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Multiple Myeloma

Article in Atlas of Genetics and Cytogenetics in Oncology and Haematology · November 2018
DOI: 10.4267/2042/69009

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 Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL INIST-CNRS

Leukaemia Section
Review

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

patient outcome.
Abstract
Keywords
Multiple Myeloma (MM) is a cancer of plasma multiple myeloma, bone marrow
cells resulting from the abnormal proliferation of microenvironment, monoclonal gammopathy of
malignant plasma cells within the bone marrow undetermined significance
(BM) microenvironment. MM accounts for 1.3% of
all malignancies and 12% of hematologic cancers, Identity
and is the second most commonly diagnosed blood
cancer after non-Hodgkin lymphoma. The hallmark Other names
characteristics of MM include: high levels of intact Plasma cell myeloma, Myelomatosis, Kahler's
monoclonal immunoglobulin or its fragment (free disease
light chain) in serum or urine, and excess Note
monotypic plasma cells in the bone marrow in This paper is an update of Multiple myeloma in
conjunction with evidence of end organ damage 2004.
related to MM: (1) hypercalcemia, (2) renal failure,
(3) anemia, and (4) osteolytic bone lesions or severe
osteopenia, known as CRAB criteria. Even though
Clinics and pathology
novel agents targeting MM cells in the context of Disease
the BM microenvironment such as proteasome MM is a plasma cell cancer which is preceded by
inhibitors, immunomodulatory drugs (IMiDs), and an asymptomatic, premalignant condition called
monoclonal antibodies have significantly prolonged monoclonal gammopathy of undetermined
survival in MM patients, the disease remains significance (MGUS) which then progresses to MM
incurable. A deeper understanding of the molecular or related malignancies with a rate of about 1% per
mechanisms of MM growth, survival, and year (Zingone and Kuehl 2011).
resistance to therapy, such as genomic instability,
clonal heterogeneity and evolution, as well as MM- Phenotype/cell stem origin
BM microenvironmental host immune and other Antigen-selected, post-germinal center, terminally
factors, will provide the framework for differentiated plasma cell (Anderson and Carrasco
development of novel therapies to further improve 2011)

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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/

of the superfamily of tumor necrosis factor, (5)

Etiology
transforming growth factor beta1 (TGFB1), and (6)
Etiology not known. No confirmed predisposing interleukin-10 ( IL10) (Palumbo and Anderson
factors. 2011). Coupled with various genetic changes, these
Possible (unconfirmed and controversial) risk abnormal microenvironmental interactions between
factors include (Sundar Jagannath et al 2016): MM cells and BM cells contribute to aberrant
Environmental factors such as radiation exposure, angiogenesis and MM disease progression
occupational exposure (agricultural, chemical, (Palumbo and Anderson 2011).
metallurgical, rubber plant, pulp, wood, paper), and
chemical exposure (formaldehyde, epichlorohydrin, Epidemiology
Agent orange, hair dyes, paint sprays, asbestos) See table below.
Viral infection: Herpesvirus 8 infection noted in
some patients with MM Clinics
Genetic predisposition The most common presenting symptoms of MM are
The transformation of normal plasma cells into fatigue and bone or back pain. Multiple myeloma
myeloma cells is thought to result from one of two cells typically grow within the BM of the spine,
primary genetic events: either (1) hyperdiploidy or skull, ribs, sternum, pelvis, humeri, and femora,
(2) aberrant class switch recombination (CSR), causing pain, osteopenia, and frequently
likely occurring in the germinal center, leading to pathological fractures (Palumbo and Anderson
MGUS. Secondary cytogenetic abnormalities result 2011).
in the progression of MGUS to SMM, MM, and Myeloma cells typically secrete an excess of a
plasma cell leukemia (PCL) (see below: monoclonal immunoglobulin or its fragments (free
Cytogenetics). MM cells are dependent upon the light chain), which can then be detected in the
BM microenvironment for growth, survival, and patient's serum and/or urine via protein
drug resistance, due both to tumor cell adhesion to electrophoresis and serum free light chain (sFLC)
BM accessory cells and release of growth factors testing, respectively. Immunofixation shows the
and cytokines including (1) interleukin-6 ( IL6), (2) myeloma (M) protein to be monoclonal in nature
vascular endothelial growth factor ( VEGFA), (3) and identifies heavy (IgG/IgA/IgM/IgD, in order of
insulin-like growth factor 1 ( IGF1), (4) members frequency) and light chain ( κ/λ) specific isotype.

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Multiple Myeloma Ho M, et al.

