Центральная нервная система Множественная миелома: обновление 2026 года.

Introduction

Multiple myeloma (MM) is a hematologic malignancy originating from abnormal plasma cells, classically presenting with CRAB features. While the advent of novel agents has significantly improved systemic survival, disease relapse remains a challenge. In relapsed/refractory MM (RRMM), extramedullary disease (EMD), particularly central nervous system involvement (CNS-MM), heralds a highly aggressive phase with a historically poor prognosis [ 1 , 2 ].

CNS-MM is rare (~ 1%), and is classified as primary (presenting at diagnosis) or secondary (occurring at relapse). Diagnosis relies on neuroimaging and cerebrospinal fluid (CSF) analysis, yet unified response criteria are lacking. The blood-brain barrier (BBB) is the primary obstacle, restricting the efficacy of many conventional chemotherapies and resulting in dismal outcomes measured in months. However, the therapeutic landscape is rapidly evolving.

Current multimodal strategies integrate local control with BBB-penetrating agents and immunotherapy. Alongside standard Novel Agents (NAs), bispecific antibodies (BsAbs) and CAR-T therapy now offer genuine potential for extended remission. Although clinical data remain limited by rarity, accumulating evidence is defining a new standard of care.

This review delineates modern epidemiology, risk factors, and diagnostic methodologies. Moving beyond historical strategies, we synthesize current evidence on these evolving therapeutic options, specifically highlighting what is essential for clinical decision-making.

Epidemiological characteristics

Recent retrospective studies consistently report a low incidence of CNS-MM, accounting for approximately 0.7% to 1.2% of all MM patients [ 2 – 4 ]. Unlike the general MM population (median diagnosis age 69 years), CNS-MM patients tend to be younger, with a median age at initial MM diagnosis around 58 years [ 3 , 5 , 6 ], and they often present CNS diseases at a median age of 62 years [ 3 , 4 , 5 , 6 ]. The median time from MM diagnosis to CNS involvement in recent studies ranges from 14.2 to 28 months [ 3 , 5 , 6 , 7 ].

CNS-MM is classified as primary (diagnosed at presentation) or secondary (occurring at relapse). The proportion of primary CNS-MM varies across cohorts [ 3 , 5 , 6 , 7 ]. Whether the incidence is biologically rising due to novel agents or merely reflects improved survival time of MM remains debated [ 8 ].

To provide more detailed epidemiological context and to highlight the heterogeneity across studies, a summarized data from major retrospective cohorts is shown in Table 1 . The prevalence of primary CNS-MM shows considerable variation, with estimates as high as roughly 20% in the French cohort and as low as 0% in the Chinese study. These differences likely reflect variations in referral bias and the degree of CNS evaluation at initial diagnosis. Importantly, the inadvertent inclusion of osteo-dural multiple myeloma (OD-DMM) patients into CNS-MM cohorts could significantly inflate the proportion of primary disease and overestimate survival outcomes. Therefore, a clear distinction between true CNS-MM and OD-DMM is a prerequisite for accurate interpretation of the literature.

Risk factors for CNS involvement

Lactate dehydrogenase (LDH) and extramedullary disease (EMD)

Elevated serum LDH is a frequently reported predictor of CNS-MM, but it primarily reflects aggressive systemic EMD rather than CNS-specific tropism and most cited studies do not distinguish between these two possibilities. Given that 54% of CNS-MM patients have concomitant EMD in the study of Katodritou et al. [ 3 ], LDH should be interpreted as a marker of systemic tumor burden, and its role as an independent CNS risk factor requires validation through multivariate analysis. Additionally, the presence of concurrent EMD at other sites is a major risk factor, indicating a systemic propensity for the plasma cell clone to breach normal tissue barriers and invade sanctuaries like the CNS [ 3 , 7 ].

Monoclonal immunoglobulin isotype

The distribution of M-protein isotypes in CNS-MM generally mirrors MM (predominantly IgG, followed by IgA) [ 3 , 5 , 9 ]. While early data suggested associations between specific isotypes (e.g., IgD) and CNS aggressiveness [ 7 ], larger modern cohorts have not confirmed these as robust independent risk factors [ 3 ]. Thus, isotype alone is insufficient for prognostic stratification.

Malignant Plasma Cell Immunophenotype

CSF flow cytometry focuses on identifying immunophenotypic signatures of invasion. Loss of CD56 (NCAM) is the most frequently cited marker associated with enhanced migratory capacity and CNS tropism, although heterogeneity exists [ 10 – 13 ]. Expression of CD28 and CD20 remains under investigation but shows less consistent correlation in recent studies.

