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Multiple Myeloma in 2017

Written2017-01Matthew 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. matthew_ho@dfci.harvard.edu; kenneth_anderson@dfci.harvard.edu; giada_bianchi@dfci.harvard.edu

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.

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Identity

ICD-Topo C420,C421,C424,C41.0, C41.2, C41.3, C41.4, C41.9, C49.3b
ICD-Morpho 9732/3 Plasma cell myeloma / Multiple myeloma
Atlas_Id 1776
Note This paper is an update of Multiple myeloma in 2004
Other namesPlasma cell myeloma, Myelomatosis, Kahler's disease

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)
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
    Incidence114,000 (global); 33,330; 6.5 per 100,000 persons (US)
    Prevalence230,000 (global); 95,688 (US)
    5-year overall survival48.5% (US)
    Median age at diagnosis70 years old (37% of patients younger than 65 years; 26% between ages 65-74; 37% are 75 years or older) (Palumbo and Anderson 2011)
    Ethnicitytwice as common in African Americans as in Caucasian population  US) (Waxman, Mink et al. 2010), low in ethnic Chinese (TW) (Huang, Yao et al. 2007)
    GenderMen affected more frequently than women (1.6:1 ratio)
    Geographicalhighest in industrialized regions of Australia/New Zealand, Europe, and North America (Becker 2011)
    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. 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 DefinitionProgression ratePrimary 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
  • NASome 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
    NAMM
    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 yearMM, 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 yearWaldenstrom 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 yearLight 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 yearsMM
    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 yearsMM
    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
  • Castleman's 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
  • NANA
    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)
    NASome patients might develop MM

    Revised International Staging System (R-ISS) (Palumbo, Avet-Loiseau et al. 2015):
      Stage I Stage IIStage III
    Serum albumin>3.5g/dL<3.5 g/dL (and β2-MG<3.5mg/L)N/A
    Serum β2-MG<3.5mg/L3.5-5.5mg/L>5.5mg/L
    Serum LDH<=; upper limit of normalNot R-ISS stage I or II> upper limit of normal
    iFISHStandard-risk chromosomal abnormalities*Not R-ISS stage I or IIHigh-risk chromosomal abnormalities*
    Median Survival62 months44 months29 months

    *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)
     
    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 <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.
     
    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)
    Complete response (CR)Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and <5% plasma cells in bone marrow aspirates
    Very good partial response(VGPR)Serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum M-protein plus urine M-protein level <100 mg per 24 h
    Partial response (PR)≥50% reduction of serum M-protein plus reduction in 24 h urinary M-protein by ≥90% or to <200 mg per 24 h; If the serum and urine M-protein are unmeasurable, a ≥50% decrease in the difference between involved and uninvolved FLC levels is required in place of the M-protein criteria; If serum and urine M-protein are unmeasurable, and serum-free light assay is also unmeasurable, ≥50% reduction in plasma cells is required in place of M-protein, provided baseline bone marrow plasma-cell percentage was ≥30%. In addition to these criteria, if present at baseline, a ≥50% reduction in the size (SPD) of soft tissue plasmacytomas is also required
    Minimal response (MR)≥25% but ≤49% reduction of serum M-protein and reduction in 24-h urine M-protein by 50-89%. In addition to the above listed criteria, if present at baseline, a ≥50% reduction in the size (SPD) of soft tissue plasmacytomas is also required
    Stable disease (SD)Not recommended for use as an indicator of response; stability of disease is best described by providing the time-to-progression estimates. Not meeting criteria for complete response, very good partial response, partial response, minimal response, or progressive disease
    Progressive diseaseAny one or more of the following criteria:
    (1) Increase of 25% from lowest confirmed response value in one or more of the following criteria:
  • Serum M-protein (absolute increase must be ≥05 g/dL);
  • Serum M-protein increase ≥1 g/dL, if the lowest M component was ≥5 g/dL;
  • Urine M-protein (absolute increase must be ≥200 mg/24 h);
  • In patients without measurable serum and urine M-protein levels, the difference between involved and uninvolved FLC levels (absolute increase must be >10 mg/dL);
  • In patients without measurable serum and urine M-protein levels and without measurable involved FLC levels, bone marrow plasma-cell percentage irrespective of baseline status (absolute increase must be ≥10%);

