n=12, 39% in MGUS-N; p 0.05), higher levels of lactat dehydrogenase (LDH) (n=33, 18% vs. demyelinating symmetric polyneuropathy. In MGUS-NN (without neuropathy) and in MGUS-N, progression to smoldering MM, MM or Waldenstrom’s macroglobulinemia (WM) occurred in 17% of the pts. The Immunoglobulin subtype was predominantly IgG in MGUS-NN and IgM in MGUS-N and 5.5% plasma cells in the bone-marrow predicted progression to MM and AL-amyloidosis in MGUS-NN and to WM in MGUS-N (p 0.05). NS 309 Conclusion Due to the substantial prevalence of neuropathies, MGUS pts. should be monitored carefully and referred to a specialized center if neurological symptoms occur. strong class=”kwd-title” Keywords: monoclonal gammopathy of undetermined significance, MGUS, MGUS associated neuropathy, multiple myeloma INTRODUCTION Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant disorder with a 0.5-1.5% per year risk of progression to multiple myeloma (MM) or other related hematological malignancies [1, 2]. According to the International Myeloma Working Group (IMWG), MGUS is characterized by a monoclonal (M)-protein in the serum of 30 g/l, a clonal plasma cell count in the bone marrow of 10%, and the absence of clinical symptoms [3]. Risk factors for a progression include an M-protein 15 g/l, an abnormal ratio of free kappa () and lambda () light chains, and the non-IgG isotype [4]. MGUS NS 309 associated neuropathies (MGUS-N) are heterogeneous with respect to the clinical presentation and the underlying pathophysiology and can be caused by deposition of immunoglobulins or amyloid as well NS 309 as through the interaction with specific antigens on peripheral nerves. Although the prevalence of neuropathy among MGUS patients (pts.) varies considerably in IL3RA the literature and the identification often depends on patient selection and diagnostic procedures, it is estimated at about 17% [5C7]. Vice versa, 5-10% of pts. investigated for neuropathy have a monoclonal gammopathy [8]. There are three major forms of neuropathy in paraproteinemic disorders: axonal sensory-motor neuropathy, chronic inflammatory demyelinating polyneuropathy (CIDP), and distal acquired demyelinating symmetric (DADS) polyneuropathy. Axonal neuropathy usually presents with sensory symptoms (paresthesia, dysesthesia, anesthesia, neuropathic pain) of distal lower limbs and slowly evolving motor weakness in a length-dependent fashion. It may be associated with IgG/A/M MGUS, but the causal link between the serum paraprotein and axonal nerve damage remains elusive in many cases, although severe pain and autonomic dysfunction may raise the suspicion of amyloidosis [6]. In the demyelinating entities CIDP and DADS a causal relationship with NS 309 monoclonal gammopathy is considered likely [6, 9]. CIDP is a relapsing or progressive immune mediated neuropathy with proximal and distal weakness and sensory deficits of upper and lower limbs and 22-30% of CIDP pts. are described to have MGUS, commonly IgG or IgA subtypes [10C12]. DADS neuropathy is characterized by predominant distal sensory impairment, ataxia and often tremor, but little or no weakness and has a close association with IgM kappa monoclonal gammopathy that is present in about two-thirds of pts. [13]. In 50-67% of these pts. the IgM monoclonal protein binds to myelin-associated-protein (MAG) [13, 14] causing a characteristic widening of myelin lamellae in nerve biopsies [15]. Despite potent agents in the treatment of pts. with MGUS associated neuropathies, e.g. immunomodulatory agents, plasmapheresis or monoclonal antibodies, some pts. may still present with a high morbidity [9]. The aim of this retrospective single center analysis was to describe the prevalence of neurological manifestations in MGUS pts. and to compare clinical features and risk factors for disease progression in MGUS pts. with and without neuropathy. RESULTS Patient characteristics 223 pts. fulfilled the criteria for MGUS according to the International Myeloma Working Group (IMWG) criteria, thereof 187 pts. had a MGUS without (MGUS-NN; 84%) and 36 showed a MGUS associated with neuropathy (MGUS-N; 16%). Table ?Table11 summarizes demographic data and laboratory features of MGUS-NN and MGUS-N pts. Table 1 Demographic data and laboratory.