Clinical Guide to Biomarkers in Multiple Myeloma

Multiple myeloma is a cancer of plasma cells, the antibody-producing specialists in your bone marrow. Biomarkers are the fingerprints this disease leaves behind in blood, urine, marrow, and imaging. Read them well, and you can tell where the disease is, how fast it is moving, how treatment is working, and what to watch next. This guide translates the key tests into plain language, with just enough medical precision to help you interpret results with your care team.

The myeloma spectrum: from "watch and wait" to treat now

Myeloma does not appear overnight. It usually progresses along a spectrum:

MGUS (Monoclonal Gammopathy of Undetermined Significance) is the "quiet background noise." There is a small population of abnormal plasma cells making a monoclonal protein, but there is no organ damage. Most people with MGUS never develop myeloma, but a fraction do over years, which is why periodic monitoring matters.

Smoldering myeloma sits in the middle. The abnormal plasma cell clone is larger than in MGUS, but there are still no symptoms or organ damage. Certain biomarker patterns identify higher risk smoldering cases that may tip into active myeloma. These people need closer follow-up.

Multiple myeloma is diagnosed when the clone causes organ damage or hits specific high-risk biomarker thresholds that predict imminent damage. Clinicians use the CRAB criteria and myeloma-defining events.¹

CRAB stands for hypercalcemia, renal impairment, anemia, and bone lesions. If any are caused by the myeloma, treatment is indicated.¹

Myeloma-defining events (MDEs) predict very near-term organ damage even before symptoms. These include any one of: 60% or more clonal plasma cells in bone marrow, an involved to uninvolved serum free light chain ratio of 100 or greater with the involved light chain at least 100 mg/L, or more than one focal bone or marrow lesion on MRI at least 5 mm in size. These are established by the International Myeloma Working Group and widely used in practice.¹

The core blood and urine tests

1) The "M-spike" on serum protein electrophoresis (SPEP) and immunofixation

SPEP spreads blood proteins across a gel and shows a spike if a single clone of plasma cells is churning out a uniform antibody. That spike is the "M-protein" or "M-spike." It looks like a skyscraper on an otherwise low, rolling skyline. The height of the spike helps estimate tumor burden. Immunofixation then labels the spike to tell you its type (for example, IgG kappa or IgA lambda).

Key interpretive notes:

• SPEP quantifies the spike but cannot identify tiny amounts. Immunofixation is more sensitive but not quantitative.
• Inflammation can raise background immunoglobulins in a broad hump rather than a narrow spike. This is different from a monoclonal spike.
• Different labs use different gels and software. Small shifts from one lab to another may reflect technique rather than biology, so try to track results in the same lab when possible.

2) Serum free light chains (sFLC) and the kappa/lambda ratio

Antibodies are built from heavy and light chains. Plasma cells sometimes overproduce light chains alone. The serum free light chain assay picks up circulating "loose" light chains and calculates a kappa to lambda ratio. In myeloma, one type often skyrockets while the other is suppressed, pushing the ratio far off center.²

How to read it:

• The "involved" light chain is the one produced by the clone. The "uninvolved" is the other one.
• A ratio of 100 or more with the involved light chain at least 100 mg/L is a myeloma-defining event even without symptoms.¹
• Kidney function affects clearance of light chains. In chronic kidney disease, both kappa and lambda can rise and the normal ratio range is wider, so the reference interval is different. Labs often provide a renal reference range to prevent overcalling disease in CKD.

3) Urine studies: Bence Jones proteins

Excess free light chains spill into urine. A 24-hour urine collection with protein electrophoresis and immunofixation confirms and quantifies these proteins. Many centers now rely more on serum free light chains for convenience and sensitivity, but urine can still be useful, especially in light chain predominant disease.

Interpretive cautions:

• Random spot urine is convenient but can miss variability. If urine is used for response assessment, 24-hour collection is preferred for consistency.
• Albuminuria reflects glomerular leakage, while light chain proteinuria reflects tubular overload. In myeloma, the latter is more typical.

4) Organ function labs that define the "CRAB" features

Calcium rises when bone is being broken down faster than it is rebuilt. In myeloma, osteoclasts are activated and bone becomes "moth-eaten," which releases calcium into the blood.

