Are neurological complications of monoclonal gammopathy of undetermined significance underestimated?

Objectives Monoclonal gammopathy of undetermined significance (MGUS) is a premalignancy preceding multiple myeloma (MM) or related disorders. Neurological symptoms caused by the monoclonal immunoglobulins or free light-chains are often associated with a high morbidity. We analyzed the prevalence of neuropathy, clinical features and the long-term outcome in 223 patients (pts.) with MGUS. Patients and Methods Between 1/2005 and 3/2015, 223 adult pts. with MGUS were identified in our database. Results In36/223 pts. (16%) a neuropathy was diagnosed (MGUS associated neuropathy, MGUS-N). 20 pts. (55%) had a distal symmetric axonal neuropathy, 10 pts. (28%) had a chronic inflammatory demyelinating polyneuropathy and 6 pts (17%) a distal acquired 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). Conclusion Due to the substantial prevalence of neuropathies, MGUS pts. should be monitored carefully and referred to a specialized center if neurological symptoms occur.


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 (κ) and lambda (λ) light chains, and the non-IgG isotype [4].
MGUS 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 as through the interaction with specific antigens on peripheral nerves. Although the prevalence of neuropathy among MGUS patients (pts.) varies considerably in the literature and the identification often depends on patient selection and diagnostic procedures, it is estimated at about 17% [5][6][7]. 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,

Research Paper
dysesthesia, anesthesia, neuropathic pain) of distal lower limbs and slowly evolving motor weakness in a lengthdependent 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 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 [10][11][12]. 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.
In the MGUS-N group 20 pts. (55%) had an axonal neuropathy, 10 pts. (28%) a CIDP, and 6 pts (17%) presented with a DADS polyneuropathy. Anti-myelinassociated glycoprotein (MAG) antibodies were identified in 4 pts. with IgM-MGUS and demyelinating neuropathy (3 DADS and 1 CIDP phenotype). Table 2 specifies clinical symptoms and severity of neuropathy, associations with immunoglobulin isotypes and treatment modalities in MGUS-N pts. Severity of neuropathy was graded by review of pt. records as mild (sensory symptoms and/or mild distal weakness without impairment of walking), moderate (weakness and/or ataxia interfering with walking) or severe (walking with aid or wheelchairbound). Figure 1 shows an overview of the study population with regard to the progression to MM or other lymphoproliferative disorders. A total of 38 pts. (17%) progressed after a median time to progression of 48 months (range 2-276 months). 6 pts. progressed in the MGUS-N cohort, thereof 4 pts. to Waldenstrom's macroglobulinemia (67%) and 2 pts. to MM (33%). In the MGUS-NN cohort, a total of 32 pts. progressed, thereof more than half of the pts. to MM (n=17; 53%), 6 pts. to smoldering MM (19%), 7 pts. to AL-amyloidosis (22%), and 2 pts. progressed to Waldenstrom's macroglobulinemia (6%). Comparing the two cohorts MGUS-NN and MGUS-N, the rate of progressions was identical in the two groups (17%). However, significantly more progressions to Waldenstrom's macroglobulinemia were observed in MGUS-N pts. (67% vs. 6%; p<0.05), and significantly more progressions to MM and AL-amyloidosis were seen in the MGUS-NN cohort (53% vs. 33% and 22% vs. 0%, respectively; both p=<0.05). Information on pts. who had a disease progression is shown in Table 3.

Survival and time to progression (TTP) in MGUS-NN and MGUS-N pts
Median follow-up for the whole cohort (n=223) was 79 months and evaluated patient-years were 1,595. Median overall survival (OS) for the total study population www.impactjournals.com/oncotarget was 255 months. In the progressed 38 pts. a progression rate in the first year of 26% was seen. The progression rate was 1% per year in the MGUS-N cohort and 0.5% per year in the MGUS-NN cohort. Median TTP in the cohort that progressed (MGUS-NN and MGUS-N; n=38) was 48 months (95% CI 20-76). TTP was longer in the MGUS-NN group than in the MGUS-N cohort (median TTP 54 months, 95%CI=30-78 vs. median TTP 12 months, 95%CI=8-16; p>0.05). Kaplan-Meier plots on progression for the whole cohort (n=223) and stratified for MGUS-NN and MGUS-N are shown in Figure 2.

