Central Nervous System Myeloma Research Articles

Central Nervous System Myeloma and Unusual Extramedullary Localizations: Real Life Practical Guidance.

Central nervous system localization of multiple myeloma (CNS-MM) accounts for about 1% of all MM during disease course or even rarer at diagnosis. A difference in the origin, i.e., osteodural or primary dural vs leptomeningeal/intraparenchymal, seems to define two distinct types of intracranial myeloma, with different clinical behavior. CNS-MM may occur also as a presentation of MM. Treatment is still unsatisfactory and many treatments have been reported: chemotherapy, intrathecal therapy, and radiotherapy, with dismal prognosis. Other sites of myeloma localization could be also of interest and deserve description. Because of the rarity and aggressiveness of the disease clinicians are often doubtful on how to treat it since there is no general agreement. Moreover, recent drugs such as the anti CD38 monoclonal antibody, immunomodulatory drugs, and proteasome inhibitors have changed the treatment of patients with MM with a significant improvement in overall response and survival. The role of novel agents in CNS MM management and unusual presentations will be discussed as well as the potential role of other new immunomodulatory drugs and proteasome inhibitors that seem to cross the blood-brain barrier. The purpose of this review is to increase awareness of the clinical unusual presentation and neuroradiological findings, give practical diagnostic advice and treatment options algorithm.

Real World Data on the Efficacy and Safety of Ixazomib in Combination with Lenalidomide and Dexamethasone in Relapsed/Refractory Multiple Myeloma: Data Collected from the Hungarian Ixazomib Named Patient Program

Background: Ixazomib-lenalidomide-dexamethasone (IRD) is an all-oral treatment protocol which showed remarkable efficacy and safety in the TOURMALINE-MM1 trial leading to its approval in relapsed/refractory multiple myeloma (MM). However clinical trials are different from real world use for many reasons including less rigorous patient selection, greater flexibility with dosing and country specific funding restrictions making real world data very important for clinicians. Regarding IRD real world data is currently very limited.Aims and Methods: The aim of this study was to evaluate the efficacy and safety of IRD in the real world practice in a retrospective analysis using case records of patients taking part in the Hungarian Ixazomib Named-Patient Program. The scope of this study was to analyze response rate, progression free survival (PFS), treatment duration, adverse events (AEs), dose modifications and treatment discontinuations. Patients who have not completed at least one cycle were excluded. Statistical analyses were performed using the SPSS (version 20.0) software package.Results: 77 patients were treated at 7 sites. Patients were heavily pretreated, 29, 34 and 37% had 1, 2 and 3 lines of prior treatment which included a proteasome inhibitor in all and an IMiD in all but one patients. 60% had an autologous transplantation, 37% had high risk cytogenetics. Treatment continued until progression, unacceptable toxicity or death, the median number of IRD cycles applied was 5.5. AEs over grade 3 were uncommon, the most frequent AEs were cytopenias, infections and diarrhea (Table 1), leading to dose reduction in 6 patients. Overall response rate was 60% with 40% partial, 8% very good partial, and 12% complete responses. 19% showed stable disease, 16% progressive disease, and 5% of the patients had no formal disease re-assessment due to early death. With 8.5 months median follow up and 52% of patients still on treatment the 12 month PFS was 46% in all patients and 55% in those reaching at least stable disease (Figure 1). The known prognostic markers (fluorescence in situ hybridization, international staging system) all affected the outcome, and patients with high risk clinical features (plasma cell leukemia, extramedullary disease, central nervous system myeloma) had poor outcome.Conclusion: Our results highlight the differences between patients treated in routine practice and those treated in clinical trials. In our dataset less than a third of patients were treated at first relapse, whereas in the TOURMALINE trial the majority were. Also, in the TOURMALINE trial only 21% had high risk cytogenetics which was 37% in our patients. This probably accounts for the shorter PFS observed in our heavily pretreated patient group. Based on our results IRD is an effective treatment option for relapsed/refractory MM with good safety profile. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Presentation Patterns and Management Strategies for Central Nervous System Involvement in Multiple Myeloma: A Systematic Review of Literature