Creatinine and eGFR estimate kidney function. Light chains can clog and inflame kidney tubules. Dehydration, infection, and certain medications make this worse. Creatinine changes help detect this early.

Hemoglobin drops as the marrow fills with plasma cells and normal blood production is crowded out. Anemia is common at diagnosis.

These are not just lab numbers. They flag organ stress that prompts treatment even when someone feels otherwise well.

5) Beta-2 microglobulin (B2M), albumin, and LDH

These three are the backbone of staging because they reflect tumor biology and host factors:³

Beta-2 microglobulin rises with higher tumor burden and reduced kidney clearance. Higher is generally worse and places people into a higher stage.

Albumin falls in chronic inflammation and illness. Lower albumin at diagnosis tracks with more aggressive disease.

LDH is a cellular stress enzyme. Elevated LDH usually signals faster-growing myeloma and is part of modern staging.

Imaging: seeing what the blood cannot

Low-dose whole-body CT is the current workhorse to spot lytic lesions. These are punched-out areas of bone loss that can be completely painless yet structurally important. If the CT shows one or more obvious lytic lesions not explained by other causes, that qualifies as bone involvement.

MRI highlights the marrow itself. It can reveal focal lesions before bone is visibly damaged. More than one focal lesion at least 5 mm is an MDE and meets criteria to treat. MRI also helps in back pain scenarios where you need to distinguish routine degeneration from vertebral involvement.

FDG PET-CT adds metabolic information. Areas lighting up with high glucose uptake can indicate active myeloma, including outside the marrow. PET is especially useful at relapse or when the blood markers are not telling the full story.

Bone marrow and genetic biomarkers

A bone marrow biopsy answers three big questions: how many plasma cells are present, are they clonal, and do they carry genetic changes linked to risk.

Plasma cell percentage: Normal marrows have very few plasma cells. In myeloma, the percentage jumps. Sixty percent or more clonal plasma cells is an MDE even without symptoms.¹

Flow cytometry: Abnormal plasma cells have a recognizable immunophenotype. Flow cytometry can quantify the clonal population, confirm plasma cell identity, and later detect very low levels of persistent disease in minimal residual disease testing.

FISH cytogenetics: Certain chromosomal changes carry prognostic weight. High-risk features include deletion 17p (TP53), translocations t(4;14) and t(14;16), and amplification or gain of 1q.⁴ People with these abnormalities are staged higher and often monitored more closely. These markers do not mandate a single "best" regimen by themselves, but they sharpen risk estimates and follow-up intensity.

Staging with biomarkers: ISS, R-ISS, and R2-ISS

Staging summarizes risk at the start so the team can plan therapy and surveillance. Three systems are commonly referenced:

ISS (International Staging System) uses beta-2 microglobulin and albumin. Stage I is B2M less than 3.5 mg/L with albumin at least 3.5 g/dL. Stage III is B2M 5.5 mg/L or higher. Others are Stage II. This is simple and still informative.

R-ISS (Revised ISS) adds high-risk cytogenetics and LDH. If high-risk cytogenetics are present or LDH is elevated, the stage increases. This better separates outcomes in modern therapy.⁵

R2-ISS refines further by giving weight to 1q gain and stratifying risk more granularly.⁵ Many academic centers use this newer model in discussions and trials.

These stages do not predict exactly what will happen to an individual. They set expectations and shape monitoring plans. Real-world survival has improved for all stages in recent years according to pooled international data, though more research is still clarifying how to personalize risk beyond these categories.

Response and monitoring: reading the arc of treatment

Once therapy starts, biomarkers tell you how well it is working. The International Myeloma Working Group defines standard response categories:⁶

Complete response (CR) means no detectable M-protein on immunofixation and fewer than 5% plasma cells in marrow. A "stringent" CR adds a normal free light chain ratio and no clonal plasma cells on advanced techniques.⁶

Very good partial response (VGPR) is at least a 90% drop in serum M-protein or urine M-protein levels under 100 mg per 24 hours.⁶

Partial response (PR) is a 50% or greater M-protein reduction.⁶

Because light chains have a short half-life, serum free light chains often fall quickly in the first days to weeks of effective therapy. Heavy chain M-protein declines more slowly. This difference helps clinicians separate early responders from slower decliners when interpreting week-by-week labs.