    (2) Appearance of a new lesion(s),
  • ≥50% increase from nadir in SPD of >1 lesion, or ≥50% increase in the longest diameter of a previous lesion >1 cm in short axis;
  • ≥50% increase in circulating plasma cells (minimum of 200 cells per μL) if this is the only measure of disease
  • Clinical relapseClinical relapse requires one or more of the following criteria:
  • Direct indicators of increasing disease and/or end organ dysfunction (CRAB features) related to the underlying clonal plasma-cell proliferative disorder. It is not used in calculation of time to progression or progression-free survival but is listed as something that can be reported optionally or for use in clinical practice;
  • Development of new soft tissue plasmacytomas or bone lesions (osteoporotic fractures do not constitute progression);
  • Definite increase in the size of existing plasmacytomas or bone lesions. A definite increase is defined as a 50% (and ≥1 cm) increase as measured serially by the SPD of the measurable lesion; Hypercalcaemia (>11 mg/dL);
  • Decrease in haemoglobin of ≥2 g/dL not related to therapy or other non-myeloma-related conditions;
  • Rise in serum creatinine by 2 mg/dL or more from the start of the therapy and attributable to myeloma;
  • Hyperviscosity related to serum paraprotein
  • Relapse from complete response (to be used only if the end point is disease-free survival)Any one or more of the following criteria:
  • Reappearance of serum or urine M-protein by immunofixation or electrophoresis;
  • Development of ≥5% plasma cells in the bone marrow;
  • Appearance of any other sign of progression (ie, new plasmacytoma, lytic bone lesion, or hypercalcaemia see above)
  • IMWG MRD criteria (requires a complete response as defined above)
    Sustained MRD-negativeMRD negativity in the marrow (NGF or NGS, or both) and by imaging as defined below, confirmed minimum of 1 year apart. Subsequent evaluations can be used to further specify the duration of negativity (eg, MRD-negative at 5 years)
    Flow MRD-negativeAbsence of phenotypically aberrant clonal plasma cells by NGFç on bone marrow aspirates using the EuroFlow standard operation procedure for MRD detection in multiple myeloma (or validated equivalent method) with a minimum sensitivity of 1 in 105 nucleated cells or higher
    Sequencing MRD-negativeAbsence of clonal plasma cells by NGS on bone marrow aspirate in which presence of a clone is defined as less than two identical sequencing reads obtained after DNA sequencing of bone marrow aspirates using the LymphoSIGHT platform (or validated equivalent method) with a minimum sensitivity of 1 in 105 nucleated cells or higher
    Imaging plus MRD-negativeMRD negativity as defined by NGF or NGS plus disappearance of every area of increased tracer uptake found at baseline or a preceding PET/CT or decrease to less mediastinal blood pool SUV or decrease to less than that of surrounding normal tissue
    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

    Cytogenetics

    Cytogenetics Morphological Primary Cytogenetic Abnormalities
    (Normal plasma cell --> MGUS/SMM)