Introduction:Central Nervous System (CNS) involvement in multiple myeloma (MM) is a rare extramedullary manifestation which occurs in less than 1% of MM cases. The median survival after the diagnosis (Dx) is 1-2 months (M). Literature review revealed us of various treatment modalities i.e. systemic chemotherapy (CT), intrathecal therapy (IT), and radiotherapy (RT). The primary aim of our analysis is to summarize published literature on presentation patterns and review effective management strategies regarding CNS involvement in MM and its outcome.Methods:We performed a systematic review of 2533 articles published from 2005 using five databases (PubMed, Embase, Cochrane Library, Web of Science and ClinicalTrials.gov). After a detailed screening, 28 studies were included.Results:A total of 550 patients (pts) data is included. Eighty-eight (16%) pts had CNS involvement at the time of their initial presentation and 462 (84%) pts had disease detected at the time of relapse / refractory (R/R) disease . The median reported follow up, from the time of initial Dx, was 18 months (M) [range (r) = 3.4-75M]. The median age of pts was 58 years (y) (r= 40-71). The clinical presentations were heterogeneous with cranial nerve palsy (21%), headache (17%), confusion (17%), visual disturbances (17%), extremity weakness (9%), cord symptoms (5%) and nausea / vomiting (5%). The CNS region involved was identified in 366 pts: 163 (44.5%) pts had leptomeningeal (LM) involvement, 98 (26.8%) pts had dural (D)/osteodural (OD) involvement, 10 (2.7%) pts had LM + D/OD involvement, 90 (24.6%) pts had intraparenchymal (IP) involvement and 5 (1.4%) pts had LM + IP involvement. Hundred twenty-nine pts had International Staging System (ISS) information availabe at the time of MM Dx, out of which 39 (30%) pts had stage I disease, 32 (25%) pts had stage II disease and 58(45%) pts had stage III disease. The median time ( reported in studies) for CNS involvement after MM Dx ranges from 2.5-122 M in pts who underwent systemic treatment and 7-96 M in patients who underwent stem cell transplant (SCT). Five hundred twelve (93%) pts underwent treatment, out of which 42 (8.2%) pts had IT therapy with methotrexate and/or cytarabine, 44 (8.5%) pts had RT, 170 (33.2%) pts had CT, 103 (20.1%) pts had IT + RT + CT, 77 (15%) pts had RT + CT, 16 (3.1%) pts had IT + RT and 60 (11.7%) pts had IT + CT. One hundred two pts had SCT along with the other therapies. Among the pts who received systemic treatment, 34 patients received therapy with conventional agents (CA), 80 patients received therapy with novel agents (NA), 347 patients were treated with combination therapy of CA and NA. Data regarding the rest 51 patients were not available. Bortezomib (V) based regimens were given in 158 pts; immune-modulators (IMiD) based regimens in 153 pts; vincristine, adriamycin, dexamethasone (VAd) regimen in 21 pts; alkylators in 85 pts; carfilzomib in 7 pts; bendamustine in 5 pts; pomalidomide in 5 pts and daratumumab was given in 2 pts. The mOS in patients who received NA therapy was 4-25 M. The mOS in patients who received CA therapy was 2.7-8 M. The mOS in patients who received both CA and NA was 2-7.4 M. Seventy-five out of 512 patients were evaluated for efficacy, out of which, 30 pts showed complete response (CR), 6 pts showed very good partial response (VGPR), 17 pts showed partial response (PR) and progressive disease (PD) was seen in 22 pts. Death was reported in 370 out of total 550 pts.Conclusion:Our analysis demonstrated that systemic CT with CA & NA, RT and IT therapy either alone or in combination are the currently available strategies employed in treating CNS myeloma. Furthermore, NA therapies have shown an increase in the overall survival i.e. up to 25 months. The IMiD have shown good CNS penetrance [thalidomide (30-40%), lenalidomide (11%) and pomalidomide (39-49%)] and effectiveness in the clearance of myeloma cells from CSF. There is no established standard of care for CNS myeloma. As prognosis remain dismal for such patients, newer innovative approaches need to be tested in clinical trials (use of drugs like thiotepa, IT Daratumomab, combination regimens for IT therapy coupled with CNS penetrating systemic therapy etc.) to improve current treatment outcomes. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Central Nervous System Myeloma and New Drugs: Can we Begin the Fight?

