Novel Insights in Anti-CD38 Therapy Based on CD38-Receptor Expression and Function: The Multiple Myeloma Model

Abstract

Multiple myeloma (MM) is a hematological disease characterized by the proliferation and accumulation of malignant plasmacells (PCs) in the bone marrow (BM). Despite widespread use of high-dose chemotherapy in combination with autologous stem cell transplantation (ASCT) and the introduction of novel agents (immunomodulatory drugs, IMiDs, and proteasome inhibitors, PIs), the prognosis of MM patients is still poor. CD38 is a multifunctional cell-surface glycoprotein with receptor and ectoenzymatic activities. The very high and homogeneous expression of CD38 on myeloma PCs makes it an attractive target for novel therapeutic strategies. Several anti-CD38 monoclonal antibodies have been, or are being, developed for the treatment of MM, including daratumumab and isatuximab. Here we provide an in-depth look atCD38 biology, the role of CD38 in MM progression and its complex interactions with the BM microenvironment, the importance of anti-CD38 monoclonal antibodies, and the main mechanisms of antibody resistance. We then review a number of multiparametric flow cytometry techniques exploiting CD38 antigen expression on PCs to diagnose and monitor the response to treatment in MM patients.

Keywords: CD38; CD38 antigen expression in various tissues; anti-CD38 monoclonal antibodies; bone marrow microenvironment; multiple myeloma; plasmacells.

Figure 1

Schematic representation of the effects induced by therapeutic antibodies on multiple myeloma (MM) cells. The antibody-target ligation induces a redistribution of CD38 together with morphological modifications leading to release of antibody-covered microvesicles (MVs). Such MVs can be internalized by different subsets of immune cells, thus enhancing anti-tumor response and even potentially leading to a sort of autovaccination whose main actors are MV-activated dendritic cells.

Figure 2

Normal bone marrow plasma cells (PCs) are identified by means of the co-expression of CD38^bright and CD138 (Plot 1-gate A) backgated on forward vs. side scatter (Plot 2-gate B) and then on side scatter and CD45^int (Plot 3-gate C). The four populations of normal PCs (CD19+CD56−, violet; CD19+CD56+, green; CD19−CD56+, black; and CD19−CD56−, blue) and their relative proportions are identified in Plot 4 and for each of them the cytoplasmic kappa/lambda expression (polyclonal) is shown (Plots 5–8). The analysis shown is the result of a data set merge of five different normal bone marrow samples (as depicted in the insert in Plot 1, where time vs. CD45 is shown).

Figure 3

Peripheral blood plasmablasts analysis. The plasmablasts are identified as CD19+ve CD20 − ve cells (gating strategy is displayed in Plots 1–4). This cell subset is CD20 − ve, CD38 + high, and represents only 4% (the average of five peripheral blood from healthy subject) of the entire CD19 + ve cells (Plot 5), is negative for both CD5 and CD10 (Plot 6), is strongly positive for CD38 and CD27 (Plot 7), is expressed on the cell surface of both kappa/lambda immunoglobulin light chains (pink colored) at very low intensity when compared to the expression of kappa/lambda light chains on the other CD19+ cells (blue colored) (Plot 8). The analysis shown is the result of a data set merge of five different normal peripheral blood samples (as depicted in the insert in Plot 1, where time vs. CD45 is shown).