Multiple myeloma is diagnosed through a combination of blood tests, urine tests, bone marrow biopsy, and imaging. No single test confirms the disease on its own. Instead, doctors piece together results from several steps, starting with routine bloodwork that may raise suspicion and moving toward more specific tests that confirm the diagnosis and determine how advanced it is.
What Doctors Look for First
The diagnostic process often begins when routine blood tests reveal something unexpected: abnormally high protein levels, low blood counts, elevated calcium, or impaired kidney function. These findings prompt a more targeted workup. The initial round of testing is broad, including a complete blood count, kidney function markers, calcium levels, and specialized protein tests in both blood and urine.
The cornerstone of early detection is a test called serum protein electrophoresis. This separates the proteins in your blood by size and electrical charge, producing a pattern that can reveal an abnormal spike of identical protein, known as an M-protein or M-spike. A sharp, well-defined peak in the gamma region of the results signals that a single clone of plasma cells is producing large quantities of one antibody. In myeloma, this spike is often greater than 3 g/dL, but up to one-fifth of patients have a spike below 1 g/dL, so the size alone doesn’t rule the disease in or out.
Here’s the catch: about 18% of people with multiple myeloma don’t show a visible spike on the blood test at all. Some instead show unusually low levels of normal antibodies (hypogammaglobulinemia), and roughly 10% have no detectable M-protein in the blood. That’s why urine protein electrophoresis is recommended for anyone still suspected of having the disease after a normal-looking blood result. Some myeloma cells produce only light chains, smaller protein fragments that pass into the urine rather than accumulating in the blood. A serum free light chain assay, which measures the ratio of two types of light chains (kappa and lambda), adds another layer of detection.
Bone Marrow Biopsy
Blood and urine tests can flag the abnormal protein, but confirming myeloma requires looking directly at the bone marrow. During a bone marrow biopsy, a needle is inserted into the back of the hip bone to withdraw a small sample of marrow tissue and liquid. The procedure typically takes 15 to 30 minutes and is done under local anesthesia, though you’ll feel pressure and brief sharp pain when the sample is drawn.
Pathologists examine the sample to count the percentage of plasma cells present. Normal bone marrow contains fewer than 5% plasma cells. A count above 10% clonal (identical) plasma cells is the primary threshold for a myeloma diagnosis. If plasma cells reach 60% or higher, that alone qualifies as a myeloma-defining event, meaning treatment is warranted even without other symptoms. A count below 10% with a small M-protein and no organ damage points instead to a precursor condition called MGUS (monoclonal gammopathy of undetermined significance), which requires monitoring but not treatment.
Genetic Testing on Marrow Samples
Once a bone marrow sample is collected, it undergoes genetic analysis using a technique called FISH (fluorescence in situ hybridization). This identifies chromosomal abnormalities in the myeloma cells that influence how aggressively the disease is likely to behave and which treatments work best.
The standard panel checks for several specific changes: deletions on chromosome 17p (which removes a key tumor-suppressing gene), gains on chromosome 1q, deletions on chromosome 1p, and rearrangements involving the immunoglobulin heavy chain gene. When a rearrangement is found, additional testing identifies the specific translocation partner, such as t(4;14), t(11;14), t(14;16), or t(14;20). Some of these, particularly del(17p) and t(4;14), classify the disease as high-risk, which affects treatment planning and expected outcomes. This genetic information doesn’t change whether you have myeloma, but it shapes the strategy for treating it.
Imaging for Bone Damage
Myeloma cells weaken bone by accelerating its breakdown and slowing new bone formation. Detecting this damage is part of the diagnostic criteria and helps determine disease stage. Whole-body low-dose CT is now recommended as the first-line imaging method for assessing bone disease in myeloma. It’s significantly more sensitive than traditional X-ray skeletal surveys at detecting the characteristic “punched-out” holes (lytic lesions) in bone, along with cortical thinning and soft tissue masses growing from bone.
MRI and PET/CT scans are used in specific situations. MRI is particularly good at detecting marrow involvement before bone destruction becomes visible, and finding one or more focal lesions on MRI can itself qualify as a myeloma-defining event. PET/CT combines metabolic and structural information, helping distinguish active disease from old damage. Your doctor will choose the imaging approach based on what the other tests have already revealed.
The CRAB Criteria and Myeloma-Defining Events
To formally diagnose active multiple myeloma that needs treatment, doctors require two things: evidence of clonal plasma cells (above 10% in bone marrow or a confirmed plasmacytoma) plus at least one sign of organ damage or a specific biomarker of malignancy. The signs of organ damage are summarized by the acronym CRAB:
- C (Calcium): Elevated blood calcium, caused by accelerated bone breakdown releasing calcium into the bloodstream
- R (Renal): Kidney impairment, defined as serum creatinine above 2 mg/dL or creatinine clearance below 40 mL/min due to myeloma
- A (Anemia): Low red blood cell count, because myeloma cells crowd out normal blood-producing cells in the marrow
- B (Bone): One or more lytic bone lesions found on imaging
In 2014, the International Myeloma Working Group added three biomarkers that can trigger a diagnosis even before organ damage appears. These myeloma-defining events are: 60% or more clonal plasma cells in the bone marrow, a serum free light chain ratio of 100 or higher (with the involved chain at a certain minimum level), and more than one focal lesion on MRI. The reasoning is that patients meeting any of these thresholds have such a high probability of developing organ damage within two years that early treatment produces better outcomes than waiting.
How Myeloma Differs From Precursor Conditions
Not every abnormal protein in the blood means myeloma. The diagnostic workup also distinguishes between three related conditions that exist on a spectrum:
- MGUS: Fewer than 10% clonal plasma cells in the bone marrow, a relatively small M-protein level, and no CRAB features or myeloma-defining events. Low-risk MGUS is characterized by an M-protein below 1.5 g/dL, IgG type, and a normal free light chain ratio. MGUS progresses to myeloma at a rate of roughly 1% per year and requires regular monitoring.
- Smoldering myeloma: Higher levels of M-protein or plasma cells (10% to 59% in the marrow) but still no organ damage or myeloma-defining events. The risk of progression is higher than MGUS, and monitoring is more frequent.
- Active multiple myeloma: Meets the full diagnostic criteria with CRAB features or myeloma-defining events present. This is the stage that requires treatment.
Staging After Diagnosis
Once myeloma is confirmed, staging determines how advanced it is. The Revised International Staging System (R-ISS) combines blood markers with genetic findings to place patients into one of three stages.
Two blood proteins drive the staging: beta-2 microglobulin (a marker of tumor burden) and albumin (a marker of overall health). Stage I requires beta-2 microglobulin below 3.5 mg/L and albumin at or above 3.5 g/dL, along with standard-risk genetics and normal LDH (a marker of cell turnover). Stage III applies when beta-2 microglobulin reaches 5.5 mg/L or higher, combined with either high-risk chromosomal abnormalities or elevated LDH. Stage II covers everything in between. These stages correlate with prognosis and help guide treatment intensity, with Stage I carrying the most favorable outlook and Stage III indicating more aggressive disease.
The entire diagnostic process, from initial blood tests through biopsy, imaging, and staging, typically unfolds over one to several weeks depending on how quickly results come back and whether additional testing is needed. Understanding each step can make the process feel less overwhelming, since every test serves a clear purpose in building the complete picture.