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).

Antigen-selected, post-germinal center, terminally differentiated plasma cell (Anderson and Carrasco 2011)

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).

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

Plasma Cell Disorder	Definition	Progression rate	Primary progression events
Multiple myeloma (MM)	(1) Clonal bone marrow plasma cells ≥ 10% or (2) Biopsy proven bony or extramedullary plasmacytoma and any one or more of the following myeloma-defining events: End organ damage (CRAB) Hypercalcemia: Ca > 2.75 mmol/L (>11mg/dL) Renal insufficiency: Cr > 177 mol/L (>2mg/dL) Anemia: Hb < 100g/L or >20g/L below normal Bone lesions: One or more osteolytic lesion on skeletal radiography, CT, or PET/CT (if BM <10% clonal plasma cells, more than one bone lesion required to distinguish from solitary plasmacytoma with minimal marrow involvement) Biomarkers of malignancy ≥60% clonal plasma cells on bone marrow examination Serum involved/uninvolved free light chain ratio of 100 or greater, provided the absolute level of the involved light chain is at least 100mg/L More than one focal lesion on MRI ≥5mm in size	NA	Some patients may develop plasma cell leukemia
Smoldering multiple myeloma (SMM)	Both criteria must be met: (1) Serum monoclonal protein (IgG or IgA) ≥30g/L or urinary monoclonal protein ≥500mg per 24h and/or clonal bone marrow plasma cells 10-60% (2) Absence of myeloma defining events or amyloidosis	NA	MM
Non-IgM monoclonal gammopathy of undetermined significance (non-IgM MGUS)	(1) Serum monoclonal protein (non-IgM type) <30 g/L (2) Clonal bone marrow plasma cells <10% (3) Absence of end-organ damage such as hypercalcaemia, renal insufficiency, anaemia, and bone lesions (CRAB) or amyloidosis that can be attributed to the plasma cell proliferative disorder	1% per year	MM, solitary plasmacytoma, immunoglobulin-related amyloidosis (AL, AHL, AH)
IgM monoclonal gammopathy of undetermined significance (IgM MGUS)	(1) Serum IgM monoclonal protein <30 g/L (2) Bone marrow lymphoplasmacytic infiltration <10% (3) No evidence of anaemia, constitutional symptoms, hyperviscosity, lymphadenopathy, hepatosplenomegaly, or other end-organ damage that can be attributed to the underlying lymphoproliferative disorder	1.5% per year	Waldenstrom macroglobulinemia (WM), immunoglobulin-related amyloidosis (AL, AHL, AH
Light-chain monoclonal gammopathy of undetermined significance (Light chain MGUS)	(1) Abnormal FLC ratio (<026 or >165) Increased level of the appropriate involved light chain (increased  κ FLC in patients with ratio >165 and increased λ FLC in patients with ratio <026) (2) No immunoglobulin heavy chain expression on immunofixation Absence of end-organ damage such as hypercalcaemia, renal insufficiency, anaemia, and bone lesions (CRAB) or amyloidosis that can be attributed to the plasma cell proliferative disorder (3) Clonal bone marrow plasma cells <10% (4) Urinary monoclonal protein <500 mg/24 h	0.3% per year	Light chain MM, immunoglobulin light-chain amyloidosis
Solitary plasmacytoma	(1) Biopsy-proven solitary lesion of bone or soft tissue with evidence of clonal plasma cells (2) Normal bone marrow with no evidence of clonal plasma cells Normal skeletal survey and MRI (or CT) of spine and pelvis (except for the primary solitary lesion) (3) Absence of end-organ damage such as hypercalcaemia, renal insufficiency, anaemia, or bone lesions (CRAB) that can be attributed to a lymphoplasma cell proliferative disorder	About 10% within 3 years	MM
Solitary plasmacytoma with minimal marrow involvement	(1) Biopsy-proven solitary lesion of bone or soft tissue with evidence of clonal plasma cells (2) Clonal bone marrow plasma cells <10% Normal skeletal survey and MRI (or CT) of spine and pelvis (except for the primary solitary lesion) (3) Absence of end-organ damage such as hypercalcaemia, renal insufficiency, anaemia, or bone lesions (CRAB) that can be attributed to a lymphoplasma cell proliferative disorder	60% (bone) or 20% (soft tissue) within 3 years	MM
POEMS syndrome	(1) Polyneuropathy (2) Monoclonal plasma cell proliferative disorder (almost always λ) (3) Any one of the following three other major criteria: Sclerotic bone lesions Castlemans disease Elevated levels of VEGFA (4)Any one of the following six minor criteria: Organomegaly (splenomegaly, hepatomegaly, or lymphadenopathy) Extravascular volume overload (oedema, pleural effusion, or ascites) Endocrinopathy (adrenal, thyroid, pituitary, gonadal, parathyroid, pancreatic) Skin changes (hyperpigmentation, hypertrichosis, glomeruloid haemangiomata, plethora, acrocyanosis, flushing, white nails) Papilloedema Thrombocytosis/polycythaemia	NA	NA
Systemic AL amyloidosis	(1) Presence of an amyloid-related systemic syndrome (eg, renal, liver, heart, gastrointestinal tract, or peripheral nerve involvement) (2) Positive amyloid staining by Congo red in any tissue (eg, fat aspirate, bone marrow, or organ biopsy) (3) Evidence that amyloid is light-chain-related established by direct examination of the amyloid using mass spectrometry-based proteomic analysis, or immunoelectronmicroscopy, and (4) Evidence of a monoclonal plasma cell proliferative disorder (serum or urine monoclonal protein, abnormal free light-chain ratio, or clonal plasma cells in the bone marrow)	NA	Some patients might develop MM