Central Nervous System Myeloma and New Drugs: Can we Begin the Fight?

Myelomatous Involvement Of The Central Nervous System: Mayo Clinic Experience

BackgroundLimited data exist with respect to outcome and optimal therapeutic strategies in patients with central nervous system (CNS) involvement in multiple myeloma (MM). We present a single center experience of patients with myelomatous CNS involvement in newly diagnosed and relapsed / refractory MM. MethodsOf 4060 patients with MM seen at Mayo Clinic, Rochester, MN between January, 1st 1998 and December, 31st 2012, 26 patients had identifiable CNS involvement confirmed by biopsy / presence of plasma cells in the cerebrospinal fluid (CSF) and/or identification of intraparenchymal or meningeal involvement by imaging (MRI/CT). Patients were risk stratified by mSMART (Mayo Stratification for Myeloma And Risk-adapted Therapy) criteria. Overall survival (OS) from diagnosis and the time of CNS involvement was calculated using the Kaplan-Meier method. ResultsMyelomatous CNS involvement occurred in 26 (0.6%) patients with MM of whom 3 were newly diagnosed. The median time to detection of CNS involvement was 24 months (range: 0-125) from diagnosis of MM. Median age at CNS myeloma diagnosis was 58 years (range 37-80) and 73% were male. Abnormally high LDH was observed in 11 out of 22 patients at the time of CNS involvement. Lumbar puncture was performed on 16 patients, 13 (81%) of whom had plasma cells in the CSF detected by cytology/flow-cytometry. Two patients, without evidence of plasma cells, had abnormally high CSF protein and 1 had normal CSF analysis. Of the 25 patients who underwent MRI, 16 (64%) had at least one of the following significant abnormalities; intraparenchymal disease (37%), leptomeningeal enhancement (68%) or direct extension of MM (31%). The neurological symptoms at or after diagnosis of CNS myeloma included headache (38%), cranial nerve palsy (38%), visual disturbance (38%), gait disturbance (35%), paresthesias (35%), limb weakness (31%), confusion (30%), nausea/vomiting (15%), dysarthria (12%), seizures (8%) and urinary incontinence (4%). Fluorescent in-situ hybridization (FISH n=7), cytogenetics (n=8) and/or plasma cell labeling index (PCLI n=12) were available in 18 patients prior to the diagnosis of CNS disease. Ten (56%) out of those 18 patients had high-risk features at least by one criterion. At the time of CNS involvement, six additional patients demonstrated high risk features [5 by PCLI (≥ 3%) and 1 by FISH]. Overall, 16 out of 26 (62%) patients were classified as high risk by mSMART criteria prior to or at the time of CNS involvement. Four (27%) out of 15 had a deletion p53 or monosomy 17 chromosomal abnormality. Median OS was 42 (95% CI, 19-55) months from the diagnosis of MM and 3 months (95% CI: 1-7.9) from the time of CNS involvement (Figure). OS of patients with high risk features was significantly worse (27 months) compared to standard risk disease (67 months, p=0.02) from diagnosis of MM. Eighteen patients received radiation therapy for CNS myeloma. Five of those patients also received intrathecal (MTX and ARA-C) therapy. One patient received intrathecal and systemic chemotherapy. Four patients did not receive any treatment. Novel agents, including bortezomib (23%), thalidomide (15%), and pomalidomide (4%) were administered to the patients post diagnosis of CNS disease. Six (23%) patients underwent autologous stem cell transplant post diagnosis of CNS disease with a median OS of 19 months (95% CI: 10-122 months) from the time of CNS involvement. [Display omitted] ConclusionCNS involvement is a rare complication of MM that portends a poor survival outcome. It is likely that the rates in this study are an underestimate of the true incidence due the perceived futility of CNS directed therapy in this disease. Among those recognized, high-risk genetic and markers of increased proliferative activity, including deletion p53 / monosomy 17 and elevated PCLI (≥ 3%) appear to cluster in this cohort. Current therapeutic approaches are largely ineffective in managing this aggressive subset of myeloma patients. Disclosures:No relevant conflicts of interest to declare.

