Abstract
2015 was a groundbreaking year for the multiple myeloma community partly due to the breakthrough approval of the first two monoclonal antibodies in the treatment for patients with relapsed and refractory disease. Despite early disappointments, monoclonal antibodies targeting CD38 (daratumumab) and signaling lymphocytic activation molecule F7 (SLAMF7) (elotuzumab) have become available for patients with multiple myeloma in the same year. Specifically, phase 3 clinical trials of combination therapies incorporating daratumumab or elotuzumab indicate both efficacy and a very favorable toxicity profile. These therapeutic monoclonal antibodies for multiple myeloma can kill target cells via antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity, and antibody-dependent phagocytosis, as well as by direct blockade of signaling cascades. In addition, their immunomodulatory effects may simultaneously inhibit the immunosuppressive bone marrow microenvironment and restore the key function of immune effector cells. In this review, we focus on monoclonal antibodies that have shown clinical efficacy or promising preclinical anti-multiple myeloma activities that warrant further clinical development. We summarize mechanisms that account for the in vitro and in vivo anti-myeloma effects of these monoclonal antibodies, as well as relevant preclinical and clinical results. Monoclonal antibody-based immunotherapies have already and will continue to transform the treatment landscape in multiple myeloma.
Highlights
Multiple myeloma is the second most common hematologic malignancy, characterized by the proliferation of malignant plasma cells in the bone marrow and excessive production of immunoglobulins [1,2]
The development of monoclonal antibodies targeting selective multiple myeloma antigens represents an important advance in the improvement of effective immunotherapies for patients with multiple myeloma
In addition to various mechanisms mediated via FcR-expressing effector cells (ADCC, complement-dependent cytotoxicity (CDC) or ADCP), monoclonal antibodies can produce immunomodulatory effects on immune cells in the bone marrow microenvironment by decreasing the function and number of immunosuppressive cells and restoring the tumor-killing activities of immune effector cells (Table 1)
Summary
Multiple myeloma is the second most common hematologic malignancy, characterized by the proliferation of malignant plasma cells in the bone marrow and excessive production of immunoglobulins [1,2]. Bone marrow stromal cells (BMSCs), osteoclasts (OCs), and plasmacytoid dendritic cells (pDC), as well as cytokines, i.e., interleukin-6 (IL-6), Macrophage colony-stimulating factor (M-CSF), interleukin-10 (IL-10), tumor necrosis factor beta (TGFβ), C-C Motif Chemokine Ligand 2 (CCL2), and vascular endothelial growth factor (VEGF), play important roles in maintaining an immunosuppressive environment in the bone marrow of multiple myeloma patients [25,27] These findings suggest that an effective anti-myeloma treatment will require targeting the malignant plasma cell itself and restoring the anti-tumor responses of immune effector cells via blockade of tumor evasion and disruption of inhibitory signals on effector cells. Monoclonal antibody-based treatments which provide additional effector cell-mediated tumor killing mechanisms when compared with targeted small molecules are successful therapeutic strategies for cancer. Clinical investigations of above agents are ongoing. * The clinical trials of PD-1 inhibitors (pembrolizumab and nivolumab) have been hold by Food and Drug Administration (FDA)
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