Revised International Staging System (R-ISS) (Palumbo, Avet-Loiseau et al. 2015):

	Stage I	Stage II	Stage III
Serum albumin	>3.5g/dL	<3.5 g/dL (and β2-MG<3.5mg/L)	N/A
Serum β2-MG	<3.5mg/L	3.5-5.5mg/L	>5.5mg/L
Serum LDH	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 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 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 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) 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/ 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 (NCCN guidelines version 3.2017) IMWG RESPONSE CRITERIA (Kumar, Paiva et al. 2016) Standard IMWG response criteria Stringent complete response (sCR) Complete response as defined below plus normal FLC ratio and absence of clonal cells in bone marrow biopsy by immunohistochemistry ( κ/λ ratio ≤4:1 or ≥1:2 for  κ and λ patients, respectively, after counting ≥100 plasma cells) 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 Genes Involved and Proteins Gene name 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% Gene name NSD2 (MMSET) Location 4p16.3 Note Involved in t(4;14)(p16;q32) Gene name CCND1 (B-cell leukemia/lymphoma 1) Location 11q13.3 Note Involved in t(11;14)(q13;q32) Note Incidence: 15-20% Gene name CCND3 (cyclin D3) Location 6p21.1 Note Involved in t(6;14)(p21;q32) Note Incidence: 5% Gene name MAF (v-maf musculoaponeurotic fibrosarcoma oncogene homolog (avian)) Location 16q23.2 Note Involved in t(14;16)(q32;q23) Note Incidence: 4-10% Gene name IRF4 (interferon regulatory factor 4) Location 6p25.3 Note Involved in t(6;14)(p25;q32) Note Incidence: 5% Gene name MYC v-myc myelocytomatosis viral oncogene homolog (avian) Location 8q24.21 Note Involved in t(8;14)(q24;q32) Note Incidence: Gene name MAFB (v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog B) Location 20q12 Note Involved in t(14;20)(q32;q11) Note Incidence: 1 - 5% Gene name BCL9 (B-cell CLL/lymphoma 9) Location 1q21.2 Note Incidence: Frequent Note Both BCL9, IL6R, and MCL1 can be deleted Gene name IL6R (interleukin 6 receptor) Location 1q21.3 Note Incidence: Frequent Gene name MCL1 (MCL1, BCL2 family apoptosis regulator) Location 1q21.2 Note Incidence: Frequent Article Bibliography Pubmed ID Last Year Title Authors 21261519 2011 Pathogenesis of myeloma. Anderson KC et al 21509679 2011 Epidemiology of multiple myeloma. Becker N et al 17594697 2007 Epidemiology of multiple myeloma in Taiwan: increasing incidence for the past 25 years and higher prevalence of extramedullary myeloma in patients younger than 55 years. Huang SY et al 17582068 2007 Clinical course and prognosis of smoldering (asymptomatic) multiple myeloma. Kyle RA et al 24282993 2013 Non-secretory myeloma: a clinician's guide. Lonial S et al 22495321 2012 The genetic architecture of multiple myeloma. Morgan GJ et al 26240224 2015 Revised International Staging System for Multiple Myeloma: A Report From International Myeloma Working Group. Palumbo A et al 26517360 2015 Interpretation of cytogenetic results in multiple myeloma for clinical practice. Rajan AM et al 25439696 2014 International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Rajkumar SV et al 19286761 2009 Myeloma bone disease: recent advances in biology, diagnosis, and treatment. Sezer O et al Summary Fusion gene WHSC1/IGH Fusion gene FGFR3/IGH Fusion gene IRF4/IGH Fusion gene CCND3/IGH Fusion gene MYC/IGH Fusion gene CCND1/IGH Fusion gene MAF/IGH Fusion gene MAFB/IGH Note This paper is an update of Multiple myeloma in 2004 Citation Kenneth C. Anderson ; Giada Bianchi ; Matthew Ho Zhi Guang Multiple Myeloma Atlas Genet Cytogenet Oncol Haematol. 2017-01-01 Online version: http://atlasgeneticsoncology.org/haematological/1776/multiple-myeloma External Links OMIM database Cosmic database Genecards database Mitelman database Generate PDF × Please, confirm that you want to generate a PDF file of this page. This may take some seconds once process has started. Then it will be opened automatically. Wait a moment, we are generating the document... Generate PDF Aditional Info × Loading, wait... Close