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Arterial and venous thromboses occur in patients with POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein level, and skin changes) syndrome at a previously reported rate of 20%. We reviewed the University College London Hospitals (UCLH) POEMS Registry to determine the rate of venous thromboembolism (VTE), arterial events, and risk factors. This registry, established in 1999 and comprising 103 patients at the time of this study, is the largest single-center cohort in Europe. Of the 83 assessable patients, median age at presentation was 52 years (range, 31-84). Twenty-five patients experienced clinically apparent arterial or venous events, and 2 had concurrent arterial and venous thromboses. Eleven patients had VTEs, including deep vein thrombosis (DVT; 3 of 11), pulmonary embolism (4 of 11), and peripherally inserted central catheter–associated DVT, which occurred during autologous stem cell transplantation (3 of 11). Sixteen patients experienced arterial events: stroke (7 of 16), peripheral arterial occlusion (5 of 16), myocardial infarction (3 of 16), and microvascular disease (1 of 16), with no discernible relationship with thrombocytosis or polycythemia. Thirty percent of POEMS patients have arterial and venous thromboses, higher than previously reported. There were more arterial than venous events, and most occurred during active disease, before the start of chemotherapy, indicating the need for a preemptive approach to thromboprophylaxis.

Background IgM paraprotein-associated peripheral neuropathies (PN) are a heterogenous group of disorders seen in patients with IgM MGUS and Waldenström's Macroglobulinaemia (WM). Anti-myelin associated glycoprotein (MAG) antibodies are causally identified in ~50% of such cases, but other neuropathies with other IgM-targets are described, along with AL amyloidosis and cryoglobulinaemic vasculitis amongst others. Presence of neuropathy alone is typically not an indication for treatment, but progressive disability is. Due to their relative rarity and heterogeneity, the true prevalence and optimal management of these neuropathies is currently unclear. Methods The Rory Morrison WMUK Registry, a national IgM-related disorders database incorporating 18 centres, was searched for all patients with PN and retrospective data clinical data extracted. Research ethics approval was obtained. Results IgM-related PN was identified 153 patients, of whom 99 (64.7%) had underlying WM and 54 (35.3%) had IgM MGUS. Anti-MAG neuropathy was present in 83 (54.6%) patients, anti-ganglioside in 3 (2%), AL amyloid in 7 (4.3%), cryoglobulinemia in 6 (3.7%), one (0.6%) case of CANOMAD syndrome, and a non-MAG IgM-neuropathy in 53 (34.5%%). PN was present at diagnosis in 143 (93.5%) whereas 10 (6.5%) were diagnosed during the course of their disease. Median age at diagnosis was 64 years (30-92) and 101/153 (66%) were male. Table 1 details results at diagnosis. κ-light chain was present in 80.3%, λ in 11.8% and 7.9% had multiple M-protein bands expressing both light chains. MYD88L265P was identified in 44/55 tested patients (80%) and in 23/30 (76.7%) cases of anti-MAG. In those with an IgM-related disorder, 13/20 (65%) had MYD88L265P, higher than in other IgM MGUS patients (7/14, 50%). CXCR4MUT were found in 3/22 (13.6%). Median bone marrow infiltration on trephine was 13% (range 0-85%), but 10 patients had no evidence of disease, 5 had disease on flow cytometry only, 2 an isolated finding of MYD88L265P and 1 isolated CXCR4MUT on PCR. IgM-related PN was seen in 99/719 (13.8%) of all registry patients with WM. At diagnosis, the bone marrow burden, M-protein and B2M were all significantly lower (p Therapy had been required in 81 (53.3%) patients, including at time of diagnosis in 23 (15%). Median time from diagnosis to treatment was long, at 6.7 years (95% CI 3.2-9.1 years). PN was the sole treatment indication in 64/81 (79%) cases. Time to treatment commencement did not appear to be affected by M-protein quantity or marrow burden, but patients with WM were more likely to have received treatment for their PN (59/108, 54.6%). Frontline treatment incorporated rituximab (R) in 66/81 (81.5%) patients, including R-monotherapy in 30, DRC 20, R-CHOP/R-CVP eight and BR in seven. A major biochemical response was seen in 19/34 (55.9%) patients. Clinical response was seen in 34 of 45 evaluable cases (75.6%), with improvement in 13 (28.9%) and stabilisation in 21 (46.7%). Clinical response or stabilisation was significantly more likely with R-containing therapy (82.1% vs 33.3%, p 0.04), non-amyloid related PN (82% vs 0%, p = 0.01) and attainment of ≥ partial response. All patients (n=12) with normal BMAT or isolated MYD88L265P responded