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1736 Part XI: Malignant Lymphoid Diseases Chapter 107: Myeloma 1737

are commonly mutated in myeloma reaching a standard significant tumor burden and poor outcomes. The SDF-1/CXCR4 axis regulates
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threshold. Five of them (KRAS, NRAS, FAM46C, DIS3, and TP53) specific homing of myeloma cells to the marrow, but also mobilization
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are relatively frequent. 100,108 Approximately 30 to 50 percent of newly or marrow egress, being possibly accountable for the multifocal mar-
diagnosed patients have RAS mutations at codons 12 or 13, 82,114–117 row localization and blood circulation of myeloma cells. 140,141 Moreover,
often in association with t(11;14), but mutually exclusive with t(4;14) other chemokine receptors, such as CXCR3, CCR1, CCR2, and CCR5
that constitutively activates the MAPK pathway via FGFR3 upregula- can be expressed by myeloma conferring different migration capabili-
tion. 115,118,119 Because RAS mutations are rare in MG, they are consid- ties to medullary and extramedullary cells. Accessory cells (BMSCs,
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ered a possible driver to progression. Conversely, TP53 mutations endothelial cells, osteoclasts, and osteoblasts) secrete factors including
are a late event in myeloma, 91,121,122 an independent poor prognostic IL-6, 143–146 IGF-1, 147–149 vascular endothelial growth factor (VEGF), 150,151
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factor, and are associated in one-third of patients with concomitant tumor necrosis factor-α (TNF-α), fibroblast growth factor (FGF),
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hemizygous deletion of chromosome 17. 90,124 Mutations in FAM46C stromal cell-derived factor 1α (SDF-1α), and B-cell activating factor
and DIS3, genes possibly involved in RNA processing, are present in (BAFF) ; all capable of promoting expression of survival factors such
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10 to 21 percent of patients, often coupled with loss-of-heterozygosity as NF-κB. IL-6 and other survival signals also induce phosphatidyli-
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in the remaining allele. Other significant genes are BRAF (4 percent of nositol 3′-kinase (PI3K)/AKT, 156,157 STAT3 and MAPK signaling (Fig.
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patients), TRAF3, CYLD, RB1, PRDM1, and ACTG1. TRAF3 and CYLD 107–3). BMSCs, myeloma cells and osteoclasts also secrete growth
mutations, together with homozygous deletions in BIRC2/BIRC3, NIK factors and cytokines such as VEGF, basic fibroblast growth factor
overexpression and mutations in other genes (CARD11 and MYD88) (bFGF), and IL-8, to promote marrow angiogenesis, which increases
contribute to constitutively activation of the NF-κB pathway. 100,105,107,112 delivery of oxygen and nutrients to myeloma cells. Moreover, the same
Genes involved in protein homeostasis, the unfolded protein response, endothelial cells produce growth factors (IL-6 and IGF-1), to favor
or lymphoid/plasma cell development, such as PRDM1 involved in plas- plasma cell survival 150,151,158,159 and express deregulated genes important
macytic differentiation, and XBP1, IRF4, LRRK2, SP140, and LTB form for ECM and bone remodeling, cell adhesion, migration and resis-
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a cluster of genes mutated in myeloma. Other recurrent mutated genes tance to apoptosis. The degree of marrow angiogenesis, as assessed
are ROBO1, a transmembrane receptor involved in β-catenin and MET by microvessel density (MVD) is higher in active myeloma compared
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signaling; EGR1 transcription factor; FAT3, a transmembrane protein with MG and is also related to myeloma proliferation and infiltration,
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belonging to cadherin superfamily; and histone-modifying genes (MLL, negatively affecting patient prognosis. Also lymphoid and myeloid
MLL2, MLL3, WHSC1/MMSET, WHSC1L1, and UTX, among oth- cells are part of marrow microenvironment and can modulate myeloma
ers). 100,108,112 Plasma cell leukemia patients possess different aberrancies, survival. Myeloid cells, such as macrophages, mast cells and neutrophils
including p14 ARF promoter methylation, PTEN loss, RB1 mutations and control both pro- and antiinflammatory responses and regulate antigen
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higher rates of TP53 mutations and deletions. Finally, a novel intrigu- presentation. For instance, a specific group of myeloid cells, named
