Central Nervous System (CNS) Involvement with Multiple Myeloma (MM) – Longterm Survival Can Be Achieved with Radiation, Intrathecal (IT) Chemotherapy, and Immunomodulatory Agents (IMiDs),
Authors: Chen Christine , Rabea Ahmed M. , Masih-Khan Esther , Chu Chia-Min , Kukreti Vishal , Trudel Suzanne , Tiedemann Rodger E. , Reece Donna E. 
Published: October 2019

Abstract
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.