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).
    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 <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.
    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% , Incidence: 15-20% , Incidence: 5% , Incidence: 4-10% , Incidence: 5% , Incidence: <10% , Incidence: 1 - 5% , Both BCL9, IL6R, and MCL1 can be deleted
    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)
    Gene name
    CCND3 (cyclin D3)
    Location
    6p21.1
    Note
    Involved in t(6;14)(p21;q32)
    Gene name
    MAF (v-maf musculoaponeurotic fibrosarcoma oncogene homolog (avian))
    Location
    16q23.2
    Note
    Involved in t(14;16)(q32;q23)
    Gene name
    IRF4 (interferon regulatory factor 4)
    Location
    6p25.3
    Note
    Involved in t(6;14)(p25;q32)
    Gene name
    MYC v-myc myelocytomatosis viral oncogene homolog (avian)
    Location
    8q24.21
    Note
    Involved in t(8;14)(q24;q32)
    Gene name
    MAFB (v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog B)
    Location
    20q12
    Note
    Involved in t(14;20)(q32;q11)
    Gene name
    BCL9 (B-cell CLL/lymphoma 9)
    Location
    1q21.2
    Note
    Incidence: Frequent
    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 , FGFR3/IGH , IRF4/IGH , CCND3/IGH , MYC/IGH , CCND1/IGH , MAF/IGH , 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