ing concept is the idea of intratumor heterogeneity in myeloma, where myeloid-derived suppressor cells (MDSCs), are highly represented in
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different subclones can emerge and become predominant following the marrow of myeloma individuals in comparison to healthy persons,
different mechanisms of evolution, including linear, branching, parallel and increase with disease progression, facilitating tumor development,
or convergent evolution. 108,126 Clonal diversity is indeed a fundamental growth, and immune escape, by blocking T-cell (CD8+ T and natural
process akin to Darwinian selection, favoring cancer progression and killer [NK] T) antitumor immune responses. 165
adaptation to therapy. Next-generation sequencing analyses show that
most patients have a subclonal structure at diagnosis, with one predom-
inant clone and several others which can reappear at different stages or BONE METABOLISM
following treatment. 108,110,111 Gene-expression profiling of myeloma cells The presence of osteolytic bone lesions, bone pain, increased risk
helps categorize patients into distinct subgroups 127,128 and can predict of pathologic fractures and generalized bone loss (or osteoporosis)
therapeutic responsiveness to specific drugs, although the role of spe- is a well-defined feature of myeloma. Indeed, as myeloma burden
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cific genetic signatures in risk stratification is still under debate. 129 increases, an imbalance between osteoblast and osteoclast activities
ensues, with suppression of bone formation by osteoblasts and uncou-
ROLE OF MARROW MICROENVIRONMENT IN pled activation of osteoclasts (Fig. 107–4). 167–169 The ligand for recep-
MYELOMA tor activator of NF-κB (RANKL) binds to RANK receptor to stimulate
osteoclast differentiation, formation and survival ; myeloma cells
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The marrow microenvironment is composed of extracellular matrix produce RANKL and upregulate RANKL expression in BMSCs and
(ECM) proteins, such as fibronectin, collagen, laminin and osteopontin; osteoblasts via direct contact interaction, signaling induction 171–173 or
and cells, including hematopoietic stem cells, BMSCs, and endothelial production of IL-7. Moreover, they promote suppression of osteopro-
cells, as well as osteoclasts and osteoblasts (Fig. 107–3) (Chap. 5). 130–133 tegerin (OPG), 174–176 a decoy receptor that normally prevents RANK–
Myeloma cells physically interact with ECM proteins and accessory RANKL interaction 177,178 via soluble factors, integrin α β -vascular cell
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cells to gain growth, survival, and drug resistance advantages. Among adhesion molecule (VCAM)-1 interaction, production of Dickkopf-
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others, CD44, very-late antigen 4 (VLA4), neuronal adhesion molecule 1(DKK1), or inactivation by syndecan-mediated internalization into
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(NCAM), intercellular adhesion molecule (ICAM)-1, and syndecan myeloma cells. Interestingly, OPG levels are decreased in the serum of
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1 (CD138) mediate the adhesion of myeloma cells to the marrow and myeloma patients and correlate with lytic bone lesion development ;
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ECM, activating signaling pathways, such as nuclear factor-κB (NF-κB), a high RANKL-to-OPG ratio is associated with worse prognosis.
to obtain CAM-DR to conventional chemotherapy. 134,135 In particular, Recombinant OPG constructs, soluble RANK, OPG peptidomimet-
CD138 (syndecan-1) is a transmembrane heparan sulphate bearing pro- ics 175,178,184,185 and an anti-RANKL antibody, denosumab, 186–189 have been
teoglycan, expressed during the plasma cell stage of B-cell maturation, developed to modulate the RANKL/OPG axis and reduce osteoclast
that can bind to type I collagen inducing expression of metalloprotein- activity in myeloma. Macrophage inflammatory protein (MIP)-1α, or
ases, and promoting bone resorption and invasion. Moreover, CD138 chemokine C-C motif ligand, is also produced by myeloma cells and
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can be shed in the ECM, trapping growth-promoting and proangio- promotes maturation of precursor cells into osteoclasts 190–192 ; MIP-1α
genic cytokines. 137,138 Increased soluble CD138 levels correlate with signals via CCR1 and CCR5 on osteoclasts and can further upregulate

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