Multiple%20myeloma Diagnosis

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	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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