Multiple myeloma pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Hannan Javed, M.D.[2]; Haytham Allaham, M.D. [3]; Shyam Patel [4]

Overview

Multiple myeloma, a disorder of clonal late B-cells, arises from post-germinal center plasma cells that are normally involved in production of human immunoglobulins.[1][2][3] Although the exact pathogenesis and the stage at which myeloma cells arise from post-germinal B-cells remain unclear, a variety of factors have been implicated in pathogenesis of multiple myeloma. Of these, chromosomal abnormalities are thought to be the most important. It has been suggested that all cases of multiple myeloma pass through MGUS. Renal involvement by multiple myeloma is catergorized into three entities: light chain cast nephropathy, monoclonal immunoglobulin deposition disease, and amyloidosis. Osseous involvement by multiple myeloma is based on cytokine and cellular interactions that lead to bone breakdown. On microscopic histopathological analysis, abundant eosinophilic cytoplasm, eccentrically placed nucleus, and Russell bodies are characteristic findings of multiple myeloma.[4]

Pathophysiology

Normal physiology and development of plasma cells

Stem cells → Pre-B cells → Immature B-cells → Mature B-cells (naïve) → Activated B-cells → Memory B-cells and Plasmablasts → Plasma cells

Interferon regulatory factor 4 (IRF4) → Down-regulation of BCL6 → Up-regulation of B-lymphocyte-induced maturation protein 1 (BLIMP1) → Down-regulation of paired box gene 5 (PAX5) and Up-regulation of X box binding protein 1 (XBP1).[11][12][13]

For more information on plasma cells, click here.

Normal physiology and development of Immunoglobulins

For more information on immunoglobulins, click here.

Pathogenesis

The pathogenesis of multiple myeloma is complex and probably is a result of multiple and multi-step oncogenic events such as hyperdiploidy and deregulation of cyclin D1, and interaction of myeloma cells with marrow environment. Recently it has been suggested that all cases of multiple myeloma pass through an MGUS phase. The events surrounding the progression of MGUS into multiple myeloma are not well-defined but environmental and genetic factors have been proposed to have an association. A brief description of events thought to play a role in pathogenesis of multiple myeloma is given here.

Biology of myeloma cells

Environmental and hereditary factors

Environmental and hereditary risk factors
* Likely influenced by environmental and behavioral confounding factors.

Chromosomal aberrations

Translocations
Hyperdiploidy
Chromosomal aberrations in multiple myeloma (MM)
Chromosomal Abnormality Chromosome(s)/Protein(s) affected Consequence
Trisomies Odd-numbered chromosomes with the exception of chromosomes 1, 13, and 21
t(11;14)(q13;q32)

t(6;14q)(p21;32)

t(12;14)(p13;q32)

Cyclin D1

Cyclin D3

Cyclin D2

Over-expression; cell cycle dysregulation
t(4;14)(p16;q32) FGFR3 or MMSET Over-expression and activation; multiple myeloma cell proliferation/apoptosis prevention MMSET probably linked to crucial transforming event
t(14;16)(q32;q23)

t(14;20)(q32;q11)

t(8;14)(q24;q32)

c-MAF

MAFB

MAFA

Over-expression; involvement in IL-4 regulation
del 17p13 p53 Cell-cycle dysregulation/apoptosis
Monosomy 14 Chromosome 14
Chromosome 13 deletion and monosomy Chromosome 13
Gain(1q21) Chromosome 1
Abbreviations used: FGFR3:fibroblast growth factor receptor 3; MMSET:multiple myeloma SET domain; MAF:musculoaponeurotic fibrosarcoma oncogene homolog.

Mutations in myeloma

Tumor suppressors
Tumor suppressor genes commonly affected in myeloma
FAM46C (family with sequence similarity 46, member C)
DIS3 (Exosome complex exonuclease RRP44)
CYLD (Cylindromatosis)
Baculoviral IAP repeat containing protein 2 (BIRC2; also known as cIAP1)
BIRC3 (Baculoviral IAP repeat containing protein 3)
tumor necrosis factor receptor associated factor 3 (TRAF3)
CDKN2C
CDKN2A
TP53
NFKB alterations
Genes mutated associated with canonical signaling Genes mutated associated with non-canonical signaling
TLR4

TNFRSF1A

IKBKB

IKBIP

CARD11

MAP3K1

RIPK4

CYLD

BTRC

MAP3K14

TRAF3

Epigenetic changes in multiple myeloma
Bone marrow microenvironment and multiple myeloma
Cytokines in multiple myeloma pathogenesis
Cytokines Mechanism Effects on tumor cells and pathogenesis
Interleukin 6

IL-6

Activates signal transduction pathways

(JAK/STAT3 and PI3K/Akt)

