Study of MGUS-Series: Disease Evolution, Coexistant Disorders and Other Clinical Observations
Authors: Maltezas Dimitrios , Eftychia Nikolaou , Papaioannou Paraskevi , Bitsani Aikaterini , Tzenou Tatiana , Dimou Maria , Iliakis Theodoros , Kotsanti Sotiria , Petsa Panagiota , Panayiotidis Panayiotis , Kyrtsonis Marie-Christine 
Published: October 2019

Abstract
Introduction: Monoclonal Gammopathy of undetermined significance (MGUS) is an asymptomatic premalignant plasma cell disorder occurring mainly in the elderly population. Its evolution, association with various diseases and behavior is an interesting study field in an attempt to understand its pathogenesis and disease course.
Aim: To study the grade of coexistence of non-malignant and malignant diseases along with disease evolution and behavior in patients with MGUS, diagnosed in a single center.
Patients and methods:We studied 138 MGUS-patients that were diagnosed in our center and then followed up to a median of 36 months (6months - 22 years). Median age was 66 years (27-92 years). 57% were of female sex. Monoclonal heavy chain was IgG in 76%, IgA in 14% and IgM in 10% of the patients while 63% presented k-chain clonality. Non-malignant and malignant preexisting diseases were documented at the time point of MGUS-Diagnosis. Patients with B-NHL expressing monoclonal Protein were not classified as MGUS since malignant B-Lymphocytes can be responsible for its production.
Results: 10.9% of the patients presented solid tumors. The most common malignancy was Prostate-Cancer in 8.5% of the male patients followed by Thyroid-Cancer which was present in 2.2% of the whole patient group.Hematological malignancies were existent in 10.9% of the patients. 4.3% presented myeloproliferative neoplasms while myelodysplastic syndromes were represented in 5% of the patients.18.1% of the patients presented with diverse benign tumors, 8% had been diagnosed with Diabetes Mellitus while 32.6% presented cardiovascular disease, mainly hypertension (23.2%). Hyperlipidemia was present in 8.7%. Finally 18.1% of the patients presented non-malignant thyroid disease, mainly hypothyroidism (10.9%) which is increased compared to the general population.17 MGUS-Patients (12%) presented disease evolution. 3 Patients evolved directly to multiple myeloma while 3 more evolved initially to smoldering myeloma (SMM) before developing overt myeloma. 8 patients evolved to SMM without any further progression. 2 patients with IgM-MGUS presented Waldenström's maroglobulinemia in the follow up while one patient developed a B-NHL. We performed a statistical analysis, where only abnormal serum free light chain ratio (sFLCR) was found to have a prognostic impact on MGUS-progression (p=0.03).Within this group of evolving MGUS-patients two of them presented a very remarkable course. The first one was diagnosed with MGUS while she was in remission after Hodgkin's Lymphoma. She evolved then to SMM confirmed by bone marrow biopsy with more than 10% plasma cell infiltration by immunohistochemistry. After being stable for several months, monoclonal protein was no longer detectable and plasma cells in the bone marrow were normal without any treatment. The second patient was initially diagnosed with MGUS with a high sFLCR of 60. She then evolved to SMM with further sFLCR-increase up to 100 but remained without treatment according to the guidelines at that time. Four years later she developed anemia and the final diagnosis was B-NHL.
Conclusion: In our study group MGUS was associated with numerous malignant and non-malignant disorders. Hypothyroidism was a common finding, increased compared to the general population. MGUS-evolution was also observed however disease course was unexpected in some patients showing the heterogeneity of the disease. sFLCR was confirmed as a prognostic factor. Further study is necessary to investigate any possible implication of the above findings in the disease pathogenesis and course.

Disclosures
Kyrtsonis: Genesis: Honoraria; Millenium: Research Funding; Lilly: Research Funding; Amgen: Research Funding.