Immunotherapy in Multiple Myeloma

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Background

Multiple myeloma (MM) still remains an incurable disease despite recent improvements in its treatment. The crosstalk between MM cells and the bone marrow (BM) microenvironment plays a critical role in MM pathogenesis by promoting (i) tumor cell growth; (ii) cell survival; (iii) drug resistance and (iv) bone disease. The high expression of several surface molecules on MM cells involved in mediating adhesion to cells within the BM microenvironment has stimulated the development of monoclonal antibodies (moAbs) with a significant impact on the improvement of the standard therapeutic treatment options for MM.

Recently, the Food and Drug Administration (FDA) approved two monoclonal IgG-k antibodies, Daratumumab (DARA) and Elotuzumab (Elo), directed against CD38 and SLAMF7 (signalling lymphocytic activation molecule F7) respectively, for the treatment of relapsed or refractory MM (RRMM) patients, in combination with Lenalidomide and Dexamethasone. CD38 is a transmembrane glycoprotein highly expressed on MM cells that acts as both a receptor and an ectoenzyme. It is also involved in the activation and proliferation of immune cells. SLAMF7 is a surface glycoprotein receptor expressed on plasma cells (PCs) and on natural killer (NK) cells that is implicated in adhesion to stromal cells and in the activation of NK cell effector function. Both DARA and Elo act to recruit the immune system to enhance cellular cytotoxicity directed against myeloma cells. However, Elo acts only through NK cells and its effect is enhanced in combination with immunomodulatory drugs (IMiDs). In contrast, DARA shows a broad spectrum of activity, including (i) antibody-dependent cellular cytotoxicity (ADCC), (ii) antibody-dependent cell-mediated phagocytosis, and (iii) complement-dependent cytotoxicity, (iv) direct induction of apoptosis of MM cells and it exhibits promising results even as a single-agent.

Beyond moAbs against surface molecules, several agents targeting immune checkpoints (e.g. CTLA-4, LAG3, PD-1/PD-L1, ICOS) expressed on immune cells have also been recently developed as a therapeutic strategy to activate T-cell mediated anti-tumor immunity. Specifically, the PD-1/PD-L1 axis has emerged as a central immune checkpoint that controls anti-tumor immune responses and also plays a critical role in the metabolic reprogramming of cancer cells within solid tumors. However, its role in MM progression remains to be clarified. Discordant results have been reported on PD-1/PD-L1 expression on PCs and BM niche cells, thus suggesting the need to better define PD-1/PD-L1 distribution amongst cells within the MM tumor microenvironment. Moreover, single-agent studies on PD-1/PD-L1 inhibitors have not demonstrated clear and significant responses in MM patients. On the other hand, pre-clinical studies have demonstrated the ability of IMiDs to enhance anti-MM immune activity mediated by PD-1/PD-L1 inhibition. Additional clinical trials are currently underway, combining IMiDS and checkpoint inhibitor-based therapy.

Finally, soluble factors produced by MM cells and/or the BM microenvironment could also be suitable targets for immunotherapy in MM patients. In particular, the most promising moAbs currently being investigated in pre-clinical MM models and in clinical trials are (i) anti-RANKL moAb (Denosumab), (ii) anti-Dkk-1 moAb (BHQ880), and (iii) anti-sclerostin moAb (Romosozumab). These antibodies have shown a significant effect on MM–induced bone disease and at least, in part, on MM progression.

This Research Topic aims to provide a comprehensive overview of current issues on immunotherapeutic strategies currently approved or under investigation for Multiple Myeloma. We welcome the submission of Review, Mini-Review and Original Research articles that cover, but are not limited, to the following topics:

1. Pathogenesis and molecular mechanisms of immune dysfunctions in Multiple Myeloma (MM).
2. Expression profile of CD38, SLAMF7 and immune checkpoints in MM BM microenvironment and the role of these molecules in MM pathogenesis and progression.
3. Molecular mechanisms regulating the expression of these molecules on plasma cells and on other immune cell types.
4. Mechanism(s) of action of anti-CD38 and anti-SLAMF7 moAbs in MM and their effects on PC proliferation and immune cell activity.
5. Role of checkpoint inhibitors in MM.
6. Role of soluble molecules and blocking antibodies in MM progression and bone disease.
7. Clinical update on the immunotherapy of MM and future perspectives.
8. Cell-based therapies for MM including CAR-T cell and NK cell-based therapies.

Keywords: Immunotherapy, Multiple myeloma, Checkpoint inhibitors, CD38, SLAMF7, Myeloma, Daratumumab, Elotuzumab

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