multiple%20myeloma
MULTIPLE MYELOMA

Multiple myeloma is a bone marrow disease characterized by the presence of malignant plasma cells, & abnormal serum &/or urine immunoglobulin secondary to clonal plasma cell expansion.

It accounts for 1-2% of all cancers worldwide & mostly affects patients at ages 65-74 years old.

Patient usually presents with bone pain & nonspecific symptoms, or due to abnormalities in laboratory exams.

 

Classification

Types of Multiple Myeloma

Smoldering (Asymptomatic) Multiple Myeloma

  • Also called smouldering or indolent myeloma
  • The more advanced premalignant stage next to MGUS & before progression to active multiple myeloma
  • Patient presents symptom-free & without any end-organ impairment; usually diagnosed based on laboratory findings
  • Progression rate of 10% per year within the first 5 years after confirmed diagnosis

Active (Symptomatic) Multiple Myeloma

  • The symptomatic form of multiple myeloma w/ additional biomarker-confirmed events
  • Patient presents w/ bone pain, nonspecific constitutional symptoms, & other symptoms related to end-organ damage

Evaluation

Definition of Monoclonal Gammopathy of Undetermined Significance (MGUS)

  • Non-IgM MGUS: Serum monoclonal protein <3 g/dL, clonal bone marrow plasma cells <10%, & absence of CRAB criteria or amyloidosis attributable to plasma cell proliferative disorder
  • IgM MGUS: Serum monoclonal protein <3 g/dL, & absence of anemia, constitutional symptoms, hyperviscosity, lymphadenopathy, hepatosplenomegaly, or other end-organ damage attributable to plasma cell proliferative disorder
  • Light-chain MGUS: Increased κ FLC ratio of >1.65 & increased λ FLC ratio of <0.26, Ig heavy chain expression absent on immunofixation, absence of CRAB criteria or amyloidosis attributable to plasma cell proliferative disorder, clonal bone marrow plasma cells <10%, & urinary monoclonal protein <500 mg/24 hours

Diagnostic Criteria for Smoldering Myeloma

  • Presence of both of the following:
    • Serum monoclonal protein ≥3 g/dL or Bence-Jones protein ≥500 mg/24 hours &/or 10-60% clonal bone marrow plasma cells
    • Absence of myeloma-defining events (CRAB criteria) or amyloidosis

Diagnostic Criteria for Active Multiple Myeloma

  • ≥10% clonal bone marrow plasma cells or biopsy-proven bony or extramedullary plasmacytoma plus
  • One or more of the following:
    • CRAB criteria:
      • Elevated Calcium levels [>0.25 mmol/L (>1 mg/dL) higher than the upper limit of normal or >2.75 mmol/L (>11 mg/dL)
      • Renal insufficiency [serum creatinine >2 mg/dL (>177 μmol/L); creatinine clearance <40 mL/min]
      • Anemia (hemoglobin <10 g/dL or hemoglobin >2 g/dL below the lower limit of normal)
        ≥1 osteolytic Bone lesion/s on skeletal radiography, CT scan or PET/CT
    • Biomarkers:
      • ≥60% clonal bone marrow plasma cells
      • Serum free light-chain (FLC) ratio ≥100
      • >1 focal lesion on MRI (each lesion ≥5 mm)

Staging

Staging Systems

International Staging System (ISS)

  • A risk stratification algorithm based on serum beta-2 microglobulin level & serum albumin
  • Preferred & most widely used staging system for the determination of prognosis in patients w/ multiple myeloma
  • The revised ISS (R-ISS) includes the parameters for ISS plus results from serum lactate dehydrogenase (LDH) & FISH measurements
    • This newer staging system can effectively predict the progression-free survival (PFS) & overall survival (OS) rates in multiple myeloma patients
Stage ISS R-ISS
I Serum beta-2 microglobulin <3.5 mg/L, serum albumin ≥3.5 g/dL ISS Stage I & standard-risk* chromosomal abnormalities by FISH & serum LDH ≤ the upper limit of normal
II Not ISS Stage I or III Not R-ISS stage I or III
III Serum beta-2 microglobulin ≥5.5 mg/L ISS Stage III & either high-risk** chromosomal abnormalities by FISH or serum LDH more than the upper limit of normal

Adapted from: National Comprehensive Cancer Network. Multiple myeloma. Version 4.2018. Feb 2018.
*Standard-risk findings by FISH defined as absence of any high-risk chromosomal abnormality
**High-risk findings by FISH includes the presence of del(17p) &/or translocation t(4;14) &/or translocation t(14;16)


