Multiple myeloma (MM) is a neoplasm defined by the clonal proliferation of malignant plasma cells (PC) within the bone marrow (BM). Multiple myeloma (MM) originates from the asymptomatic proliferation of pre-malignant plasma cells, categorized as monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SMM). Patients with MGUS exhibit low serum M-protein levels (< 3 g/dL) and monoclonal plasma cells in bone marrow (< 10%), while patients with SMM demonstrate elevated serum M-protein levels (≥ 3 g/dL) and/or plasma cells in the bone marrow (≥ 10%). Conversely, the diagnosis of multiple myeloma necessitates the identification of end-organ damage correlated with the presence of serum M-spike and/or monoclonal plasma cells in the bone marrow.

This protein is a type II transmembrane glycoprotein encoded on chromosome 4 (4p15.32) and comprises three domains: a 21-amino acid intracellular domain (N-terminus), an alpha-helix transmembrane domain, and a 256-amino acid extracellular domain (C-terminus). This extracellular domain exhibits multifunctional enzymatic activity. CD38, originally characterized as an ADP-ribosyl cyclase, catalyzes the cyclization of nicotinamide adenine dinucleotide (NAD) to cyclic ADP-ribose (cADPR).

It is essential to emphasize the role of CD38 in multiple myeloma, one of the most thoroughly researched CD38-related conditions. Numerous studies have demonstrated significant and elevated CD38 expression on malignant plasma cells in bone marrow samples of multiple myeloma patients. CD38, a glycoprotein, interacts with CD31, which is co-expressed on multiple myeloma cells, and plays a role in several cellular processes. These encompass T cell activation and proliferation, B cell differentiation, and the chemotaxis of neutrophils and monocytes. Furthermore, as an ectoenzyme, CD38 regulates intracellular NAD + levels, which are essential for sustaining low glycolytic activity that facilitates cell proliferation and survival (Morandi et al., 2018). Under varying pH settings, CD38 facilitates the transformation of NAD + into adenosine (ADO), a mediator of calcium signaling that enhances tumor survival and immune evasion. Alongside CD38, several ectoenzymes including CD39, CD73, and CD203a contribute to the extracellular synthesis of adenosine (ADO), with their concentrations indicating disease progression. Furthermore, CD38 functions as a metabolic sensor through its interaction with osteoclasts (OCs) during adult skeletal remodeling. Osteoclasts, essential for bone remodeling, are influenced by CD38 inhibition, which not only impedes bone resorption but also reinstates T-cell functionality, thus preventing the advancement of bone disease.

The increase of CD38 on cancer cells and its role in cancer progression has prompted researchers to create various monoclonal antibodies (mAbs) that target CD38. Commercially available CD38 monoclonal antibodies for multiple myeloma treatment include daratumumab. Additional novel drugs are currently in clinical trials, including MOR202 (Felzartamab) (completely human), TAK079 (Mezagitamab) (fully human), FTL004 (humanized Ig1), SAR442085 (totally human engineered), and TNB-738 (entirely human). Their anticancer efficacy relies on Fc-dependent immunological effector mechanisms and immunomodulatory actions that eradicate CD38 regulatory T cells, hence reinstating T-cell and NK-cell-mediated antitumor immune responses.