Approach

Diagnosis is based on the presence of well-defined criteria that help distinguish MM from other plasma cell neoplasms and B-cell malignancies associated with paraprotein (M-protein) production.[3][4]​​ See Classification.

Initial diagnostic work-up includes a full history and physical examination with key diagnostic tests providing definitive diagnosis.[44][45]

History and clinical features

Family history of lymphohaematopoietic cancer (particularly MM), male sex, black ethnicity, and exposure to ionising radiation or petroleum products are associated with a higher risk for MM.[9][11][12]​​[14][15][16][17][18]

MM is preceded by the asymptomatic premalignant disorder monoclonal gammopathy of undetermined significance (MGUS).

Initial symptoms of MM are usually non-specific (e.g., fatigue, bone pain) and are a result of the end-organ damage caused by myeloma cell infiltration and/or the associated paraproteinaemia. Bone pain (typically localised to the back) and anaemia are the most common presenting features, affecting 60% to 70% of patients.[5][6]​​ Other features include renal insufficiency, hypercalcaemia, and symptoms associated with infection.[5][6][7]

Initial laboratory work-up

Initial tests to order include a full blood count with differential and platelet counts, peripheral blood smear, serum urea, serum creatinine, serum electrolytes (including calcium), serum uric acid, liver function tests (LFTs), serum albumin, C-reactive protein (CRP), serum lactate dehydrogenase (LDH), serum beta2-microglobulin, and N-terminal prohormone of brain natriuretic peptide (NT-proBNP) or BNP (if NT-proBNP is unavailable).[44][45]

These baseline laboratory tests can help guide diagnosis (e.g., by assessing end-organ damage) and inform prognostication and risk stratification.

Diagnostic tests

Tests used to establish a diagnosis include:[3][4][44][45][46][47]

  • Serum quantitative immunoglobulins

  • Serum and urine protein electrophoresis

  • Serum and urine immunofixation

  • Serum free light-chain assay

  • Imaging studies (e.g., whole-body imaging with low-dose computed tomography [CT] scan, 18F-fluorodeoxyglucose-positron emission tomography/CT [FDG-PET/CT], or in some cases magnetic resonance imaging [MRI])

  • Bone marrow evaluation

The vast majority of patients with MM present with an M-protein in the serum and/or urine (on electrophoresis or immunofixation). However, an M-protein is not detectable in 1% to 5% of patients. These patients are defined as having non-secretory MM.[6][48][49]​​​ With the availability of the serum free light-chain assay, non-secretory as well as oligosecretory MM can be easily diagnosed.[48][50]​​​ An M-protein is sometimes seen on serum protein electrophoresis in asymptomatic patients because of increased globulin fractions.

Mass spectrometry may be used as an alternative to immunofixation for the detection of M-proteins.[51]​ Mass spectrometry is more sensitive than immunofixation, and can also assist in distinguishing between therapeutic monoclonal antibodies (administered to a patient) and endogenous M-proteins.[52]

[Figure caption and citation for the preceding image starts]: A: serum protein electrophoresis (SPEP) of normal serum. B: SPEP of multiple myeloma serum showing a monoclonal immunoglobulin (M-protein) in the gamma region. C: densitometry tracing of normal serum (A) showing the 5 zones of the high resolution agarose electrophoresis. D: densitometry tracing of multiple myeloma serum (B) showing a monoclonal spike (M spike)Courtesy of Dr M Murali and the Clinical Immunology Laboratory, Massachusetts General Hospital; used with permission [Citation ends].com.bmj.content.model.Caption@69bc1665

Imaging

Imaging to assess bone disease is essential for diagnosis and guiding treatment, and should be performed in all patients with suspected MM.[3][4][46][47]

Whole-body low-dose CT or FDG-PET/CT is recommended for the initial diagnostic work-up for MM.[45][46][47]​​ Whole-body MRI should be considered if CT or FDG-PET/CT is negative or inconclusive, and suspicion remains high for MM.[45][46][47]

Conventional skeletal survey (radiography) is less sensitive at detecting osteolytic lesions compared with CT, FDG-PET/CT, and MRI, but it may be considered if these advanced imaging modalities are not available.[47][53][54][55]

MRI can detect focal lesions and bone marrow infiltration. It has prognostic value in asymptomatic patients because the presence of small focal lesions (i.e., <5 mm) in these patients is a strong predictor of progression to symptomatic MM.[56]

FDG-PET/CT and MRI are particularly useful during treatment follow-up as they can detect residual focal lesions and inform prognosis.[57][58][59][60]

Bone marrow evaluation

Bone marrow biopsy and aspirate are required to verify the presence of monoclonal plasma cells in the bone marrow, and to confirm the diagnosis of MM.[3][4]

The proportion of clonal bone marrow plasma cells can help to differentiate MM from MGUS. See Classification.

