Долговременная ремиссия CNS с эгранатамабом и внутритехологическая терапия в многократной миеломе.

Introduction

Central nervous system (CNS) involvement in multiple myeloma (MM) is a rare and aggressive complication, occurring in less than 1% of patients and typically associated with relapsed or refractory disease and poor prognosis [ 1 , 2 ]. Management remains challenging due to limited drug penetration across the blood–brain barrier and the absence of standardized treatment approaches. Recent advances in immunotherapy, particularly BCMA-targeted bispecific antibodies, have shown promising activity in heavily pretreated MM; however, data in CNS involvement are limited. Here, we report a case of high-risk MM with leptomeningeal disease achieving durable CNS remission with elranatamab combined with intrathecal therapy.

Case presentation

A 73-year-old woman was diagnosed with IgG kappa multiple myeloma in November 2016. At diagnosis, genetic risk assessment demonstrated TP53 [del(17p)] and 13q deletion, both conferring a high-risk profile. She was initially treated with two cycles of bortezomib, cyclophosphamide, and dexamethasone (VCD), achieving a minimal response (40%). After a total of six cycles of VCD, a very good partial response (VGPR) was obtained, and she underwent stem cell mobilization with cyclophosphamide 3 g/m² followed by autologous stem cell transplantation (ASCT) in April 2017. Lenalidomide maintenance was initiated thereafter.

Two years post-transplant (April 2019), she presented with a pathological fracture of the right humerus. MRI revealed a 7.2 cm expansile intramedullary lesion with cortical destruction, new compared with prior whole-body imaging. Lenalidomide was discontinued, palliative radiotherapy was delivered, and zoledronic acid was re-initiated. She was subsequently treated with ixazomib and dexamethasone and remained stable for 16 cycles until a new progressive lesion developed in the left humerus (July 2020). Radiotherapy was delivered, and therapy was switched to carfilzomib, lenalidomide, and dexamethasone (KRd). A partial response was achieved; however, during the sixth cycle she developed a pulmonary embolism, leading to discontinuation of lenalidomide and continuation as carfilzomib–dexamethasone with enoxaparin anticoagulation.

In September 2021, parasternal and scalp subcutaneous plasmacytomas developed and were treated with radiotherapy; treatment was escalated to daratumumab, lenalidomide, bortezomib, and dexamethasone (Dara-VRd), with rivaroxaban replacing enoxaparin. During the twelfth cycle (March 2022), she developed acute confusion, and MRI revealed a left parietal lesion consistent with plasmacytoma, which was treated with radiotherapy while Dara-VRd was maintained. In May 2022, transcatheter aortic valve implantation (TAVI) was performed for aortic stenosis without complication. After 14 cycles of Dara-VRd (April 2023), a new right temporal 3.5 cm lesion with surrounding edema and hemiparesis prompted urgent surgical resection, initiation of antiepileptic therapy, and focal radiotherapy, followed by total marrow irradiation (TMI) and a second ASCT in June 2023.

Three months later, whole-body MRI revealed widespread disease involving the calvarium, sternum, vertebrae, and long bones. Therapy was changed to isatuximab, pomalidomide, and dexamethasone (Isa-Pd) in September 2023. After 14 months of this regimen (October 2024), a right frontal dura-based lesion was identified and treated with radiotherapy; however, subsequent imaging confirmed leptomeningeal progression with intracranial disease progression.

In summary, prior to elranatamab, the patient had received six lines of therapy and was triple-class refractory, having progressed on proteasome inhibitors (bortezomib, ixazomib, carfilzomib), immunomodulatory agents (lenalidomide, pomalidomide), and anti-CD38 monoclonal antibodies (daratumumab, isatuximab), in addition to two autologous stem cell transplants. Most of these earlier lines were administered at external institutions prior to referral. Notably, lenalidomide was reintroduced within the KRd and Dara-VRd regimens despite prior progression on lenalidomide maintenance, which does not conform to guideline-preferred sequencing. This reflected the national reimbursement policy in effect during that period, under which novel agents such as carfilzomib, pomalidomide, and daratumumab were not reimbursed in combination with one another; lenalidomide, which was reimbursable as a combination partner, was therefore added to these agents, accounting for its repeated use. Following the pulmonary embolism, lenalidomide was discontinued and was only later reintroduced under therapeutic anticoagulation.

