Matthew Ho Zhi Guang, Kenneth C. Anderson, Giada Bianchidocuments.irevues.inist.fr/bitstream/handle/2042/... · This paper is an update of Multiple myeloma in 2004. Clinics and pathology

Leukaemia Section Review

Atlas Genet Cytogenet Oncol Haematol. 2017; 21(12) 451

Atlas of Genetics and Cytogenetics

in Oncology and Haematology

INIST-CNRS OPEN ACCESS JOURNAL

Multiple Myeloma Matthew Ho Zhi Guang, Kenneth C. Anderson, Giada Bianchi

LeBow Institute for Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center, Department

of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, 02115.

[email protected]; [email protected];

[email protected]

Published in Atlas Database: January 2017

Online updated version : http://AtlasGeneticsOncology.org/Anomalies/MultipleMyelomaID1776.html

Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/69009/01-2017-MultipleMyelomaID1776.pdf DOI: 10.4267/2042/69009

This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2017 Atlas of Genetics and Cytogenetics in Oncology and Haematology

Abstract

Multiple Myeloma (MM) is a cancer of plasma

cells resulting from the abnormal proliferation of

malignant plasma cells within the bone marrow

(BM) microenvironment. MM accounts for 1.3% of

all malignancies and 12% of hematologic cancers,

and is the second most commonly diagnosed blood

cancer after non-Hodgkin lymphoma. The hallmark

characteristics of MM include: high levels of intact

monoclonal immunoglobulin or its fragment (free

light chain) in serum or urine, and excess

monotypic plasma cells in the bone marrow in

conjunction with evidence of end organ damage

related to MM: (1) hypercalcemia, (2) renal failure,

(3) anemia, and (4) osteolytic bone lesions or severe

osteopenia, known as CRAB criteria. Even though

novel agents targeting MM cells in the context of

the BM microenvironment such as proteasome

inhibitors, immunomodulatory drugs (IMiDs), and

monoclonal antibodies have significantly prolonged

survival in MM patients, the disease remains

incurable. A deeper understanding of the molecular

mechanisms of MM growth, survival, and

resistance to therapy, such as genomic instability,

clonal heterogeneity and evolution, as well as MM-

BM microenvironmental host immune and other

factors, will provide the framework for

development of novel therapies to further improve

patient outcome.

Keywords

multiple myeloma, bone marrow

microenvironment, monoclonal gammopathy of

undetermined significance

Identity

Other names

Plasma cell myeloma, Myelomatosis, Kahler's

disease

Note

This paper is an update of Multiple myeloma in

2004.

Clinics and pathology

Disease

MM is a plasma cell cancer which is preceded by

an asymptomatic, premalignant condition called

monoclonal gammopathy of undetermined

significance (MGUS) which then progresses to MM

or related malignancies with a rate of about 1% per

year (Zingone and Kuehl 2011).

Phenotype/cell stem origin

Antigen-selected, post-germinal center, terminally

differentiated plasma cell (Anderson and Carrasco

2011)

Multiple Myeloma Ho M, et al.


Top: Normal Bone Marrow; Bottom: Multiple Myeloma Bone Marrow (note: ≥ 10% clonal bone marrow plasma cells). Image taken from: http://www.thrombocyte.com/causes-of-multiple-myeloma-cancer/

Etiology

Etiology not known. No confirmed predisposing

factors.

Possible (unconfirmed and controversial) risk

factors include (Sundar Jagannath et al 2016):

Environmental factors such as radiation exposure,

occupational exposure (agricultural, chemical,

metallurgical, rubber plant, pulp, wood, paper), and

chemical exposure (formaldehyde, epichlorohydrin,

Agent orange, hair dyes, paint sprays, asbestos)

Viral infection: Herpesvirus 8 infection noted in

some patients with MM

Genetic predisposition

The transformation of normal plasma cells into

myeloma cells is thought to result from one of two

primary genetic events: either (1) hyperdiploidy or

(2) aberrant class switch recombination (CSR),

likely occurring in the germinal center, leading to

MGUS. Secondary cytogenetic abnormalities result

in the progression of MGUS to SMM, MM, and

plasma cell leukemia (PCL) (see below:

Cytogenetics). MM cells are dependent upon the

BM microenvironment for growth, survival, and

drug resistance, due both to tumor cell adhesion to

BM accessory cells and release of growth factors

and cytokines including (1) interleukin-6 ( IL6), (2)

vascular endothelial growth factor ( VEGFA), (3)

insulin-like growth factor 1 ( IGF1), (4) members

of the superfamily of tumor necrosis factor, (5)

transforming growth factor beta1 (TGFB1), and (6)

interleukin-10 ( IL10) (Palumbo and Anderson

2011). Coupled with various genetic changes, these

abnormal microenvironmental interactions between

MM cells and BM cells contribute to aberrant

angiogenesis and MM disease progression

(Palumbo and Anderson 2011).

Epidemiology

See table below.

Clinics

The most common presenting symptoms of MM are

fatigue and bone or back pain. Multiple myeloma

cells typically grow within the BM of the spine,

skull, ribs, sternum, pelvis, humeri, and femora,

causing pain, osteopenia, and frequently

pathological fractures (Palumbo and Anderson

2011).

Myeloma cells typically secrete an excess of a

monoclonal immunoglobulin or its fragments (free

light chain), which can then be detected in the

patient's serum and/or urine via protein

electrophoresis and serum free light chain (sFLC)

testing, respectively. Immunofixation shows the

myeloma (M) protein to be monoclonal in nature

and identifies heavy (IgG/IgA/IgM/IgD, in order of

frequency) and light chain ( κ/λ) specific isotype.

http://www.thrombocyte.com/causes-of-multiple-myeloma-cancer/



Rarely, MM may be non-secretory and neither a

monoclonal Ig nor an excess sFLC can be

identified. The diagnosis of MM is made based on

the percentage of bone marrow involvement by

clonal MM cells, size of M protein spike, and

presence/absence of end-organ damage (CRAB) or

myeloma-defining biomarkers (Rajkumar,

Dimopoulos et al. 2014).

CRAB criteria:

Hypercalemia -> (C) Up to 20% of newly diagnosed patients have

hypercalcemia due to bone destruction.

Hypercalcemia is associated with high tumor

burden and requires prompt treatment with

aggressive hydration and loop diuretic therapy,

bisphosphonates, calcitonin, and anti-myeloma

therapy for disease control.

Renal Failure -> (R) Renal dysfunction (anuria or oliguria) resulting

from direct tubular damage by free light chain

tubular or glomerular deposition, hypercalcemia,

dehydration, and nephrotoxic medications (NSAIDs

for pain control, IV radiographic contrast,

bisphosphonates) is present in 20 to 40% of newly

diagnosed patients.

Light-chain cast nephropathy is the most common

cause of renal failure in MM. Other causes include

amyloidosis and light-chain deposition disease.

Anemia-> (A) At diagnosis, symptomatic normocytic,

normochromic anemia (typically secondary to

myelophthisis and hyporegenerative BM) is present

in approximately 73% of patients. Mean

corpuscular volume (MCV) may be macrocytic; an

artifact related to rouleaux formation.

Bone Disease -> (B) Up to 58% of patients report bone pain (especially

from compression fractures of vertebrae or ribs),

and up to 80% of newly diagnosed patients have

bony lesions.

The characteristic "punched-out" osteolytic lesions

result from lytic bone destruction that is uncoupled

from reactive bone formation. MM cells increase

the activity of osteoclasts by upregulating osteoclast

inducers (i.e. TNFSF11 (RANKL, TRANCE),

CCL3 and CCL4 (MIP-1 alpha /beta), CXCL12

(SDF-1 alpha), IL1B (IL-1 beta), TNF (TNF-

alpha), IL6,) and downregulating TNFRSF11B

(OPG, decoy receptor for RANKL).

