SPEP and free light chains: what an M-spike, kappa and lambda light chains and the kappa/lambda ratio mean

An M-spike means a single clone of plasma cells (or, for IgM, lymphoplasmacytic cells) is producing one antibody in excess. The size of the spike, the type of antibody, the light-chain ratio and whether there is any organ damage sort the finding into categories. MGUS is an M-spike under 3 g/dL, fewer than 10 percent plasma cells in the marrow, and no related anemia, high calcium, kidney damage or bone lesions (the CRAB features). It needs no treatment, only monitoring. Smoldering myeloma is an M-spike of 3 g/dL or more and/or 10 to 59 percent marrow plasma cells, still without organ damage; it progresses at about 10 percent a year for the first five years. Active myeloma is 10 percent or more marrow plasma cells plus a CRAB feature or one of three biomarkers: 60 percent or more marrow plasma cells, an involved/uninvolved light-chain ratio of 100 or more with the involved chain at least 100 mg/L, or more than one focal lesion on MRI.

The Mayo Clinic risk model for MGUS uses three findings: an M-spike of 1.5 g/dL or more, a non-IgG type (IgA or IgM), and an abnormal free light chain ratio. With none of these, the 20-year risk of progression is about 5 percent; with all three it is about 58 percent. Low-risk MGUS is rechecked at six months and then every two to three years if stable; higher-risk MGUS is checked yearly. An IgM spike raises the different possibility of Waldenström macroglobulinemia or lymphoma. A light chain only abnormality (abnormal ratio with no heavy-chain spike) is light-chain MGUS, which progresses at about 0.3 percent a year, or, when the involved chain is very high, light-chain myeloma.

An abnormal kappa/lambda ratio without an M-spike has three main explanations. If one chain is high and the other normal or low, a small clone is likely and immunofixation plus urine electrophoresis follows. If both chains are high and the ratio is normal or only mildly skewed toward kappa, the cause is reduced kidney clearance or polyclonal overproduction from inflammation, infection or autoimmune disease, not a clone. A ratio far outside the range (for example 8 or 0.05) is almost always clonal. A broad polyclonal rise in gamma globulins on SPEP, with no spike, points to chronic liver disease, chronic infection (including HIV and hepatitis C), rheumatoid arthritis, lupus, Sjögren's syndrome or sarcoidosis rather than a plasma-cell disorder. Raised free light chains with an abnormal ratio can also be the first sign of AL amyloidosis, in which the light chains deposit in the heart, kidneys and nerves; a difference between involved and uninvolved chains above 50 mg/L in someone with unexplained heart failure, heavy proteinuria or neuropathy prompts testing for it.

Common causes

1. 1.

   Monoclonal gammopathy of undetermined significance (MGUS)

   The most common cause of an M-spike, found in about 3 percent of people over 50, 5 percent over 70 and more often in Black Americans and in people with an affected relative. The spike is under 3 g/dL, marrow plasma cells are under 10 percent and there is no organ damage. About 1 percent a year progress to myeloma, Waldenström or amyloidosis.

2. 2.

   Smoldering (asymptomatic) multiple myeloma

   An M-spike of 3 g/dL or more or 10 to 59 percent marrow plasma cells without CRAB features or myeloma-defining biomarkers. Risk of progression is about 10 percent a year for five years, then falls; high-risk smoldering disease is sometimes treated in trials.

3. 3.

   Multiple myeloma

   A clonal plasma-cell cancer with marrow plasma cells of 10 percent or more plus anemia, calcium above 11 mg/dL, creatinine above 2 mg/dL, lytic bone lesions, or one of the biomarkers (60 percent plasma cells, light-chain ratio 100 or more, more than one MRI lesion). Most are IgG or IgA; about 15 to 20 percent make only light chains and show little or no SPEP spike.

4. 4.

   Light-chain myeloma and light-chain MGUS

   The clone makes only kappa or only lambda, so SPEP may be normal while the free light chain ratio is grossly abnormal and the urine contains Bence Jones protein. This is why sFLC is added to SPEP in every screen; sFLC plus SPEP plus IFE detects over 97 percent of clonal disorders.

5. 5.

   Waldenström macroglobulinemia and lymphoma

   An IgM M-spike comes from lymphoplasmacytic cells rather than classic plasma cells. Large IgM spikes thicken the blood (hyperviscosity) and cause nosebleeds, blurred vision and headache. IgM MGUS progresses to Waldenström or lymphoma at about 1.5 percent a year.

6. 6.

   AL (light chain) amyloidosis

   A small clone produces misfolded light chains (lambda in about 70 percent) that deposit in heart, kidneys, nerves, gut and tongue. The M-spike is often small or absent; the sFLC ratio is abnormal in about 90 percent. Suspected with unexplained heart failure with thick ventricular walls, nephrotic-range proteinuria, peripheral or autonomic neuropathy, or an enlarged tongue.

7. 7.

   Reduced kidney function

   Free light chains are cleared by the kidney, so as eGFR falls both chains rise and the ratio drifts up toward 2 or 3 even without a clone. A renal reference ratio of 0.37 to 3.1 is applied; a ratio within it with both chains raised in proportion is not clonal.