Initial Presentation Of Multiple Myeloma As Intraparenchymal Brain Mass

Case presentation38 year old African female presented with complaints of severe headache which had started couple of weeks prior to presentation and was progressively becoming worse. Patient underwent a CT scan of the head which revealed a 3.2 X 3.3 X 3.7 cm lobulated hyperdense periventricular mass in the left temporoparietal area with surrounding vasogenic edema with mass effect on the adjacent left lateral ventricle and 0.6 cm midline shift to the right with uncal herniation and effacement of left cerebral peduncle with dilatation of left temporal horn. MRI of the brain revealed a 3.1 X 2.6 X 3.6 cm lobulated mass in left lateral ventricle trigone. Radiologically, differential diagnoses included intraventricular meningioma, lymphoma, choroid plexus papilloma or metastasis. Patient underwent left craniotomy for tumor resection. Patient had an uneventful post-operative recovery and the resected tumor was high grade malignant neoplasm with plasmablastic features and immunohistochemical stains revealed that the tumor cells were positive for CD138, CD30, MUM-1, Bcl-2, vimentin and lambda light chains and were negative for kappa light chains, CD3, CD20, PAX-5, CD79a, GFAP, cytokeratin, AE1/AE3, synaptophysin, chromogranin, EMA, S-100, Melan-A, CD45, CD56 and EBV(EBER-ISH). Ki-67 was about 80%. Serum protein electrophoresis (SPEP) was sent that showed an M-spike of 3.3 g/dl that was IgG lambda. A bone marrow biopsy showed 100 % infiltration with plasma cells. Patient underwent a CT chest/abdomen/pelvis and a PET/CT scan which revealed multiple scattered subcutaneous masses throughout the body and an asymptomatic mass near spinal cord at C1. Patient was treated with VTD-PACE regimen (bortezomib, thalidomide, decadron, cisplatin, liposomal doxorubicin, cyclophosphamide, and etoposide). She received two cycles of VTD-PACE chemotherapy regimen with excellent response to the treatment. Her M-spike protein which prior to treatment was 3.3 g/dl disappeared after second cycle of chemotherapy and her subcutaneous lesion also dramatically improved on repeat PET/CT scan. The C1 dural lesion also had significant improvement after the chemotherapy. Her IgG also decreased from 5070 mg/dl to 791 mg/dl. She was referred for autologus stem cell transplant. She was subsequently started on weekly cyclophosphamide, bortezomib and decadron. DiscussionMalignancies of plasma cells comprise 1% of malignant neoplasms which includes multiple myeloma, solitary plasmacytomas (including solitary bone plasmacytoma and extramedullary plasmacytomas) and immunoglobulin deposition syndromes. Central nervous system (CNS) involvement of multiple myeloma itself is not a common entity. Fassas et al. published data of 18 cases over a course of 10 years. Gozzetti et al. published their data of 50 patients in 2012. Of these 50 patients, 76% had osteo-dural or primary dural multiple myeloma (OD-DMM) and 24% had central nervous system myelomatosis. They found that patients treated with novel agents had better outcome than patients treated with conventional drugs. Cases with initial presentation of intracranial plasmacytomas are even rarer. Patients with CNS myeloma have poor prognosis with median survival being around 4- 5 months. Our patient had excellent response with two cycles of VTD-PACE regimen with negative M-spike, normalization of IgG and decrease in size of subcutaneous nodules and C1 spinal lesion. She has survived for 5 months without autologus transplant and is currently on weekly cyclophosphamide, bortezomib and decadron. Disclosures:No relevant conflicts of interest to declare.

