sorting with a\u0026thinsp;\u0026ge;\u0026thinsp;20% positivity threshold); (4) clinical timeline (interval from MM diagnosis to CNS-MM diagnosis); (5) prior treatment history (number and types of therapies before CNS involvement); (6) neuroimaging findings; (7) cerebrospinal fluid (CSF) evaluations (cytology and flow cytometry); (8) CNS-directed therapies (number and types of interventions); and (9) survival outcomes (OS, PFS, causes of death). This comprehensive framework aimed to systematically characterize MM-CNS profiles and identify prognostic determinants.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eCriteria for central nervous system involvement\u003c/h3\u003e\n\u003cp\u003eThe diagnostic criteria for MM-CNS were defined based on previously reported criteria[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] : the presence of plasma cells in CSF and/or imaging evidence of leptomeningeal, dural, or parenchymal brain involvement, confirmed by CSF analysis, magnetic resonance imaging (MRI), computed tomography (CT), and/or histopathological biopsy.\u003c/p\u003e\n\u003ch3\u003eTreatment Protocols and Response Criteria\u003c/h3\u003e\n\u003cp\u003eTreatment regimens included systemic chemotherapy, radiotherapy, and intrathecal therapy. Systemic chemotherapy comprised cytotoxic drugs, proteasome inhibitor (PI)-based regimens, immunomodulatory drug (IMiD)-based regimens, and CD38 monoclonal antibody-based regimens. Intrathecal therapy involved triple intrathecal injections (methotrexate/cytarabine/corticosteroids) or dexamethasone monotherapy. Autologous hematopoietic stem cell transplantation (ASCT) was administered as consolidation therapy post-remission, while chimeric antigen receptor T-cell (CAR-T) therapy served as salvage treatment.\u003c/p\u003e\u003cp\u003eTreatment efficacy for systemic MM was evaluated according to the International Myeloma Working Group (IMWG) response criteria[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. For MM-CNS, therapeutic response was defined based on previously reported studies[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] as follows: Complete response (CR) was defined as complete disappearance of the mass and complete disappearance of monoclonal plasma cells in the CSF; Very good partial remission (VGPR) was defined as a\u0026thinsp;\u0026ge;\u0026thinsp;75% reduction in the size of the mass; Partial response (PR) was defined as a\u0026thinsp;\u0026ge;\u0026thinsp;50% but \u0026lt;\u0026thinsp;75% reduction in the size of the mass; Nonresponse (NR) was defined as a reduction in the size of the mass of \u0026lt;\u0026thinsp;50%.\u003c/p\u003e\n\u003ch3\u003eFollow-up and Survival Definitions\u003c/h3\u003e\n\u003cp\u003eAll patients were followed until October 2024. The median follow-up duration was 19.1 months (range: 0.1\u0026ndash;46.8). OS was defined as the time from confirmed CNS involvement to death from any cause or the end of follow-up. PFS was defined as the time from confirmed CNS involvement to disease relapse/progression, death from any cause, or the end of follow-up.\u003c/p\u003e\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003ch2\u003eStatistical Analysis\u003c/h2\u003e\u003cp\u003eStatistical analyses were performed using SPSS 26.0, GraphPad Prism 8, and R 4.4.2. Continuous variables were expressed as median (range), and between-group comparisons were analyzed with the Mann-Whitney U test. Categorical variables were presented as frequency (percentage), and between-group differences were assessed using the chi-square test or Fisher\u0026rsquo;s exact test. Independent prognostic factors for MM-CNS were identified via Cox regression models for OS. Survival curves were generated using the Kaplan-Meier method. A two-sided \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e\u003c/div\u003e"},{"header":"RESULT","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003cdiv id=\"Sec9\" class=\"Section3\"\u003e\u003ch2\u003eClinical characteristics of patients\u003c/h2\u003e\u003cp\u003eOver a seven-year multicenter study period, 35 consecutive cases of MM-CNS were identified across nine Chinese centers. Baseline demographic and clinical characteristics are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The cohort included 16 males (45.7%) and 19 females (54.3%), with a median age of 55 years (range: 40\u0026ndash;83) at the time of MM-CNS diagnosis. Synchronous CNS involvement (diagnosed concurrently with initial MM) was observed in 11 patients (31.4%), while 24 cases (68.6%) developed CNS manifestations during disease progression after prior systemic therapy.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eBaseline demographic and clinical characteristics (n\u0026thinsp;=\u0026thinsp;35)\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCharacteristics\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCNS involvement at initial MM diagnosis (n\u0026thinsp;=\u0026thinsp;11)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCNS involvement at MM relapse (n\u0026thinsp;=\u0026thinsp;24)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSex, male\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e7 (63.