Risk factors for disease progression
Clinical data of the two cohorts, MGUS-NN and MGUS-N, were evaluated in terms of risk factors for disease progression.

DISCUSSION
In this retrospective study, 223 MGUS pts. were evaluated in terms of neurological manifestations. 187 MGUS-NN pts. were compared to 36 MGUS-N pts. regarding clinical characteristics, disease progression and risk factors predicting progression to a malignant hematological disorder. The strengths of this study are the large number of included pts., all collected in the local database of our medical university, and the follow-up time of 10 years. Limitations existed in the partly incomplete documentation of pts.' data intended for the analysis. Moreover, pts. treated at a University Hospital might create a selection bias in favor of MGUS-N pts.
The prevalence of several clinical and laboratory features (immunoglobulins, anemia, renal dysfunction, elevated calcium level, elevated β2-microglobulin, LDH level, incidence of second tumors, progression to different hematological diseases) differed between MGUS-NN and MGUS-N (Table 1). A significantly higher incidence of anemia was found in MGUS-NN. A potential explanation could be the significantly higher prevalence of IgG immunoglobulins in the MGUS-NN cohort, which can lead to monoclonal gammopathy of renal significance including chronic kidney disease with renal anemia [16,17].
The annual risk of progression to MM in pts. with MGUS is about 1% [1]. The risk of progression to MM   Figure 1). It was shown that pts. affected by MGUS-NN, progressed significantly more often to smoldering MM, MM and AL-amyloidosis compared to the MGUS-N group. By contrast, more progressions to Waldenstrom's macroglobulinemia were seen in the MGUS-N group. In particular, the immunoglobulin isotype, the M-protein concentration and the free light chains ratio are known to be risk factors related to progression [1,4,18]. Recently, Sigurdardottir and coworkers demonstrated that regular follow-up of MGUS pts. may be associated with the outcome in MM [19]. Thus, the guidelines recommend annual monitoring in high risk MGUS pts. and follow-up in low risk MGUS pts. presenting with clinical symptoms [4]. As optional investigation, in IgM-MGUS with higher risk for progression into Waldenstrom's macroglobulinemia than non-IgM MGUS, an evaluation of lymphadenopathy and/ or spleen size by sonography could be done. In our cohort, 36 pts. (16%) with MGUS had an associated neuropathy. This finding is in line with the study of Nobile-Orazio et al., who described 17% MGUS-N in their population (thereof 6% in IgG-MGUS, 14% in IgA-MGUS, and 31% in IgM-MGUS pts.) [5]. Axonal neuropathy was the most frequent entity among our pts. (55% of MGUS-N) and most of these cases probably had a coincidental association with MGUS not requiring specific treatment except agents for neuropathic pain [9,20]. Some pts. with IgG and IgA paraproteinaemic axonal neuropathy, however, may benefit from immunotherapy [21], as was seen in two pts. from our cohort; therefore these pts. should not be a priori excluded from these treatment options.
IgM-MGUS has the highest prevalence in monoclonal gammopathy associated with neuropathy, that usually manifests with distal symmetric sensorimotor and atactic features [6,22,23]. These findings (IgM-MGUS-N in our total IgM cohort of 42 pts. was 31%) and the results of Kristinsson et al., that MGUS of IgM type is associated with a higher progression risk to Waldenstrom's macroglobulinemia [24], are confirmed by our study. In our cohort, all 6 pts. who progressed to Waldenstrom's macroglobulinemia had previously IgM-MGUS-NN or IgM-MGUS-N, respectively (see Table 3). The MGUS-N group showed significantly more progressions to Waldenstrom's macroglobulinemia compared to the MGUS-NN group (4 of 6 progressed pts. in MGUS-N; 67% vs. 2 of 32 progressed pts. in MGUS-NN; 6%; p<0.05). The disease course of neuropathy due to IgM-MGUS with or without antibodies against MAG is highly variable [25] and studies assessing the efficacy of intravenous immunoglobulins [26,27] and Rituximab [28,29] showed inconsistent results. In CIDP associated with monoclonal gammopathy, steroids, intravenous immunoglobulins and plasma exchanges represent the main therapeutic options as in idiopathic CIDP and 66-80% of pts. respond to one of these treatments [11,30,31]. On long-term follow-up, however, progression of functional deficits is greater in MGUS-CIDP pts. compared to idiopathic CIDP [32].
In our total study population, a threshold of ≥5.5% plasma cells in the bone marrow was found to be a strong predictor for disease progression. Although this  was described previously [33,34], nevertheless it is an important finding and should be evaluated in the future as a risk factor for disease progression. Hitherto, special molecular alterations and drivers for disease progression in MGUS and MM are still unknown, but it has been shown that changes in the bone marrow microenvironment develop early and consistently [35]. It might be suggested that clonal proliferation of plasma cells increases genetic instability with possible driver mutations in different subclones [36,37]. The higher the clonal expansion, the higher the number of potential triggers. Therefore, in our opinion, for MGUS pts. with a percentage of ≥5.5% plasma cells in the bone marrow, a close-meshed monitoring to detect progression to MM or other related hematological disorders is recommended. However, a routine bone marrow examination in newly diagnosed MGUS pts. is not currently indicated.
In summary, in this study we analyzed the prevalence of neurological manifestations in MGUS pts. and demonstrated differences in clinical features and risk factors for disease progression in a large cohort of MGUS-NN and MGUS-N pts. In our study population, a considerable part of MGUS pts. (16%) had a neuropathy. Peripheral neuropathy associated with monoclonal gammopathy is a complex problem in clinical practice. As MGUS pts. frequently are not referred to a specialized center, that may result in an underestimation of neurological symptoms and their complications or in a non-detection of a correlation with MGUS-N disease. Therefore, it is important that MGUS pts. are monitored carefully and referred to a specialized center if neurological symptoms occur, particularly those with progressive sensorimotor deficits and ataxia. Furthermore, due to the risk of progression to MM or other related diseases (17% of the pts. in both groups), the important goal for MGUS pts. must be the detection of an early progression into MM and the prevention of complications. MGUS pts. should be considered for riskand-response stratified therapy monitoring even in terms of neurological manifestations, and an early supportive treatment should be conducted to improve their quality of life, as well as immunomodulatory and /or specific treatments in pts. with progressive neuropathies.