Emergence of central nervous system myeloma in the era of novel agents

Although multiple myeloma (MM) remains an incurable disease, considerable improvements in survival have been made with the introduction of autologous stem cell transplantation and new drugs. Central nervous system (CNS) MM is a rare complication associated with poor survival. Historically, CNS disease developed early in the course of MM; however recently, patients often present with CNS disease following multiple lines of therapy. It is hypothesized that exposure to novel agents (thalidomide, lenalidomide and bortezomib) changes the natural history of MM, increasing the lifetime risk of CNS disease. We analysed the baseline characteristics, treatment and outcome data of patients who presented with CNS MM at Peter MacCallum Cancer Centre between 2001 and 2010. Seven patients were identified, from 2005 onwards. All patients were Durie-Salmon stage IIIA or IIIB and International Staging System Scores I to III at baseline. All had received at least three lines of therapy, including high-dose chemotherapy with autologous stem cell transplantation and a novel agent, prior to developing CNS MM. Median time from diagnosis to CNS disease was 24 months (range 10-42). All patients died after developing CNS disease with median survival post-CNS disease of 2 months (range 1-23). The incidence of CNS MM is increasing, and time to development of CNS manifestations is prolonging, associated with increased use of high-dose chemotherapy and novel agents. Whether this is due to improved overall survival or specific characteristics of these therapies is not clear. Despite the availability of novel agents, survival after CNS MM remains poor.

Central Nervous System (CNS) Involvement with Multiple Myeloma (MM) – Longterm Survival Can Be Achieved with Radiation, Intrathecal (IT) Chemotherapy, and Immunomodulatory Agents (IMiDs),

