Atacicept in relapsed/refractory multiple myeloma or active Waldenström's macroglobulinemia: a phase I study

Abstract

BACKGROUND: Advanced multiple myeloma (MM) and Waldenströ m's macroglobulinemia (WM) are incurable B-cell malignancies. This is the first full clinical report of atacicept, a fusion protein that binds to and neutralises the B-cell survival factors, B-lymphocyte stimulator (BLyS) and A proliferation-inducing ligand (APRIL), in MM and WM. METHODS: In this open-label phase-I study, 16 patients with advanced disease (12 MM, 4 WM) received one cycle of five once-weekly subcutaneous injections of atacicept (2, 4, 7 or 10 mg kg À1 ). Patients with stable disease after cycle 1 entered an extension study (either two additional cycles (2, 4 and 7 mg kg À1 cohorts) or 15 consecutive weekly injections of atacicept 10 mg kg À1 ).

Soluble B-Cell Maturation Antigen Mediates Tumor-Induced Immune Deficiency in Multiple Myeloma

“…Soluble BCMA administration to immune-competent mice significantly reduces normal antibody levels, and we have shown an inverse relationship between serum BCMA levels and polyclonal antibody levels in multiple myeloma patients. Our current findings may explain why therapeutic agents that have been developed to inhibit the function of BAFF, have yielded disappointing results in the clinic while also resulting in marked reduction in polyclonal antibody levels (37). This is the first study identifying a specific solubilized protein, BCMA, from multiple myeloma cells that directly contributes to the humoral immune-deficient state that so often occurs in multiple myeloma patients.…”

“…Therapies targeting its ligands, BAFF and APRIL, have been of minimal benefit for the treatment of multiple myeloma patients. Atacicept (TACI.Fc) is a fusion protein that binds soluble BAFF and APRIL; it reduces levels of these free ligands that prevent them from interacting with their corresponding receptors (37). A clinical study evaluating atacicept for treating multiple myeloma and Waldenstrom's macroglobulinemia patients showed little clinical benefit (37).…”

“…Atacicept (TACI.Fc) is a fusion protein that binds soluble BAFF and APRIL; it reduces levels of these free ligands that prevent them from interacting with their corresponding receptors (37). A clinical study evaluating atacicept for treating multiple myeloma and Waldenstrom's macroglobulinemia patients showed little clinical benefit (37). Notably, a significant decrease in polyclonal antibodies was observed in 54% of multiple myeloma patients in this trial, and the authors stressed the need for infectious disease surveillance due to a possible association between suppression of normal antibody production and risk of infection.…”

Pathogenic Long-Lived Plasma Cells and Their Survival Niches in Autoimmunity, Malignancy, and Allergy

“…Deprivation of APRIL and BAFF by TACI-Ig consequently increases the efficiency of dexamethasone and anti-IL-6 treatment, and it eliminates nearly all MMCs in culture (62). Moreover, atacicept reduces the amount of MMCs in the bone marrow and slows disease progression in 82% of patients with relapsed/refractory MM (77). Hematopoietic niche components.…”

Targeting B-Cell Maturation Antigen in Multiple Myeloma

“…It inhibits proliferation and induces apoptosis of patient MM cells [19,21]. It shows clinical and biological activity consistent with its mechanism of action when tested in MM and WM [60]. The first therapeutic APRIL neutralizing mAb was recently evaluated in preclinical studies in MM [61].…”