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e9 (37.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.273\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge, years, median, (range)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e55 (46\u0026ndash;66)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e54 (40\u0026ndash;83)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.913\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eImmunoglobulin isotype\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.617\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIgG\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4 (36.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e14 (58.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIgA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4 (36.4%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e7 (29.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIgD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2 (18.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2 (8.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003elight-chain\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1 (9.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1 (4.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eISS stage\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.186\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3 (27.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2 (8.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eII\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1 (9.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e7 (29.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIII\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e7 (63.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e15 (62.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCSF abnormalities\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2/7 (28.6%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e10/11(90.9%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.012\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eAnatomical involvement patterns\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eimeningeal infiltration\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e8 (33.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.030\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eparenchymal lesions\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e11 (100%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e18 (75.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.146\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSoft-tissue plasmacytomas\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5 (45.5%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4 (16.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.103\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePleural plasmacytomas\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1 (9.1%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2 (8.3%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.000\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePlasma cell leukemia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1 (4.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCytogenetic aberrations\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6/9 (66.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e9/20 (45.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.427\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e\u003cp\u003eInterval from MM diagnosis to CNS progression\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e22.8 (2.4\u0026thinsp;~\u0026thinsp;77.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePreceding treatment lines\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2 (1\u0026ndash;8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePrior therapy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePI-based\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e22 (91.7%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIMiD-based\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e12 (50.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e\u003cp\u003eCD38-targeted monoclonal antibodies\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e7 (29.2%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eASCT\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e6 (25.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"4\"\u003eMM, Multiple Myeloma; CNS, Central nervous system; IgG, Immunoglobulin G; IgA, Immunoglobulin A; IgD, Immunoglobulin D; PI, proteasome inhibitor; IMiD, immunomodulators; CD38, Cluster of differentiation 38; ASCT, autologous stem cell transplantation\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eImmunoglobulin heavy-chain isotype analysis showed IgG dominance (n\u0026thinsp;=\u0026thinsp;18/35, 51.4%), followed by IgA (n\u0026thinsp;=\u0026thinsp;11/35, 31.4%) and IgD (n\u0026thinsp;=\u0026thinsp;4/35, 11.4%), with light-chain-only disease observed in 5.7% (n\u0026thinsp;=\u0026thinsp;2/35). Notably, λ light-chain restriction predominated across the cohort (n\u0026thinsp;=\u0026thinsp;19/35, 54.3%). Concurrent extramedullary manifestations included soft-tissue plasmacytomas (25.7%, n\u0026thinsp;=\u0026thinsp;9/35), pleural plasmacytomas (8.6%, n\u0026thinsp;=\u0026thinsp;3/35), and secondary plasma cell leukemia (2.9%, n\u0026thinsp;=\u0026thinsp;1/35). Disease staging by the International Staging System (ISS) revealed high-risk features predominance, with 62.9% (n\u0026thinsp;=\u0026thinsp;22/35) classified as stage III, 22.9% (n\u0026thinsp;=\u0026thinsp;8/35) as stage II, and 14.3% (n\u0026thinsp;=\u0026thinsp;5/35) as stage I.