Background Multiple myeloma (MM) is a malignant plasma cell disease, nearly half of patients have MM-related renal impairment (KI) at diagnosis, which is associated with increased mortality. Early recognition and treatment of KI has the potential to reverse renal function and improve patient's survival. Neutrophil gelatinase-associated transporter (NGAL) , T-cell immunoglobulin mucin receptor 1 (TIM-1) , vascular cell adhesion molecule-1 (VCAM-1) , and activin A are associated with the pathological processes such as cell proliferation, tumor invasion, and KI. The above indicators are promising as relevant indicators for the early diagnosis of MM related KI.
Objective To investigate the significance of novel biomarkers NGAL, TIM-1, VCAM-1 and activin A in the MM disease evolution, staging and prognosis of newly diagnosed MM (NDMM) with KI.
Methods A total of 70 patients with MM were screened as the research subjects, they were admitted to the our hospital from January 2017 to February 2022, including 62 NDMM patients, 8 smoldering MM (SMM) patients, and 12 cases with MGUS, 7 cases with MGRS, and 20 healthy controls (HC) were admitted to this study, their urine and serum samples were stored for analysis. The clinical data of all subjects were collected, and the bone marrow biopsy, M protein examination and imaging examination of MGUS, MGRS and NDMM patients were statistically analyzed. It was detected using ELISA method of urinary or serum concentration of NGAL, TIM-1, VCAM-1 and activin A. According to the disease state, they were divided into four groups MGUS, MGRS, NDMM and HC group. According to whether there was KI, they were divided into two groups KIgroup of 40 cases and the non-KI (NKI) group of 30 cases. KI group was divided into MM three subgroups according to dynamic disease treatment status, pre-treatment MM, above partial response (PR) after treatment (>PR) group (20 cases) , and disease recurrence (relapsed MM) group of 11 cases. Spearman correlation analysis was used to analyze the correlation of each factor, receiver operating characteristic (ROC) curves were plotted to analyze the diagnostic value of each detected factor for NDMM with KI, and optimal cut off values and other indicators were calculated and divided into higher than the optimal cut off value group and lower than the optimal cut off value group according to the optimal cut off value of each detected factor, and Kaplan-Meier method was used to analyze the overall survival (OS) status of each detected factor in the higher than the optimal cut off value group and lower than the optimal cut off value group. Cox proportional hazards regression was used to analyze the influencing factors of all-cause mortality in NDMM patients with KI.
Results The levels of uNGAL, uTIM-1, uVCAM-1, sTIM-1, and uActivin A in the NDMM group were higher than those in the MGUS and HC groups (P<0.05) . The levels of uNGAL, uTIM-1, uVCAM-1, sTIM-1, and uActivin A in the MGRS group were higher than those in the MGUS group (P<0.05) . The levels of uNGAL, uTIM-1, uVCAM-1, sTIM-1, and uActivin A in the KI group were higher than those in the NKI group (P<0.05) . The levels of uNGAL, uTIM-1, uVCAM-1, sTIM-1 and uActivin A in pre-treatment MM subgroup and relapsed MM subgroup were higher than those in > PR subgroup (P<0.05) . The uNGAL, uTIM-1, uVCAM-1, sTIM-1, and uActivin A were positively correlated with creatinine, β2-microglobulin, and R-ISS stages and negatively correlated with glomerular filtration rate (eGFR) (P<0.05) . The uNGAL, uTIM-1, sTIM-1, and uActivin A were positively correlated with 24 h urinary light chain levels (P<0.05) . The uNGAL and uTIM-1 were positively correlated with the proportion of clonal plasma cells (P<0.05) . According to the ROC curve, the optimal cut off values of uNGAL, uTIM-1, uVCAM-1 and uActivin A for the diagnosis of MM related KI were 14.774 ng/mL, 1.978 ng/mL, 144.400 ng/mL, and 33.730 pg/mL respectively. Kaplan-Meier analysis showed that patients above the respective optimal cutoff values of uNGAL, uTIM-1, sTIM-1, uVCAM-1, and uActivin A had worse OS (P<0.05) . Multivariate Cox proportional hazards regression analysis showed that uNGAL and R-ISS stages were the factors influencing all-cause mortality in NDMM patients with KI (P<0.05) .
Conclusion The uNGAL, uTIM-1, uVCAM-1 and uActivin A may be associated with the progression of MM and MM kidney injuried, and the early markers of tubular injury, which were helpful for the early diagnosis and treatment of myeloma patients with kidney injuried. uNGAL, uTIM-1, uVCAM-1, uActivin A were related with β2-microglobulin, R-ISS stage, 24 h urinary light chain, proportion of clonal plasma cells and other tumor burden indicators and the overall survivals (OS) of MM patients. These results suggest that these factors were not only serve as an effective supplement to novel biomarkers of kidney injury in clinical practice in addition to serum creatinine, but also as novel anti-MM therapeutic targets in the future. The uNGAL, uTIM-1, uVCAM-1, and uActivin A may be associated with MM disease progression and KI. They are early markers of tubular injury, facilitate the early diagnosis and treatment of MM patients with KI, and are associated with tumor burden indicators such as R-ISS stage, 24 h urinary light chain, and clonal plasma cell ratio and overall survival of MM patients.