Elranatamab initiation and treatment course

In January 2025, elranatamab was initiated in combination with weekly intrathecal methotrexate (15 mg) and dexamethasone (8 mg). Elranatamab was administered subcutaneously using the standard MagnetisMM step-up dosing schedule (12 mg on day 1 and 32 mg on day 4, with hospitalization for monitoring during these first two step-up doses, followed by the full 76 mg dose weekly). Premedication with dexamethasone, an antihistamine, and acetaminophen was given prior to each step-up dose. Infective prophylaxis consisted of acyclovir and trimethoprim-sulfamethoxazole, and intravenous immunoglobulin was administered for hypogammaglobulinemia. No cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome (ICANS) was observed, and no tocilizumab or corticosteroid rescue was required. During maintenance, the patient experienced only occasional mild (grade 1–2) infections, limited to urinary tract infections, which were managed on an outpatient basis without hospitalization or interruption of therapy. No grade ≥ 3 infections or significant cytopenias occurred throughout the treatment course.

Baseline cerebrospinal fluid (CSF) cytology showed abundant atypical plasma cells, including binucleated forms and clusters (Fig.  1 a–c). MRI at the time of CNS relapse demonstrated diffuse leptomeningeal enhancement along the cortical sulci, most prominently in the bilateral temporal regions and along the sylvian fissures, consistent with leptomeningeal involvement (Fig.  2 a). After one month of therapy, neurological function improved, neurocognitive recovery was observed, and plasma cells in the CSF markedly decreased. Two months later (March 2025), MRI revealed no intracranial mass or leptomeningeal disease, and the CSF was acellular (Figs.  1 d and 2 b).

Cerebrospinal fluid (CSF) cytology before and after treatment (Romanowsky staining). ( a – c ) Pre-treatment (baseline) CSF demonstrating numerous atypical plasma cells with irregular nuclear contours, binucleation, and clustering, consistent with leptomeningeal involvement of multiple myeloma (original magnification ×400). ( d ) Post-treatment (week 8) CSF showing an acellular background following two months of combined elranatamab and intrathecal therapy, consistent with complete cytologic remission (original magnification ×100)

Contrast-enhanced T1-weighted brain MRI before and after treatment. ( a ) Pre-treatment image demonstrating linear leptomeningeal enhancement along the cortical sulci, most prominently in the bilateral temporal regions and along the sylvian fissures (arrows), consistent with leptomeningeal involvement. ( b ) Post-treatment image showing complete resolution of leptomeningeal enhancement following therapy, consistent with radiologic remission. Both images were acquired using the same contrast-enhanced T1-weighted protocol; minor differences in vascular enhancement between the two time points reflect technical and timing-related variation in contrast acquisition rather than differences in sequence or protocol

Intrathecal therapy course

Intrathecal therapy was administered weekly for 8 doses over the first two months, followed by biweekly administration for an additional 8 doses over the subsequent four months (16 doses in total), alongside weekly elranatamab. CNS response was assessed by serial CSF cytology and contrast-enhanced MRI; CSF flow cytometric immunophenotyping was not used as the primary basis for response assessment in this case.

Response assessment

At the six-month evaluation, serum immunofixation, serum protein electrophoresis, and serum free light chains had all normalized, with no detectable monoclonal band or M-protein, and CSF immunofixation was negative. Neurological deficits had completely resolved. These findings were consistent with a complete response by IMWG criteria; however, as a bone marrow biopsy was not performed at this time point, stringent complete response (sCR) was not formally assessed. Thereafter, intrathecal therapy was administered every two weeks in combination with biweekly elranatamab maintenance. The patient remains in sustained complete remission, ongoing at 18 months following elranatamab initiation.

Discussion

Central nervous system (CNS) involvement in multiple myeloma (MM) represents one of the rarest and most aggressive manifestations of the disease, with an estimated incidence of less than 1% [ 1 , 2 ]. It is associated with a dismal prognosis, with reported median overall survival typically ranging from 3 to 7 months, even in the era of novel agents [ 2 , 3 ]. The present case demonstrates a remarkably durable CNS remission achieved through combined treatment with elranatamab and intrathecal methotrexate plus dexamethasone, following multiple relapses and exposure to nearly all major anti-myeloma drug classes. As both agents were administered concurrently, the relative contribution of elranatamab versus intrathecal chemotherapy to the observed CNS response cannot be determined from a single case, and our observations should be interpreted within this limitation.

