Activin A is a multifunctional cytokine of the TGFβ superfamily. It contributes to a broad range of cellular pathways, including bone homeostasis, bone marrow erythropoiesis, and skeletal muscle mass. It is abnormally regulated in cancers, including breast, prostate, ovarian, and hepatocellular carcinoma, and has been associated with tumor aggressiveness [
41]. Activin A signals through the type 2A receptors on bone cells (both osteoblasts and osteoclasts) and stromal cells. Its role in both bone resorption and bone formation suggests that inhibitors would be bone-anabolic agents. Vallet and colleagues [
42] found that activin A was elevated in both the bone marrow and peripheral blood of patients with MM. Co-culture with MM cells increases activin A in bone marrow stromal cells and osteoclasts. Terpos and colleagues [
43] correlated activin A to extent of bone involvement and poor survival in patients with MM. Activin A receptor antagonists increase bone formation in monkeys and in postmenopausal women as well as prevent development of MM bone lesions and decrease tumor burden in a murine model of MM, suggesting that they enhance bone formation
in vivo [
42],[
44]. A recently completed phase II randomized trial of sotatercept (ACE-011), a soluble activin receptor type 2A IgG-Fc fusion protein, in MM patients with osteolytic lesions (ClinicalTrials.gov identifier NCT00747123) showed increased bone-specific alkaline phosphatase and decreased bone resorption marker C-terminal telopeptide (CTX), when used with melphalan and prednisone, compared with melphalan + prednisone controls, in bisphosphonate-naïve patients. Sotatercept also promotes red blood cell production and therefore was evaluated in a phase II trial of patients with chemotherapy-induced anemia and metastatic breast cancer [
45]. Although improvement of hemoglobin and a favorable toxicity profile were observed, bone was not included as an endpoint in the study. A similar fusion protein increased bone formation and inhibited growth of breast cancer and MM in bone in preclinical models [
46]. The benefit of activin A antagonists against solid tumor bone metastases certainly warrants further evaluation.