Durie-Salmon Staging System

  • Based on tumor cell mass, hemoglobin concentration, serum calcium level, presence of bone lesions, serum & urinary paraprotein, & kidney function
Stage
I
    All of the following must be present:
  • Hgb >10 g/dL
  • Low serum paraprotein production rate: IgG <5 g/dL or IgA <3 g/dL
  • Serum calcium within normal limits or ≤12 mg/dL
  • Urinary light chains <4 g/day
  • Imaging studies negative for lytic bone lesions
II
    Not Durie-Salmon stage I or III
III
    Any of the following may be present:
  • Hgb <8.5 g/dL
  • High serum paraprotein production rate: IgG >7 g/dL or IgA >5 g/dL
  • Serum calcium >12 mg/dL (>3 μmol/L)
  • Urinary light chains >12 g/day
  • >3 lytic bone lesions in imaging studies

Physical Examination

  • Patients usually have no obvious abnormalities upon examination
  • Pallor (due to anemia)

Laboratory Tests

Urinalysis

  • Should include 24-hour urine analysis for total protein, urine protein electrophoresis (UPEP), & urine immunofixation electrophoresis (UIFE)

Other Laboratory Examinations

  • Complete blood count, w/ differential & platelet count
  • Peripheral blood smear examination
  • Blood urea nitrogen (BUN)
  • Serum creatinine
  • Serum electrolytes
  • Serum calcium
  • Albumin
  • Lactate dehydrogenase (LDH)
  • Beta-2 microglobulin

Screening

Serum Free Light-Chain (FLC) Assay

  • Quantifies serum κ & λ light immunoglobulin chains unbound to heavy chains
  • Abnormal FLC ratio is present in 90% of patients w/ multiple myeloma
  • Used in screening for plasma cell abnormalities, especially for the detection of MGUS, smoldering myeloma, active myeloma, immunoglobulin light-chain amyloidosis, & solitary plasmacytoma
  • Used alongside serum protein electrophoresis (SPEP) & serum immunofixation electrophoresis (SIFE)
  • Also used for the assessment of prognosis, quantitative monitoring of patients w/ light-chain amyloidosis & oligosecretory myeloma
    • Normal FLC ratio is a required criteria for stringent complete response

Bone Marrow Aspiration & Biopsy w/ Trephine

  • Main procedure used to obtain bone marrow specimen for confirmation & quantification of abnormalities in the bone marrow plasma cells using immunophenotyping, cytogenetic studies, & FISH

Immunophenotyping

  • Eg immunohistochemical staining, immunofluorescent studies, flow cytometry
  • Used to detect the presence of either λ or κ chains in bone marrow plasma cell cytoplasm
  • Distinguishing feature in patients w/ multiple myeloma is the presence of CD19, CD56, CD38, CD45, κ & λ light chains

Serum Immunofixation (IFX) Test

  • Detemines the type of abnormal immunoglobins
  • Done together w/ serum protein electrophoresis (SPEP) test to measure the amount of abnormal serum Ig present

Cytogenetic Studies

Fluorescence in situ Hybridization (FISH)

  • Uses the specimen obtained in bone marrow aspiration for detection of chromosomal abnormalities
    • Chromosomal aberrations identified in multiple myeloma patients include del17p13, IGH gene rearrangement at 14q32, 14q32 translocations [t(11;14)(q13;q32), t(4;14)(p16;q32), t(14;16)(q32;q23), t(14;20)(q32;q12)], chromosome 1 abnormalities 
  • Also used for evaluation of disease prognosis

Karyotyping (Conventional Cytogenetics)

  • Used to detect the presence of chromosomal abnormalities including 13q14 deletion, chromosome 13 monosomy, & hypodiploidy

Imaging

Imaging Procedures

  • The International Myeloma Working Group (IMWG) recommends at least one imaging modality to be done in patients w/ smoldering multiple myeloma, depending on availability & cost

Computed Tomography (CT)

  • Used to assess tumor load & for the assessment of symptoms
  • Whole body low-dose CT (WBLD-CT) is the preferred imaging modality for the detection & for baseline assessment of bone involvement

Magnetic Resonance Imaging (MRI)

  • Should be considered for patients w/ possible spinal cord compression & other central nervous system involvement
  • Whole body MRI is preferred but may limit to the spine & pelvis if not possible
    • Spinal & pelvic MRI is recommended if focal bone marrow lesion is highly likely 
  • Preferred in patients suspected to have smoldering multiple myeloma if without bone lesions on CT & no symptoms of end-organ damage

Positron Emission Tomography w/ CT (PET-CT)

  • Used to evaluate bone lesions
  • Preferred modality for patients suspected to have extramedullary disease outside of the spine
  • May be used for the early detection of bone marrow involvement in patients w/ solitary plasmacytoma
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