\u003c/p\u003e\u003cp\u003eFluorescence in situ hybridization (FISH) analyses were successfully performed in 29 patients (82.9% of the cohort), identifying high-risk cytogenetic aberrations: 1q21 amplification (n\u0026thinsp;=\u0026thinsp;14/29, 48.3%), \u003cem\u003eTP53\u003c/em\u003e deletions (n\u0026thinsp;=\u0026thinsp;3/29, 10.3%), and immunoglobulin heavy chain (IgH) translocations\u0026mdash;specifically t(4;14)(p16;q32) (n\u0026thinsp;=\u0026thinsp;4/29, 13.8%), t(11;14)(q13;q32) (n\u0026thinsp;=\u0026thinsp;1/29, 3.4%), and t(14;16)(q32;q23) (n\u0026thinsp;=\u0026thinsp;1/29, 3.4%). Conventional karyotyping, available for 14 patients (40.0%), revealed complex karyotypes (\u0026ge;\u0026thinsp;3 chromosomal abnormalities) in 35.7% (n\u0026thinsp;=\u0026thinsp;5/14) of evaluable cases.\u003c/p\u003e\u003cp\u003eMM-CNS diagnosis was confirmed through multimodal approaches: histopathological verification via biopsy (n\u0026thinsp;=\u0026thinsp;2/35, 5.7%), CSF analysis (n\u0026thinsp;=\u0026thinsp;12/35, 51.4%), and neuroimaging (n\u0026thinsp;=\u0026thinsp;21/35, 42.9%). Anatomical involvement patterns included isolated meningeal infiltration (n\u0026thinsp;=\u0026thinsp;6/35, 17.1%), solitary parenchymal lesions (n\u0026thinsp;=\u0026thinsp;27/35, 77.1%), and combined meningeal-parenchymal disease (n\u0026thinsp;=\u0026thinsp;2/35, 5.7%). Among 18 patients undergoing CSF analysis, key findings comprised elevated protein levels in 66.7% (n\u0026thinsp;=\u0026thinsp;12/18), morphology identified malignant plasma cells in 61.1% (n\u0026thinsp;=\u0026thinsp;11/18), and clonal plasma cell confirmation by flow cytometric immunophenotyping (CD38+/CD138+/CD56\u0026thinsp;+\u0026thinsp;with light-chain restriction) in 83.3% (n\u0026thinsp;=\u0026thinsp;10/12) of tested cases.\u003c/p\u003e\u003cp\u003eAmong patients developing CNS involvement at MM relapse (n\u0026thinsp;=\u0026thinsp;24, 68.6% of the cohort), the median number of preceding treatment lines was 2 (range: 1\u0026ndash;8), with all patients exposed to multi-agent regimens. The median interval from initial MM diagnosis to CNS progression was 22.8 months (range: 2.4\u0026ndash;77.7). Prior therapeutic exposures included PI-based combinations (n\u0026thinsp;=\u0026thinsp;22/24, 91.7%), IMiD-based regimens (n\u0026thinsp;=\u0026thinsp;12/24, 50.0%), CD38-targeted monoclonal antibodies (n\u0026thinsp;=\u0026thinsp;7/24, 29.2%), and ASCT (n\u0026thinsp;=\u0026thinsp;6/24, 25.0%).\u003c/p\u003e\u003cp\u003eCompared to patients with CNS involvement at initial MM diagnosis (n\u0026thinsp;=\u0026thinsp;11), those developing CNS relapse post-treatment exhibited significantly higher rates of meningeal infiltration (33.3% vs. 0%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.030) and CSF abnormalities, including elevated protein or clonal plasma cells (90.9% vs. 28.6%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.012).\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\n\u003ch3\u003eTreatment Regimens and Efficacy\u003c/h3\u003e\n\u003cp\u003eTherapeutic strategies for MM-CNS are summarized in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Within the cohort, 33 patients (94.3%) received CNS-directed therapy, including multimodal approaches: systemic chemotherapy (n\u0026thinsp;=\u0026thinsp;31/35, 88.6%), intrathecal therapy (n\u0026thinsp;=\u0026thinsp;18/35, 51.4%), and radiotherapy (n\u0026thinsp;=\u0026thinsp;6/35, 17.1%). One patient underwent surgical resection of a symptomatic parenchymal mass. Consolidation therapies included ASCT post-induction (n\u0026thinsp;=\u0026thinsp;5/35, 14.3%) and CAR-T cell therapy as salvage treatment for refractory disease (n\u0026thinsp;=\u0026thinsp;4/35, 11.4%).\u003c/p\u003e\u003cp\u003eSystemic chemotherapy regimens universally employed combination strategies to address blood-brain barrier penetration challenges and therapeutic resistance. PIs formed the backbone of therapy in 82.9% of cases (n\u0026thinsp;=\u0026thinsp;29/35). These were frequently combined with cytotoxic chemotherapy (n\u0026thinsp;=\u0026thinsp;22/35, 62.9%). IMiDs were integrated into 42.9% of regimens (n\u0026thinsp;=\u0026thinsp;15/35), while CD38-targeted monoclonal antibody therapy (daratumumab) demonstrated limited utilization (20.0%, n\u0026thinsp;=\u0026thinsp;7/35).