Preface

Multiple myeloma is a malignant disease characterized by the proliferation of clonal plasma cells in the bone marrow and by the secretion of monoclonal immunoglobulins detected in the serum or urine. Considerable advances have been made in understanding the biology of multiple myeloma through the study of the bone marrow microenvironment. The bone marrow niche appears to play an important role in differentiation, migration, proliferation, survival, and drug resistance of the malignant plasma cells. In multiple myeloma, malignant plasma cells colonize and modify the bone marrow microenvironment through cytokine production and interactions with other cell types. Multiple myeloma cells induce myeloidderived suppressor cells (MDSC) development and survival. MDSCs promote tumor growth and induce immune suppression. Moreover, antimyeloma therapies such as dexamethasone, melphalan, cyclophosphamide, or immunomodulatory drugs can expand and potentiate MDSC immunosuppressive effects. In contrast to these agents, daratumumab depletes MDSCs. Therefore, MDSC suppression could become an important strategy for potentiation of the efficacy of novel immunotherapies (e.g., chimeric antigen receptor T cells or T-cell engager bispecific antibodies). Daratumumab, a CD38 antagonist, functions through different mechanisms of action including an immune-mediated effect (antibody-dependent cytotoxicity; complement-dependent cytotoxicity; antibody-dependent phagocytosis). It can also cause apoptosis through a direct antitumor effect. New findings have helped the development of novel therapeutic drugs for use in combination with cytostatic therapy. Engineering a proper transgenic mouse model for multiple myeloma is very important for understanding biology by defining the relevance of specific genetic lesions in tumorigenesis and the interaction between malignant cells and their surrounding microenvironment. This book discusses all these areas. The introductory chapter deals with selinexor, approved in combination with dexamethasone at earlier relapse. Chapter 2 provides a review of prognostic and predictive factors in newly diagnosed multiple myeloma. Chapter 3 discusses treatment approaches for multiple myeloma. Chapters 4–6 introduce antibody therapies for multiple myeloma and, finally, Chapter 7 analyzes three-dimensional (3D) models mimicking multiple myeloma bone marrow–microenvironment interactions.

> **Ota Fuchs, PhD** Institute of Hematology and Blood Transfusion, Department of Genomics, Prague, Czech Republic

**1**

**Chapter 1**

Introductory Chapter: Oral

Refractory to Proteasome

Agents and Monoclonal

Antibodies

*Ota Fuchs*

**1. Introduction**

Selinexor, a Selective Inhibitor of

Nuclear Export in the Treatment

Inhibitors, Immunomodulatory

of Patients with Multiple Myeloma

The export of proteins from the nucleus to the cytoplasm plays an important role in the development of cancer and drug resistance [1–3]. The major mammalian nuclear export receptor protein is exportin 1 (XPO1, also known as chromosomal maintenance 1/ CRM1/) [1–5]. The crystal structure of this protein showed a complex with the Ran protein (Ras-related nuclear protein) bound to GTP [6, 7]. XPO1 interacts also with nucleoporins in the nuclear pore complex and transports multiple tumor suppressor proteins (eg p53, FOXO, p21 pRB, BRCA1/2), growth regulators, and oncoprotein mRNAs (eg c-myc, Bcl-xL, MDM2, cyclins) containing a leucine rich nuclear export signal (NES) (**Figure 1**) [8]. XPO1 is also involved in regulation of cytoplasmic localization and translation of c-myc and other oncoprotein mRNAs (eg cyclin D1, Bcl-6, Mdm2, and Pim) through complexing with eukaryotic initiation factor 4E (eIF4E) [9]. The XPO1 protein level is increased in many types of cancer including multiple myeloma [10–13]. As a result of the increased nuclear-cytoplasmic transport in cancer cells, an elevated level of multiple tumor suppressor proteins and oncoproteins in the cytoplasm leads to advanced disease, resistance to therapy, and poor survival. Thus, XPO1 is a promising cancer drug target. Leptomycin B (LMB) is a Streptomyces metabolite that inhibits the function of XPO1 in NES-dependent nuclear export of proteins [14]. However, clinical studies found serious side effects of LMB. In order to find a more specific inhibitor of XPO1 without side effects, many natural and synthetic compounds have been tested. These compounds include selinexor (KPT-330, XPOVIO™), verdinexor (KPT-335), KPT-185, KPT-276, KPT-251, and KPT-8602 [15–18]. These agents are a family of small molecules that block nuclear export through covalent