Immunoglobulin suppression (immunoparesis) often reverses with a deep response. Tracking uninvolved immunoglobulins can show recovery of normal antibody production over time, which may correlate with fewer infections.

Minimal residual disease (MRD): microscopic but meaningful

MRD testing looks for one cancer cell among 100,000 to 1,000,000 normal cells using next-generation flow cytometry or next-generation sequencing. If MRD is negative at that sensitivity, people tend to stay in remission longer. Large pooled analyses and multiple clinical trials have shown this correlation.⁷ Testing methods include standardized flow panels and sequencing of the unique myeloma immunoglobulin gene rearrangement. MRD does not replace clinical judgment, and the role of MRD in changing or stopping therapy is still being defined, but it is increasingly used to benchmark depth of response.

Relapse and biochemical progression

Relapse can be clinical, with new bone lesions, pain, anemia, or kidney issues, or it can be purely biochemical. The IMWG defines biochemical progression by percentage and absolute increases, for example a 25% rise and an absolute increase from baseline of at least 0.5 g/dL in serum M-protein, or at least 200 mg per 24 hours in urine M-protein, or a significant increase in the involved free light chain with an abnormal ratio. Repeat trends matter more than one-off blips. Infections and dehydration can temporarily nudge numbers, so confirm with repeat testing before labeling a change as relapse unless there are urgent symptoms.

Special subtypes and their biomarker playbooks

Light chain predominant myeloma

Here the serum protein electrophoresis may look almost normal because there is little intact antibody. The heavy lifting is done by the serum free light chain assay and urine studies.⁸ The kappa or lambda level and the ratio become the primary disease markers. Renal function changes can heavily influence levels, so trends and ratios are more reliable than single absolute values.

Non-secretory and oligo-secretory myeloma

In a small fraction, there is little or no measurable M-protein and free light chains are not helpful. Monitoring relies on imaging, bone marrow assessment, and MRD techniques. PET-CT and MRI become more central. When NGS can track a clonal immunoglobulin sequence from the marrow, that sequence can be used to follow MRD even if serum markers are absent.

IgA, IgD, and the hyperviscosity angle

IgA myeloma sometimes causes serum hyperviscosity, where the blood becomes thicker and sludgier. IgM does this more commonly in a related condition called Waldenström macroglobulinemia, but it is worth noting in IgA myeloma if symptoms like headaches, blurred vision, or nosebleeds appear. Serum viscosity measurement is available when clinically indicated.

Plasma cell leukemia

When plasma cells spill into the bloodstream at high levels, it is called plasma cell leukemia. A complete blood count with differential and flow cytometry on peripheral blood flag this. It is an aggressive variant and managed urgently.

Overlap with AL amyloidosis

Some patients have both myeloma and AL amyloidosis, a condition where light chains deposit as misfolded protein in organs such as the heart and kidneys. In these cases, serum free light chains guide clone control, while organ-specific biomarkers (like NT-proBNP and troponin for cardiac involvement) track organ response.⁹ This requires careful, multidisciplinary interpretation.

How to read a lab report in context: examples

Numbers feel less abstract when you tie them to the biology they represent. Here are three quick scenarios:

• An IgG kappa M-spike of 2.4 g/dL, hemoglobin 10.8 g/dL, normal calcium and creatinine, marrow plasma cells 18%: This profile can fit smoldering myeloma if there is no organ damage and imaging is clean. The spike is significant, but the absence of CRAB features and MDEs points to close monitoring rather than immediate treatment.
• Kappa free light chain 1,200 mg/L, lambda 8 mg/L, ratio 150, creatinine 2.1 mg/dL: The ratio is above 100 with a high absolute involved light chain, which is an MDE. Kidney function is impaired, possibly from light chain injury. This scenario meets criteria to treat even if bone pain is absent.
• After therapy, M-spike undetectable by immunofixation, involved free light chain normalized, marrow plasma cells 3%, MRD negative at 10^-5: This is a stringent complete response with MRD negativity. Studies associate this depth of response with longer remissions, though continued follow-up is essential.

