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 workup includes a full history and physical exam with key diagnostic tests providing definitive diagnosis.[43][44]

History and clinical features

Family history of lymphohematopoietic cancer (particularly MM), male sex, black ethnicity, and exposure to ionizing radiation or petroleum products are associated with a higher risk for MM.[9][10][11]​​[13][14][15][16][17]​​

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

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

Initial laboratory workup

Initial tests to order include a complete blood count with differential and platelet counts, peripheral blood smear, serum blood urea nitrogen (BUN), 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).[43][44]

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][43][44][45][46]

  • 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 nonsecretory MM.[6][47][48]​ With the availability of the serum free light-chain assay, nonsecretory as well as oligosecretory MM can be easily diagnosed.[47][49]​​​ 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.[50]​ 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.[51]

[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@5230551

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][45][46]

Whole-body low-dose CT or FDG-PET/CT is recommended for the initial diagnostic workup for MM.[44][45][46]​​ Whole-body MRI should be considered if CT or FDG-PET/CT is negative or inconclusive, and suspicion remains high for MM.[44][45][46]

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.[46][52][53][54]

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.[55]

FDG-PET/CT and MRI are particularly useful during treatment follow-up as they can detect residual focal lesions and inform prognosis.[56][57][58][59]

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.[44][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@7c51405b[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@6235efd3[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@56e48be6[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@6ed8ce47

Cytogenetic testing

Cytogenetic analysis (e.g., fluorescence in situ hybridization [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.[43][44]

Prognostication and risk stratification

Important prognostic markers include serum beta2-microglobulin, serum albumin, cytogenetic abnormalities, creatinine, BUN, 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.[60]

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.[61] 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.[62][63]​​ See Criteria.

Poor prognosis is associated with:[5][64][65]

  • Increased creatinine and BUN, 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:[44]

  • 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.[66]

  • 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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