Tumor necrosis factor α

TNF

Activation of NF-κB

Activation of the MAPK pathways

B-cell activating factor

(BAFF)

Activation of NF-κB
Insulin-like growth factor-1

(IGF-1)

Activation of PI3K/Akt

Activation of IKK/NF-κB

  • Increased growth and proliferation
  • Decreased apoptosis and increased survival
Vascular endothelial growth factor

(VEGF)

VEGF Receptor activation
Interleukin 17

(IL-17)

Interleukin 17 receptors activation
  • Increased survival
  • Increased cytokines production
  • Lytic bone lesions

Pathophysiology of renal involvement

Abnormal antibody fragments are produced in multiple myeloma and are deposited in various organs, such as the kidneys. There are three major forms of renal damage in patients with multiple myeloma.

  • Cast nephropathy: End-organ damage to the kidneys is typically due to light chain cast nephropathy. The pathophysiology of this type of renal involvement is based on light chain deposition in the renal tubules, which results in obstruction. Free light chains are readily filtered at the glomerulus and are reabsorbed in the proximal tubule of the nephron. This reabsorption occurs via the megalin-cubulin transport system.[69] In patients with multiple myeloma, there is excess production of free light chains, and the ability of the nephron to resorb light chains in the proximal tubule cannot meet the demands of the freely filtered light chains. This results in excess secretion of free light chains in the urine (known as Bence-Jones protein). Eosinophilic proteinaceous casts and crystalline structures can be seen. Cast formation occurs in the tubules due to excess abundance of free light chains that interact with Tamm-Horsfall proteins in the thick ascending loop of Henle.[69] Tubular obstruction ensues, triggering local inflammation which results in interstitial nephritis and fibrosis.[69] The onset of cast nephropathy can be very quick, requiring prompt treatment. Risk factors for development of cast nephropathy include monoclonal immunoglobulin secretion of >10 g/day, sepsis, and volume depletion.[70] Patients can also develop Fanconi syndrome, resulting in dysfunctional reabsorption ability by the proximal tubule, and type II renal tubular acidosis.
  • Monoclonal immunoglobulin deposition disease (MIDD): In this subtype of renal involvement by multiple myeloma, the initial pathophysiological process is filtration of monoclonal immunoglobulins and subsequent deposition of immunoglobulins along the tubular or glomerular basement membrane.[70] Deposits of immunoglobulin can have a similar appearance as Kimmelstein-Wilson lesions (seen in diabetes). The immunoglobulins can appear fibroblast-like.
  • Light chain amyloidosis: The pathophysiology of renal involvement by light chain amyloidosis begins with beta-pleated sheet formation in the tubules or glomeruli. Beta-pleated sheets form as a result of electrostatic interactions between heparan sulfate proteoglycan and amyloid proteins. Amyloid fibrils usually consist of immunoglobulin light chains (usually lambda light chain) and deposit in the basement membrane. The size of the fibrils vary from 7 to 10 nanometers. A diagnosis of this type of renal involvement is made by the visualization of apple green birefringence upon Congo red staining of the renal specimen.[70] It is frequently associated with nephrotic range proteinuria, in which greater than 3 grams of protein is excreted daily.

Pathophysiology of osseous involvement

Bone disease characterized by progressive osteolytic bone lesions leading to bone resorption is hallmark of multiple myeloma. Abnormal bone remodeling is thought to be the cause. It has been reported that up to 80% of the patients have characteristic osteolytic bone lesions at presentation and 60% of the patients with multiple myeloma will develop at least one pathological fracture at some stage.The pathophysiology of bony involvement in multiple myeloma is complex and is briefly described here..[71][72][73]

Increased osteoclastic activity

Osteoclasts are large, multinucleated cells of monocytemacrophage lineage and play a crucial role in bone remodeling. Myeloma cells, in addition to their direct interaction with other cells, produce and release a number of factors which promote osteoclast differentiation and activation. Some of these factors and interactions have been described below in the tables.[71][74][75]

Cell-cell interactions Consequences
Myeloma cells to bone marrow stromal cells
  • Decreased production of OPG
  • Increased RANKL expression
Alpha4-beta1 integrin to vascular cell adhesion molecule 1 (VCAM-1) interaction
Myeloma cells to osteoblasts Decreased production of OPG
Myeloma cells to osteoclasts Direct adherence of myeloma cells to osteoclasts may result in
Myeloma cells to immune cells Increased production of cytokines, chemokines and factors associated with growth,

survival and migration.

.