Simultaneously, MM cells suppress osteoblast

differentiation and function (by producing DKK1)

resulting in an imbalance favouring bone resorption

(osteoclast activation) over bone formation

(osteoblast suppression) (Sezer 2009).

Revised International Staging System (R-ISS) (Palumbo, Avet-Loiseau et al. 2015)*Standard-risk: No high-risk chromosomal abnormality. High-risk: Presence of del(17p) and/or translocation t(4;14) and/or translocation t(14;16)





International Myeloma Working Group (IMWG) diagnostic criteria (Rajkumar, Dimopoulos et al. 2014)



M-protein Left: Serum protein electrophoresis showing characteristic "M-protein" spike. Image taken from:

http://bestpractice.bmj.com/best-practice/images/bp/en-gb/179-5-iline_default.gif and http://www.aafp.org/afp/1999/0401/p1885.html; Right: Urine protein electrophoresis showing gamma-globulin peak

corresponding to Bence-Jones proteinuria. Image taken from: https://ahdc.vet.cornell.edu/sects/clinpath/test/immun/electro.cfm

Pathology

MM is characterized by the presence of ≥10%

malignant plasma cells in the bone marrow. MM

can be divided into (1/>= secretory MM, (2)

oligosecretory MM (aka light chain MM), and (3)

non-secretory MM based on whether M-protein is

secreted and detectable (Lonial and Kaufman

2013). Non-secretory MM accounts for <5% of

cases and can be further divided into producer (i.e.

patients who have detectable M-protein within MM

cells but do not secrete M-protein) and non-

producer MM (patients who do not have detectable

M-protein even within MM cells) (Lonial and

Kaufman 2013). The presence of Bence-Jones

protein (BJP) in the urine indicates the excessive

production of monoclonal light-chain proteins that

exceeds the re-absorptive ability of the proximal

tubules. These filtered light-chains are, in their

various forms (free, tubular casts, amyloid),

nephrotoxic and are responsible for the most

common cause of renal failure in patients with MM.

Another hallmark feature of MM is the presence of

osteolytic bone lesions that results from an

imbalance favoring bone resorption over bone

formation due to increased osteoclast activity and

reduced osteoblast differentiation and function,

secondary to secreted factors from MM cells (Sezer

2009). Associated with bone destruction are

complications such as bone pain, pathological

fractures, and hypercalcemia. Anemia is another

frequent finding in patients with MM that results

from multiple mechanisms including anemia of

chronic disease, EPO deficiency (secondary to renal

impairment), myelosuppression from

chemotherapy, and bone marrow infiltration by

plasma cells.

Osteolytic bone lesions (a-d) X-rays showing characteristic osteolytic bone lesions typical sites such as the (a) skull, (b) tibia, (c) femur, and (d) pelvis. Image taken from: http://orthoinfo.aaos.org/topic.cfm?topic=A00086 ; (e) Sagittal CT showing multiple

osteolytic bone lesions of the vertebral column. Image taken from: https://radiopaedia.org/cases/multiple-myeloma-skeletal-survey

https://radiopaedia.org/cases/multiple-myeloma-skeletal-survey

https://radiopaedia.org/cases/multiple-myeloma-skeletal-survey



MM kidney disease Left: Normal kidney biopsy; Right: Monoclonal protein-containing casts surrounded by histiocytes and giant cells. Note the presence of acute tubular injury and interstitial nephritis which are commonly seen in MM kidney disease. Images

taken from: https://ajkdblog.org/2012/06/14/test-your-knowledge-myeloma-and-the-kidney/#prettyPhoto (courtesy of Dr. Tibor Nadasdy)

Natural History of MM Monoclonal Gammopathy of Undetermined Significance (MGUS; premalignant; asymptomatic) -> Smoldering Multiple Myeloma (SMM; pre-malignant; asymptomatic) -> Multiple Myeloma (MM; malignant; symptomatic) -> Plasma cell Leukemia (PCL), extramedullary disease. MM remains incurable in the long-term as most patients inevitably, yet

unpredictably, develop refractory relapse disease (i.e. disease that fails to respond to induction or salvage therapy, or progresses within 60 days of last therapy). Images taken from: Kyle et al, NEJM, Volume 356:2582-2590 (Kyle, Remstein et al. 2007) and