Cytogenetic abnormalities

CNS-MM is driven by high-risk cytogenetics. The most frequently observed aberrations include IgH translocations, 1q gain/amplification, del(17p)/TP53 loss, and MYC abnormalities [ 3 , 5 , 6 , 14 ]. Emerging evidence links specific mutations, such as CIC mutations, to acquired resistance and CNS localization [ 15 ].

Clinical features and diagnostics

Clinical manifestations

CNS-MM presentations are highly heterogeneous and non-specific, often mimicking other neurologic disorders like metastasis or infection. Symptoms vary by anatomical location (Table 2 ).

Radiographic findings

In modern practice, CNS-MM is radiographically classified as either intraparenchymal (solid plasmacytomas) or leptomeningeal (diffuse infiltration) [ 21 ]. The incidence of leptomeningeal disease ranges from 50% to 66%, while intraparenchymal lesions account for 30% to 40% [ 3 , 6 , 7 ]. Prior reviews suggested an equal distribution [ 22 ]. Magnetic Resonance (MR) offers superior soft tissue contrast for detecting both intraparenchymal masses and leptomeningeal enhancement. 18 F-FDG PET/CT provides high sensitivity for detecting concomitant EMD and assessing metabolic activity of CNS lesions, which is critical for staging and treatment response assessment. Computed Tomography (CT) is used primarily to detect bone involvement or when MR is contraindicated, but has limited utility for soft tissue infiltration.

Importantly, distinct anatomical patterns of CNS involvement are associated with different prognoses and therapeutic implications. Leptomeningeal disease generally represents a more aggressive, diffuse process and portends the poorest prognosis. In contrast, focal intraparenchymal or osteo-dural lesions–particularly those that are well-circumscribed and accessible to localized radiotherapy–may achieve more durable local control and potentially improved survival outcomes when treated with radiotherapy [ 23 , 24 ]. Manzar et al. reported that patients receiving definitive radiotherapy for focal CNS-MM lesions experienced more sustained CNS responses, supporting this concept [ 23 ].

Laboratory findings

CSF Free Light Chain (FLC) Assay represents a valuable, minimally invasive adjunct. Elevated kappa/lambda ratios in the CSF suggest clonal plasma cell proliferation. This assay is particularly useful in clinical settings where rapid flow cytometry is unavailable, offering a higher diagnostic yield than routine CSF protein analysis [ 25 ].

Diagnosis and staging

Diagnostic criteria and challenges

Currently, no internationally unified diagnostic criteria exist. Diagnosis relies mainly on a comprehensive evaluation of three perspectives [ 22 ]: (1) neurological symptoms/signs suggestive of CNS involvement; (2) imaging evidence of intraparenchymal plasmacytoma or diffuse infiltration; and (3) CSF confirmation of malignant plasma cells via flow cytometry (CD38⁺CD138⁺ with κ/λ restriction) [ 9 ] (Fig. 1 ). The overarching principle is to adhere to disease definitions while considering treatment implications.

Key challenges include nonspecific symptoms that mimic infection or metastasis, diverse imaging patterns with false negatives (especially leptomeningeal disease) [ 22 ], suboptimal CSF sensitivity (false negatives from a single lumbar puncture or localized disease) [ 26 ], lack of standardized criteria impairing cross-study comparability, and difficulty obtaining tissue from deep or diffuse lesions.

Regarding CSF routine tests: while elevated CSF pressure and M-protein are frequently observed, their diagnostic specificity is low. Elevated pressure has multiple etiologies, and CSF M-protein can be present in MM without CNS involvement. Therefore, definitive CSF diagnosis requires direct detection of malignant plasma cells; routine tests serve primarily to prompt specialized investigation.

Critically, osseous/dural-based MM (OD-DMM) is biologically and prognostically distinct from true CNS-MM. OD-DMM patients have a median overall survival (OS) of approximately 25 months versus 12 months for true CNS-MM [ 21 ], warranting classification as a separate entity [ 27 ]. The appreciable proportion of OD-DMM in some cohorts suggests historical under-recognition [ 6 ]. Given profound differences in anatomy, biology, and prognosis, modern diagnostic workflows must explicitly distinguish OD-DMM from CNS-MM.

Diagnostic modalities

CT, MR, and PET/CT play complementary roles. MR is the preferred modality for CNS lesions, excelling at detecting intraparenchymal and early soft-tissue abnormalities. CT better depicts osseous destruction (relevant for OD-DMM) and serves as an alternative when MR is contraindicated. 18 F-FDG PET/CT shows high sensitivity for EMD and allows for synchronous assessment of systemic disease burden [ 28 ].

