Baseline characteristics
Thyroid function indexes of patients with MM and healthy subjects are shown in Table 1 and Figure 1. Compared of healthy individuals, newly diagnosed patients with MM had significantly increased TSH levels (P < 0.05), and significantly decreased TT4, TT3, and FT3 levels (P < 0.05) (Table 1). The clinical characteristics of all patients at diagnosis are listed in Table 1. A total of 124 patients met inclusion criteria (73 males and 51 females), with a median age of 58 years (IQR: 53-64 years). According to the DS staging system, 18 patients (14.5%) were stage II and 106 (85.5%) were stage III MM. The median survival of enrolled patients was 749 days (IQR 353-1059). The median clinical parameters of all patients were: plasma cells ratio = 34%, β2MG = 6.22 mg/L, TSH = 2.46 mIU/L, TT4 = 82.49 nmol/L, TT3=1.36 nmol/L, FT4=14.72 pmol/L, FT3 = 3.94 pmol/L, HB = 85 g/L, albumin = 33 g/L, globulin = 60 g/L, BUN = 6.2 mmol/L, Cr = 88 umol/L, and calcium = 2.24 mmol/L (Table 1).
Comparison of clinical indicators between survivors and non-survivors
All MM patients were divided into two broad categories namely, survivors (n = 69,55.6%) and non-survivors (n = 55,44.4%) based on whether they survived within 2 years of diagnosis. The clinical indicators of the two groups were compared, and the results are shown in Table 1 and Figure 1. Non-survivors had considerably lower median survival than survivors (275 vs 975 days, P < 0.001). The proportion of survivors diagnosed with Durie-Salmon Stage III was significantly lower than that of non-survivors (78.3% vs 94.5%, P = 0.019). Compared with survivors, non-survivors were older, had a higher proportion of marrow plasma cells, and had higher serum β2MG and Cr levels. The levels of hemoglobin and albumin were significantly decreased in non survivors (P = 0.020, P = 0.033, P = 0.034, P = 0.030, P = 0.001 and P = 0.003 respectively). Comparison of thyroid function indexes showed that non-survivors had significantly lower TT4, TT3, FT4, and FT3 levels than survivors (71.10 vs 92.57 nmol/L, P < 0.001; 1.17 vs 1.50 nmol/L, P < 0.001; 13.60 vs 15.09 pmol/L, P = 0.005; 3.47 vs 4.21 pmol/L respectively, P = 0.001) (Table 1 and Figure 1). There were no statistically significant differences between the two groups in terms of gender, globulin, BUN, calcium and TSH levels.
The Cutoff-value of cytokines between survivors and non-survivors
The optimal cutoff-value for predicting the prognosis of patients were determined and early risk factors suggesting poor prognosis of MM patients were explored. Cutoff value was determined by ROC curve and the results are shown in Table S1. The cutoff-value of each indicator was: age = 68 years (95% CI=0.486-0.719, P = 0.007), plasma cells = 30.75% (95% CI=0.541-0.766, P = 0.039), β2MG = 6.63 mg/L (95% CI= 0.543-0.767, P = 0.010), HB = 82 g/L (95% CI=0.588-0.783, P = 0.001), albumin = 28 g/L (95% CI=0.576-0.744, P = 0.001), globulin 73.5 g/L (95% CI=0.509-0.738, P = 0.041), BUN = 6.25 mmol/L (95% CI=0.478-0.714, P = 0.202), Cr = 93 µmol/L (95% CI=0.496-0.736, P = 0.031), calcium = 2.07 mmol/L (95% CI = 0.391-0.618, P = 0.937), TSH = 1.58 mIU/L (95% CI=0.465-0.678, P = 0.192), TT4 = 67.66 nmol/L (95% CI=0.621-0.815, P = 0.001), TT3 = 1.25 nmol/L (95% CI = 0.551-0.759, P = 0.004), FT4 = 14.06 pmol/L (95% CI=0.495-0.723, P = 0.045), FT3 = 3.27 pmol/L (95% CI = 0.579-0.783, P = 0.001).
Univariate and multivariate analyses of prognosis factors for OS
To determine the impact of each statistically significant clinical indicator determined by the ROC curve on survival, Kaplan-Meier, univariate, and multivariate analyses were used. The results are shown in Table 2, Figure 2, and Figure S1. In the univariate analysis, age ≥68 years (HR = 0.297, 95% CI = 0.167-0.530, P = 0.001), DS stage Ⅲ (HR = 3.549, 95% CI =1.108-11.37, P = 0.033), plasma cell ≥30.75% (HR = 0.438, 95% CI = 0.241 0.796, P = 0.007), plasma cell ≥30.75% (HR = 0.438, 95% CI = 0.241-0.796, P = 0.007),β2MG ≥6.63 mg/L (HR = 2.178, 95% CI = 1.161-4.084, P = 0.015), HB ≤82 g/L (HR = 0.406, 95% CI = 0.233-0.710, P = 0.002), albumin ≤28 g/L (HR = 0.386, 95% CI = 0.226-0.659, P = 0.001), globulin ≥73.5 g/L (HR = 1.848, 95% CI = 1.076-3.173, P = 0.026), Cr ≥93 µmol/L (HR = 2.346, 95% CI = 1.348-4.082, P = 0.003), TT4 ≤67.66 nmol/L (HR = 0.233, 95% CI = 0.130-0.383, P = 0.001), TT3 ≤1.58 nmol/L (HR = 0.354, 95% CI = 0.207-0.607, P = 0.002), FT4 ≤14.06 pmol/L (HR=0.435, 95% CI=0.251-0.755, P=0.003), FT3≤3.27 pmol/L (HR = 0.271, 95% CI=0.159-0.462, P=0.003) were significantly associated with 2-year OS. In addition, the survival curve of MM patients based on the Kaplan-Meier method also revealed risk factors consistent with the results of univariate analysis (Figure 2A-B and Supplementary Figure S1, A-H). Multivariate regression analysis was then performed to investigate independent predictors of adverse outcomes in MM patients. Age ≥68 years (HR = 0.463, 95% CI = 0.226-0.900, P = 0.036) and TT4 ≤67.66 nmol/L (HR = 0.204, 95% CI = 0.101-0.412, P <0.001) can be an independent prognostic factor for OS in patients with MM (Table 2).
Clinical characteristics of patients with different levels in TT4
The results of the comparison of clinical characteristics of MM patients with different TT4 levels revealed that patients with higher TT4 levels had a longer survival time (808 vs 368 days, P < 0.001), lower β2MG levels (5.35 vs 9.32 mg/L, P = 0.016), higher HB levels (91 vs 74 g/L, P = 0.001), higher albumin levels (33 vs 28 g/L, P = 0.007), higher TT3 levels (1.47 vs 0.97 nmol/L, P <0.001), higher FT4 levels (15.85 vs 13.39 pmol/L, P < 0.001), and higher FT3 levels (4.14 vs 4.14 pmol/L, P < 0.001) (Table 3). However, there were no significant differences in age, plasma cells ratio, globulin, BUN, Cr, calcium, and TSH levels between the two groups.
Correlation analysis of TT4 level and other clinical indicators in patients with multiple myeloma
Correlation analysis was conducted between significant clinical indicators in different TT4 levels with different TT4 levels (Table 4). The results showed that FT4 (r= 0.729, P < 0.001), HB (r = 0.251, P = 0.005) and albumin (r = 0.350, P < 0.001) levels were positively correlated with TT4 levels. However, β2MG (r = -0.165, P = 0.099), TT3 (r = -0.131, P = 0.145) and FT3 (r = 0.071, P = 0.435) levels were not significantly correlated with TT4 levels.