Abstract 3983 Introduction:CNS involvement with MM is uncommon, estimated at 1% of patients (pts)(Fassas 2002). CNS myeloma has a reportedly dismal prognosis with median survival of only 2 months (mos) from CNS diagnosis (Nieuwenhuizen 2007). These data derive primarily from small case reports predating the use of novel agents such as the IMiDs and bortezomib. We reviewed our institutional experience with 37 CNS myeloma pts, many treated with novel agents, specifically aiming to identify longterm survivors and their disease/treatment characteristics. Methods:From 1999 to 2010, all pts with CNS MM identified by CSF plasmacytosis and/or leptomeningeal/dural disease on imaging at our institution were reviewed. Pt demographics, disease characteristics, treatments, and survival were retrospectively reviewed from charts, pharmacy records, and a myeloma database. Survival was calculated from time of CNS disease to progression (time to progression; TTP) or death (overall survival; OS). Survival analyses were performed using the Kaplan Meier method (SPSS v17.0). Results:Patient and disease characteristics:Of 758 pts diagnosed with MM at our institution over the 20 year period, 37 pts developed CNS disease (incidence 4.9%). Median age of the 37 CNS pts was 54 years (range 36–70), 51% male. A predominance of light chain subtype was noted: light chains only 32%, IgG 30%, IgA 24%, other 13%. CNS involvement was present at MM diagnosis in 9 pts (24%); at relapse in 28 pts (76%). In the relapsed pts, median number of prior therapies was 2(1–5). Median time from MM diagnosis to CNS presentation was 19.1 mos (range 4.4 weeks–11 years). Cranial nerve involvement (diplopia, facial numbness, visual blurring) was present in 24 of 37 pts (65%). Other common symptoms were headache, cognitive impairment, seizures. Fifteen pts (40%) had plasma cell leukemia (PCL) at CNS presentation. Symptomatic involvement of the orbits (11 pts; 30%) and spinal dura/epidura (17 pts; 46%) was common. Plasmacytomas of the skull adjacent to dura were seen in 65% of cases, suggesting contiguous spread. Leptomeningeal/dural enhancement or thickening on MRI was visualized in 54%, whereas parenchymal brain involvement was rare (5%). CSF plasmacytosis was reported in 24 of 34 pts tested (70%). Treatment and survival:Most pts (30/37 pts; 81%) received intrathecal (IT) chemotherapy (hydrocortisone, methotrexate, and/or cytarabine) with rapid clearance of plasma cells from CSF. Radiation was administered in 28 pts (10 craniospinal, 8 cranial only, 8 spinal only). Ten pts (30%) presented with localized CNS disease and did not require immediate systemic therapy. Various systemic therapies were used: IMiDs 16(43%), cisplatin-based (DPACE) 9(24%), bortezomib 7(19%), alkylators 5(13%), dexamethasone (DEX) alone 4(10.8%), autotransplant 1(2.7%). Consistent with the literature, median TTP from onset of CNS disease for all pts was short at 3.1 mos (95% CI 8.2–18.9). At median follow-up of 24.2 mos, median OS from CNS disease was only 4.3 mos (95% CI 3.1–5.5). However, 7 pts had prolonged survival after onset of CNS disease: 13.2, 16.1, 17.1, 34.3, 35.6, and 69.5 mos. There were no uniform laboratory or clinical features to these 7 longterm survivors. Although 2 of these pts had stable systemic disease at time of CNS onset, 3 had PCL, 5 had aggressive bone/soft tissue plasmacytomas. Three longterm survivors presented with CNS disease at time of MM diagnosis, 4 at relapse. Though all 7 underwent radiation, 6 of 7 pts received repeated IT chemotherapy (4 received maintenance IT chemotherapy every 1–2 mos), and 5 of 7 pts received thalidomide as TD (thalidomide, DEX), CTD (cyclophosphamide, thalidomide, DEX) or DTPACE (DEX, thalidomide, cisplatin, adriamycin, cyclophosphamide, etoposide). Conclusion:Although CNS disease is considered an aggressive complication of MM, in our review of 37 pts, one of the largest single-institution reports of CNS myeloma in the literature, clinical presentation and outcomes are heterogeneous. The high rate of PCL and skull-based plasmacytomas suggest that both hematogenous and contiguous spread from bone can occur. With our experience, longterm survival can be achieved with cranial/spinal irradiation, multi-dosing IT chemotherapy, and oral thalidomide, previously reported to cross the blood-brain barrier. This triple modality approach, using DPACE with or without thalidomide, is being further evaluated at our institution. Disclosures:Chen:Celgene: Consultancy, Honoraria, Research Funding. Kukreti:Celgene: Honoraria. Reece:Bristol, Meyers, Squibb: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Johnson&Johnson: Research Funding; Merck: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Millennium: Research Funding; Amgen: Honoraria.

MYELOMA OF THE CENTRAL NERVOUS SYSTEM: REPORT OF A SINGLE CENTER CASE SERIES

Background: Neurologic manifestations often complicate the course of multiple myeloma, but direct involvement of the central nervous system (CNS) is rare.Objective: To describe the clinical course, neurological symptoms, laboratory findings and imaging of patients with CNS myeloma. This additional information may contribute to better recognition and more effective management of this complication in the future.Methods: We retrospectively identified 6 MM patients with CNS involvement diagnosed at our centre between April 2003 and April 2009. The clinical, biochemical and imaging data were collected and compared with previously reported cases.Results: At time of diagnosis of CNS myeloma, 3 patients had progressive disease and 3 were in good partial remission. The presenting symptoms included diplopia, vision loss, extremity weakness and paresis. All cases showed one or more features of aggressive disease at diagnosis, including high tumour burden, plasmablastic morphology and high-risk cytogenetic abnormalities. Prognosis was poor with a median survival of 4.8 months.Conclusion: CNS myeloma should be considered in patients with aggressive MM and unexplained neurological symptoms. The prognosis is poor despite intensive therapy.