\u003c/p\u003e\u003cp\u003eAs shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, systemic therapeutic efficacy was categorized as follows: disease progression in 7 patients (20.0%), stable disease in 4 (11.4%), and partial or complete responses in the remaining 22 (62.9%). Among responders, 8 patients (36.4%) achieved complete remission (CR), 2 (9.1%) attained very good partial remission (VGPR), and 12 (54.5%) showed partial remission (PR) per IMWG criteria. Notably, 14 of the 22 responders (63.6%) experienced disease relapse within a median of 3.1 months (range: 1.2\u0026ndash;8.4), underscoring the transient nature of therapeutic responses.\u003c/p\u003e\u003cp\u003eFor CNS-specific outcomes, objective responses were documented in 21 patients (60.0%), suggesting activity against CNS-infiltrating myeloma cells, though standardized criteria for CNS-MM response assessment remain lacking.\u003c/p\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eSurvival analysis\u003c/h2\u003e\u003cp\u003eWith a median follow-up duration of 19.1 months (range: 0.1\u0026ndash;46.8), the median OS from CNS involvement diagnosis was 13.0 months (range: 0.1\u0026ndash;43.1), and the median PFS was 4.2 months (range: 0.1\u0026ndash;19.3). Kaplan-Meier curves for OS and PFS are presented in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. Patients with CNS involvement at initial MM diagnosis exhibited significantly prolonged survival compared to those developing CNS relapse post-treatment (median OS: 34.0 months [95% CI: 18.6\u0026ndash;49.4] vs. 12.8 months [95% CI: 7.1\u0026ndash;18.5]; log-rank \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.01, Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e\u003cp\u003ePrognostic factors for OS were evaluated using univariate and multivariate Cox proportional hazards models (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Univariate analysis identified post-treatment CNS involvement (HR\u0026thinsp;=\u0026thinsp;4.735, 95% CI: 1.313\u0026ndash;17.077, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.018) as significant predictors of poor survival. This survival disparity persisted after adjusting for age, ISS stage and anatomical involvement patterns (adjusted HR\u0026thinsp;=\u0026thinsp;4.825, 95% CI: 1.323\u0026ndash;17.596, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.017).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eUnivariate and Multivariate Cox Regression Analysis for Overall Survival\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVariable\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eUnivariate Analysis\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003eMultivariate Analysis\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHR (95% CI)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eP-value\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAdjusted HR (95% CI)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eP-value\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge (\u0026ge;\u0026thinsp;60 years old)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.717 (0.629\u0026ndash;4.689)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.292\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2.188 (0.743\u0026ndash;6.452)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.155\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e\u003cp\u003ePost-treatment CNS involvement\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4.735 (1.313\u0026ndash;17.077)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.018\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e4.825(1.323\u0026ndash;17.596)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.017\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMeningeal infiltration\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.151 (0.317\u0026ndash;4.182)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.831\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.580 (0.421\u0026ndash;5.882)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.496\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eISS stage III\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.063 (0.416\u0026ndash;2.720)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.898\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.372(0.461\u0026ndash;4.082)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.570\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"5\"\u003eCNS, Central nervous system; ISS International Staging System\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThis multicenter retrospective study systematically elucidated the clinical characteristics, treatment patterns, and prognostic trends of MM-CNS. As a rare complication of MM (with an incidence rate well under 1% overal[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] ), CNS involvement exhibits complex underlying mechanisms and is associated with extremely poor prognosis[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], demonstrating a median OS of 13.0 months based on our cohort analysis. Our findings describe the characteristics, treatment patterns, and prognosis of the MM-CNS population in China, providing baseline data and preliminary insights for understanding this clinical challenge.