Multiple myeloma with central nervous system involvement – case series

Introduction: Central nervous system involvement in multiple myeloma (CNSMM) is a very rare entity accounting for less than 1% of all extramedullary multiple myeloma, which manifests as a variety of neurological deficits. Treatment modalities can be locally administered therapy, including intrathecal chemotherapy and radiotherapy, as well as systemic therapy, including autologous/allogeneic hematopoietic stem cell transplantation (AHSCT).

The aim: This article aims to present the experience of our center in the treatment of this rare entity.

Case reports: The first patient was diagnosed with multiple myeloma BJ lambda CS IIIA R-ISS 2 with a tumor mass located at the base of the skull, causing right facial nerve paralysis. The patient underwent six treatment cycles of the CVD (cyclophosphamide, bortezomib, dexamethasone) regimen, achieving partial remission, followed by palliative radiation and autologous stem cell transplantation. The treatment was continued with the DaraRd (daratumumab, lenalidomide, dexamethasone) regimen aimed at a second stem cell transplant which is to be carried out upon deepening remission. The overall survival of the patient, so far, is 20 months. The second patient with multiple myeloma BJ kappa CS IIIA ISS 2 developed CNS involvement with the first recurrence of the disease. Cranial radiation and seven cycles of the PAD (bortezomib, doxorubicin, dexamethasone) regimen were carried out, leading to disease progression and death. The overall survival of the patient was 48 months, with 25 months survival since the diagnosis of CNS infiltration.

Conclusion: Despite advances in diagnosis and treatment, the prognosis for CNS-MM remains poor because of its complex and aggressive clinical behavior. Due to its low incidence, available data are limited indicating the need for further studies involving this small group of patients.

INTRODUCTION

Central nervous system involvement in multiple myeloma (CNS-MM) is a very rare entity with an incidence lower than 1% of all extramedullary multiple myeloma [1]. Over the past decade, an increase in the incidence of this entity was observed, primarily due to the improvement of diagnostics, treatment, and consequent prolongation of survival time of the affected patients [2]. It can be diagnosed at the onset of the disease, but it is more often determined in recurrence, i.e., during the progression of the disease [1]. Dissemination can be hematogenous or by direct invasion, and the lesions can be intraparenchymal and/or leptomeningeal, with an array of neurological manifestations [3]. It has been shown that meningeal involvement is associated with the worst prognosis, with a median overall survival (mOS) of two to six months [1],[3],[4], while in other cases mOS is up to 25 months [5],[6].

Diagnostics, in addition to the standard procedures for multiple myeloma, include CT/MR of the endocranium and spine, lumbar puncture and analysis of cerebrospinal fluid, as well as tumor tissue biopsy [4],[7]. Treatment modalities can be local, including intrathecal chemotherapy and radiotherapy, or systemic, including autologous/allogeneic hematopoietic stem cell transplantation (HSCT) [4].

Despite developments in diagnostics and treatment, the prognosis for CNS-MM remains poor due to its complex and aggressive clinical behavior, stemming most often from the progression of the disease and previously applied therapeutic modalities [4,8–10]. Due to low incidence, available data are limited, indicating the need for further studies aimed at this small group of patients.

This paper aims to present the experience of our center in the treatment of this rare entity.

