Elevated Levels of Circulating Activin-A Correlate with Features of Advanced Disease, Extensive Bone Involvement and Inferior Survival In Patients with Multiple Myeloma

Abstract 2967

Activin-A is a member of the transforming-growth factor-beta superfamily most commonly associated with embryogenesis and gonadal hormone signaling. Activin-A is also involved in bone homeostasis having growth stimulatory effects on osteoclasts, but unclear effects on osteoblast function. A recent study showed that, in multiple myeloma (MM) microenvironment, activin-A is a stromally derived osteoblast inhibitor induced by myeloma cells and thus it seems to be implicated into the pathogenesis of myeloma bone disease (Vallet et al, PNAS 2010;107:5124). The aim of this study was to evaluate the circulating levels of activin-A in newly-diagnosed and relapsed patients with MM and explore possible correlations with clinical and laboratory data, including lytic bone disease and survival. We studied 113 MM patients (63M/50F, median age 69 years, range 31–92 years): 98 newly-diagnosed patients (13 with asymptomatic and 85 with symptomatic MM) and 15 patients with relapsed MM after previous response to front-line therapy, who received the combination of lenalidomide and high-dose dexamethasone (RD). All symptomatic patients received frontline treatment with novel agent-based regimens. For newly-diagnosed patients, serum was stored at -80°C at the time of diagnosis, while for relapsed patients serum was stored on day 1 of the first RD cycle and then on day 28 of the 4^th cycle. Serum activin-A was measured using ELISA methodology (R&D Systems, Minneapolis, MN, USA) along with a series of markers of bone resorption (C-terminal cross-linking telopeptide of collagen type-1, CTX and tartate-resistant acid phosphatase isoform-5b, TRACP-5b) and bone formation (bone-specific alkaline phosphatase and osteocalcin). Evidence of bone involvement was documented using plain radiographs in patients at diagnosis and at the time of relapse. Activin-A and the above bone markers were also measured in 10 MGUS patients and in 17, gender- and age-matched, healthy controls. Circulating levels of activin-A of newly-diagnosed patients with symptomatic MM (median: 555 pg/mL, range: 129–2336 pg/mL) and of relapsed patients (677 pg/mL, 272–2088 pg/mL) were increased compared to controls (393 pg/mL, 204–899 pg/mL; p<0.001 for both comparisons). There was no significant difference between asymptomatic patients (462 pg/mL, 255–840 pg/mL), MGUS patients (457 pg/mL, 361–839 pg/mL) and controls. Circulating levels of activin-A strongly correlated with disease stage at diagnosis; the median values (range) for ISS-1, ISS-2 and ISS-3 were: 462 pg/mL (255-840 pg/mL), 536 pg/mL (210-1183 pg/mL) and 681 pg/mL (302-2336 pg/mL), respectively; p(ANOVA)=0.002. Activin-A levels also significantly correlated with serum creatinine (r=0.519, p<0.001), beta2-microglobulin (r=0.450, p<0.001) and LDH (r=0.247, p=0.034) at diagnosis. Regarding bone markers, serum activin-A showed strong correlations with both markers of bone resorption: CTX (r=0.574, p<0.001) and TRACP-5b (r=0.481, p<0.001), but no correlation with markers of bone formation. Patients with extensive bone disease (more than 3 osteolyses and/or a fracture) had higher levels of circulating activin-A (618 pg/mL, 211–2043 pg/mL) compared to all others (477 pg/mL, 129–2336 pg/mL; p=0.03). The median survival of newly-diagnosed, symptomatic MM patients was 63 months. In the univariate analysis, low levels of activin-A were associated with superior overall survival: the median survival of patients who had a serum activin-A of <442 pg/mL (lower quartile, n=24 patients) has not been reached yet, while the median survival of all other patients was 59 months (p=0.04). However, in the multivariate model, activin-A was not an independent factor for survival, possibly due to its strong correlation with beta2-microglobulin. In relapsed patients, treatment with RD did not reduce circulating activin-A levels, which remained elevated (710 pg/mL, 302–2384 pg/mL) after 4 cycles of therapy compared to controls (p<0.001). We conclude that circulating activin-A is elevated in patients with newly-diagnosed symptomatic MM and in patients with relapsed MM. High activin-A levels correlated with advanced disease features and high bone resorption. These results reveal activin-A as a possible target (i.e. by using RAP-011, a soluble activin-A receptor) for the development of novel anti-myeloma therapies.