    AbnormalityGene(s)/chromosomes affected Frequency (%)Clinical Interpretation in SMMClinical Interpretation in MM
    Hyperdiploidy : Trisomy(ies) without IgH abnormalityTrisomy of odd-numbered chromosomes (but not chromosomes 1, 13, 21)4Progression risk: Intermediate
    Median TTP: 3 years
    Prognosis: Good
    Risk Stratification: Standard
    Median OS: 7-10 years
    Associated with: High incidence of MM bone disease at diagnosis
    Treatment recommendation: Highly responsive to revlimid-based therapy
    IgH-translocations 30  
    t(11;14) CCND115Progression risk: Standard
    Median TTP: 5 years
    Prognosis: Good
    Risk Stratification: Standard
    Median OS: 7-10 years
    t(4;14)FGFR-3 and MMSET6Progression risk: High
    Median TTP: 2 years
    Prognosis: Poor
    Risk Stratification: Intermediate
    Median OS: 5 years
    Associated with: Less bone disease
    Treatment recommendations: Induction with velcade-based therapy + early ASCT (if eligible), consolidation/maintenance with velcade-based therapy
    t(14;16)C-MAF4Progression risk: Standard
    Median TTP: 5 years
    Median OS: 3 years
    Risk Stratification: High
    Associated with: High levels of FLC and high rate of kidney damage
    t(14;20) MAFB<1Progression risk: Standard
    Median TTP: 5 years
    Risk Stratification: High
    Median OS: 3 years)
    Other IgH translocationsCCND3 in t(6;14) MM5Progression risk: Standard
    Median TTP: 5 years
    Prognosis: Good
    Risk Stratification: Standard
    Median OS: 7-10 years
    IgH translocations with trisomy(ies)Trisomy + any one of recurrent IgH translocations in same patient/TD>15Progression risk: Standard
    Median TTP: 5 years
    May improve prognosis in patients with high-risk IgH translocations and del 17p
    Isolated monosomy 14Few cases may represent 14q32 translocations involving unknown partner chromosomes4.5Progression risk: Standard
    Median TTP: 5 years
    Effect on prognosis unclear
    Other cytogenetic abnormalities in absence of (1) IgH translocations, (2) trisomy(ies), or (3) monosomy 14 5.5  
    NormalNA3Progression risk: Low
    Median TTP: 7-10 years
    Prognosis: Good
    Median OS: >7-10 years

    Ref : Rajan and Rajkumar (2015)

    Secondary Cytogenetic Abnormalities
    (MGUS/SMM --> MM --> RR MM, PCL)

    AbnormalityGene(s) affectedFrequency (%)
    Gain  
    1qCKS1B and ANP32E40
    12pLTBR 
    17qNIK 
    Deletions  
    1pCDKN2C, FAF1, and FAM46C30
    6q 33
    8p 25
    11qBIRC2 and BIRC37
    13RB1 and DIS345
    14qTRAF338
    16qCYLD and WWOX35
    17pTP538
    Translocations  
    t(8;14)MYC<10
    t(4;14)FGFR3 and MMSET6
    t(14;16)C-MAF4
    t(14;20)MAFB<1
    Other non-IGH@ translocations  

    Ref : Morgan, Walker et al. (2012)

    Genes involved and Proteins

    Gene Name FGFR3
    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 WHSC1
    Location 4p16.3
    Note Involved in t(4;14)(p16;q32)
    Gene Name CCND1
    Location 11q13
    Note Involved in t(11;14)(q13;q32)
    Incidence: 15-20%
    Gene Name CCND3
    Location 6p21
    Note Involved in t(6;14)(p21;q32)
    Incidence: 5%
    Gene Name MAF
    Location 16q23
    Note Involved in t(14;16)(q32;q23)
    Incidence: 4-10%
    Gene Name IRF4
    Location 6p25
    Note Involved in t(6;14)(p25;q32)
    Incidence: 5%
    Gene Name MYC
    Location 8q24
    Note Involved in t(8;14)(q24;q32)
    Incidence: <10%
    Gene Name MAFB
    Location 20q11
    Note Involved in t(14;20)(q32;q11)
    Incidence: 1 - 5%
    Gene Name BCL9
    Location 1q21-34
    Note Incidence: Frequent
    Both BCL9, IL6R, and MCL1 can be deleted
    Gene Name IL6R
    Location 1q21-34
    Note Incidence: Frequent
    Gene Name MCL1
    Location 1q21-34
    Note Incidence: Frequent

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    Palumbo A, Avet-Loiseau H, Oliva S, Lokhorst HM, Goldschmidt H, Rosinol L, Richardson P, Caltagirone S, Lahuerta JJ, Facon T, Bringhen S, Gay F, Attal M, Passera R, Spencer A, Offidani M, Kumar S, Musto P, Lonial S, Petrucci MT, Orlowski RZ, Zamagni E, Morgan G, Dimopoulos MA, Durie BG, Anderson KC, Sonneveld P, San Miguel J, Cavo M, Rajkumar SV, Moreau P
    J Clin Oncol 2015 Sep 10;33(26):2863-9
    PMID 26240224
     
