Past, Present, and a Glance into the Future of Multiple Myeloma Treatment

Abstract

Multiple myeloma (MM) is a challenging hematological cancer which typically grows in bone marrow. MM accounts for 10% of hematological malignancies and 1.8% of cancers. The recent treatment strategies have significantly improved progression-free survival for MM patients in the last decade; however, a relapse for most MM patients is inevitable. In this review we discuss current treatment, important pathways for proliferation, survival, immune suppression, and resistance that could be targeted for future treatments.

Keywords: B-cell malignancy; bone marrow microenvironment; drug resistance; immunotherapies; multiple myeloma; proteasome inhibitors.

Figure 1

Major signaling pathways in MM. MM receives several survival and proliferation signals: JAK2/STAT3 pathway activates antiapoptotic proteins and activates NF-κB, the PI3K/AKT/mTOR pathways become activated when stromal-derived factor 1 α (SDF-1α) binds to CXCR4 and/or antigen binds to B-cell receptor (BCR). The RAS/MEK/ERK pathway becomes activated by BCR and CD19. Wnt/β-catenin pathway activation enhances differentiation, survival, migration, and antiapoptotic signals. Ras: rat sarcoma; Raf: rapidly accelerated fibrosarcoma; MEK: mitogen-activated protein kinase kinase. Created by Biorender.com.

Figure 2

MM microenvironment. MM cells interact with several cells in the BMM such as BMSCs, osteoclasts, osteoblasts, cytotoxic T-cell (CTLs), natural killer (NK) cells, adipocytes. This interaction enhances MM survival and inhibits immune cells. VCAM: vascular cell adhesion protein; LFA-1: lymphocyte function-associated antigen-1; ICAM-1: intercellular adhesion molecule 1; IGF-1: insulin-like growth factor-1. Created by Biorender.com.

Figure 3

Proteasome inhibitors (PIs) induce apoptosis and inhibit CAM-DR. PIs induce protein accumulation, which leads to ER stress and activates JNK, which in turn activates caspase-8 and caspase-3, increases Fas, and generates ROS. In addition, PI enhances pro-apoptotic proteins, NOXA and BAX, and inhibits Mcl-1, which leads to apoptosis. Moreover, PI inhibits CAM-DR through inhibition of adhesion molecules (adapted from [86]). Created by Biorender.com.

Figure 4

The direct and indirect effect of IMiDs on MM. IMiDs enhances apoptosis and inhibits MM proliferation through the cyclin-dependent pathway. IMiDs works indirectly through activating the immune cells. CRBN: Cereblon, DDB1: DNA damage-binding protein 1, CUL4: Cullin-4A, and ROC1: RING box protein-1. Created by Biorender.com.

Figure 5

The effect of HDACis on MM. HDACis cause proteasomal degradation of CXCR4 and PPP3CA and enhance the expression of tumor suppressors. Created by Biorender.com.

Figure 6

Immunotherapy. (A) Generation of CAR-T. (B) The different generations of CAR-T. (C) CAR-T recognizes an antigen on MM and causes apoptosis. (D) Bispecific antibody binds both MM and an immune cell. (E) Antibody–drug conjugate recognizes MM and releases cytotoxic agent. Created by Biorender.com.