Solitary plasmacytoma, which may progress to MM, is confirmed by the presence of a solitary lesion of bone (or soft tissue) on biopsy, with evidence of clonal plasma cells.[3] Bone marrow is normal and there is no evidence of clonal bone marrow plasma cells. Imaging studies are normal (except for the solitary lesion); there is no end-organ damage.[3]

Immunohistochemistry and flow cytometry may be performed on bone marrow samples to confirm the presence of monoclonal plasma cells and to accurately quantify plasma cell involvement.[45][Figure caption and citation for the preceding image starts]: Bone marrow biopsyCourtesy of Dr Robert Hasserjian, Hematopathology, Massachusetts General Hospital; used with permission [Citation ends].com.bmj.content.model.Caption@3f9557bf

[Figure caption and citation for the preceding image starts]: Bone marrow biopsy after histochemical analysis for kappa light chainCourtesy of Dr Robert Hasserjian, Hematopathology, Massachusetts General Hospital; used with permission [Citation ends].com.bmj.content.model.Caption@524b23e9

[Figure caption and citation for the preceding image starts]: Bone marrow biopsy after histochemical analysis for lambda light chainCourtesy of Dr Robert Hasserjian, Hematopathology, Massachusetts General Hospital; used with permission [Citation ends].com.bmj.content.model.Caption@11baa40f[Figure caption and citation for the preceding image starts]: Aspirate showing plasma cell infiltrateCourtesy of Dr Robert Hasserjian, Hematopathology, Massachusetts General Hospital; used with permission [Citation ends].com.bmj.content.model.Caption@1bee1f3a

Cytogenetic testing

Cytogenetic analysis (e.g., fluorescence in situ hybridisation [FISH]) should be performed on bone marrow samples to identify chromosomal abnormalities considered to increase risk for progression/relapse, for example: del(13q), del(17p), t(4;14), t(11;14), t(14;16), t(14:20), 1q21 gain/amplification, 1p deletion, MYC translocation.[44][45]

Prognostication and risk stratification

Important prognostic markers include serum beta2-microglobulin, serum albumin, cytogenetic abnormalities, creatinine, urea, CRP, serum LDH, and NT-proBNP/BNP.

Serum beta2-microglobulin correlates with clinical stages in the Durie Salmon staging system and is considered the single most important factor for predicting survival.[61]

Serum albumin levels combined with serum beta2-microglobulin levels have been shown to improve prognostic significance, and this forms the basis of the International Staging System (ISS) classification system used to risk-stratify patients with MM.[62]​ See Criteria.

Serum LDH and high-risk cytogenetic abnormalities, such as del(17p), t(4;14), t(14;16), and 1q gain/amplification, have been incorporated into revised versions of the ISS classification system (RISS and R2-ISS) to improve risk stratification and prognostication.[63][64]​ See Criteria.

Poor prognosis is associated with:[5][65][66]

  • Increased creatinine and urea, which indicates renal impairment and is reported in up to 50% of patients

  • Elevated CRP, serum LDH, and NT-proBNP/BNP, indicative of more extensive disease

Additional tests to consider

The following tests may be considered:[45]

  • Single nucleotide polymorphism (SNP) and/or next-generation sequencing (NGS) testing on bone marrow specimens; provides further detail about clonal plasma cell genetics that may inform prognostication and aid minimal residual disease (MRD) testing/monitoring during treatment.[67]

  • Serum viscosity, if hyperviscosity is suspected (particularly those with high levels of M-protein).

  • Screening for hepatitis B and C, HIV, herpes simplex virus, and varicella zoster virus, as clinically indicated.

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