Cell of Origin and Genetic Alterations in the Pathogenesis of Multiple Myeloma

Abstract

B cell activation and differentiation yields plasma cells with high affinity antibodies to a given antigen in a time-frame that allows for host protection. Although the end product is most commonly humoral immunity, the rapid proliferation and somatic mutation of the B cell receptor also results in oncogenic mutations that cause B cell malignancies including plasma cell neoplasms such as multiple myeloma. Myeloma is the second most common hematological malignancy and results in over 100,000 deaths per year worldwide. The genetic alterations that occur in the germinal center, however, are not sufficient to cause myeloma, but rather impart cell proliferation potential on plasma cells, which are normally non-dividing. This pre-malignant state, referred to as monoclonal gammopathy of undetermined significance or MGUS, provides the opportunity for further genetic and epigenetic alterations eventually resulting in a progressive disease that becomes symptomatic. In this review, we will provide a brief history of clonal gammopathies and detail how some of the key discoveries were interwoven with the study of plasma cells. We will also review the genetic and epigenetic alterations discovered over the past 25 years, how these are instrumental to myeloma pathogenesis, and what these events teach us about myeloma and plasma cell biology. These data will be placed in the context of normal B cell development and differentiation and we will discuss how understanding the biology of plasma cells can lead to more effective therapies targeting multiple myeloma.

Keywords: B cell; IgH translocations; MGUS; MYC; epigenetics; genetics; multiple myeloma; plasma cell.

Figure 1

Plasma cell differentiation and myelomagenesis. (A) Schematic of B cell differentiation, plasma cell development, and myelomagenesis. Lightning bolts represent genetic mutations common in myeloma. (B) Diagram of stages of myeloma progressing from a normal plasma cell to monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), newly diagnosed multiple myeloma (NDMM), and relapse/refractory multiple myeloma (RRMM). Below are common mutations in myeloma and the stages at which they appear.

Figure 2

Genetic events in newly diagnosed multiple myeloma (NDMM). Circos plot showing copy number losses (blue) and gains (orange) in the outer ban (gray lines indicate 10% of the population). Mutations are shown on the inner ban, where the frequency of non-synonymous mutations and the variant allele frequency (VAF) are shown for 500 kb regions. Translocations are shown on the inside where the frequency is denoted by line thickness (key bottom left) and color denotes the VAF. Data are from 850 NDMM patients part of the MMRF CoMMpass study (dbGaP phs000748.v7.p4).

Figure 3

Epigenetic mechanisms of gene regulation in plasma cells and multiple myeloma. Epigenetic modifications associated with gene repression are shown (left) and include histone 3 lysine 27 trimethylation (H3K27me3), lack of histone 3 lysine 4 methylation (H3K4me0), as well as enhancer and/or promoter DNA methylation. Epigenetic modifications permissive to gene transcription are shown (right) and include H3K36me2 (mediated in part by WHSC1), histone 3 lysine 27 acetylation (H3K27ac), H3K4me1/2 at enhancers, H3K4me3 at promoters, and absence of enhancer and promoter DNA methylation. Gene bodies (far right) of actively transcribed genes are often demarcated with H3K36me3 and DNA methylation. Certain enzymes that mediate activating (top) and repressive (bottom) epigenetic modifications relevant to multiple myeloma are shown (middle).

Figure 4

Therapeutic modalities in multiple myeloma. Cellular targeted therapies (top) include chimeric antigen receptor T-cells (CAR-T cells) that target B cell maturation antigen (BCMA) and Bispecific T cell engagers (BiTE), which are two conjugated antibodies, one that recognizes the CD3 receptor on T cells while the other antibody recognizes BCMA. Monoclonal antibodies elotuzumab and daratumumab target SLAMF7 and CD38, respectively and result in myeloma cell killing by Natural Killer (NK) cell mediated antibody-dependent cellular cytotoxicity (ADCC) and in the case of daratumumab also by Macrophage antibody-dependent cellular phagocytosis (ADCP). Molecular modalities include immunomodulatory imide drugs (IMiD; top right) that bind Ikaros (IKZF1) and Aiolos (IKZF3) to Cereblon (CRBN) as part of an E3 ubiquitin ligase complex, which subsequently ubiquitinates IKZF1 and IKZF3 marking them for proteasomal degradation. Proteasome inhibitors (center) result in proteotoxic stress and the unfolded protein response, which plasma cells are particularly sensitive due to their high levels of antibody production. Anti-apoptosis inhibitors (middle left) include MCL1 inhibitors (MCLi) and BCL2 inhibitors such as venetoclax which induce mitochondrial outer membrane permeabilization (MOMP) and apoptosis. Therapeutics targeted at intracellular signaling include the cyclin dependent kinase 4 and 6 (CDK4/6) inhibitor abemiciclib and the mutant IDH2 inhibitor enasidenib. FGFR3 which is highly expressed in most t(4;14) myeloma and sometimes has activating mutations, is targeted with erdafitinib. FGFR3 feeds into RAS / MEK / MAPK signaling, which is targeted with drugs against BRAF (vemurafenib) and MEK (cobimetinib). Finally, a new class of drugs that target transcriptional activators such as bromodomain and extra-terminal (BET) inhibitors the block or degrade BRD4 are being used to target the enhancer machinery present at large enhancers that are often translocated in myeloma such as those found at the immunoglobulin loci.