Case report 1

In the case of a 62-year-old patient, the disease manifested as a pathological fracture of the left clavicle and left humerus, in December 2022. CT imaging revealed diffuse osteolytic lesions in the long bones, cervical and thoracic spinal vertebrae, and the skull. In the same month, resection and stabilization of the left humerus with biopsy were performed at the Institute for Orthopedic Surgery Banjica. Pathohistological findings verified the diagnosis of well-differentiated plasmacytoma. Additional diagnostic procedures were carried out at the Institute of Oncology and Radiology of Serbia, in March 2023. Bone marrow biopsy revealed a 60% pathological plasma cell infiltration. Monoclonal lambda light chains were registered with electrophoresis and immunofixation of serum and urine. Cytogenetic FISH analysis (fluorescence in situ hybridization) detected 13q deletion in 80% of nuclei and TP23 deletion in 25% of nuclei. A definitive diagnosis of multiple myeloma BJ lambda CS IIIA, R-ISS 2 was established. In the further course of the disease, peripheral paralysis of the right n. facialis developed, which is why a CT scan of the endocranium was performed, revealing a tumorous lesion in the base of the skull with the destruction of a segment of the right sphenoid and temporal bones. The patient was treated with six cycles of the CVD (cyclophosphamide, bortezomib, dexamethasone) regimen, ending in September 2023. Upon reevaluation of the disease, the following were found in the bone marrow biopsy: infiltration with 25% of pathological plasma cells, values of lambda light chains in the serum, proteinuria, and a value of beta2 microglobulin reduced by more than 50%. The therapeutic effect was evaluated as partial remission. Palliative radiotherapy of residual changes in the base of the skull was carried out with 25 Gy in 10 fractions, concluding in October 2023. In the further course of treatment, the patient underwent autologous hematopoietic stem cell transplantation, which was carried out in February 2024. When the therapeutic effect after transplantation was evaluated, the patient was found to be in partial remission. In June 2024, after the monoclonal anti-CD38 antibody daratumumab was added to the positive list of drugs of the Republic Fund of Health Insurance of Serbia, the treatment of this patient was continued with the DaraRd (daratumumab, lenalidomide, dexamethasone) regimen, with the aim of deepening remission and conducting a second cycle of AHSCT. The second cycle of this therapy is now in progress. The patient’s overall survival to date is 20 months.

Case report 2

In a 40-year-old female patient, the disease manifested as sudden paraparesis, in 2012. An MRI examination of the spine was performed, which revealed infiltration of the Th4 vertebral body with extraosseous paravertebral and epidural propagation, significant stenosis of the lumen of the vertebral canal, and consequent compression of the spinal cord. In July 2012, at the Institute of Orthopedic Surgery Banjica, decompression and stabilization of the Th3-5 thoracic spine segment were performed, along with a biopsy of the infiltrated Th4 body. A well-differentiated plasmacyte was verified pathohistologically. A complete diagnostic workup was carried out at the Institute of Oncology and Radiology of Serbia. Bone marrow biopsy showed an 80% pathological plasma cell infiltration. Monoclonal light kappa chains were detected with electrophoresis and immunofixation of serum and urine. Cytogenetic FISH analysis was not performed. A diagnosis of multiple myeloma BJ kappa, CS IIIA, ISS 2 was established. In August and September of the same year, palliative radiotherapy of the affected vertebra with 40 Gy in 20 fractions was performed. The patient was put on systemic therapy with the CTD regimen (cyclophosphamide, thalidomide, dexamethasone) – she underwent eight cycles achieving partial remission (infiltration of the bone marrow with 40% of pathological plasma cells; decrease in the value of kappa chains by 50%). This was followed by maintenance thalidomide therapy for 10 months. In June 2014, the patient developed neurological symptoms – headaches, diplopia, and unsteady gait. Due to the clinical suspicion of CNS involvement, a complete diagnostic work-up was performed. Radiographically, diffuse focal lesions of the skull were described with progression to the thoracic and lumbar spinal vertebrae. MRI examination of the endocranium revealed a soft tissue tumorous lesion in the left frontoparietal area with infiltration of the brain parenchyma. In the further course, radiation therapy of the endocranium was carried out in five fractions. The patient was treated with seven cycles of the PAD protocol (bortezomib, doxorubicin, dexamethasone), resulting in disease progression. In July 2016, the disease ended in a fatal outcome. The overall survival of the patient was 48 months, while her survival time from diagnosis of central nervous system involvement until death was 25 months.

DISCUSSION

A review of the currently available literature reveals that in most studies the median age of patients is above 60 years, which correlates with the predilection age for the onset of multiple myeloma in the general population [11],[12]. However, several studies have shown that CNSMM can occur in younger patients as well [1],[5],[13],[14]. In a study by Chen et al., the median age was 53 years [4]. Our patient was diagnosed with the disease at the age of 40, which makes her one of the youngest patients diagnosed with CNS-MM documented in literature. The onset of CNS-MM at a younger age may be associated with a more aggressive course of the disease. The disease predominantly occurs in women [14].