\u003c/p\u003e\u003cp\u003eIn our cohort, 68.6% of CNS involvement cases emerged after MM treatment (with a median time to onset of 22.8 months), suggesting that therapeutic pressures may drive tumor cell CNS infiltration through clonal selection. This observation aligns with previous reports: a multicenter retrospective study of 172 patients demonstrated CNS infiltration at relapse in 78% of cases[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e], while another retrospective study identified CNS involvement at initial diagnosis versus relapse in 24% and 76% of 76 evaluated cases, respectively[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Notably, the post-treatment CNS involvement group exhibited significantly higher rates of leptomeningeal involvement (53.3% vs. 0%) and cerebrospinal fluid (CSF) abnormalities (83.3% vs. 33.3%) compared to the diagnosis-time CNS involvement group (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). This temporal association suggests that prolonged therapeutic exposure may select for aggressive subclones with enhanced neurotropic potential. Molecularly, the high prevalence of high-risk cytogenetic aberrations (51.7%) and complex karyotypes (35.7%) in our cohort is consistent with the genetic profiles associated with high risk of CNS invasion reported before[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. These genetic aberrations likely promote CNS metastasis by upregulating homing receptors and driving extracellular matrix remodeling [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] .\u003c/p\u003e\u003cp\u003eWhile neuroimaging findings demonstrated substantial diagnostic utility in detecting CNS involvement, CSF confirmation rates remained suboptimal, highlighting persistent challenges in diagnostic standardization. Notably, discordant results between conventional cytomorphological assessments and flow cytometric analyses were observed in a subset of cases, emphasizing the critical need for integrating advanced detection modalities, such as high-sensitivity immunophenotyping or molecular profiling techniques, to overcome limitations inherent to single-method diagnostic paradigms.\u003c/p\u003e\u003cp\u003eOur study demonstrates a significant survival advantage in MM-CNS at initial diagnosis (n\u0026thinsp;=\u0026thinsp;9, median OS 34.0 months) compared to those developing CNS involvement post-treatment (n\u0026thinsp;=\u0026thinsp;26, median OS 12.8 months; p\u0026thinsp;=\u0026thinsp;0.01), a finding consistent with prior observations from a Japanese nationwide multicenter study of 77 patients (48.5 vs. 2.7 months for diagnosis-time vs. relapsed CNS involvement)[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. This discrepancy may be attributed to the diagnosis-time group having received fewer prior therapy and thus exhibiting greater sensitivity to systemic treatment and the post-treatment group having accumulated high-risk genetic abnormalities due to multiple relapses.\u003c/p\u003e\u003cp\u003eRegarding therapeutic strategies, current literature supports multimodal approaches for MM-CNS management, including IT, radiotherapy, and systemic regimens such as IMiDs, PIs, cytotoxic chemotherapy, CD38-targeted monoclonal antibody, high-dose dexamethasone, ASCT, and CAR-T cell therapy[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Recent evidence highlights the promise of CAR-T therapy, with one study reporting comparable outcomes in 17 MM-CNS patients receiving idecabtagene vicleucel (ide-cel) versus non-CNS myeloma (mPFS 10.5 vs 8.5 mo, p\u0026thinsp;=\u0026thinsp;0.59; mOS 13 vs 10.6 mo, p\u0026thinsp;=\u0026thinsp;0.92; ORR 82% vs 80%)[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Another study of 10 MM-CNS patients treated with ide-cel (n\u0026thinsp;=\u0026thinsp;6) or ciltacabtagene autoleucel (n\u0026thinsp;=\u0026thinsp;4) demonstrated an 80% best overall response rate (\u0026ge;\u0026thinsp;VGPR) and 100% CNS response rate, with median OS and PFS of 13.3 and 6.3 months at median 381-day follow-up[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Given that most patients develop CNS involvement after multiple prior lines of therapy and exhibit short remission durations (3.1 months in this cohort), combination therapies are often necessary[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. However, significant heterogeneity in treatment protocols (e.g., 51.4% receiving IT therapy, 17.1% combined with radiotherapy) and limited sample size (n\u0026thinsp;=\u0026thinsp;35) preclude comparative efficacy analysis across modalities, a limitation also observed in other retrospective studies[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] .\u003c/p\u003e\u003cp\u003eThe retrospective design and sample size limitations of this study suggest that our conclusions warrant further validation in prospective trials. While our findings reveal critical associations between treatment timing and survival outcomes, deeper exploration of molecular mechanisms and microenvironmental interactions remains necessary. Future research should prioritize the establishment of standardized diagnostic frameworks, the development of dynamic monitoring tools to track disease progression, and the integration of systemic and localized interventions through innovative therapeutic paradigms. Strengthening interdisciplinary collaboration, constructing risk stratification models, and deepening molecular subtyping studies will be pivotal in advancing breakthroughs for this clinical challenge.