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.

 

Multiple%20myeloma Diagnosis

Classification

Types of Multiple Myeloma

Smoldering (Asymptomatic) Multiple Myeloma

  • Also called smouldering or indolent myeloma
  • The more advanced premalignant stage next to MGUS and before progression to active multiple myeloma
  • Patient presents symptom-free and 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 with additional biomarker-confirmed events
  • Patient presents with bone pain, nonspecific constitutional symptoms, and 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%, and absence of CRAB criteria or amyloidosis attributable to plasma cell proliferative disorder
  • IgM MGUS: Serum monoclonal protein <3 g/dL, <10% bone marrow lymphoplasmacytic infiltration and 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 and 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%, and 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 and/or 10-59% 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
  • CRAB criteria (≥1 of the following):
    • 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) or 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 (≥1 of the following):
    • ≥60% clonal bone marrow plasma cells
    • Involved/uninvolved serum free light-chain (FLC) ratio ≥100 (involved FLC ≥100 mg/L)
    • >1 focal lesion based on skeletal MRI ≥5 mm in size

Staging

Staging Systems

International Staging System (ISS)

  • A risk stratification algorithm based on serum beta-2 microglobulin level and serum albumin
  • Preferred and most widely used staging system for the determination of prognosis in patients with multiple myeloma
  • The revised ISS (R-ISS) includes the parameters for ISS plus results from serum lactate dehydrogenase (LDH) and FISH measurements
    • This newer staging system can effectively predict the progression-free survival (PFS) and 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 and standard-risk* chromosomal abnormalities by FISH and 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 and either high-risk** chromosomal abnormalities by FISH or serum LDH > the upper limit of normal

Adapted from: National Comprehensive Cancer Network. Multiple myeloma. Version 1.2021. Oct 2020.
*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) and/or translocation t(4;14) and/or translocation t(14;16)


Durie-Salmon Staging System

  • Based on tumor cell mass, hemoglobin concentration, serum calcium level, presence of bone lesions, serum and urinary paraprotein, and 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), and urine immunofixation electrophoresis (UIFE)

Other Laboratory Examinations

  • Complete blood count, with differential and platelet count
  • Peripheral blood smear examination
  • Blood urea nitrogen (BUN)
  • Serum creatinine
  • Creatinine clearance
  • Serum electrolytes
  • Serum calcium
  • Serum uric acid
  • Liver function tests (LFTs)
  • Albumin
  • Lactate dehydrogenase (LDH)
  • Beta-2 microglobulin
  • Single nucleotide polymorphism (SNP) array on bone marrow and/or next-generation sequencing (NGS) panel on bone marrow
    • Help identify additional abnormalities which allows for further categorization and for prognostication

Screening

Bone Marrow Aspiration and Trephine Biopsy (BMAT)

  • Main procedure used to obtain bone marrow specimen for confirmation and quantification of abnormalities in the bone marrow plasma cells using immunophenotyping, cytogenetic studies, and 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 with multiple myeloma is the presence of CD19, CD56, CD38, CD45, κ and λ light chains

Serum Free Light-Chain (FLC) Assay

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

Serum Immunofixation Electrophoresis (SIFE) Test

  • Determines the type of abnormal immunoglobins
  • Done together with SPEP test to measure the amount of abnormal serum Ig present

Serum Protein Electrophoresis (SPEP)

  • Used to identify monoclonal protein (myeloma protein, serum M-protein) used in the diagnosis and clinical response to treatment
  • Determine quantity of monoclonal protein

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, and hypodiploidy

Imaging Procedures

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

Computed Tomography (CT)

  • Used to assess tumor load and for the assessment of symptoms
  • Whole body low-dose CT (WBLD-CT) is the preferred imaging modality for the detection and for baseline assessment of bone involvement
    • Statistically significantly superior in terms of sensitivity compared to conventional skeletal survey for the detection of osteolytic lesions, with shorter procedure time and better positional comfort
      • Superior to skeletal survey for detection of lesions in areas that are difficult to visualize such as ribs and skull
    • Recommended for patients with suspected high-risk non-IgM MGUS

Magnetic Resonance Imaging (MRI)

  • Should be considered for patients with negative results on skeletal survey and those with possible spinal cord compression and other central nervous system involvement
  • Preferred modality for patients with newly diagnosed solitary bone plasmacytoma
  • Used to distinguish smoldering myeloma from multiple myeloma if WBLD-CT or PET/CT is negative
  • Whole body MRI is preferred but may be limited to the spine and pelvis if not possible
    • Recommended for patients negative on WBLD-CT and without any other myeloma-defining signs and symptoms 
    • Spinal and 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 and no symptoms of end-organ damage

Positron Emission Tomography with CT (PET-CT)

  • Used to evaluate bone lesions that cannot be confirmed with plain CT or MRI imaging
    • Superior to MRI when assessing focal lesion viability
  • Preferred modality for patients suspected to have extramedullary disease and as baseline imaging for treatment response assessment
  • May be used for the early detection of bone marrow involvement in patients with solitary plasmacytoma

Skeletal Survey

  • Imaging modality option used for the determination of lytic lesions
    • Inferior to whole body low-dose CT (WBLD-CT) and should not be used for the initial evaluation of bone disease in multiple myeloma
  • Should include the spine, pelvis, skull, humeri and femurs
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