Infiltration of the central nervous system is, in most cases, seen in relapse/progression of the disease [4],[5],[7],[9],[10],[13]. However, a small number of studies show it being diagnosed at the onset in a larger number of patients [14]. What makes this entity a therapeutic challenge in its late stage is its refractoriness to previously applied treatment. The presence of high-risk cytogenetic mutations contributes to a more aggressive clinical course, of which 13q deletion and 17p deletion are the most common [15]. In their study, Chang et al. demonstrated a 17p deletion in 89% of patients [10], while Jurczyszyn et al. found a 13q deletion in 39% and a 17p deletion in 23% of patients [9]. In one of our patients, a 13q deletion was detected, while in the other patient, at the time of diagnosis, the cytogenetic analysis did not fall within the diagnostic standard. An increased value of lactate dehydrogenase (LDH), which is one of the parameters of the R-ISS scoring system (Revised International Staging System) [16], can also indicate a more aggressive course of the disease and potential CNS involvement. Initially, our second patient had a multiply elevated LDH level, but due to the lack of FISH analysis, the R-ISS score could not be calculated.

The clinical presentation can be dominated by an array of neurological deficits, resulting from an infiltration of the spinal cord, spinal roots, meninges, or brain parenchyma. In half of the patients, the dominant symptom is headache accompanied by visual disturbance [14], which was the manifestation of the disease in one of our patients. Neurological symptomatology can be related to the metabolic state, most often hypercalcemia, which is often the initial manifestation of newly diagnosed multiple myeloma [17],[18].

The standard of treatment is not clearly defined and is based on experience with a small number of patients. Apart from low incidence, CNS involvement is often an exclusion criterion for large studies aimed at investigating new therapeutic modalities in the treatment of multiple myeloma [2],[8],[14]. The basis of systemic treatment consists of monoclonal antibodies and immunomodulators, which, unlike the most commonly used proteasome inhibitors, can cross the blood-brain barrier [19],[20],[21],[22]. Radiotherapy, as a local therapy, is mostly applied in the rapid control of neurological symptoms [23]. Hematopoietic stem cell transplantation represents the standard of treatment in newly diagnosed patients with multiple myeloma who are eligible for transplantation, however, in this limited group of patients, its effectiveness, as well as its method and time of administration, are not clearly defined. The reason for this is the short survival time, the effectiveness of conditioning regimens in terms of penetration of the hematoencephalic barrier, and the expected complications of the procedure itself [24],[25].

Median overall survival varies among studies and ranges from two to 40 months in the available literature [3],[6],[9]. Differences in mOS are the result of the time of occurrence of CNS infiltration, as well as the localization of the disease. In the GIMEMA study, it was shown that patients with osteodural infiltration (Mos 25 months), compared to patients with leptomeningeal infiltration (mOS 6 months), had a better survival time [6]. In our patients, the mOS is 34 months, while the mOS from the moment of diagnosis of CNS involvement is 22.5 months, which correlates with the survival data of patients who did not have leptomeningeal infiltration.

Given the low incidence of CNS involvement, but also the aggressive nature of its rapid progression, it is necessary to evaluate each new neurological symptom in detail. The neurotoxicity of systemic therapy is a particular differential diagnostic challenge. In our patient, in whom CNS involvement occurred during the relapse of disease, the neurological manifestation could also correspond to the neurotoxicity of the administered therapy. Several cases of the development of progressive multifocal leukoencephalopathy (PML) during the administration of daratumumab have been described in literature [21]. The most common neurotoxicity of proteasome inhibitors and immunomodulators is peripheral neuropathy [26],[27], especially during combined administration. Thrombocytopenia and prothrombogenic states caused by immunomodulators can, in rare cases, be directly related to stroke symptomatology [28].

CONCLUSION

Although a rare entity, CNS-MM represents a major diagnostic, clinical, and therapeutic challenge that requires further investigation for the purpose of prolongin the survival time of patients.