High-risk cytogenetic abnormalities, particularly TP53 deletion [del(17p)] and 13q deletion, are well-recognized drivers of genomic instability and are strongly associated with extramedullary dissemination, CNS tropism, and early relapse [ 4 , 5 ]. These alterations impair DNA repair and apoptotic pathways, promoting subclonal evolution and treatment resistance [ 4 ]. Patients harboring del(17p) consistently demonstrate inferior progression-free and overall survival and are overrepresented among cohorts with CNS involvement, supporting the concept that CNS-MM reflects selection of highly proliferative, microenvironment-independent clones capable of hematogenous spread [ 2 , 5 ].

Management of CNS-MM remains challenging and is largely based on multimodal strategies combining radiotherapy, intrathecal chemotherapy, and systemic therapy [ 2 , 6 ]. CNS involvement may manifest as leptomeningeal disease or as parenchymal or dura-based plasmacytomas. Importantly, CNS progression may become dissociated from systemic disease control: Tyczyńska et al. described a patient in whom multiple myeloma progressed locally into a dura mater plasmacytoma mimicking a brain tumor, in the absence of any concurrent systemic relapse, illustrating that the CNS can behave as a sanctuary site with distinct clonal dynamics [ 7 ]. This phenomenon is directly relevant to our patient, who developed a right frontal dura-based lesion and subsequent leptomeningeal disease during a period of otherwise controlled systemic myeloma, and it underscores that CNS relapse may be radiologically and biologically distinct from the systemic compartment. Such dissociation carries practical implications: it highlights the diagnostic difficulty of distinguishing CNS myeloma from primary intracranial pathology, the need for a low threshold for CSF evaluation and dedicated neuroimaging in symptomatic patients, and the rationale for combining CNS-penetrating local therapy with systemically active agents. However, outcomes remain poor, with median survival typically under one year even in intensively treated cohorts. A major limitation is the blood–brain barrier (BBB), which restricts penetration of most anti-myeloma agents. Among available therapies, immunomodulatory drugs (IMiDs) demonstrate partial CNS penetration, whereas proteasome inhibitors and most alkylating agents achieve limited intracranial bioavailability at conventional doses [ 1 , 2 , 6 ].

Monoclonal antibodies targeting CD38, such as daratumumab and isatuximab, have shown occasional activity in CNS-MM; however, evidence remains limited and largely anecdotal [ 8 ]. These agents, while highly effective systemically, do not reliably achieve durable intracranial disease control without adjunctive CNS-directed therapy, likely reflecting restricted BBB penetration [ 1 ].

In this context, bispecific antibodies (BsAbs) targeting B-cell maturation antigen (BCMA) and GPRC5D represent a major therapeutic advance [ 9 ]. These agents redirect cytotoxic T cells toward malignant plasma cells, inducing potent immune-mediated cytolysis. Elranatamab, a BCMA/CD3 bispecific antibody, has demonstrated response rates exceeding 60% in heavily pretreated MM, with durable responses reported in the MagnetisMM-3 study [ 10 ]. Although data regarding CNS involvement have been limited, emerging clinical evidence suggests that BsAbs may exert meaningful activity within the CNS compartment [ 11 ].

The multicentre cohort reported by Noveihed et al. represents the first systematic evaluation of bispecific antibodies in CNS-MM, demonstrating encouraging CNS responses among evaluable patients [ 11 ]. Notably, some patients achieved CNS remission, providing early clinical evidence that BsAbs may possess intrinsic CNS activity, and the absence of significant neurotoxicity in that cohort further supports the hypothesis that BCMA and GPRC5D expression is minimal in normal neural tissue, potentially limiting on-target CNS toxicity.

Our findings are consistent with the report by Mutlu et al., in which elranatamab induced both systemic and CNS remission [ 12 ]. In the present case, CSF cytology initially demonstrated dense infiltration by atypical plasma cells, which became completely acellular within two months of therapy. This was accompanied by complete radiologic resolution of leptomeningeal disease and full neurological recovery, with sustained remission ongoing beyond one year. These observations may hypothetically be explained by a model in which intrathecal chemotherapy provides rapid local cytoreduction and could transiently modulate blood–brain barrier permeability, potentially facilitating trafficking of activated T cells into the CNS and augmenting the efficacy of bispecific antibodies [ 9 ]. However, such a mechanism remains speculative, and a single case cannot establish synergy; this hypothesis should be regarded as generating a question for future study rather than a conclusion.

