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Author: Blue Whale Xiaohu
This article is authorized by the author to be published by Yimaitong, please do not reprint
it without authorization.
Multiple myeloma (MM) accounts for 1% of all cancers and about 10%
of all hematologic malignancies.
The incidence is slightly higher in men than in women, and the median age at diagnosis is about 65 years
.
Unlike metastatic bone tumors, osteolytic lesions caused by MM are not accompanied by new bone formation
.
Osteolytic lesions are the main cause of disability in MM and can be detected using low-dose whole-body computed tomography (WB-CT), fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT), or magnetic resonance imaging (MRI
).
Other major clinical manifestations of MM include anemia, hypercalcaemia, renal failure, and increased
risk of infection.
About 1%~2% of patients have extramedullary lesions (EMD) at the initial diagnosis, and 8% of patients develop EMD
later in the course of the disease.
Evolution of the course of the disease: MGUS→SMM→MM
Almost all patients with MM develop from an asymptomatic precancerous stage, monoclonal gammopathy (MGUS), which is of unknown significance
.
MGUS is seen in about 5% of people
over the age of 50.
MGUS progresses to MM and its associated malignancies
at a rate of 1% per year.
MGUS can progress to a more advanced asymptomatic precancerous stage called smoke-producing multiple myeloma (SMM).
SMM progresses to MM at a rate of about 10% per year for the first 5 years after diagnosis, at a rate of 3% per year over the next 5 years, and at a rate of 1.
5% per year thereafter, with a proportion of progression related to the type of cytogenetics of the disease, t (4; 14) Patients with translocation, del(17p) and gain(1q) are at higher risk of progression from MGUS or SMM to multiple myeloma
.
MM's inspection items
The following surveillance programs are important guides for the diagnosis and molecular typing of MM and related diseases:
When MM is clinically suspected, a combination of assays should be used to detect the presence of M protein, including serum protein electrophoresis (SPEP), serum immunofixation electrophoresis (SIFE), and serum free light chain (FLC).
Bone marrow examination should be performed at initial diagnosis and should include fluorescent in situ hybridization (FISH) probes designed to detect t(11; 14)、t(4; 14)、t(14; 16)、t(6; 14)、t(14; 20) Trisomy and del (17p) to clarify risk stratification
Gene expression profiling provides additional prognostic value
Osteolytic lesions are the main cause of disability in MM: focal osteolytic lesions can be detected using low-dose whole-body computed tomography (WB-CT), fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT), or magnetic resonance imaging (MRI).
Diagnostic criteria for MM
The diagnosis of MM requires the presence of ≥ 1 myeloma-defining event (MDE), i.
e.
, end-organ damage (CRAB), and three specific markers (Table 1),
in addition to bone marrow examination findings ≥ 10% clonal plasma cells or evidence of plasmacytoma confirmed by biopsy.
Patients with MM have an approximately 80% risk of progressing to symptomatic end-organ damage in the presence of any of these markers, and testing these indicators can help diagnose MM and initiate treatment
before end-organ damage occurs.
Table 1.
Myeloma defines events
End Organ Damage (CRAB) | Specific biomarkers |
• Hypercalcaemia (C): serum calcium above the upper limit of normal >0. • Renal insufficiency (R): creatinine clearance < 40 mL/min/1. • Anemia (A): haemoglobin values below the lower limit of normal > 20 g/L, or hemoglobin < 100 g/L • Bone injury (B): CT/PET-CT shows ≥ 1 osteolytic lesion | • Clonal bone marrow plasma cells≥ 60% • Serum free light chain (FLC) ratio≥ 100 (premised: FLC level≥ 100 mg/L) • MRI shows more than one focal lesion |
Patients who meet the diagnostic criteria for MM should be diagnosed with plasma cell leukemia
if the circulating plasma cells on the conventional peripheral blood smear ≥5%.
The latest revised diagnostic criteria for MM and related diseases by the International Myeloma Working Group (IMWG) are shown in Table 2
.
Table 2.
