Proteasome Inhibitors in the Treatment of Multiple Myeloma

Special Article - Multiple Myeloma

Ann Hematol Oncol. 2016; 3(7): 1102.

Proteasome Inhibitors in the Treatment of Multiple Myeloma

Raghupathy R1 and Margaret HL Ng2,3*

1Department of Clinical Oncology, Chinese University of Hong Kong, China

2Department of Anatomical and Cellular Pathology, Chinese University of Hong Kong, China

3State Key Laboratory in Oncology in South China, Chinese University of Hong Kong, China

*Corresponding author: Margaret HL Ng, Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China

Received: July 05, 2016; Accepted: August 20, 2016; Published: August 23, 2016


Proteasome inhibitors have become indispensable in myeloma management in transplant eligible and ineligible patients in both induction and salvage settings. Excellent efficacy and a manageable toxicity profile haves made these agents the backbone of myeloma care. After the first in class drug bortezomib was approved, several newer agents have been developed. The parenteral second generation drug carfilzomib has less peripheral neuropathy incidence than bortezomib. Oral proteasome inhibitors such as ixazomib, oproxomib and marizomib attempt to overcome the administration difficulties of the parenteral agents and have a differentiated toxicity profile. This review will focus on the role of proteasome inhibitors in myeloma treatment.

Keywords: Multiple myeloma; Proteasome; Bortezomib; Carfilzomib; Apoptosis; Ixazomib


MM: Multiple Myeloma; ASCT: Autologous Stem Cell Transplant; PI: Proteasome Inhibitors; BMSC: Bone Marrow Stromal Cells; VLA4: Very late antigen 4; VCAM1: Vascular Cell Adhesion Molecule 1; CXC: Chemokine Receptor Type 4; CXCR4; CXCL12: Motif Chemokine 12; IL6: Interleukin 6; NF-kB: Nuclear Factor Kappa B; UPR: Unfolded Protein Response; SNP: Single Nucleotide Polymorphism; PFS: Progression Free Survival; OS: Overall Survival; RRMM: Relapsed Refractory Multiple Myeloma; ORR: Overall Response Rate; VMPT: Velcade Melphalan Prednisone, Thalidomide


The landscape of MM treatment was revolutionized with the introduction of novel agents. Till the late 1990s treatment options for myeloma were limited to steroids, alkylators, anthracyclines and ASCT. The first breakthrough in MM management with novel agents came in 1999 when Singhal, et al. demonstrated the efficacy of thalidomide in the relapsed refractory disease [1]. Since then multiple new agents have been approved for myeloma management including proteasome inhibitors (PI), newer immunomodulators, monoclonal antibodies and epigenetic therapies. This review will address the role of PI in the management of MM and the potential mechanisms of drug resistance to this class of agents.

Basis of proteasome inhibition as a therapeutic strategy in MM

MM is a neoplasm arising from terminally differentiated, long-lived plasma cells which are responsible for immunological memory. Initial oncogenic mutations in myeloma appear to arise in the germinal center during B cell somatic hypermutation and antibody class switching; late oncogenic events including additional mutations and epigenetic changes occur after differentiation into plasma cells [2]. In addition to oncogenic mutations in the plasma cells, the bone marrow microenvironment, through direct cellular interactions and indirect effects mediated by cytokines, also plays an important role in myelomagenesis [3]. MM cells adhere to BMSC in the microenvironment. This adhesion is mediated by different molecules on the surface of MM cells and BMSC. VLA4 on MM cells binds to VCAM1 on BMSC and CXCR4 on MM cells bind to SDF- 1 (CXCL12) on BMSC [4,5]. These interactions between MM cells and BMSC stimulate IL-6 production by the BMSC [6]. IL-6 is a key growth factor for myeloma cells promoting their proliferation [7]. The production of IL-6 by BMSC is at least in part mediated by the transcription factor NF-kappa B [4].

The proteasome complex has an essential role in processing of the NF-kB1 precursor protein and activating NF-kB [8]. It also modulates expression and degradation of various adhesion molecules [9]. The intracellular ubiquitin proteasome pathway is responsible for degradation of 80-90% of intracellular dysfunctional proteins. In addition it modulates the turnover of key proteins involved in cell cycle progression and apoptosis [10-12]. While the proteasome complex is responsible for maintaining homeostasis in normal cells, cancer cells appear more susceptible to the inhibition of this complex than normal cells. Compared to peripheral blood mononuclear cells or bone marrow cells of normal controls, myeloma cell lines and patient samples showed about 170-fold greater sensitivity to effects of bortezomib mediating apoptosis [13]. This differential sensitivity of cancer cells has in part been attributed to NF-kB activation in cancer cells. Therefore targeting the proteasome is an attractive strategy for the treatment of myeloma.

First in class proteasome inhibitor: Bortezomib

Mechanisms of action of bortezomib: Bortezomib, a dipeptide boronic acid analogue, reversibly inhibits the 26S proteasome subunit, disrupting various signaling pathways and NFkB function resulting in cell cycle arrest and apoptosis [13,14]. Transcriptional and protein level changes of apoptotic regulators occur with bortezomib therapy. Gene expression profiling in bortezomib treated multiple myeloma cell lines have shown bortezomib mediated transcriptional upregulation of multiple proapoptotic molecules including pro caspase-8, pro-caspase-1, pro-caspase-7, caspase-4, caspase-9, and pro-caspase-5. Propoptotic BAX and BIM are stabilized. Transcription of antiapoptotic BCL2 and BIRC3 are decreased [15]. Bortezomib also functionally activates the intrinsic and extrinsic apoptotic pathways. These functional effects of bortezomib at protein level mostly occur through modulation of the ubiquitin proteasome pathway. Inhibition of proteasomal degradation of IkB by bortezomib results in cytoplasmic sequestration of prosurvival transcription factor NFkB and decreased cell proliferation [13]. Lack of proteasomic degradation of misfolded proteins results in their sequestration in the endoplasmic reticulum, activating a stress signaling pathway called the unfolded protein response (UPR) which inhibits cell cycle progression and activates apoptosis through the proapoptotic target CHOP/GADD 153 [16]. Bortezomib selectively inhibits proteasomedependent degradation of proapoptotic p53, p21, Noxa, and TRAIL receptors DR4 and DR5 [17]. Together these effects of bortezomib appear to cause apoptosis of the malignant plasma cells. Plasma cells appear uniquely sensitive to PI since their ability to turnover proteins is reduced during the differentiation process [18] (Figure 1).

Citation: Raghupathy R and Margaret HL Ng. Proteasome Inhibitors in the Treatment of Multiple Myeloma. Ann Hematol Oncol. 2016; 3(7): 1102. ISSN : 2375-7965