Rarely, MM may be non-secretory and neither a amyloidosis and light-chain deposition disease.
monoclonal Ig nor an excess sFLC can be Anemia-> (A)
identified. The diagnosis of MM is made based on At diagnosis, symptomatic normocytic,
the percentage of bone marrow involvement by normochromic anemia (typically secondary to
clonal MM cells, size of M protein spike, and myelophthisis and hyporegenerative BM) is present
presence/absence of end-organ damage (CRAB) or in approximately 73% of patients. Mean
myeloma-defining biomarkers (Rajkumar, corpuscular volume (MCV) may be macrocytic; an
Dimopoulos et al. 2014). artifact related to rouleaux formation.
CRAB criteria: Bone Disease -> (B)
Hypercalemia -> (C) Up to 58% of patients report bone pain (especially
Up to 20% of newly diagnosed patients have from compression fractures of vertebrae or ribs),
hypercalcemia due to bone destruction. and up to 80% of newly diagnosed patients have
Hypercalcemia is associated with high tumor bony lesions.
burden and requires prompt treatment with The characteristic "punched-out" osteolytic lesions
aggressive hydration and loop diuretic therapy, result from lytic bone destruction that is uncoupled
bisphosphonates, calcitonin, and anti-myeloma from reactive bone formation. MM cells increase
therapy for disease control. the activity of osteoclasts by upregulating osteoclast
Renal Failure -> (R) inducers (i.e. TNFSF11 (RANKL, TRANCE),
Renal dysfunction (anuria or oliguria) resulting CCL3 and CCL4 (MIP-1 alpha /beta), CXCL12
from direct tubular damage by free light chain (SDF-1 alpha), IL1B (IL-1 beta), TNF (TNF-
tubular or glomerular deposition, hypercalcemia, alpha), IL6,) and downregulating TNFRSF11B
dehydration, and nephrotoxic medications (NSAIDs (OPG, decoy receptor for RANKL).
for pain control, IV radiographic contrast, Simultaneously, MM cells suppress osteoblast
bisphosphonates) is present in 20 to 40% of newly differentiation and function (by producing DKK1)
diagnosed patients. resulting in an imbalance favouring bone resorption
Light-chain cast nephropathy is the most common (osteoclast activation) over bone formation
cause of renal failure in MM. Other causes include (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)

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Multiple Myeloma Ho M, et al.

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Multiple Myeloma Ho M, et al.

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

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Multiple Myeloma Ho M, et al.

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 various forms (free, tubular casts, amyloid),

nephrotoxic and are responsible for the most
MM is characterized by the presence of ≥10%
common cause of renal failure in patients with MM.
malignant plasma cells in the bone marrow. MM
Another hallmark feature of MM is the presence of
can be divided into (1/>= secretory MM, (2)
osteolytic bone lesions that results from an
oligosecretory MM (aka light chain MM), and (3)
imbalance favoring bone resorption over bone
non-secretory MM based on whether M-protein is
formation due to increased osteoclast activity and
secreted and detectable (Lonial and Kaufman
reduced osteoblast differentiation and function,
2013). Non-secretory MM accounts for <5% of
secondary to secreted factors from MM cells (Sezer
cases and can be further divided into producer (i.e.
2009). Associated with bone destruction are
patients who have detectable M-protein within MM
complications such as bone pain, pathological
cells but do not secrete M-protein) and non-
fractures, and hypercalcemia. Anemia is another
producer MM (patients who do not have detectable
frequent finding in patients with MM that results
M-protein even within MM cells) (Lonial and
from multiple mechanisms including anemia of
Kaufman 2013). The presence of Bence-Jones
chronic disease, EPO deficiency (secondary to renal
protein (BJP) in the urine indicates the excessive
impairment), myelosuppression from
production of monoclonal light-chain proteins that
chemotherapy, and bone marrow infiltration by
exceeds the re-absorptive ability of the proximal
plasma cells.
tubules. These filtered light-chains are, in their

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

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Multiple Myeloma Ho M, et al.

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)

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Multiple Myeloma Ho M, et al.

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Multiple Myeloma Ho M, et al.