Molecular pathways and factors associated with increased osteoclastic activity Association with multiple myeloma
RANK/RANKL pathway

Binding of RANKL to RANK → fusion of osteoclast precursors into multinucleated cells → mature osteoclasts → ↑ bone resorption

Osteoprotegerin (OPG) is a soluble decoy receptor for RANKL → ↓ binding of RANKL to RANK → ↓ bone resorption

Myeloma cells lead to increased RANKL and decreased OPG causing bone resorption and destruction. RANKL/OPG ratio is an idependent

prognostic factor in multiple myeloma

Notch pathway

Binding of Notch receptors to its ligands → ↑ RANKL production → ↑ bone resorption

Myeloma cells express Notch 1,2,3 and their ligands Jagged 1,2 and Delta-like 1,3,4. This pathway, in addition to bone resorption, may also be involved in metastasis of myeloma cells by increasing expression of adhesion molecules, migratory chemokines, and angiogenetic factors, and disruption of the immune surveillance.
CCL-3 (MIP-1α)/CCL-20
Activin A

Binds to type II transmembrane serine/threonine kinase receptor (ActRIIA/B) → recruitment and phosphorylation the type I receptor

(ActRI, also called activin receptor-like kinase 4 (ALK4) receptor) → heterodimer formation → activation of the Smad signaling cascade → translocation of Smad2/3/4 complex in the nucleus → action as transcriptional factorRANK expression and activation of NF-κB pathway → increased osteoclast differentiation

Osteopontin
Interleukin 3 (IL-3)
Vascular endothelial growth factor (VEGF)
Interleukin 6 (IL-6)
Interleukin 17 (IL-17)
B cell-activating factor (BAFF)

Binding to its receptor → activation of NF-κB → ↑ MM cell survival

Bruton’s tyrosine kinase (BTK)

Osteoclast precursors with CXC chemokine receptor type 4 (CXCR4) and Bruton’s tyrosine kinase (BTK) expression → migration towards stromal cell-derived factor-1α (SDF-1α) → ↑ activation of Bruton’s tyrosine kinase (BTK) in myeloma cells.

Stromal cell-derived factor-1α (SDF-1α)

Osteoclast precursors with CXC chemokine receptor type 4 (CXCR4) and Bruton’s tyrosine kinase (BTK) expression → migration towards stromal cell-derived factor-1α (SDF-1α) → ↑ activation of Bruton’s tyrosine kinase (BTK) in myeloma cells.

Annexin II (Annexin A2)
PU.1
Decreased osteoblast activity

Inhibition of osteoblasts leading to decreased bone formation is now considered to be a critical event in bone disease in multiple myeloma. This inhibition leads to bone loss as well as inability to repair the osteoytic lesions caused by increased osteoclastic activity. Several pathways and factors have been associated with suppressed osteoblastic activity. Some of them are mentioned below in the table.[71][74][75]

Molecular pathways and factors associated with osteoblastic activity Association with multiple myeloma
Wingless and integration-1 (Wnt) signaling

Activation of Wnt pathway → binding of Wnt ligands to Wnt co-receptors LRP5/6 and one trans-membrane receptor of the FDZ family →

formation of DVL–Axin–FRAT1GSK-3β complex → translocation of β-catenin from cytoplasm to nucleus

activation of T cell factor/lymphoid enhancer factor (TCF/LEF) transcription factors → ↑ bone formation and ↓ bone resorption

  • Non-canonical WNT–planar cell polarity (WNT–PCP) pathway

Formation of WNT ligandreceptor tyrosine kinase-like orphan receptor 2 (ROR2) or the receptor-like tyrosine kinase (RYK)–FZD–DVL complex

→ activation of one of these 3 pathways: 1) Disheveled-associated activator of morphogenesis 1 (DAAM1)–RHO–RHO-associated kinase (ROCK) pathway; 2) RAC–Jun kinase (JNK)–RUNX2 pathway; WNT–Ca2+ pathway

Dickkopf 1 (Dkk-1)

Sclerostin

Secreted frizzled related protein-2 (sFRP-2)

Periostin

Runt-related transcription factor 2 (Runx2)/corebinding factor runt domain alpha subunit 1 (CBFA1)

EphrinB2/EphB4 signaling pathway

Binding of ligands called ephrins (Eph receptor-interacting proteins) → activation of two cascades: 1) the forward signaling → ↑ osteoblast

differentiation by downregulating RhoA; 2) the reverse signaling → ↓ osteoclast differentiation by ↓ Fos and Nfatc1 transcription