Test limitations, interferences, and real-world caveats

No test is perfect. Knowing the pitfalls helps avoid missteps:

Assay variability: SPEP quantitation can differ slightly across platforms. Free light chain assays vary by manufacturer and calibration. Track results in the same lab whenever feasible to keep trends consistent.

Renal function: Reduced kidney function elevates both kappa and lambda and widens the normal ratio.¹⁰ Many labs provide a renal-adjusted reference interval. Interpreting the ratio with attention to kidney status prevents overdiagnosis.

Antigen excess (hook effect): Extremely high analyte levels can paradoxically read low on some nephelometric or turbidimetric assays. Labs mitigate this by automatic dilution protocols. If results seem inconsistent with the clinical picture, a repeat with dilutions often resolves it.

Inflammation and infections: Acute illness can transiently raise background immunoglobulins and tilt light chains. Recheck once the illness settles if a single data point seems off-pattern.

IVIG therapy: Intravenous immunoglobulin can produce a temporary polyclonal hump on SPEP and obscure minor monoclonal bands. Let the lab know about recent IVIG so immunofixation is interpreted appropriately.

Paraprotein interference in other lab tests: Very high M-protein can interfere with certain chemistry assays and produce spurious results (for example, pseudohyponatremia on older platforms). Modern analyzers reduce this, but if a result is physiologically implausible, clinicians will repeat it using a different method.

Timing and kinetics: Light chains drop quickly with effective therapy, while the M-spike declines slowly. Early in treatment, a flat M-spike with falling light chains can still indicate response. Interpreting both together gives a clearer picture.

Dialysis and adsorption therapies: Specialized dialysis membranes or adsorption columns can remove light chains and transiently change levels. Documenting these interventions ensures the team does not misread an artificial dip as disease control.

Life-stage and demographic considerations

Multiple myeloma is primarily a disease of older adults. Age influences baseline kidney function, bone density, and marrow reserve, which can color how biomarker changes are interpreted. For example, a mild anemia in an older adult may have several contributing causes, and marrow involvement is just one possibility that needs confirmation. Pediatric and pregnancy-associated myeloma are rare; there is limited evidence to suggest specific biomarker differences by sex or pregnancy state beyond routine physiologic changes. In pregnancy, some reference ranges shift for plasma volume and proteins, but myeloma decisions in that setting are individualized and specialist driven.

What is emerging and what is not yet standard

Mass spectrometry for M-protein can detect and characterize monoclonal proteins with higher sensitivity than immunofixation.¹¹ Early clinical studies suggest it may reduce "false negatives" and refine response assessment. It is entering clinical labs but is not yet universal.

Soluble BCMA (B-cell maturation antigen) is a circulating protein shed by myeloma cells.¹² Research shows sBCMA correlates with disease burden and tracks response, including in non-secretory disease. It is promising, though not yet part of formal guidelines for routine management.

Circulating tumor DNA for plasma cell disorders is under active investigation. The hope is to monitor genetic evolution of the clone over time without repeated marrow biopsies. Methods and clinical utility are still being clarified.

These tools may soon add precision to standard testing, but for now, SPEP/IFE, serum free light chains, marrow cytogenetics, and modern imaging remain the backbone recommended by expert groups.

Pulling it all together

Think of myeloma biomarkers as complementary lenses. The blood shows the protein signature and organ stress. The marrow shows the clone and its genetic temperament. Imaging shows the structural footprint. Over time, the same tests trace a story arc from diagnosis to response, and sometimes to relapse. No single number makes the call. Patterns do, interpreted by a team that knows your baseline, your comorbidities, and your goals.

Two final, responsible notes. First, the same values can mean different things in different contexts. A kappa/lambda ratio of 110 in a person with normal kidneys and two MRI focal lesions is not the same as a ratio of 110 in someone with severe kidney disease and a clean MRI. Second, evidence keeps evolving. Analyses from the International Myeloma Working Group and large registries have steadily sharpened definitions and cutoffs, and new modalities like MRD testing have already improved how deeply we can measure response, though how best to use those measurements for day-to-day decisions is still being studied.

If you are tracking your own results, keep a simple timeline of key markers and imaging results from the same lab when possible. Then, at each visit, look at the shape of the trends with your hematologist rather than any single data point. That approach respects both the science and the person living with the disease.