The use of T-cell–redirecting therapies in patients with CNS involvement raises important safety considerations, particularly regarding ICANS. Clinical trial data with elranatamab indicate a relatively low incidence of ICANS, with most events being low grade and manageable, likely reflecting the implementation of step-up dosing strategies and careful monitoring [ 10 , 13 ]. Despite theoretical concerns that BBB disruption and leptomeningeal disease may increase susceptibility to neurotoxicity, no ICANS or treatment-related neurological adverse events were observed in our patient. Only mild, self-limited infections occurred during prolonged therapy, consistent with the known infection risk of BCMA-directed bispecific antibodies and underscoring the importance of antimicrobial prophylaxis and immunoglobulin support [ 9 , 13 ]. This observation aligns with emerging evidence suggesting that BCMA-targeted bispecific antibodies can be administered safely in selected patients with CNS-MM under close clinical surveillance [ 11 ].

Compared with BCMA-targeted CAR-T cell therapies, which have demonstrated high efficacy but remain limited by manufacturing time, cost, and the need for bridging therapy, bispecific antibodies offer an off-the-shelf alternative that allows rapid initiation and flexible dosing [ 14 ]. The combined efficacy and favorable safety profile observed in this case, together with accumulating evidence from recent reports, support the growing role of bispecific antibodies as a practical and effective therapeutic option in CNS-MM [ 11 , 13 ].

This report has several limitations

First, as a single case, it cannot establish generalizable efficacy or synergy, and any mechanistic interpretation remains hypothesis-generating. Second, because elranatamab and intrathecal chemotherapy were administered concurrently, the individual contribution of each cannot be determined. Third, a bone marrow biopsy was not performed at the time of response assessment, so stringent complete response was not formally confirmed, and CNS response was evaluated by cytology and MRI rather than by CSF flow cytometry. Finally, the earlier treatment sequence—including the reuse of lenalidomide after prior progression, driven by reimbursement policies that did not cover combinations of novel agents—was largely determined at external centers and reflects real-world, reimbursement-constrained practice rather than guideline-optimal decision-making; this should be considered when interpreting the prior disease course.

Future management of CNS-MM will likely rely on rational multimodal strategies integrating CNS-directed therapies with systemic immunotherapy. Further research is needed to define the optimal sequencing, duration, and combination approaches, as well as to better characterize the CNS pharmacodynamics of emerging agents. Given the historically poor prognosis of CNS-MM, early recognition and timely initiation of effective therapy remain critical, and the systematic collection and sharing of well-documented cases remains essential to build collective knowledge in this rare setting [ 2 , 7 ]. This case adds to the growing body of evidence suggesting that BCMA-targeted bispecific antibodies, particularly elranatamab, may improve outcomes in this challenging clinical setting. Although a systematic review of the literature was not performed and available data remain limited, to our knowledge this durable remission of 18 months is among the longest reported in association with elranatamab in CNS myeloma.

Acknowledgements

The authors would like to thank Dr. Özden Özer for providing the cytological specimens and Mr. Emre Üstün, Nurse Practitioner, for his valuable contributions to the clinical management of the patient.

Author contributions

S.M. designed the study and wrote the manuscript. S.M. and Ö.G.S. made clinical treatment decisions, performed patient follow-up, and collected clinical data. S.M. and Ö.G.S. contributed to manuscript revision and finalization. All authors reviewed and approved the final manuscript.

Funding

This study was not supported by any sponsor or funder.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval

Ethics approval was not required for this single-patient case report in accordance with the institutional policy of Mersin University Faculty of Medicine.

Consent to participate

Written informed consent to participate was obtained from the patient’s legal representative.

Consent to publish

Written informed consent for the publication of clinical details and accompanying images was obtained from the patient’s legal representative. The authors affirm that the patient’s legal representative provided informed consent for publication of the images in Figs.  1 and 2 .

Competing interests

The authors declare no competing interests.

Footnotes

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References

Associated Data

Data Availability Statement

No datasets were generated or analysed during the current study.