Diagnostic-first blood test guide
Understand the protein tests that raise suspicion, the blood markers used for staging, and why confirmation still requires bone marrow evaluation.
Start with the direct answerPending physician review. A named MD has not yet been supplied; no medical reviewer is represented in the page schema.
The diagnostic answer first
Blood tests are the primary way multiple myeloma is first suspected. SPEP detects an abnormal M-protein, the serum free light chain assay measures kappa and lambda light chains, and beta-2 microglobulin helps determine stage. A bone marrow biopsy is required to confirm the diagnosis.
Protein-based tests—SPEP, immunofixation, quantitative immunoglobulins and sFLC—look for products made by abnormal plasma cells. A second group, including CBC, calcium, creatinine, albumin, LDH and B2M, assesses organ effects, disease burden and stage.
Galleri® is a different kind of blood test. It uses cfDNA methylation to screen for a multi-cancer signal and is under FDA review. It is not a myeloma test, does not measure M-protein or light chains, and cannot replace diagnostic blood work or biopsy.
A panel, not one result
The International Myeloma Working Group starting panel combines SPEP, serum immunofixation and serum free light chains. Blood and urine tests then clarify the type of protein, disease burden and organ effects.
SPEP separates serum proteins. A monoclonal peak, or M-spike, may reflect MGUS, smoldering myeloma or active myeloma—not diagnosis by itself. Immunofixation identifies the immunoglobulin type, such as IgG, IgA, kappa or lambda.
Measures unbound kappa and lambda chains. Typical ranges are kappa 3.3–19.4 mg/L, lambda 5.7–26.3 mg/L and a ratio of 0.26–1.65, though laboratories differ. Kidney function affects interpretation.
The ratio matters: ≥100 with the involved light chain at least 100 mg/L is an IMWG myeloma-defining event. sFLC can identify light-chain-only disease that may not create an M-spike.
A 24-hour UPEP and urine immunofixation can identify free light chains, historically called Bence Jones proteins. Serum free light chain testing has replaced urine testing for many purposes, although some centers still use both.
B2M rises with plasma-cell burden and is central to the International Staging System. It also rises when kidney function is impaired, so a high result is not a myeloma-specific measure.
CBC looks for anemia and low white cells or platelets. A comprehensive metabolic panel checks calcium, creatinine, BUN and electrolytes. Albumin and LDH inform staging; quantitative IgG, IgA and IgM can reveal suppression of uninvolved immunoglobulins.
An M-spike or abnormal ratio does not establish active cancer. The pattern, quantity, symptoms, kidney function, imaging and percentage of clonal plasma cells in bone marrow determine what the result means.
A continuum, not a binary result
Not every M-protein or abnormal light chain result means active myeloma. MGUS affects about 5% of adults over 70 and progresses at roughly 1% per year overall. Most people with MGUS never develop myeloma.
The benefit–harm question is still open
Iceland's iStopMM study enrolled 80,759 participants to test population MGUS screening and follow-up. Investigators advise against systematic screening until final survival and quality-of-life results are available.
About 54% of the eligible Icelandic population enrolled. Participants were randomized to different disclosure and follow-up strategies. MGUS prevalence rose with age—reported at 2.3% at ages 40–59, 6.2% at 60–79 and 12.9% at 80 or older—and was higher in men.
Enrollment is complete, but definitive benefit and harm data remain pending. No guideline recommends screening asymptomatic, average-risk adults for MGUS or multiple myeloma. Having a measurable precursor does not automatically make population screening beneficial.
A different signal and a different purpose
Galleri analyzes cfDNA methylation to screen for a cancer signal shared by more than 50 cancer types. GRAIL lists plasma cell neoplasm—which includes multiple myeloma—among its pre-specified 12. This does not mean Galleri detects or diagnoses myeloma.
Mechanism: Galleri looks for methylation patterns in cell-free DNA. SPEP measures M-protein, sFLC measures light chains and B2M helps estimate burden. These approaches answer different questions and are complementary, not competing.
Case-control caveat: CCGA3 included people already known to have cancer. Its secondary-reported plasma cell neoplasm result was 72.3% (34/47; 95% CI 58.2–83.1%). Case-control performance can overstate real-world screening performance, and the primary figure remains to be verified before publication.
Prospective evidence: PATHFINDER 2 followed 35,878 adults aged 50 or older without clinical suspicion of cancer. The 69.8% figure combines all 12 pre-specified cancers. There is no published myeloma-only prospective estimate.
