Growth Differentiation Factor 15 Plasma Level in patients with Multiple Myeloma: A Study of Intergroupe Francophone Du Myelome

We previously reported that bone marrow mesenchymal stem cells (BMMSCs) from multiple myeloma (MM) patients were abnormal. In particular, we showed that Growth Differentiation 15 (GDF15) expression was higher in MM BMMSCs than in normal BMMSCs and that GDF15 was a growth factor for the MOLP-6 stromal cell-dependant myeloma cell line. GDF15 is a divergent member of the human TGFβ superfamily. In normal human subjects, it is highly expressed in the placenta and its serum concentration increases during pregnancy. GDF15 concentration is increased in the serum of patients with prostate, colorectal or pancreatic cancers. However, GDF15 has never been studied in haematological malignancies. The first objective of this study was to evaluate the relashionship between GDF15 plasma concentration (pGDF15) of 131 MM patients and main prognostic factors of the disease. We found a significant relationship with ISS (p<0.003) and DS stage (p<0.02), b2 microglobulin, haemoglobin, creatinin, calcemia (p<0.001), deletion of chromosome 13 (p<0.004), serum monoclonal protein, bone status (p<0.02), and albumin (p<0.05). The second objective of this study was to appreciate the potential relationship between pGDF15 and survival. We demonstrate such a relationship. Indeed, in the group of 81 patients with high pGDF15, the probabilities of event-free and overall survival 30 months after diagnosis is 50 percent and 75 percent, respectively. In the group of 50 patients with low pGDF15, the probabilities of event-free and overall survival 30 months after diagnosis is 80 percent and 97 percent, respectively (p<0.0045 and p<0.013, respectively). On the opposite, pGDF15 is not related to response to treatment. We analysed impact of known prognostic factors and pGDF15 on event-free survival for all the 131 patients. In univariate analysis, event-free survival was significantly related to age (p=0.003), ISS (p=0.09), b2-microglobulin (p=0.02) and pGDF-15 (p=0.003). In multivariate analysis, event-free survival was significantly related to age (p=0.001) and pGDF15 (p=0.04). In conclusion, our study demonstrates a significant relationship between GDF15 and MM survival. This result strongly suggests the implication of microenvironment in the disease evolution. The exact role of GDF15 in MM physiopathology (directly responsible or simple reflect of an abnormal microenvironment) is still unclear and should be investigated.