Roman Hajek, Intech open, DOI: 10.5772/55366 (Hajek 2013)





Treatment

See tables

(NCCN guidelines version 3.2017) and IMWG

RESPONSE CRITERIA (Kumar, Paiva et al. 2016)

Prognosis

Varies greatly depending on:

-Stage of disease (see above: ISS)

-Cytogenetics (see below: cytogenetics)

-LDH levels (high levels associated with

extramedullary disease, plasma cell leukemia,

plasmablastic disease, plasma cell hypoploidy, drug

resistance, and poor outcomes)

-Plasma cell labeling index

-C-reactive protein (high levels associated with

poor outcomes)

-Plasmablastic histology

-Extramedullary disease

-Age

Type of treatment available

- Conventional therapy: OS ~3 years; EFS <2 years

- High-dose chemotherapy and stem-cell

transplantation: 5-year OS >50%

In general, poor prognosticators include:

-Large tumor burden

- Hypercalcemia

- High LDH

- Bence-Jones proteinuria

- Renal impairment

- IgA subtype

- Extramedullary disease at presentation

Genetics See figure below.

Cytogenetics

Cytogenetics morphological

See figures below.

Genes involved and proteins

FGFR3 (Fibroblast Growth Factor Receptor 3)

Location

4p16.3

Note

Involved in t(4;14)(p16;q32)

Both FGFR3 and WHSC1 (MMSET) are

implicated in the translocation with IGH

Incidence: 6-12%

NSD2 (MMSET)

Location

4p16.3

Note


CCND1 (B-cell leukemia/lymphoma 1)

Location

11q13.3

Note

Involved in t(11;14)(q13;q32)

Incidence: 15-20%



Genetics



Primary Cytogenetic Abnormalities (Normal plasma cell --> MGUS/SMM). Ref : Rajan and Rajkumar (2015)



Secondary Cytogenetic Abnormalities (MGUS/SMM --> MM --> RR MM, PCL) Ref : Morgan, Walker et al. (2012).

CCND3 (cyclin D3)

Location

6p21.1

Note


Incidence: 5%

MAF (v-maf musculoaponeurotic fibrosarcoma oncogene homolog (avian))

Location

16q23.2

Note


Incidence: 4-10%

IRF4 (interferon regulatory factor 4)

Location

6p25.3

Note


Incidence: 5%

MYC v-myc myelocytomatosis viral oncogene homolog (avian)

Location

8q24.21

Note


Incidence: <10%

MAFB (v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog B)

Location

20q12

Note


Incidence: 1 - 5%

BCL9 (B-cell CLL/lymphoma 9)

Location

1q21.2

Note

Incidence: Frequent

Both BCL9, IL6R, and MCL1 can be deleted



IL6R (interleukin 6 receptor)

Location

1q21.3

Note

Incidence: Frequent

MCL1 (MCL1, BCL2 family apoptosis regulator)

Location

1q21.2

Note

Incidence: Frequent

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Becker N. Epidemiology of multiple myeloma. Recent Results Cancer Res. 2011;183:25-35

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Kyle RA, Remstein ED, Therneau TM, Dispenzieri A, Kurtin PJ, Hodnefield JM, Larson DR, Plevak MF, Jelinek DF, Fonseca R, Melton LJ 3rd, Rajkumar SV. Clinical course and prognosis of smoldering (asymptomatic) multiple myeloma N Engl J Med 2007 Jun 21;356(25):2582-90

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This article should be referenced as such:

Ho M, Anderson KC, Bianchi G. Multiple Myeloma. Atlas Genet Cytogenet Oncol Haematol. 2017; 21(12):451-463.

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Matthew Ho Zhi Guang, Kenneth C. Anderson, Giada Bianchidocuments.irevues.inist.fr/bitstream/handle/2042/... · This paper is an update of Multiple myeloma in 2004. Clinics and pathology