PATIENTS AND METHODS
Between January 2005 and March 2015, a total of 223 adult pts. aged between 26 and 97 years with MGUS according to the International Myeloma Working Group (IMWG) criteria [3], were identified by an exploration in our local database. Observation period in some pts. lasted over 10 years since the initial diagnosis was made before 2005. Sampling and evaluation of pts.' data was approved by the local institutional ethics committee (vote number: AN2015-0193 352/4.13) and was conducted in accordance with the principles of the Declaration of Helsinki. The study included pts.' data about the clinical presentation, physical examination and laboratory tests. Two cohorts, MGUS-NN and MGUS-N pts., were compared and were analyzed for disease progression. "Progression" is used in the whole paper as term for every change into other diseases. MGUS-N pts. were diagnosed by a consultant neurologist or referred to the neuromuscular unit of the Department of Neurology and classification of neuropathy was based on standard electrophysiological studies.
Statistical evaluation was performed using SPSS statistical software (version 20.0; SPSS Inc., Chicago, IL, USA). All tests for statistical significance were two-sided. Chi-squared test, unpaired t-test and survival analysis (Kaplan Meier curves, log-rank test) were used to identify differences between two groups. A p-value of <0.05 was considered as statistically significant.

ACKNOWLEDGMENTS
Author's contributions to this work: N Steiner, A Schwärzler and J Wanschitz identified the pts. from the local database. N Steiner and A Schwärzler performed the data analysis and interpretation. E Gunsilius, J Wanschitz, WN Löscher and N Steiner wrote the paper. Statistical evaluation was performed by G Göbel.