Circulating Periostin Is Elevated in Patients with Multiple Myeloma and Correlates with Advanced Disease Features and High Bone Resorption,

Abstract 3922

Periostin (previously called osteoblast-specific factor-2) is a disulfide-linked cell adhesion protein that belongs to the fasciclin family and is mainly produced by mesenchymal cells. Periostin is highly expressed in early osteoblastic cells and in the periosteum, where it acts as a regulator of bone remodeling. Recent clinical evidence suggests that periostin stimulates metastatic growth by promoting cancer cell survival, invasion and angiogenesis in several cancers. Especially, bone metastases from breast cancer induce overexpression of periostin by surrounding stromal cells and serum levels of periostin are elevated in such patients. However, there is no information on the role of periostin in multiple myeloma (MM). The aim of the study was to evaluate circulating periostin in a large number of MM patients and explore possible correlations with clinical and laboratory data, including stage and lytic bone disease.

We studied 198 MM patients (106M/92F, median age 73 years) at different phases of their disease. Thirty three patients had smoldering myeloma (SMM) at diagnosis, 105 symptomatic MM at diagnosis, 30 patients were at a plateau phase and 30 patients had relapsed MM after previous response to therapy. For newly-diagnosed and relapsed patients, serum was stored at the time of diagnosis or relapse, while for patients at the plateau phase of the disease serum was collected at the time of confirmation of the plateau (at least 6 months with stable M-protein without criteria confirming progression). Serum periostin was measured using ELISA methodology in all patients along with a series of markers of bone remodeling that were measured in symptomatic MM patients at diagnosis: i) osteoclast regulators: sRANKL and osteoprotegerin (OPG); ii) osteoblast inhibitor dickkopf-1 (Dkk-1); iii) bone resorption markers: C-telopeptide of collagen type-I (CTX) and tartrate-resistant acid phosphatase isoform-5b (TRACP-5b); and iv) bone formation markers: bone-specific alkaline phosphatase (bALP) and osteocalcin. Evidence of bone involvement was documented using plain radiographs. Periostin was also measured in 23 patients with MGUS and in 30, gender- and age-matched, healthy controls.

The circulating periostin concentrations of symptomatic MM patients at diagnosis (mean±SD: 911±694 ng/ml) were increased compared to controls (537±190 ng/ml; p<0.001), to SMM patients at diagnosis (601±351 ng/ml; p=0.001) and to MGUS patients (633±271 ng/ml; p =0.002). There was no significant difference regarding circulating periostin levels between SMM patients, MGUS patients and controls. Patients with MM at plateau phase had a borderline reduction of serum periostin concentrations (729±360 ng/ml) compared to symptomatic MM patients at diagnosis (p=0.05) but they continued to have increased levels compared to controls (p=0.013) and no difference compared to SMM and MGUS patients. Patients with relapsed MM had increased circulating periostin (938±847 ng/ml) compared to controls (p=0.016), MGUS (p=0.04) and SMM patients (p=0.04) but no significant difference compared to symptomatic patients at diagnosis. In symptomatic MM patients at diagnosis, serum periostin strongly correlated with beta2-microglobulin (r=0.384, p=0.004), LDH (r=0.428, p=0.001), and ISS stage [mean±SD of periostin values for ISS-1, ISS-2 and ISS-3 were: 542±196 ng/mL, 775±500 ng/mL and 1036±801 ng/mL, respectively; p=0.01]. High circulating periostin also correlated with increased bone resorption, as assessed by CTX levels (r=0.369, p=0.005) in symptomatic patients at diagnosis. Furthermore, patients with extensive lytic bone disease (>3 lytic lesions and/or a pathological fracture) had increased periostin levels compared to all others (p=0.01).

Our results suggest that circulating periostin is elevated in patients with symptomatic and relapsed myeloma and correlated with advanced disease features including ISS stage and high LDH. The increased levels of periostin observed in patients with advanced bone disease and its strong correlation with the bone resorption marker CTX suggest that periostin may be implicated in the biology of myeloma-related bone disease. The confirmation of periostin upregulation in myeloma patients, even at the plateau phase of the disease, may reveal periostin as a promising target of therapeutic intervention for MM in the future.