Multiple Myeloma

2017-01-01   Kenneth C. Anderson , Giada Bianchi , Matthew Ho Zhi Guang 

1.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.

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 stem cell 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 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 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
  • 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
  • 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
    Atlas Image
    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
    Atlas Image
    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
    Atlas Image
    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)
    Atlas Image
    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/
    Atlas Image
    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)
    Atlas Image

    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

    Bibliography

    Pubmed IDLast YearTitleAuthors
    212615192011Pathogenesis of myeloma.Anderson KC et al
    215096792011Epidemiology of multiple myeloma.Becker N et al
    175946972007Epidemiology 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
    175820682007Clinical course and prognosis of smoldering (asymptomatic) multiple myeloma.Kyle RA et al
    242829932013Non-secretory myeloma: a clinician's guide.Lonial S et al
    224953212012The genetic architecture of multiple myeloma.Morgan GJ et al
    262402242015Revised International Staging System for Multiple Myeloma: A Report From International Myeloma Working Group.Palumbo A et al
    265173602015Interpretation of cytogenetic results in multiple myeloma for clinical practice.Rajan AM et al
    254396962014International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma.Rajkumar SV et al
    192867612009Myeloma 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