关键词: 多发性骨髓瘤, 肾损害, 预后, 中性粒细胞明胶酶相关载脂蛋白, T细胞免疫球蛋白和粘蛋白结构域 1, 血管细胞粘附分子1, 激活素A, 游离轻链

Abstract: Multiple myeloma (MM) is a malignant plasma cell disease that tends to occur in the elderly man, and its common clinical manifestations are CRAB symptoms such as increased serum calcium (C), renal impairment (R), anemia (A), and bone impairment (B), also known as active or symptomatic myeloma (active MM). About 50% of MM patients present with renal impairment. MGUS (Monoclonal gammopathy of undetermined significance) or Monoclonal gammopathy of renal significance (MGRS) can progress to symptomatic MM. In recent years, the survival of MM patients has been gradually prolonged due to the clinical application of new tumor-targeted drugs such as proteasome inhibitors (PIs) and immunomodulators, but the terminal stage of the disease or with severe renal impairment remains associated with poor survival. MGRS requires appropriate targeted therapy once diagnosed in order to protect renal function. Neutrophil gelatinase-associated transporter (NGAL), also known as (LCN-2), is associated with cell proliferation, angiogenesis, cell invasion, metastasis and acute kidney injury. T-cell immunoglobulin mucin receptor 1 (TIM-1), also known as kidney injury factor-1 (KIM-1), is associated with activation of immune responses by T lymphocytes and proximal tubular injury. Vascular cell adhesion molecule-1(VCAM-1) is a cell adhesion molecule that contributes to the regulation of inflammation-associated vascular adhesion and leukocyte migration and is elevated in patients with MM renal impairment. Activin A is a member of the transforming growth factor (TGF) superfamily and is involved in pathological processes such as MM disease progression，renal damage, anemia, and bone disease. Objective This study aimed to investigate the association of novel biomarkers with disease progression, renal impairment, and prognosis in MM. Methods A total of 70 patients with MM were selected as the research subjects, they were admitted to the Department of Hematology and Oncology, West campus，Beijing Chaoyang Hospital from January 2017 to February 2022, including 62 NDMM patients, 8 smoldering MM (SMM) patients, and 12 patients with monoclonal agammaglobulinemia of undetermined significance (MGUS), 7 patients with monoclonal gammopathy of renal significance (MGRS), and 20 healthy controls (HC) were admitted to this study, their urine and venous blood samples were selected for analysis. According to the disease state, they were divided into four groups: MGUS, MGRS, NDMM and HC. According to whether there was kidney injuried (KI), they were divided into two groups: KI (KI) group of 40 cases and the non-KI (NKI) group of 30 cases. A dynamic study of 20 MM patients with renal impairment was performed, and they were divided into three groups: NDMM, partial remission (PR) of the above after treatment (>PR) group, and disease recurrence Relapsed MM group (11 cases). It was detected using ELISA method of urinary or serum concentration of neutrophil gelatinase-associated lipocalin (NAGL), T cell immunoglobulin and mucin domain 1 (TIM-1), vascular cell adhesion molecule 1(VCAM-1) and Activin A. Results Urinary NGAL, TIM-1, VCAM-1, activin A and serum TIM-1 levels in NDMM group were higher than those in MGUS group and control group, KI group was higher than NKI group, and NDMM group and Relapsed MM group was higher than the remission group (P<0.05). Moreover, these indexes were positively correlated with serum creatinine, β2-microglobulin, and ISS stage. According to the ROC curve, the best cut-off value for diagnosing disease progression and MM renal damage for urine NGAL, TIM-1, VCAM-1 and Activin A were 14.774 ng/ml, 1.978 ng/ml, 144.400 ng/ml and 33.730 pg/ml, respectively greater than this cutoff value may have poorer survival for MM patients. Regression analysis found that urinary NGAL was an independent risk factor for renal damage in MM, and both urinary NGAL and RISS stages were significantly associated with all-cause mortality (both P<0.05). Conclusion Urinary NGAL, TIM-1, VCAM-1, and Activin A were not only related to disease progression and serve as sensitive indicators of early tubular injured in MM, but also related to the degree ISS stage, urinary light chain level and other tumor burden in MM. Urinary NGAL is an independent risk factor for renal damage in MM, and together with RISS stage, is associated with all-cause mortality in MM patients. It is revealed that these factors play an important role in the pathological mechanism of the tumor microenvironment from MGUS/MGRS to symptomatic MM. NGAL, TIM-1, VCAM-1, and Activin A are all involved in the pathological process of disease progression and KI in MM. It is an effective supplement for novel kidney damage biomarkers, and may hopefully become a novel anti-MM therapeutic target in the future to further improve the survival of MM patients.

Key words: Multiple myeloma, Kidney injury, Prognosis, Neutrophil gelatinase-associated lipocalin, T cell immunoglobulin and mucin domain 1, Vascular cell adhesion molecule 1, Activin A, Free light chain