Adhesion Molecules in Multiple Myeloma Oncogenesis and Targeted Therapy

Figures & data

Figure 1. The process of leukocyte extravasation and the role of cell adhesion molecules.

Figure 2. Overview of the bone marrow’s immune microenvironment.

The bone marrow microenvironment is divided into endosteal, and vascular niches set within a stroma of differentiated accessory or ‘stromal’ cells, such as fibroblasts, osteoclasts, osteoblasts, adipocytes, endothelial cells, macrophages and mast cells as well as ECM proteins. As for the term ‘immune microenvironment’, it refers to a functional compartment of differentiated immune cells located throughout the marrow stroma.

DC: Dendritic cell; ECM: Extracellular matrix; MDSC: Myeloid-derived suppressor cell; PC: Plasma cell.

Figure 3. Anti-CD38 monoclonal antibodies mechanisms of action.

Top left: mAbs bind CD38. The Fc fragment is bound by C1q, initiating the complement cascade, and resulting in a membrane attack complex, leading to cell lysis and death. Top right: mAbs bind CD38. The Fc fragment is then bound by an FcR-bearing effector cell, such as a natural killer cell, leading to activation of cytotoxic processes. Bottom left: mAbs bind CD38, and its Fc fragment is then bound by an FcR-bearing macrophage, inducing phagocytosis. Bottom right: FcR-mediated crosslinking of mAbs induces direct cellular apoptosis.

ADCC: Antibody-dependent cell-mediated cytotoxicity; ADCP: Antibody-dependent cellular phagocytosis; CDC: Complement-dependent cytotoxicity; MAC: Membrane attack complex; MM: Multiple myeloma.

Table 1. Cell adhesion molecules phenotypic expression on normal versus myeloma plasma cells.

Plasma cell CAMs expressed	Normal plasma cell expression	Myeloma plasma cell expression
H-CAM (CD44)	Weak express +	Weak express +
VLA-4 (CD49d/CD29)	Weak expression +	Weak expression +
ICAM-1 (CD54)	Strong expression ++	Strong expression ++
N-CAM (CD56)	Weak/absent expression +/-	• Strong expression ++ • Absent expression in extramedullary involvement-
VLA-5- immature (CD49e/Cd29)^†	Weak expression +	Absent/weak expression-/+
VLA-5+ mature (CD49e/CD29)^†	Weak expression +	Absent/weak expression
CD38	Very strong expression +++	Very strong expression +++
CD19	Strong expression ++	Absent/weak expression-/+
LFA-1 (CD11a)	Strong expression ++	Weak expression +
CD40	Weak expression +	Weak expression +
LFA-3 (CD58)	Absent expression -	Strong expression ++
Syndecan	Strong presentation ++	Expression on small fraction
VLA-2 (CD49b)	Absent expression	Weak/moderate expression +/++
E-Selectin	Absent expression	Increased expression in progressing MM +++
CXCR4	Weak expression +	Strong expression ++
MAC-1	Absent expression	Strong expression ++
N-Cadherin	Strong expression ++	Strong expression in newly diagnosed patients ++
E- Cadherin	Strong expression +	Strong expression ++
PSGL-1	Strong expression ++	Very strong expression ++

† VLA-5 (CD49e/CD29) is expressed in cells which show a lower proliferative potential. It has a good potential for paraprotein product ion [20,23].

Table 2. Mechanism of actions of various molecules in multiple myeloma.

Drugs	Mechanism of action
Non-mAb
Thalidomide^†, Lenalidomide^†, Pomalidomide^†, Iberdomide	Immunomodulator
Panobinostat^†, Vorinostat, Abexinostat, Belinostat, Givinostat, Romidepsin, Entinostat, Tacedinaline	Histone deacetylase inhibitors
Sotatercept	Activin inhibitor
Evofosfamide	Hypoxia-activated prodrug
Plerixafor	CXCR4 antagonist
Anti-CD19, anti-CD138, anti-BCMA, anti-SLAM7 CAR—T cells	Chimeric antigen receptor (CAR) T cells
Venetoclax	BCL-2 inhibitor
DANFIN	NF-κB inhibitor
Sorafenib, Vemurafenib, Cobimetinib, Selumetinib	RAS/RAF/MEK/ERK inhibitors
Palbociclib	CDK4/6 inhibitor
Dovitinib, BGJ398, MFGR1877S, AZD4547	FGFR inhibitors
Clioquinol, SC-06, BEZ235, BAY80-6946, MK-2206	PI3K/AKT/mTOR inhibitors
Selinexor^†	Selective inhibitor of nuclear export
mAb
Blinatumomab, AMG 701, REGN5458	Bispecific T cell engagers
Ulocuplumab	Anti-CXCR4 mAb
Nivolumab, Pembrolizumab, Cemiplimab, Cetrelimab	Anti-PD-1 mAbs
Atezolizumab, Avelumab, Pidilizumab	Anti-PD-L1 mAbs
Ipilimumab	Anti-CTLA-4 mAb
Alemtuzumab	Anti-CD52 mAb
Siltuximab	Anti-IL-6 mAb
BI-505	Anti-ICAM-1 mAb
Daclizumab	Anti-CD25 mAb
AVE1642	Anti-IGF1R mAb
BHQ880	Anti-DKK1 mAb
Bevacizumab	Anti-VEGF mAb
Tabalumab	Anti-Baff mAb
Daratumumab^†, Isatuximab^†	Anti-CD38 mAb
Elotuzumab^†	Anti-SLAMF7 mAb
Denosumab^†	Anti-RANKL mAb
Belantamab mafodotin^†	Anti-BCMA conjugated mAb

† mAb-approved drugs.

mAb: monoclonal antibody.

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