Multiple myeloma patients have decreased expression of both EphrinB2 and EphB4 in bone marrow stromal cells.
Transforming growth factor-β (TGF-β) Inhibition of Transforming Growth Factor-β have been shown to prevent myeloma cells to block osteoblastic differentiation.
Bone morphogenetic proteins (BMPs)
  • belong to TGFβ superfamily
  • promote osteoblastogenesis through Smad-dependent and Smad-independent pathways
Myeloma cells express negative regulators of bone morphogenetic proteins that result in decreased activity of these proteins which in turn causes decreased osteoblastogenesis.
Hepatocyte growth factor (HGF)
Interleukin 3 (IL-3) Elevated levels had been demonstrated in bone marrow of myeloma patients.
Interleukin 7 (IL-7)
  • Causes
    • increased osteoclastic activity
    • decreased osteoblasts stimulation and maturation
    • decreased Runx2/CBFA1 activity
Growth factor independence-1 (GFI1) Bone marrow stromal cells (BMSCs) in myeloma patients have been shown to over-express growth factor independence-1 (GFI1).
Tissue necrosis factor-α (TNF-α)
  • inhibits osteoblast differentiation through
    • inhibits osteoblast precursor recruitment
    • suppresses RUNX2 and its transcriptional co-activator, TAZ
Tissue necrosis factor-α (TNF-α) levels are increased in multiple myeloma and it is thought to play a complex role in pathogenesis of multiple myeloma.
Adiponectin

adipocyte-derived hormone thought to act on osteoblasts and osteoclasts

Increased adiponectin secretion through pharmacologic interventions have shown to decrease osteolytic lesions in myeloma.
Renal involvement in multiple myeloma

Renal involvement is common in multiple myeloma as up to 50% of the patients go on to develop kidney disease at some point during the disease course. Half of these patients recover kidney function while the rest of them develop chronic kidney dysfunction. The causes of renal involvement in multiple myeloma are multiple and diverse. They can broadly be classified into Ig dependent and Ig independent mechanisms. Some of them have been discussed below in the table and then described briefly.[76][77][70]

Ig-dependent renal injury Ig-independent renal injury
Cause Notes Cause Notes
Cast nephropathy (myeloma kidney) Risk factors Volume depletion May cause
Monoclonal Ig deposition disease
  • May be associated with systemic syndrome
  • Ig deposition may be demonstrated in either tubules or glomeruli but typically not in both
Sepsis May cause
Light chain amyloidosis (AL) Hypercalcemia May result in acute kidney injury directly or contribute to cast nephropathy
Glomerulonephritis Following types have been demonstrated Tumor lysis syndrome Caused by uric acid or phosphate nephropathy
Tubulointerstitial nephritis May be caused be either Ig-dependent or Ig-independent mechanisms Direct parenchymal invasion by plasma cells Rare cause. Association with advanced or aggressive multiple myeloma
Minimal change disease Often with albuminuria and light chain proteinuria Pyelonephritis Rare cause. Pathogenesis is typically multifactorial and may include:
Hyperviscosity syndrome Seen primarily in cases of IgA, IgG3, or IgM myeloma Medication toxicity Following drugs may cause kidney injury:
Henoch–Scholein purpura/IgA nephropathy Associated with IgA myeloma
Immunotactoid glomerulopathy (and possibly fibrillary GN) Rare conditions. The association between fibrillary disease and paraproteins is is not understood at this point.
Thrombotic microangiopathy (TMA) Endothelial injury caused by paraprotein leads to thrombotic microangiopathy.
Membranous glomerulopathy

Cast nephropathy (myeloma kidney)
Factors associated with increased risk

of AKI or CKD in multiple myeloma

Mechanism of injury
Volume depletion Increased FLC concentration

Decreased GFR

Pre-renal azotemia

Hypercalcemia Renal vasoconstriction

Decreased GFR

Pre-renal azotemia

Iodinated contrast media Nephrotoxicity
Nonsteroidal anti-inflammatory drugs Renal vasoconstriction

Decreased GFR

Medullary hypoxia

Diuretics Increased sodium chloride concentration

Increased cast formation

Aminoglycosides Renal vasoconstriction

Decreased GFR

Hyperuricemia
Comorbidities such as chronic kidney disease, diabetes, aging, hypertension, and cardiovascular disease.
Hypercalcemia
Light-chain glomerulopathy
Light chain deposition disease (LCDD)
Immune dysfunction in multiple myeloma

Gross Pathology

Microscopic Pathology

On microscopic histopathological analysis, multiple myeloma is characterized by the following:[4]

  • Abundant eosinophilic cytoplasm
  • Eccentrically placed nucleus
  • Clock face morphology of the nucleus due to chromatin clumps around the edges
  • Russell bodies which are eosinophilic, large (10-15 micrometres), homogenous immunoglobulin-containing inclusions
  • Dutcher bodies which are PAS stain +ve intranuclear crystalline rods
  • Shown below is a series of microscopic images seen in multiple myeloma:

References

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