to R-containing frontline therapy, another positive prognostic factor (p = 0.08). Progression of PN occurred after an initiation period of clinical response in 7/34 (20.5%), necessitating re-treatment at a median of 4.3 years after frontline therapy. Median time to 2nd line therapy was 6.7 years, longer than for other WM treatment indications (p = 0.04). Conclusions IgM-related PN is a cause of morbidity for a significant proportion of patients with WM, with a prevalence of 13.7%. However, a third of cases occur in those with IgM MGUS and even very small clonal populations seem capable of causing disease but appear responsive to rituximab therapy. Patients typically have comparatively low systemic disease burden and low rates of CXCR4MUT, perhaps representing a more indolent phenotype or a product of earlier diagnosis. PN is frequently the sole indication for treatment, reflecting this. Clinical improvement or stabilisation was seen in 75% of treated patients, and attainment of ≥50% reduction in IgM (PR) and treatment with rituximab is associated with a more favourable outcome, whereas AL amyloid neuropathy appears to be more treatment resistant. Disclosures Lindsay: Amgen: Other: Travel Expenses; Takeda: Honoraria, Other: Travel Expenses; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses. Carr:Lupin: Honoraria; CSL: Honoraria; Grifols: Other: Travel support. McCarthy:Janssen: Honoraria; Abbvie: Membership on an entity's Board of Directors or advisory committees. El-Sharkawi:Roche: Other: Conference fees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Pratt:Binding Site Ltd: Other: Personal fees; Amgen: Other: Personal fees; Janssen: Other: Personal fees; Celgene: Other: Personal fees; Takeda: Other: Personal fees; Gilead: Other: Personal fees; Sanofi-Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Beigene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. D'Sa:Janssen: Honoraria, Research Funding; Sanofi: Honoraria; BeiGene: Honoraria, Research Funding.

BACKGROUND Bing-Neel Syndrome (BNS), characterised by the direct infiltration of central nervous system (CNS) with clonal lymphoplasmacytic lymphoma cells, is a rare cause of neurological complications in patients with Waldenström Macroglobulinaemia (WM). The pathophysiology/neurotropism of BNS is not well understood. Various treatments that appear to cross the blood-brain barrier are used, including chemoimmunotherapy combinations and Ibrutinib. High-dose methotrexate (HDM)-based regimens, including MATRix (methotrexate [MTX], cytarabine, thiotepa, rituximab)1and R-IDARAM (rituximab, MTX [intrathecal and intravenous], cytarabine, dexamethasone) are also used, based on the experience in high-grade CNS lymphoma; however, there are concerns regarding the appropriateness of these regimens in the indolent setting, largely due to their toxicity. This study aimed to determine the efficacy and tolerability of HDM-based, frontline treatment in a large cohort of BNS patients. METHODS A single-centre retrospective review of consecutive patients with BNS treated with HDM based regimens was undertaken. Comprehensive laboratory and CNS imaging results were collated (including whole-brain/spine MRI, bone marrow biopsy, and CSF biochemistry, cytology and MYD88 L265P mutation). Best responses achieved, according to IWWM response assessment criteria, were determined. RESULTS Between 2011 and 2020, 27 patients were treated with HDM-based chemoimmunotherapy: 14 (51.9%) with MATRix, 5 (18.5%) with MTX/cytarabine/rituximab (MAR), 2 (7.4%) with HDM only, and 6 (22.2%) with R-IDARAM. Median time from WM diagnosis to BNS diagnosis was 60 months (0-572 months), including 10 patients (37.0%) who were diagnosed with WM at the time of BNS presentation/diagnosis. Median age at diagnosis with BNS was 66 years (43-75 years), and 15/27 (55.6%) were male. CR was achieved in 6 patients (22.2%), PR in 7 (25.9%), and non-response in 8 (29.6%); PD on therapy occurred in 4 cases (14.8%) and 2 patients died before response could be assessed. Of the 14 patients who received MATRix, 5 (31.2%) achieved PR, 6 (42.9%) had stable disease and 3 (21.4%) progressed while on treatment (Figure 1A). Of the 7 who received MAR or HDM only, 4 (57.1%) achieved CR, with 1 PR and 1 SD; 1 patient died before response could be assessed. Response was not affected by prior chemotherapy (for WM), and no biological or radiological feature predicted response in this highly heterogenous population. Predicted overall survival plateaued at 71.5% 1 year after start of treatment (Figure 1B). At a median follow up of 19.4 months, 7 patients (25.9%) had died: 3 (11.1%) from progressive BNS (1 patient had received each of MATRix, R-IDARAM and HDM only), and 4 (14.8%) from treatment-related