CSF analysis is the cornerstone of CNS-MM diagnosis. Conventional cytology has high specificity but limited sensitivity [ 26 ]. Flow cytometry offers superior sensitivity via the detection of CD38⁺CD138⁺ clonal plasma cells with κ/λ restriction [ 9 , 26 ]. False-negative rates remain a significant challenge, primarily due to low cell count in the CSF samples patchy leptomeningeal involvement, or delayed sample processing [ 22 , 26 ].

Given the limitations of any single test, a multimodal diagnostic approach is strongly advised. CSF flow cytometry results should be integrated with neuroimaging findings. For instance, typical MR findings may support a diagnosis even if flow cytometry is negative; conversely, positive flow cytometry alone warrants a diagnosis of CNS-MM regardless of imaging findings.

M-protein detection offers only adjunctive clues, while cytogenetic testing (FISH, SNP array) provides essential prognostic information. The FLC assay, although promising as a diagnostic adjunct [ 25 ], requires further validation. Histopathological confirmation via surgical biopsy has high specificity [ 29 , 30 ] but is often limited by lesion accessibility.

Beyond these established methods, modern molecular diagnostics are emerging as a promising frontier. In primary CNS lymphoma (PCNSL), next-generation sequencing (NGS)-based detection of circulating tumor DNA (ctDNA) in CSF has become an increasingly important tool for diagnosis, genotyping, and monitoring of minimal residual disease (MRD) [ 31 ]. By contrast, no standardized NGS-based CSF assay currently exists for CNS-MM. However, given that MM is characterized by recurrent mutations detectable by modern genomic panels, CSF ctDNA analysis holds significant theoretical promise for non-invasive diagnosis and monitoring.

Limitations of conventional staging systems

Standard MM staging systems (Durie-Salmon, ISS, Revised ISS, and R2-ISS) exhibit limited utility in CNS-MM. Retrospective studies indicate no significant difference in ISS/R-ISS distribution between CNS-MM and MM cohorts [ 3 , 7 ], and these systems fail to stratify OS within the CNS-MM population [ 5 , 23 ]. While older studies report a higher proportion of D-S Stage III patients (reflecting tumor burden) [ 14 , 26 ], validation remains suboptimal.

These systems fail because: (1) they do not capture the unique biology of CNS-MM (BBB penetration, CNS microenvironment colonization); (2) CNS involvement itself is a dominant adverse factor that overwhelms the discriminatory power of conventional indices; and (3) CNS-specific parameters are not integrated. Thus, a novel prognostic model incorporating CNS-specific variables, molecular markers, and systemic disease status is urgently needed.

Therapy and prognosis

CNS-MM therapy presents a major challenge characterized by extreme aggressiveness and BBB sequestration. Due to rarity, prospective trials are lacking; current practice relies on retrospective data aimed at maximizing CNS control through multimodal integration. Treatment selection is individualized based on lesion characteristics, patient factors, and disease timing. Key modalities include Radiotherapy (RT), Intrathecal chemotherapy (IT), stem cell transplantation, BBB-penetrating novel agents and CAR-T therapy (Fig. 2 ). Despite poor overall outcomes, multimodal combinations and early detection are correlated with improved OS [ 3 , 5 , 32 ].

A significant prognostic disparity exists between primary and secondary CNS-MM, with primary cases consistently showing superior survival. Multicenter data show a median OS of 48.5 months for primary CNS-MM versus 2.7 months for secondary disease (1-year survival: 66.67% vs. 6.76%) [ 5 ]. Chen et al. validated longer progression-free survival (PFS) and OS in primary cases [ 32 ], and other centers reported a median OS of 7.4 months, still significantly better than secondary disease ( p < 0.01) [ 33 ]. Notably, the prevalence of primary cases may have been historically underestimated.

Conventional therapies and stem cell transplantation

Radiotherapy (RT) is a crucial local control modality for focal lesions, correlating with prolonged OS despite variable survival impacts across studies [ 5 ]. Manzar et al. reported that among 45 CNS-MM patients treated with CNS-directed RT, 68.9% received CSI(craniospinal irradiation) or whole brain RT (median 20 Gy/10 fractions), yielding a CR rate of 66.7% in evaluable patients. Focal brain disease was associated with significantly improved overall survival. However, this study does not provide data on long-term tolerability of whole brain RT, nor does it directly compare whole brain RT versus focal RT. Besides the study did not assess neurocognitive toxicity, and 53% of patients could not be evaluated, highlighting the poor overall prognosis even with RT [ 23 ]. For large lesions causing mass effect, early surgical resection combined with RT is vital [ 34 ].