MGUS remains unresolved: there is no evidence that Galleri detects MGUS, nor that it can distinguish MGUS from active myeloma. A published review identifies this as an open overdiagnosis concern.
NHS-Galleri produced mixed aggregate results: its primary endpoint was not met, while Stage IV diagnoses fell by more than 20% in rounds two and three. Myeloma is not TNM-staged, so that endpoint does not map cleanly to it. No per-stage plasma cell values are shown here because the available figures are secondary-sourced and unverified.
Blood tests establish stage
The ISS combines beta-2 microglobulin and albumin. The revised system adds LDH and high-risk cytogenetics to improve prognostic stratification.
B2M below 3.5 mg/L and albumin at least 3.5 g/dL.
Results that meet neither Stage I nor Stage III criteria.
B2M at least 5.5 mg/L.
R-ISS incorporates normal versus elevated LDH and cytogenetic risk. High-risk findings include del(17p), t(4;14) and t(14;16). Stage helps estimate prognosis and guide treatment planning; it is not the same as the CRAB criteria used to define organ damage.
The gold standard is in the marrow
A definitive diagnosis requires bone marrow aspiration and biopsy. Blood tests can raise suspicion and characterize proteins, but the marrow establishes the proportion and clonality of plasma cells.
Active myeloma can be diagnosed with at least 10% clonal marrow plasma cells or a biopsy-proven plasmacytoma plus a myeloma-defining event. CRAB captures elevated Calcium, Renal insufficiency, Anemia and Bone lesions.
IMWG criteria also recognize biomarkers that can justify treatment before CRAB injury: marrow plasma cells at least 60%, an involved/uninvolved sFLC ratio at least 100 with adequate involved-chain concentration, or more than one focal MRI lesion. Low-dose whole-body CT, PET/CT or MRI assesses bone disease; FISH identifies prognostic chromosome changes.
Clear answers
Rarely. About 1–2% of myelomas are non-secretory and do not produce detectable M-protein or abnormal light chains. SPEP and sFLC may therefore look normal. Diagnosis then depends on bone marrow biopsy and imaging. There are no data showing that Galleri identifies non-secretory myeloma.
Anemia is the most common finding and is present in about 60–70% of newly diagnosed patients. Platelets and white cells may also be low when plasma cells crowd the marrow. Some people have a normal CBC at diagnosis, so a CBC alone cannot screen for myeloma.
The standard starting panel is SPEP, serum immunofixation and a serum free light chain assay. Together they identify most cases, while no single test is sufficient. SPEP can miss light-chain-only disease, and blood results still require clinical interpretation and often bone marrow biopsy.
MGUS is a precursor condition with M-protein below 3 g/dL, fewer than 10% marrow plasma cells and no myeloma-related organ damage. It progresses at about 1% per year overall, meaning most people with MGUS never develop myeloma.
There is no published evidence that Galleri detects MGUS. Galleri is designed to screen for a cancer signal, not a precursor condition. Because MGUS and myeloma share biological features, whether Galleri may signal in some MGUS cases remains an unresolved research concern.
Predisposition is not detection
Whole genome sequencing does not detect existing myeloma or MGUS and is not part of the diagnostic panel. Although family history can raise risk, no validated single-gene test guides population myeloma screening.
For a suspected case, SPEP, immunofixation, sFLC and a hematology evaluation are the appropriate pathway. A genome cannot replace them, and no guideline recommends genomic testing of unaffected relatives solely for myeloma screening.
See what the $599 genome service includes. For this question, whole genome sequencing adds limited actionable information; Galleri and WGS are optional and answer different questions.
Key sources: Rajkumar et al., Lancet Oncology (2014, IMWG criteria); NCCN Multiple Myeloma Guidelines (2025); Greipp et al., Journal of Clinical Oncology (2005, ISS); Palumbo et al., Journal of Clinical Oncology (2015, R-ISS); Kyle et al., New England Journal of Medicine (2002, MGUS progression); Sigurdardottir et al., Blood (2021, iStopMM); Klein et al., Annals of Oncology (2021, CCGA3 case-control); Schrag et al., Lancet (2023, PATHFINDER); GRAIL PATHFINDER 2 and NHS-Galleri releases (2026); GRAIL HCP performance page; and FDA advisory materials (September 2026). The 72.3% plasma cell neoplasm figure is case-control, secondary-sourced and pending verification against the primary figure.