Multiple%20myeloma Diagnosis

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

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
• Patients with ≥2 of the following risk factors are considered to have high risk of progression to multiple myeloma:
  • Bone marrow plasma cells >20%
  • M-protein >2 g/dL
  • Free light-chain (FLC) ratio >20

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 (Hgb) <10 g/dL or Hgb >2 g/dL below the lower limit of normal]
  • ≥1 osteolytic Bone lesion/s on skeletal radiography, CT scan or fluorodeoxyglucose (FDG) PET/CT
• Biomarkers (≥1 of the following):
  
  • ≥60% clonal bone marrow plasma cells
  • Involved/uninvolved serum FLC ratio ≥100 (involved FLC ≥100 mg/L)
  • >1 focal lesion based on skeletal MRI ≥5 mm in size

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

Adapted from: National Comprehensive Cancer Network. Multiple myeloma. Version 4.2022. Dec 2021.
*Standard-risk findings by FISH defined as absence of any high-risk chromosomal abnormality
**High-risk findings by FISH include 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 (Hgb) concentration, serum calcium level, presence of bone lesions, serum and urinary paraprotein, and kidney function

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

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

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

• 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