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments:\u0026nbsp;\u003c/strong\u003eThe authors acknowledge all patients who participated in this study and their families.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding Declaration\u003c/strong\u003e\u003cstrong\u003e:\u003c/strong\u003e This study was supported by National Natural Science Foundation of China (82470198), and Clinical Research Incubation Project (Beijing Chao-Yang Hospital, Capital Medical University, CYFH202208).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHuman Ethics and Consent to Participate declarations:\u003c/strong\u003e The study protocol was conducted in accordance with the principles of the Declaration of Helsinki and approved by the Health Human Research Ethics Committee of Beijing Chaoyang Hospital, Affiliated to Capital Medical University. Written informed consent was obtained from the participates.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability declaration:\u003c/strong\u003e The data that support the results of this study are available from the corresponding authors upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict-of-interest disclosure:\u003c/strong\u003e The authors declare no competing financial interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contribution:\u0026nbsp;\u003c/strong\u003eContribution: W.G. designed the study, interpreted the data, and reviewed the manuscript; W.-J.L.interpreted the data and wrote the manuscript. W.-J.L., T.-W.W., J.M., L.-Y.L., Z.-H.L., J.L., G.-R. 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Hematol Oncol Abbr 30:170\u0026ndash;174. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1002/hon.1021\u003c/span\u003e\u003cspan address=\"10.1002/hon.1021\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Multiple myeloma, Central nervous system involvement, Characteristics, Therapy, Prognosis","lastPublishedDoi":"10.21203/rs.3.rs-7484907/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7484907/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eCentral nervous system (CNS) involvement is a rare and aggressive complication of multiple myeloma (MM), with limited data on its clinical characteristics and prognosis. This multicenter study characterizes the largest Chinese cohort of MM patients with CNS involvement (MM-CNS) to date.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eWe conducted a multicenter retrospective study across nine hematology centers in China (July 2017-June 2024), analyzing clinical records of MM-CNS patients. Data collection encompassed diagnostic parameters, treatment regimens, and survival outcomes.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eAmong 35 identified MM-CNS cases (median age 55 years, range 40\u0026ndash;83), CNS manifestations presented at initial MM diagnosis in 31.4% (11/35) versus relapse in 68.6% (24/35), with median latency of 22.8 months from MM diagnosis. Predominant features included IgG subtype (51.4%), λ light chain restriction (54.3%), and high-risk cytogenetics: 1q21 amplification (48.3%), t(4;14) translocation (13.8%), and complex karyotypes of chromosome (35.7%). Diagnostic confirmation combined CSF analysis (protein elevation, plasma cell detection) with neuroimaging (meningeal/parenchymal lesions). Treatments included systemic chemotherapy (88.6%), intrathecal therapy (51.4%), radiotherapy (17.1%), chimeric antigen receptor T-cell (CAR-T) therapy (11.4%), and autologous stem cell transplantation (ASCT) (14.3%). Despite 62.9% overall response rate (36.4% complete remission), 56% relapsed within median 3.1 (range 1.2\u0026ndash;8.4) months. The median follow-up duration was 19.1 months (range: 0.1\u0026ndash;46.8). Median overall survival (OS) at 13.0 months (range 0.1\u0026ndash;43.1) with 60% mortality (21/35).\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e\u003cp\u003eCNS involvement in MM is associated with aggressive disease and poor prognosis. Despite transient responses to multimodal therapies, rapid progression and high mortality persist. Novel strategies are urgently needed to improve outcomes in this high-risk population.\u003c/p\u003e","manuscriptTitle":"Clinical characteristics and prognosis of central nervous system involvement in multiple myeloma: a multicenter retrospective analysis from China","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-12 15:13:40","doi":"10.21203/rs.3.rs-7484907/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"0ab35162-3881-4da0-a874-d0fdd7a97ca2","owner":[],"postedDate":"September 12th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-09-19T14:08:34+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-12 15:13:40","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7484907","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7484907","identity":"rs-7484907","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}