    Interpretation of cytogenetic results in multiple myeloma for clinical practice
    Rajan AM, Rajkumar SV
    Blood Cancer J 2015 Oct 30;5:e365
    PMID 26517360
     
    International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma
    Rajkumar SV, Dimopoulos MA, Palumbo A, Blade J, Merlini G, Mateos MV, Kumar S, Hillengass J, Kastritis E, Richardson P, Landgren O, Paiva B, Dispenzieri A, Weiss B, LeLeu X, Zweegman S, Lonial S, Rosinol L, Zamagni E, Jagannath S, Sezer O, Kristinsson SY, Caers J, Usmani SZ, Lahuerta JJ, Johnsen HE, Beksac M, Cavo M, Goldschmidt H, Terpos E, Kyle RA, Anderson KC, Durie BG, Miguel JF
    Lancet Oncol 2014 Nov;15(12):e538-48
    PMID 25439696
     
    Myeloma bone disease: recent advances in biology, diagnosis, and treatment
    Sezer O
    Oncologist 2009 Mar;14(3):276-83
    PMID 19286761
     
    Multiple Myeloma and Other Plasma Cell Dyscrasias
    Sundar Jagannath, Paul G. Richardson, Nikhil C. Munshi
    Cancer Network
     

    Citation

    This paper should be referenced as such :
    Ho M, Anderson KC, Bianchi G
    Multiple Myeloma in 2017;
    Atlas Genet Cytogenet Oncol Haematol. in press
    On line version : http://AtlasGeneticsOncology.org/Anomalies/MultipleMyelomaID1776.html


    Translocations implicated (Data extracted from papers in the Atlas)

     t(4;14)(p16;q32) WHSC1/IGH
     t(4;14)(p16;q32) FGFR3/IGH
     t(6;14)(p25;q32) IRF4/IGH
     t(6;14)(p21;q32) CCND3/IGH
     t(8;14)(q24;q32) MYC/IGH
     t(11;14)(q13;q32) CCND1/IGH
     t(14;16)(q32;q23) MAF/IGH
     t(14;20)(q32;q11) MAFB/IGH

    External links

    Mitelman databaset(4;14)(p16;q32) [Case List]    t(4;14)(p16;q32) [Association List] Mitelman database (CGAP - NCBI)
    Mitelman databaset(4;14)(p16;q32) [Case List]    t(4;14)(p16;q32) [Association List] Mitelman database (CGAP - NCBI)
    Mitelman databaset(6;14)(p25;q32) [Case List]    t(6;14)(p25;q32) [Association List] Mitelman database (CGAP - NCBI)
    Mitelman databaset(6;14)(p21;q32) [Case List]    t(6;14)(p21;q32) [Association List] Mitelman database (CGAP - NCBI)
    Mitelman databaset(8;14)(q24;q32) [Case List]    t(8;14)(q24;q32) [Association List] Mitelman database (CGAP - NCBI)
    Mitelman databaset(11;14)(q13;q32) [Case List]    t(11;14)(q13;q32) [Association List] Mitelman database (CGAP - NCBI)
    Mitelman databaset(14;16)(q32;q23) [Case List]    t(14;16)(q32;q23) [Association List] Mitelman database (CGAP - NCBI)
    Mitelman databaset(14;20)(q32;q11) [Case List]    t(14;20)(q32;q11) [Association List] Mitelman database (CGAP - NCBI)
    arrayMapMorph ( 9732/3) - arrayMap (UZH-SIB Zurich)  [auto + random 100 samples .. if exist ]   [tabulated segments]
     
     
    Disease databaseMultiple Myeloma in 2017
    REVIEW articlesautomatic search in PubMed
    Last year articlesautomatic search in PubMed
    All articlesautomatic search in PubMed


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    indexed on : Tue Mar 14 13:54:07 CET 2017


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