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Sclerostin, an osteocyte-expressed negative regulator of bone formation, is one of the inhibitors of Wnt signaling that is a critical pathway in the correct process of osteoblast differentiation. It has been demonstrated that Wnt signaling through the secretion of Wnt inhibitors, such as DKK1, sFRP-2, and sFRP-3, plays a key role in the decreased osteoblast activity associated with multiple myeloma (MM) bone disease. We provide evidence that sclerostin is expressed by myeloma cells that are human myeloma cell lines and plasma cells (CD138(+) cells) obtained from the bone marrow (BM) of a large number of MM patients with bone disease. Moreover, we show that there are no differences in sclerostin serum levels between MM patients and controls. Thus, our data indicate that MM cells, as a sclerostin source in the BM, could create a microenvironment with high sclerostin concentration that could contribute toward inhibiting osteoblast differentiation., (© 2011 New York Academy of Sciences.)

Smoldering multiple myeloma (SMM), an asymptomatic plasma cell neoplasm, is currently diagnosed according to the updated IMWG criteria, which reflect an intermediate tumor mass between monoclonal gammopathy of undetermined significance (MGUS) and active MM. However, SMM is a heterogeneous entity and individual case may go from an "MGUS-like" behavior to "early MM" with rapid transformation into symptomatic disease. This wide range of clinical outcomes poses challenges for prognostication and management of individual patients. However, initial studies showed a benefit in terms of progression or even survival for early treatment of high-risk SMM patients. While outside of clinical trials the conventional approach to SMM generally remains that of close observation, these studies raised the question of whether early treatment should be offered in high-risk patients, prompting evaluation of several different therapeutic approaches with different goals. While delay of progression to MM with a non-toxic treatment is clearly achievable by early treatment, a convincing survival benefit still needs to be proven by independent studies. Furthermore, if SMM is to be considered less biologically complex than MM, early treatment may offer the chance of cure that is currently not within reach of any active MM treatment. In this paper, we present updated results of completed or ongoing clinical trials in SMM treatment, highlighting areas of uncertainty and critical issues that will need to be addressed in the near future before the "watch and wait" paradigm in SMM is abandoned in favor of early treatment. [ABSTRACT FROM AUTHOR]

The impressive improvement of overall survival in multiple myeloma (MM) patients in the last years has been mostly related to the availability of new classes of drugs with different mechanisms of action, including proteasome inhibitors (PI), immunomodulating agents (IMiDs), and monoclonal antibodies. However, even with this increased potence of fire, MM still remains an incurable condition, due to clonal selection and evolution of neoplastic clone. This concept underlines the importance of immunotherapy as one of the most relevant tools to try to eradicate the disease. In line with this concept, active and passive immunotherapies represent the most attractive approach to this aim. Antibody-drug conjugate(s) (ADCs) and bispecific antibodies (BsAbs) include two innovative tools in order to limit neoplastic plasma cell growth or even, if used at the time of the best response, to potentially eradicate the tumoral clone. Following their promising results as single agent for advanced disease, at the recent 62nd ASH meeting, encouraging data of several combinations, particularly of ADC(s) with PI or IMiDs, have been reported, suggesting even better results for patients treated earlier. In this paper, we reviewed the characteristics, mechanism of action, and clinical data available for most relevant ADC(s) and BsAbs. [ABSTRACT FROM AUTHOR]