Treatment
Cytogenetics
See tables
(NCCN guidelines version 3.2017) and IMWG Cytogenetics morphological
RESPONSE CRITERIA (Kumar, Paiva et al. 2016) See figures below.
Prognosis
Varies greatly depending on: Genes involved and
-Stage of disease (see above: ISS) proteins
-Cytogenetics (see below: cytogenetics)
-LDH levels (high levels associated with FGFR3 (Fibroblast Growth Factor
extramedullary disease, plasma cell leukemia, Receptor 3)
plasmablastic disease, plasma cell hypoploidy, drug
resistance, and poor outcomes) Location
-Plasma cell labeling index 4p16.3
-C-reactive protein (high levels associated with Note
poor outcomes) Involved in t(4;14)(p16;q32)
-Plasmablastic histology Both FGFR3 and WHSC1 (MMSET) are
-Extramedullary disease implicated in the translocation with IGH
-Age Incidence: 6-12%
Type of treatment available
- Conventional therapy: OS ~3 years; EFS <2 years NSD2 (MMSET)
- High-dose chemotherapy and stem-cell
Location
transplantation: 5-year OS >50%
In general, poor prognosticators include: 4p16.3
-Large tumor burden Note
- Hypercalcemia Involved in t(4;14)(p16;q32)
- High LDH
- Bence-Jones proteinuria CCND1 (B-cell leukemia/lymphoma 1)
- Renal impairment Location
- IgA subtype 11q13.3
- Extramedullary disease at presentation
Note
Genetics Involved in t(11;14)(q13;q32)
Incidence: 15-20%
See figure below.

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Multiple Myeloma Ho M, et al.

Genetics

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Multiple Myeloma Ho M, et al.

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

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Multiple Myeloma Ho M, et al.

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

CCND3 (cyclin D3) MYC v-myc myelocytomatosis viral

Location oncogene homolog (avian)
6p21.1 Location
Note 8q24.21
Involved in t(6;14)(p21;q32) Note
Incidence: 5% Involved in t(8;14)(q24;q32)
Incidence: <10%
MAF (v-maf musculoaponeurotic
fibrosarcoma oncogene homolog MAFB (v-maf avian
(avian)) musculoaponeurotic fibrosarcoma
oncogene homolog B)
Location
Location
16q23.2
20q12
Note
Note
Involved in t(14;16)(q32;q23)
Involved in t(14;20)(q32;q11)
Incidence: 4-10%
Incidence: 1 - 5%
IRF4 (interferon regulatory factor 4) BCL9 (B-cell CLL/lymphoma 9)
Location Location
6p25.3 1q21.2
Note Note
Involved in t(6;14)(p25;q32) Incidence: Frequent
Incidence: 5% Both BCL9, IL6R, and MCL1 can be deleted

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 Multiple Myeloma Ho M, et al.

IL6R (interleukin 6 receptor) Sep;27(9):924-8, 930

Location Morgan GJ, Walker BA, Davies FE. The genetic

architecture of multiple myeloma Nat Rev Cancer 2012
1q21.3 Apr 12;12(5):335-48
Note Palumbo A, Avet-Loiseau H, Oliva S, Lokhorst HM,
Incidence: Frequent Goldschmidt H, Rosinol L, Richardson P, Caltagirone S,
Lahuerta JJ, Facon T, Bringhen S, Gay F, Attal M, Passera
MCL1 (MCL1, BCL2 family apoptosis R, Spencer A, Offidani M, Kumar S, Musto P, Lonial S,
regulator) Petrucci MT, Orlowski RZ, Zamagni E, Morgan G,
Dimopoulos MA, Durie BG, Anderson KC, Sonneveld P,
Location San Miguel J, Cavo M, Rajkumar SV, Moreau P. Revised
1q21.2 International Staging System for Multiple Myeloma: A
Report From International Myeloma Working Group J Clin
Note
Incidence: Frequent
Oncol 2015 Sep 10;33(26):2863-9
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Hajek, R.. Multiple Myeloma - A Quick Reflection on the B, LeLeu X, Zweegman S, Lonial S, Rosinol L, Zamagni E,
Fast Progress Jagannath S, Sezer O, Kristinsson SY, Caers J, Usmani
SZ, Lahuerta JJ, Johnsen HE, Beksac M, Cavo M,
Huang SY, Yao M, Tang JL, Lee WC, Tsay W, Cheng AL, Goldschmidt H, Terpos E, Kyle RA, Anderson KC, Durie
Wang CH, Chen YC, Shen MC, Tien HF. Epidemiology of BG, Miguel JF. International Myeloma Working Group
multiple myeloma in Taiwan: increasing incidence for the updated criteria for the diagnosis of multiple myeloma
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past 25 years and higher prevalence of extramedullary
myeloma in patients younger than 55 years Cancer 2007 Sezer O. Myeloma bone disease: recent advances in
Aug 15;110(4):896-905 biology, diagnosis, and treatment Oncologist 2009
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Kyle RA, Remstein ED, Therneau TM, Dispenzieri A,
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21;356(25):2582-90 This article should be referenced as such:
Lonial S, Kaufman JL. Non-secretory myeloma: a Ho M, Anderson KC, Bianchi G. Multiple Myeloma. Atlas
clinician's guide Oncology (Williston Park) 2013 Genet Cytogenet Oncol Haematol. 2017; 21(12):451-463.

Atlas Genet Cytogenet Oncol Haematol. 2017; 21(12) 463

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