Diagnostic criteria for MM and related diseases
MM typing | Diagnostic criteria |
MGUS | All three criteria must be met: •Blood manifest clonal protein (non-IgM type) < 3 g/dL • Bone marrow clonal plasma cells < 10% a •Absence of end-organ damage associated with plasma cell proliferative disorders, such as hypercalcaemia, renal insufficiency, anemia, and bone disease (CRAB) |
SMM | Two criteria must be met: •Blood list clonal protein (IgG or IgA) ≥3 g/dL or urine monoclonal protein ≥500 mg/24 hours and/or clonal myeloid plasma cells 10%-60% •No myeloma-related events or amyloidosis |
MM | Two criteria must be met: •Bone marrow clonal plasma cells ≥ 10% or biopsy-confirmed bone marrow/extramedullary plasmacytoma • Any one or more of the following MDEs:
|
Plasma cell leukemia | Two criteria must be met: •Meet diagnostic criteria for multiple myeloma •Plasma cells ≥ 5 percent of routine peripheral smear leukocyte differential |
IgM monoclonal gammopathy of unknown significance (IgM MGUS) | All three criteria must be met: •Serum IgM monoclonal protein <3 g/dL •Bone marrow lymphoplasma cell infiltration< 10% •Lack of evidence of anaemia, constitutional symptoms, hyperviscosity, lymphadenopathy, or hepatosplenomegaly attributable to an underlying lymphoproliferative disorder |
Light chain MGUS | All criteria must be met: • Abnormal FLC ratio (< 0. •Elevated levels of affected light chains (elevated κFLC in patients with a FLC ratio > 1. •Immunofixation did not show immunoglobulin heavy chain expression •There is no end-organ damage attributable to plasmacytoproliferative disorders • Bone marrow clonal plasma cells< 10% •Urine monoclonal immunoglobulin < 500 mg/24 hours |
Solitary plasmacytoma | All four criteria must be met •Biopsy-confirmed isolated bone or soft tissue lesions with evidence of clonal plasma cells •Normal bone marrow with no evidence of clonal plasma cells •Normal skeletal examination and MRI/CT of the spine and pelvis (except for primary isolated lesions) •Lack of end-organ damage (CRAB) attributable to lymphoplasmacytic disorders |
Solitary plasmacytoma with mild bone marrow involvement | All four criteria must be met •Biopsy-confirmed isolated bone or soft tissue lesions with evidence of clonal plasma cells • Bone marrow clonal plasma cells< 10% b •Normal skeletal examination and MRI/CT of the spine and pelvis (except for primary isolated lesions) •Absence of end-organ damage (CRAB) attributable to lymphoplasmacytic disorders |
MM molecular classification and prognostic impact
Although MM is still considered a single disease, it is actually a collection of plasma cell malignancies formed by a variety of cytogenetically distinct (Table 3).
Table 3.
The main molecular cytogenetic classification of MM
Cytogenetic subtypes | Affected genes/chromosomes | Approximate percentage in MM |
Hyperdiploid MMA | Recurrent trisomy involving odd chromosomes, with the exception of chromosomes 1, 13, and 21 | 45% |
IgH translocation MM | 40% | |
t (11; 14) (q13; q32) | CCND1 (cyclin D1) | 20% |
t (6; 14) (p21; q32) | CCND3 (cyclin D3) | 5% |
t (4; 14) (p16; q32) | NSD2 | 10% |
t (14; 16) (q32; q23) | C-MAF | 4% |
t (14; 20) (q32; q11) | MAFB | <1% |
Other IgH translocations (other cytogenetic abnormalities, or no abnormalities) | 5% | |
Trisomy (hyperdiploid MM) is present in plasma cells in about 40% of MM patients, and most of the remaining translocations involve immunoglobulin heavy chain (IgH) sites (IgH translocation MM)
on chromosome 14q32.
A small proportion of patients have both trisomy and IgH translocations
.
Trisomy syndrome and IgH translocation are considered primary cytogenetic abnormalities and are present
at the MGUS stage.
Other secondary cytogenetic abnormalities can occur during the course of MM, including gain(1q), del(1p), del(17p), del(13), and secondary translocations
involving MYC.
Both primary and secondary cytogenetic abnormalities can affect disease course, response to treatment, and prognosis
.
Even for the same cytogenetic abnormality, patients have different prognostic effects depending on the stage of disease (Table 4).
Table 4.
Effect of cytogenetic abnormalities on the clinical course and prognosis of MM
Cytogenetic abnormalities | The clinical stage the patient was at when the abnormality was detected | |
SMM | MM | |
Trisomy | Moderate risk of progression with a median TTP of 3 years | Prognosis is good, standard risk MM, median OS 7~10 years |
t (11; 14) (q13; q32) | Standard progression risk, median TTP of 5 years | Prognosis is good, standard risk MM, median OS 7~10 years |
t (6; 14) (p21; q32) | Standard progression risk, median TTP of 5 years | Prognosis is good, standard risk MM, median OS 7~10 years |
t (4; 14) (p16; q32) | High risk of progression, median TTP of 2 years | Intermediate MM with a median OS of 5 years |
t (14; 16) (q32; q23) | Standard progression risk, median TTP of 5 years | High-risk MM, median OS of 3 years |
t (14; 20) (q32; q11) | Standard progression risk, median TTP of 5 years | High-risk MM, median OS of 3 years |
gain (1q21) | High risk of progression, median TTP of 2 years | Intermediate MM with a median OS of 5 years |
del(17p) | High risk of progression, median TTP of 2 years | High-risk MM, median OS of 3 years |
Trisomy + any kind of IgH translocation | Standard progression risk, median TTP of 5 years | May improve poor prognosis and is associated with high-risk IgH translocation and del 17p |
Isolated chromosome 13/14 | Standard progression risk, median TTP of 5 years | The effect on prognosis is unclear |
normal | The risk of progression was low, and the median TTP was 7~10 years | The prognosis is good, which may reflect a lower tumor burden, and the median OS > 7~10 years |
Multiple myeloma: 2022 update on diagnosis, risk stratification, and management.
Am J Hematol.
2022; 97(8):1086-1107.
Reviewed: Quinta Typesetting: Cherry Executive: Moly
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