Abstract
Multiple myeloma (MM) is a currently incurable malignancy of plasma cells. Malignant myeloma cells (MMCs) are heavily dependent upon the bone marrow (BM) microenvironment for their survival. One component of this tumor microenvironment, B-Cell Activating Factor (BAFF), has been implicated as a key player in this interaction. This review discusses the role of BAFF in the pathophysiology of MM, and the potential of BAFF-inhibitory therapy for the treatment of MM. Multiple studies have shown that BAFF functions as a survival factor for MMCs. Furthermore, MMCs express several BAFF-binding receptors. Of these, only Transmembrane Activator and CAML Interactor (TACI) correlates with the MMC's capability to ligate BAFF. Additionally, the level of expression of TACI correlates with the level of the MMC's BM dependency. Ligation of BAFF receptors on MMCs causes activation of the Nuclear Factor of κ-B (NF-κB) pathway, a crucial pathway for the pathogenesis of many B-cell malignancies. Serum BAFF levels are significantly elevated in MM patients when compared to healthy controls, and correlate inversely with overall survival. BAFF signaling is thus an interesting target for the treatment of MM. Several BAFF-inhibitory drugs are currently under evaluation for the treatment of MM. These include BAFF-monoclonal antibodies (tabalumab) and antibody-drug conjugates (GSK2857916).
Highlights
Multiple myeloma (MM) is characterized by the malignant proliferation of plasma cells, terminally differentiated B-cells which under normal circumstances are responsible for the mass production of immunoglobulins
The capability of complete or fractal immunoglobulin production is often retained in malignant myeloma cells (MMCs), resulting in the overproduction of a monoclonal protein, which can result in disease-related symptoms such as cast nephropathy and hyperviscosity
Because Transmembrane Activator and CAML Interactor (TACI) expression on MMCs correlates directly with bone marrow (BM) dependency, there is a strong rationale for the immune reaction against BCMA-positive cells
Summary
Multiple myeloma (MM) is characterized by the malignant proliferation of plasma cells, terminally differentiated B-cells which under normal circumstances are responsible for the mass production of immunoglobulins. IMiDs have multiple mechanisms of action, including the GSK2857916 is currently in a phase I clinical trial in MM patients induction of direct cytotoxicity in MMCs and the inhibition of (ClinicalTrial.gov identifier: NCT02064387) Another immune-based therapy targeting BCMA is adoptive inhibits the paracrine production of BAFF and APRIL.[68] as T-cell therapy. Atacicept is designed to bind and inactivate both BAFF and APRIL in their soluble form and thereby to inhibit their signaling.[69] Because TACI expression on MMCs correlates directly with BM dependency, there is a strong rationale for the immune reaction against BCMA-positive cells This could, in the long term, severely compromise the healthy plasma cell population and the humoral immune system, necessitating life-long immunoglobulin suppletion.
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