The combination topotecan, temozolomide and dexamethasone associated with radiotherapy as treatment of central nervous system myeloma relapse

A 46-year-old woman with IgA-lambda myeloma in partial remission, after a tandem autologous hematopoietic stem cells transplantation, complained of progressive lower back pain associated with paraplegia and neurological bladder 6 months after the second transplant. A lumbar puncture revealed atypical malignant plasma cells in the cerebral spinal fluid associated with multiple foci of altered signal intensity of brain and spinal cord demonstrated by magnetic resonance. Considering the lack of efficacious chemotherapies for neurological myeloma, an experimental systemic treatment with topotecan, temozolamide, and dexamethasone associated with concurrent radiotherapy of brain and spinal cord was initiated. During this treatment, the patient rapidly improved with disappearance of back pain, paresthesia, and urinary incontinence lasting 5 months, before dying of progressive disease. The proposed systemic chemotherapy associated with concurrent radiotherapy may have an antitumor activity against MM with CNS involvement.

Treatment of Menigeal Myelomatosis with Liposomal Cytarabine (DepoCyte®): A Case Report

Involvement of the central nervous system (CNS) in multiple myeloma (MM) is very uncommon. The incidence has been described to be approximately 1% of MM patients. The diagnosis is difficult because CNS MM presents with a wide spectrum of subtle neurological signs and symptoms which may result in some underdiagosis of this complication. The diagnosis is usually based on neurological symptoms and the detection of plasma cells in the CSF. An earlier diagnosis may be achievable by using immunoelectrophoresis and immunofixation for detection of monoclonal protein or the use of flow cytometry and cytogenetic analysis of CSF samples. No guidelines for therapy of CNS MM are available which has resulted in the use of a large variation in treatment schedules. Treatment options include intrathecal chemotherapy (IT), systemic chemotherapy (SC), cranial irradiation (CI) or a combination of these methods. A significant positive impact on overall survival (p=0.004) was recently reported for patients treated with CI when compared with patients without CI). However, even when a complete response in the CSF was achieved patients' often succumb to the aggressively progressing systemic disease. As a result the prognosis of CNS MM remains very poor with a median overall survival from the time of diagnosis of 2 months (range 0.1–25 months), despite all efforts to improve treatment. Although palliative by nature we believe that treatment of LMM is indicated, given its potential for symptomatic relief and improvement in the quality of life.We describe a case of a 54 year old female with multiple myeloma (stage III-A) involving the central nervous system and lungs. She was initially successfully treated in November 2005 with thalidomide and dexamethasone. In February 2007, the patient experienced bone pain and a re-evaluation of the disease showed 90% monoclonal plasma cells in the bone marrow. In April 2007 the patient received two cycles of DT-PACE (dexamethasone, thalidomide plus cisplatin, doxorubicin, cyclophosphamide, etoposide) but the CT scan showed a progression of extramedullary disease. Treatment was therefore changed in May 2007 and the patient received five cycles of PAD (bortezomib, doxorubicin and dexamethasone) plus RT on D9 and D11. A total body CT scan performed in November 2007 revealed progressive disease at para-vertebral sites D3, D4 D5, D8 and D9. The liver was hypodense with nodular lesions and multiple para-ovarian lesions were detected. The patient received Melpahan 200mg/m2 with reinfusion of autologous stem cells. A total body CT scan in January 2008 showed an unchanged abdominal situation and many myelomatosis infiltrations in lumbar and dorsal side of the lung. The patient was then admitted to our hospital in March 2008 now with headache and diplopia. Whilst the MRI and CT scan did not reveal evidence of CNS involvement the CSF flow cytometry analysis showed 40% plasma cells and confirmed the diagnosis of leptomenigeal myelomatosis. The patient received four doses DepoCyte® every two weeks and bendamustine 100mg/m2 day 1,2; bortezomib 1.3mg/m2 day 1,4,8,11 and prednisolone 100mg day 1,2,4,6,11 every 21 days. Flow cytometry and cytospin analysis of the CSF were performed at every LP. The headache and diplopia rapidly disappeared and the CSF was clear from plasma cells after the second DepoCyte® injection. Because of progressive systemic disease the patient refused further treatment in May 2008 and died in June 2008.Conclusions: CNS involvement in MM is rare and a late complication in the course of the disease. The prognosis of such patients is poor based on often refractory systemic disease despite aggressive systemic and local treatment. A better understanding of the biology of LMM and an early identification of patients with high-risk for CNS myeloma involvement may allow earlier treatment with better results. Liposomal cytarabine was effective and well tolerated; no drug-related side effects or haematological toxicity were recorded.

