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
- 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
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 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
Stage | |
I |
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II |
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III |
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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
- 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
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