Intrathecal (IT) chemotherapy delivers agents directly into the CSF. Retrospective data regarding OS improvement are mixed [ 5 ]. Regimens typically include methotrexate, cytarabine, methylprednisolone, or thiotepa [ 6 ].

Stem Cell Transplantation (SCT) offers a significant survival benefit in eligible patients. Studies demonstrate superior OS with Autologous SCT (ASCT) (19.2 vs. 2.1 months) and longer PFS [ 24 , 35 ], though outcomes are heterogeneous. Both ASCT and allogeneic SCT are correlated with prolonged OS [ 5 ]. However, widespread applicability remains limited by fitness, toxicity concerns, and highly variable relapse timing (2 months to 11 years) [ 36 – 40 ].

In MM, the standard high-dose conditioning regimen consists of melphalan 200 mg/m² [ 41 ]. For patients with CNS-MM undergoing ASCT, melphalan has been shown to cross the BBB (CSF-to-plasma ratio of approximately 10–20%) [ 35 ]. To date, no CNS-MM-directed modifications of transplant conditioning have been systematically explored. Case reports and small series have described the addition of intrathecal chemotherapy, radiotherapy, or agents with higher CNS penetration prior to SCT, but these approaches remain anecdotal and unvalidated in larger trials [ 36 – 40 ]. Prospective studies evaluating CNS-penetrating conditioning regimens are urgently needed.

Novel agents (NAs)

Next-generation agents, carfilzomib, lenalidomide, pomalidomide, selinexor, and daratumumab, have significantly prolonged survival in CNS-MM since their advent [ 3 ]. Multimodal strategies optimize outcomes: combinations of NAs or systemic therapy plus RT yield superior OS versus monotherapy [ 5 , 24 ]. However, after excluding OD-DMM patients, one study found no statistical difference in OS/PFS between NAs and conventional agents in true CNS-MM, though a PFS trend favored NAs [ 24 ]. BBB penetrability is the key determinant of efficacy.

Proteasome inhibitors (PIs)

Traditional PI bortezomib exhibits poor BBB penetration and limited CNS efficacy [ 5 ], though occasional cases respond under special conditions [ 42 ]; high neurotoxicity rates may obscure CNS relapse symptoms [ 43 ]. Next-generation PIs, carfilzomib and marizomib, show improved BBB penetrability [ 3 ]. Marizomib is the first PI proven to effectively cross the BBB and achieve therapeutic CNS concentrations [ 44 ], with case reports documenting remarkable neurological improvement, CSF plasmacytosis clearance, and leptomeningeal radiographic response, though large-scale data are lacking [ 45 ].

Immunomodulatory drugs (IMiDs)

Among IMiDs, pomalidomide demonstrates BBB penetration [ 3 ]. Pomalidomide-based combinations (e.g., PCD [ 46 ], PD [ 40 ]) exhibit activity in CNS-MM, especially in cases with concurrent extramedullary disease (EMD) or renal impairment. They achieve response rates of 31% [ 47 ] and serve as effective CAR-T bridging therapy [ 48 ]. Lenalidomide-based regimens show significant efficacy [ 5 ]. However, controversy persists regarding the impact of IMiDs on survival [ 49 , 50 ]. Thalidomide shows limited efficacy [ 5 ].

Monoclonal antibodies

Monoclonal antibodies: Daratumumab (anti-CD38) case reports suggest BBB penetration (evidenced by CD38-marker disappearance [ 45 ]) and efficacy when combined with pomalidomide [ 51 ]. Isatuximab (anti-CD38) plus pomalidomide/dexamethasone (IsaPD) achieved significant responses and neurological improvement in salvage therapy [ 30 ]. Elotuzumab (anti-SLAMF7) is ineffective as a monotherapy but may synergize with PIs/IMiDs [ 52 ].

Bispecific antibodies

Bispecific antibodies demonstrate groundbreaking potential. Initial case reports and single-center studies showed that elranatamab and teclistamab induced deep responses, including PET/CT-confirmed CR [ 53 ] and leptomeningeal regression [ 54 ]in heavily pretreated RRMM. A study of 8 patients confirmed clinical benefit with improved neurological function; all cytokine release syndrome (CRS) events were Grade 1 to 2, no high-grade toxicities occurred, and one patient maintained CR at 1 year, highlighting a favorable therapeutic window [ 55 ].

Larger studies solidified these findings. A pooled analysis of 24 CNS-MM patients revealed that BCMA- or GPRC5D-targeting bispecific antibodies achieved a 67% systemic overall response rate and a 58% CNS-specific response rate (37% CR), with durable responses. While infection rates (67%) were notable, CRS and immune effector cell-associated neurotoxicity syndrome (ICANS) were predominantly low-grade, with no severe cases, demonstrating manageable safety [ 56 ].