Multiple myeloma involving central nervous system: high frequency of chromosome 17p13.1 (p53) deletions

Central nervous system (CNS) involvement is an unusual manifestation in multiple myeloma (MM). The molecular basis of CNS myeloma is poorly understood. MM is characterized by translocations involving the immunoglobulin heavy chain (IgH) locus and frequent 13q deletions. Alterations of p53 or c-myc in MM may represent secondary changes associated with disease progression. We investigated nine patients with CNS MM using interphase fluorescence in situ hybridization (FISH) combined with immunofluorescence detection of the cytoplasmic light chain (cIg-FISH) for the presence of above genomic aberrations. Of nine patients studied, eight cases had hemizygous p53 deletion and 4 had 13q deletions. Of the patients with 13q deletions, two had IgH translocations, one involving 4p16.3 (FGFR3), the other involving 16q23 (c-maf). The high incidence of p53 deletions detected by cIg-FISH in CNS myeloma may be a marker for chromosomal instability, and may be associated with metastatic features of myeloma cells.

Multiple myeloma invasion of the central nervous system.

Although neurologic manifestations often complicate the course of patients with multiple myeloma (MM), direct central nervous system invasion is rare. To describe the neurologic symptoms and signs, imaging, cerebrospinal fluid findings, and the clinical course of patients with central nervous system myeloma invasion, all of whom had leptomeningeal myelomatosis. Review of 23 patients with MM and leptomeningeal myelomatosis proven by malignant plasma cells in their cerebrospinal fluid. Tertiary-care university medical center. Twenty-one patients had advanced-stage MM. Leptomeningeal myelomatosis was diagnosed up to 29 months (median, 13 months) after diagnosis of MM. Symptoms precipitating neurologic evaluation included manifestations of diffuse cerebral dysfunction, cranial nerve palsies, and spinal radiculopathies. Cerebrospinal fluid was abnormal in all patients, usually exhibiting pleocytosis and elevated protein content, plus positive cytologic findings. Specific magnetic resonance imaging findings suggestive of central nervous system invasion were found in 70% of the patients. These included leptomeningeal contrast enhancement and evidence of meningeal-based lesions sometimes masquerading as intraparenchymal lesions. Despite aggressive systemic and local treatment, the outcome was poor, reflecting the aggressiveness of the underlying MM. Leptomeningeal myelomatosis, although rare, should be considered in patients with MM and symptoms suggestive of widespread nervous system involvement.

Myeloma of the Central Nervous System: Strong Association with Unfavorable Chromosomal Abnormalities and Other High-risk Disease Features

Involvement of the central nervous system (CNS) by multiple myeloma, defined by the detection of malignant plasma cells in the cerebrospinal fluid in the presence of suggestive symptoms, is considered extremely rare. We present the characteristics of 25 such patients (18 previously reported) intended to receive high-dose treatment at the University of Arkansas over the last 12 years; an extensive review of the published literature since 1968, including 71 patients, is also presented. In both patient groups, high tumor burden was overwhelmingly present while circulating plasma cells were detected in a significant proportion of cases. We also observed a strong association of CNS involvement with unfavorable cytogenetic abnormalities (especially translocations and deletion of the chromosome 13), plasmablastic morphology and additional extramedullary myeloma manifestations. The presence of these features should alert clinicians to the possibility of CNS involvement. The prognosis of such patients is poor despite aggressive systemic and local treatment and reflects the underlying disease biology. Application of allogeneic transplantation and administration of prophylactic CNS treatment are also discussed. Further elucidation of the factors predisposing patients with high-risk disease features to CNS myeloma involvement is needed.