8. 8.

   Polyclonal gammopathy from infection, liver disease or autoimmunity

   Chronic hepatitis, cirrhosis, HIV, tuberculosis, endocarditis, rheumatoid arthritis, lupus, Sjögren's syndrome and sarcoidosis all raise the whole gamma fraction, often to 2 to 4 g/dL, as a broad hump rather than a spike, with both light chains raised and a normal ratio.

9. 9.

   Transient or secondary monoclonal bands

   Small, often temporary M-spikes appear after infections, after stem-cell or organ transplantation, with some autoimmune diseases, in chronic lymphocytic leukemia and with certain drugs. Therapeutic monoclonal antibodies (daratumumab, rituximab, and others) can themselves appear as a tiny IgG kappa band on SPEP and IFE.

10. 10.

    Other plasma-cell and related disorders

    Solitary plasmacytoma, POEMS syndrome (lambda spike with neuropathy and endocrine changes), monoclonal gammopathy of renal significance (small clone damaging the kidney), cryoglobulinemia and heavy-chain disease are less common causes identified by the pattern plus the clinical picture.

Symptoms that can go with it

• Often none; MGUS is usually found on tests done for another reason
• Fatigue, breathlessness or pallor from anemia
• Bone pain, especially in the back or ribs, or a fracture after minor stress
• Excessive thirst, constipation, confusion or nausea from high calcium
• Foamy urine, swollen legs or reduced urine output from kidney involvement
• Repeated infections, particularly chest and sinus infections, because normal antibodies are suppressed
• Numbness, tingling or burning in the feet (peripheral neuropathy), seen with MGUS, amyloidosis and POEMS
• Nosebleeds, blurred vision or headache with a large IgM spike (hyperviscosity)

A low gamma globulin band, below roughly 0.6 g/dL, is called hypogammaglobulinemia and means you are making or keeping too few antibodies. It is confirmed by measuring IgG, IgA and IgM individually; IgG below about 600 mg/dL is the usual cutoff for concern and below 400 mg/dL is severe. In adults the commonest causes are medications (long-term corticosteroids, rituximab and other B-cell therapies, some anti-seizure drugs), loss of protein through the kidney or gut, and blood cancers such as chronic lymphocytic leukemia and myeloma, which crowd out normal plasma cells so that a patient can have a big M-spike and low normal immunoglobulins at the same time. Common variable immunodeficiency, the main primary antibody deficiency diagnosed in adults, typically presents between 20 and 40 with recurrent sinus and chest infections.

Free light chains are rarely reported as low; values below the range for both chains usually mean suppressed antibody production and carry the same meaning as low gamma globulins. A single low chain alongside a high partner chain is read as a clone, not as a deficiency: in myeloma the uninvolved chain is often suppressed below normal, and recovery of the uninvolved chain is one marker of response to treatment. A low albumin band reflects inflammation, liver disease, nephrotic syndrome or malnutrition, and a low or absent alpha-1 band in someone with early emphysema or unexplained liver disease is a reason to measure alpha-1 antitrypsin directly.

Common causes

1. 1.

   Immunosuppressive and other medications

   Corticosteroids, rituximab and other anti-CD20 antibodies, mycophenolate, methotrexate, chemotherapy, and some anti-seizure drugs (phenytoin, carbamazepine) reduce antibody production. Rituximab-related hypogammaglobulinemia can last years.

2. 2.

   Multiple myeloma and chronic lymphocytic leukemia

   The malignant clone suppresses normal plasma cells, so the uninvolved immunoglobulins (and the uninvolved light chain) fall; this immunoparesis is itself a risk factor for progression in MGUS and smoldering myeloma and a reason for recurrent infections.

3. 3.

   Protein loss through the kidney or gut

   Nephrotic syndrome loses IgG into the urine (with low albumin and a high alpha-2 band); protein-losing enteropathy from Crohn's disease, celiac disease, intestinal lymphangiectasia or heart failure loses it into the bowel.

4. 4.

   Common variable immunodeficiency and other primary antibody deficiencies

   Low IgG with low IgA or IgM and a poor response to vaccines, presenting with recurrent bacterial sinus, ear and chest infections, bronchiectasis, autoimmune cytopenias or granulomas. Diagnosed by an immunologist.

5. 5.

   Severe illness, burns and malnutrition

   Critical illness, extensive burns, sepsis and prolonged undernutrition lower albumin and gamma globulins through increased loss and reduced synthesis.

6. 6.

   Alpha-1 antitrypsin deficiency (low alpha-1 band)

   A homozygous ZZ genotype produces a flat alpha-1 zone; carriers may be normal on SPEP. It causes early emphysema, especially in smokers, and liver disease; confirmed by alpha-1 antitrypsin level and genotype.

Symptoms that can go with it

• Recurrent or unusually severe sinus, ear, bronchial or lung infections
• Chronic cough with sputum (bronchiectasis) or chronic diarrhea with infections such as Giardia
• Poor response to vaccines or infections despite vaccination
• Swelling, foamy urine or weight loss when the cause is protein loss
• Breathlessness in a younger adult or non-smoker with a low alpha-1 band