A critical insight regarding the optimal application of bispecific antibodies comes from the study by Mersi et al. [ 57 ], which compared direct use in active CNS disease versus consolidation after prior CNS-directed therapy. When used directly for active disease, median overall survival was only 4.8 months. In contrast, when used as consolidation after initial chemotherapy or intrathecal therapy, median CNS progression-free survival extended to 13.4 months. This suggests that these agents are best employed as consolidation rather than upfront therapy for uncontrolled CNS disease [ 57 ]. Notably, bispecific antibodies also serve as effective bridging to subsequent CAR-T therapy, with one study reporting long-term PFS exceeding 22 months after sequential treatment [ 56 ].

In summary, bispecific antibodies demonstrate strong CNS anti-tumor activity with manageable toxicity. Their successful utilization in consolidation and bridging functions establishes a promising model for this historically challenging disease.

CAR-T therapy

CAR-T, a frontier therapy for RRMM, shows significant potential in CNS-MM. Retrospective studies and case reports demonstrate high CNS response rates (100% [ 2 ]), substantial CR rates, and a manageable ICANS risk (≤ Grade 3) [ 2 , 14 ]. An IMS 2025 retrospective study found that CAR-T extended the median survival to 5.30 months, compared with 2.53 months with conventional therapy, without severe toxicity [ 58 ]. The latest data show a sustained CNS response in 80% (8/10) of patients, with efficacy comparable to that of a matched non-CNS-MM cohort receiving idecabtagene vicleucel (ide-cel). However, non-significant statistical differences and limited patient numbers preclude definitive equivalence conclusions, necessitating larger studies [ 59 ].

Short response duration is the primary limitation, with a median PFS ranging from 6.3 months [ 2 ] to 10.5 months [ 59 ]. Relapse may occur within [ 60 ] or outside [ 61 ] the CNS. Optimizing bridging therapy (e.g., pomalidomide [ 48 ]) is crucial [ 2 ]. Limitations include high costs, restricted accessibility, target-negative clones, and long-term safety concerns [ 62 ].

Conclusion

A major obstacle in CNS-MM therapy is the absence of a standardized diagnostic and therapeutic framework. This deficit compromises both clinical practice and scientific rigor.

Standardization of diagnosis and response assessment

Current diagnosis relies on heterogeneous, institution-specific combinations of clinical, imaging, and CSF findings. This lack of comparability leads to critical problems, notably the misclassification of OD-DMM as CNS-MM. Given OD-DMM’s significantly superior OS (~ 25 vs. 12 months) and distinct biology, this taxonomic confusion biases the understanding of true CNS-MM disease kinetics and treatment efficacy. Furthermore, the lack of precise patient definitions hinders reliable response assessment. While IMWG criteria are inapplicable, CNS-specific assessments (imaging, CSF clearance) lack consensus on definitions and timing.

To overcome this, future efforts must focus on: (1) establishing unified diagnostic criteria via international collaboration, explicitly classifying OD-DMM distinct from CNS-MM; (2) developing standardized CNS-specific response criteria (CNS-CR, CNS-PR); and (3) creating prognostic models that integrate molecular markers and CNS-specific parameters for precision therapy.

Future outlook

CNS-MM represents an ultimate challenge in plasma cell malignancies, driven by clonal selection and high-risk cytogenetics [ 8 ]. Progress has expanded our arsenal—from standard modalities to BBB-penetrating novel agents and immunotherapies (bispecific antibodies, CAR-T)—yielding modest gains. However, long-term survival remains dismal.

Future improvements require multidimensional synergy: (1) immediate establishment of unified diagnostic and prognostic frameworks; (2) optimization of multimodal strategies through better sequencing; (3) development of new BBB-penetrant agents; (4) leveraging genomics and single-cell sequencing; and (5) fostering global multicenter collaboration for prospective trials. Only through such synergy can meaningful survival benefits be achieved.

Author contributions

B.W. and W.L. conceived the manuscript and contributed to drafting. M.L., H.Z., X.J., W.W., and S.G. contributed to visualization and editing. B.W., W.L., and W.G. performed critical review. W.G. gave final approval. All authors have read and agreed to the version of the manuscript.

Funding

This study is supported by National Natural Science Foundation of China (Grant ID: 82470198); Scientific Research Innovation Project of Capital Medical University 2025 (Grant ID: XSKY2025303).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Competing interests

The authors declare no competing interests.

Footnotes

Publisher’s note

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

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Associated Data

Data Availability Statement

No datasets were generated or analysed during the current study.