toxicity (including infection). Of the latter 4 patients (all male), 2 had received MATRix and 1 had received each of MAR and R-IDARAM. No objective response was seen in 6 of the 7 deceased patients; the remaining 1 patient achieved PR following full-dose MATRix, but subsequently relapsed and died of BNS 7 months later. Regarding dose intensity, 5/15 MATRix recipients (33.3%) received full-dose regimens (i.e. 3.5mg/m2 of MTX per cycle for 3-4 cycles); a further 5 patients received a dose reduction of MTX (to 50-75%) and 9 patients (60%) received CONCLUSION In the setting of indolent CNS lymphoma, the rationale for chemoimmunotherapy is unclear. Although HDM-based therapy is used in BNS, its administration is limited by toxicity, and dose reductions may undermine dose intensity in the CSF. We observed higher rates of treatment-related mortality and only modest response rates with MATRix vs other HDM-based regimens; this primarily related to treatment related toxicity necessitating dose reduction requirements. These data suggest MATRix offers no response benefit over MAR or HDM only; indeed, the omission of thiotepa appears to allow dose optimisation of MTX and cytarabine, and does not negatively impact on outcome. If patients survive the first year of their disease/treatment, survival outcome is excellent. 1. Ferreri, A.J.M., et al.The Lancet Haematology3, e217-e227 (2016). Figure 1 Disclosures Carr: Lupin: Honoraria; Grifols: Other: Travel support; CSL: Honoraria. Wechalekar:Janssen, Takeda, Caelum, Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. D'Sa:Janssen: Honoraria, Research Funding; BeiGene: Honoraria, Research Funding; Sanofi: Honoraria.

Introduction Arterial and venous events are known to occur in patients with POEMS (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal gammopathy, Skin changes) syndrome which may also include myeloproliferation, with a reported rate in the literature of around 20%. This is higher than in the myeloma cohort where the VTE rate from the UK Myeloma XI study was reported as 11.8%. The approach to optimum management of thrombosis in POEMS patients remains undefined. Method The UCLH POEMS Registry is a comprehensive tertiary centre-based UK data repository including patients from 1999 to the present. Data were collated from patients referred in for diagnosis or after treatment and included blood results, neurological and general performance status, previous and active venous thromboembolism (VTE) and arterial events and their management. Results Of the 103 patients in the UCLH POEMS Registry, 20 were excluded due to missing data. Of the 83 patients included, median age was 52 years (31-84) and 54 (65%) were male. Mean haemoglobin at diagnosis was 143 g/L (89-190), platelet count 443 x10^9 (194-741), vascular endothelial growth factor (VEGF) 3536 pg/mL (388-15422), creatinine 75 μmol/L (32-168) and albumin 40 g/L (31-50). Performance status was ≥ 3 in 15 patients. Radiotherapy was used as a treatment modality in 21/83 (25%) and 48/83 (52%) patients received autografts. There were 51 outpatient-based chemotherapy regimens prescribed. Lenalidomide and dexamethasone (LD) was the most common prescription 30/51 (59%), followed by cyclophosphamide and dexamethasone in 10/51 (20%), LD plus cyclophosphamide in 3/51 (6%), melphalan and steroids 3/51 (6%), cyclophosphamide, dexamethasone and thalidomide 2/51 (4%), LD plus ixazomib 1/51 (2%), velcade, thalidomide and dexamethasone 1/51 (2%) and carfilzomib with dexamethasone 1/51 (2%). Of these 51 outpatient-based chemotherapy scripts, 30 received documented thromboprophylaxis (TP). Prophylactic low molecular weight heparin (pLMWH) was prescribed most frequently (17/30) with 16 of these patients receiving an immunomodulatory based chemotherapy regimen. Other TP agents used include: aspirin (6/30), treatment dose LMWH (tLMWH) (2/30), rivaroxaban (2/30), warfarin (2/30) and clopidogrel (1/30). Twenty-five patients experienced a total of 35 clinically apparent arterial or venous events. Seven had more than 1 thrombotic event, 2 of which developed both arterial and venous thromboses. Three patients had a prior history of VTE;1 with historic DVT developed pulmonary emboli, and 2 had arterial events after historic VTE. Eleven patients had 14 VTEs including DVT (6/14), PE (4/14) and 4 PICC-associated DVT occurring during melphalan-based autograft. Most VTEs occurred during active disease with median VEGF 2731 (444-5000). Five venous events occurred on chemotherapy, including 4 during a melphalan-based autograft, and 1 on LD. VTE occurred despite prophylactic LMWH in 3 patients (2 unknown). Treatment comprised LMWH (4), warfarin (4), or the direct oral anticoagulants, rivaroxaban (1) and apixaban (1). One patient did not receive treatment for a PICC-associated DVT. Sixteen patients experienced 21 arterial events including stroke (7/21), peripheral vascular disease (6/21), MI (4/21) and microvascular disease (2/21). Most events occurred during active disease with median VEGF 3155 (637-10640). Three occurred on anti-POEMS therapy: one patient (VEGF 4555) developed a second stroke on LD and LMWH prophylaxis; one patient on LD (VEGF 10640) and prophylactic rivaroxaban 10mg developed PVD, and another on melphalan and prednisolone (VEGF 2000-4000) and warfarin for atrial fibrillation (target INR 2.0-3.0) developed PVD. Conclusion The venous and arterial event rate in this cohort at 35/83 (42%) is over double that previously reported. There were more arterial events than venous, and most occurred in a state of active disease and off anti-POEMS therapy (26/35), suggesting that treatment-related risk factors are less of a driver for thrombosis than the disease itself. There was no discernible relationship with thrombocytosis. Thromboprophylaxis is commonly used in POEMS patients receiving outpatient-based chemotherapy with the most common agent being prophylactic LMWH. With the high incidence of arterial events in the presence of active disease, the role for anti-platelet agents or indeed DOACs remains undefined in this patient group. Disclosures Thomas: Sanofi: Membership on an entity's Board of Directors or advisory committees. D'Sa:Janssen: Honoraria, Research Funding.

Introduction POEMS (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal gammopathy, and Skin changes) syndrome is a rare multi-system disorder characterised by a monoclonal plasma cell disorder and peripheral neuropathy in combination with a myriad of other clinical features. Several patient cohorts have previously been described leading to the formulation of diagnostic criteria. For the purposes of establishing a specialist centre in the United Kingdom we collected data of our patient cohort and compared it with previous reports. Methods Demographic data for patients currently known to our clinic with an established diagnosis of POEMS (n=52) was extracted from an already existing database. Clinic letters for these patients were retrospectively screened for clinical features, diagnostic criteria, treatments given and response to treatment, occasionally supplemented by review of historical investigation results. The data was collected in a newly established database designed to facilitate future prospective data collection. Results Our cohort currently consists of 52 patients from a mixed ethnic background, with a male to female ratio of 4.2:1 (n=42 vs 10 respectively) and a median age of 57; median age at diagnosis was 49. The majority of patients were referred to our centre from across the United Kingdom between 2009 and 2015. The prevalence of diagnostic criteria broadly resembles previously published cohorts (see table). 17 patients received radiotherapy for limited disease while 31 patients underwent autologous haematopoietic stem cell transplant (ASCT); 18 patients received at least one line of systemic chemotherapy. A subgroup review of patients who underwent ASCT showed sustained clinical improvements in 83% of patients reviewed; 61% of patients who received radiotherapy had a documented sustained improvement. Patients receiving chemotherapy showed a more variable response; of note, 4 out of 6 patients treated with a combination of lenalidomide and dexamethasone were documented to have had significant clinical improvement. 3 patients died during the period of follow-up at the ages of 70, 63 and 63, respectively. Death occurred between 4 and 15 months following diagnosis; none of the deceased patients underwent ASCT or radiotherapy. Discussion We report the basic demographic and clinical outcomes of a new cohort of patients with this rare condition. Our cohort broadly resembles other previously published reports, as does our experience with therapeutic options. Radiotherapy appears to be effective in stabilising or improving limited disease confined to a solitary plasmacytoma or few lytic foci, while autologous stem cell transplantation achieves sustained improvement in the majority of patients with more diffuse disease. Chemotherapy offers further treatment options for patients not suitable for either of those, with lenalidomide becoming an increasingly promising agent. Retrospective data collection and the establishment of a database for prospective study will enable us to further investigate this group with a view to expand our understanding of this poorly understood disease. Disclosures Yong: Autolus Ltd: Equity Ownership, Patents & Royalties: APRIL based chimeric antigen receptor; Janssen: Research Funding.