Evaluating the Relationship of GDF-15 with Clinical Characteristics, Cardinal Features, and Survival in Multiple Myeloma

Abstract

Growth differentiation factor 15 (GDF-15), a member of the transforming growth factor-β superfamily, participates in processes associated with myeloma development and its end-organ complications. It plays a significant role in both physiological and abnormal erythropoiesis and regulates iron homeostasis through modulation of hepcidin. It is abnormally secreted in marrow stromal cells of patients with multiple myeloma (MM), which may reflect the tumor microenvironment. We analyzed the associations of serum GDF-15 with clinical characteristics of 73 MM patients (including asymptomatic MM) and the laboratory indices of renal function, anemia, and inflammation. Baseline serum GDF-15 was studied as the predictor of two-year survival. We defined five clinically relevant subgroups of patients (symptomatic MM only, patients with and without remission, patients on chemotherapy, and without treatment). Increased GDF-15 concentrations were associated with more advanced MM stage, anemia, renal impairment (lower glomerular filtration and higher markers of tubular injury), and inflammation. Most of the results were confirmed in the subgroup analysis. Serum cystatin C and urine neutrophil gelatinase-associated lipocalin were associated with GDF-15 independently of other variables. In the studied MM patients, GDF-15 did not significantly predict survival (p = 0.06). Our results suggest that serum GDF-15 reflects myeloma burden and shares a relationship with several markers of prognostic significance, as well as major manifestations.

Figure 1

Serum GDF-15 concentrations according to incremental MM disease stages with reference controls (a) and among patients receiving no chemotherapy (CTx) treatment versus those on chemotherapy at baseline (b). Data are shown as median (horizontal line), interquartile range (box), nonoutlier range (whiskers), and outliers (points); p value is shown for overall comparison between groups. The numbers of patients in each group are reported in Table 2. SMM: smoldering myeloma; ISS: International Staging System for multiple myeloma.

Figure 2

Correlations between serum GDF-15 concentrations and involved serum free light chains (FLC) (a) and β2-microglobulin (b) in studied patients. Light circles represent patients with complete or partial remission (CR/PR), and dark circles represent patients without remission (stable disease or progressive disease, SD/PD). The right-skewed variables were transformed using the natural logarithm (ln) to enhance readability. The Spearman rank-order correlation coefficients (R) in the whole studied group and the subgroups are shown with associated p values.

Figure 3

Serum GDF-15 concentrations among patients with (n = 14) and without (n = 59) anemia (a). Data are shown as median (horizontal line), interquartile range (box), nonoutlier range (whiskers), and outliers (points). Correlations between serum GDF-15 and blood hemoglobin (b), serum hepcidin 25 (c), and iron (d) in the studied patients. Light circles represent patients with complete or partial remission (CR/PR) and dark circles represent patients without remission (stable disease or progressive disease, SD/PD). The right-skewed variables were transformed using natural logarithm (ln) to enhance readability. The Spearman rank-order correlation coefficients (R) in the whole studied group and the subgroups are shown with associated p values.

Figure 4

Serum GDF-15 concentrations among studied patients according to eGFR values: >60 ml/min/1.73 m² (n = 47), 30-60 ml/min/1.73 m² (n = 17), and <30 ml/min/1.73 m² (n = 9) (a). Data are shown as median (horizontal line), interquartile range (box), nonoutlier range (whiskers), and outliers (points). Correlations between serum GDF-15 and cystatin C (b) and urine NGAL (c). Light circles represent patients with remission, and dark circles represent patients without remission. The right-skewed variables were transformed using natural logarithm (ln) to enhance readability. Spearman rank-order correlation coefficients (R) in the whole studied group and the subgroups are shown with associated p values.

Figure 5

The proposed graphical representation of the bone marrow environment in multiple myeloma and end-organ involvement: abnormal bone marrow stromal cells release growth factors, cytokines, and survival factors (including GDF-15) following interactions with malignant plasma cells, which leads to uncontrolled tumor growth and progression. GDF-15 is associated with the development of the cardinal features of myeloma (anemia, renal impairment, and bone lesions), and it may be a mediator of pathways related to the development and progression of these complications.