Multiple myeloma is a cancer originating from plasma cells in the bone marrow. These abnormal plasma cells multiply uncontrollably and produce dysfunctional antibodies known as M-proteins. A definitive diagnosis involves a thorough evaluation combining several laboratory, imaging, and tissue examinations. This comprehensive assessment helps clinicians understand the disease extent and formulate a treatment plan.
Initial Laboratory and Urine Tests
The diagnostic process often begins with laboratory tests on blood and urine samples, which can raise initial suspicion. A complete blood count (CBC) routinely measures levels of red blood cells, white blood cells, and platelets. A common finding is anemia, a low red blood cell count, as cancerous plasma cells can crowd out healthy blood-producing cells in the bone marrow.
A blood chemistry panel provides insight into overall organ function and electrolyte balance. This panel checks for elevated calcium levels, known as hypercalcemia, which can result from bone breakdown caused by myeloma cells. It also assesses kidney function by measuring creatinine and blood urea nitrogen (BUN) levels, as kidney impairment is a frequent complication of the disease.
Serum protein electrophoresis (SPEP) detects and quantifies abnormal proteins in the blood. It identifies the “M-protein,” a monoclonal immunoglobulin produced by myeloma cells, appearing as a distinct spike on the electrophoresis graph. The serum free light chain (SFLC) assay measures unbound kappa and lambda light chains, which are components of antibodies, and calculates their ratio. An abnormal ratio, particularly when one type of light chain is significantly elevated, can indicate a plasma cell disorder, even in cases where M-protein is not readily detected by SPEP.
Urine tests identify abnormal protein excretion. A 24-hour urine collection measures the total amount of protein excreted over a full day, specifically looking for Bence-Jones proteins. These are free light chains that are filtered by the kidneys and can indicate the presence and activity of myeloma cells. Urine protein electrophoresis (UPEP) is then performed on this collected sample to specifically identify and quantify these Bence-Jones proteins.
Bone Marrow and Imaging Examinations
Following initial laboratory findings, bone marrow examinations and comprehensive imaging studies are performed to confirm the diagnosis and assess disease impact. A bone marrow aspiration and biopsy is a direct procedure where a small sample of liquid marrow and a solid core of bone are extracted, usually from the hip bone. This sample is then examined under a microscope to determine the percentage of abnormal plasma cells present within the bone marrow. Normal bone marrow contains less than 5% plasma cells, and an increased percentage is a significant indicator of multiple myeloma.
The bone marrow sample is also used for advanced genetic testing, such as fluorescence in situ hybridization (FISH). FISH identifies specific chromosomal abnormalities within the plasma cells that can influence disease prognosis and guide treatment decisions. These genetic changes, such as translocations involving chromosomes 4, 14, and 16, or deletions on chromosome 17, provide insights into the biological behavior of the myeloma.
Imaging studies are crucial for detecting bone damage caused by myeloma cells. Traditionally, a skeletal survey, which involves a series of X-rays of the entire skeleton, was used to identify osteolytic lesions, or “punched-out” holes in the bones. While still utilized, skeletal surveys have limitations, as they may only detect bone destruction once 30% or more of the bone mass is lost.
More sensitive imaging techniques are now frequently employed. Low-dose whole-body computed tomography (CT) scans offer greater detail than X-rays and can detect smaller lytic lesions that might be missed on conventional radiographs. Magnetic resonance imaging (MRI) is particularly effective for visualizing soft tissues and can identify early focal lesions within the bone marrow, as well as plasmacytomas, which are collections of myeloma cells. Positron emission tomography (PET) scans, often combined with CT (PET/CT), are used to assess the metabolic activity of myeloma lesions throughout the body and can help identify both bone and extramedullary disease.
The CRAB and SLiM Diagnostic Criteria
The International Myeloma Working Group (IMWG) has established specific criteria for diagnosing active multiple myeloma, which integrate findings from the various tests. A fundamental requirement for diagnosis is the presence of at least 10% clonal plasma cells in the bone marrow, as determined by a bone marrow biopsy, or a biopsy-proven plasmacytoma. Once this baseline is met, the diagnosis of active multiple myeloma is confirmed if one or more of the “CRAB” criteria or “SLiM” criteria are present.
The CRAB criteria signify end-organ damage directly attributable to the underlying plasma cell disorder, indicating a need for treatment.
C stands for Hypercalcemia: Elevated calcium levels in the blood, defined as a serum calcium level greater than 0.25 mmol/L (1 mg/dL) above the upper limit of normal, or a total serum calcium level exceeding 2.75 mmol/L (11 mg/dL).
R represents Renal insufficiency: Kidney dysfunction, characterized by a creatinine clearance rate below 40 mL per minute or a serum creatinine level greater than 177 micromol/L (2 mg/dL).
A refers to Anemia: Low red blood cell count, diagnosed when the hemoglobin value is more than 20 g/L below the lowest limit of normal for the individual, or when the hemoglobin level falls below 100 g/L.
B denotes Bone lesions: One or more osteolytic lesions observed on skeletal radiography, CT, or PET/CT scans. These are areas of bone destruction caused by the myeloma cells.
In 2014, the IMWG expanded the diagnostic criteria to include three additional biomarkers, known as the SLiM criteria, for patients without overt CRAB symptoms but who are at high risk of rapid progression. These “myeloma-defining events” also warrant treatment.
S signifies Sixty percent (≥60%) clonal plasma cells in the bone marrow. This high percentage of abnormal plasma cells indicates a significant tumor burden even in the absence of other symptoms.
Li represents a Light chain ratio ≥100: An involved-to-uninvolved serum free light chain ratio of 100 or greater, provided the absolute level of the involved free light chain is at least 100 mg/L. This highly skewed ratio indicates excessive production of one type of light chain by the cancerous plasma cells.
M stands for More than one focal lesion on MRI: This criterion applies when magnetic resonance imaging reveals more than one focal lesion, each at least 5 mm in size, in the bone marrow. These lesions represent distinct areas of myeloma infiltration and indicate a more aggressive disease pattern.
Distinguishing From Precursor Conditions
It is important to differentiate active multiple myeloma from precursor conditions, which are less severe forms of plasma cell disorders that may or may not progress to cancer. Monoclonal Gammopathy of Undetermined Significance (MGUS) is a common, non-cancerous condition where a small amount of M-protein is detected in the blood, but there are no symptoms or organ damage. In MGUS, the bone marrow contains less than 10% clonal plasma cells, and the M-protein level in the blood is below 30 g/L, with urinary M-protein less than 500 mg over 24 hours. Individuals with MGUS require regular monitoring rather than immediate treatment, as the risk of progression to multiple myeloma is low, approximately 1% per year.
Smoldering Multiple Myeloma (SMM) represents an intermediate, asymptomatic stage between MGUS and active multiple myeloma. Patients with SMM have higher levels of M-protein in the blood (at least 30 g/L) or urine (at least 500 mg per 24 hours), and/or between 10% and 59% clonal plasma cells in the bone marrow. Despite these elevated markers, individuals with SMM do not exhibit any of the CRAB or SLiM criteria that define active multiple myeloma. SMM carries a higher risk of progression to active myeloma compared to MGUS, with an average annual progression rate of about 10%. Therefore, close observation by a hematologist-oncologist is recommended for patients with SMM, and some high-risk SMM patients may be considered for early intervention in clinical trials.