20 HOW TO TREAT: A PARAPROTEIN
20 HOW TO TREAT: A PARAPROTEIN
20 MARCH 2026 ausdoc. com. au
Since malignant cells arise from a single proliferating cell line( defined as a clone), establishing that the paraprotein and the cells producing this paraprotein exhibit the same kappa or lambda light chain restricted expression is an important part of the diagnostic process. While demonstrating monoclonality alone does not prove a malignant process, it is a necessary step to diagnosing a malignancy.
An increase in light chain production compared with heavy chain is often associated with paraprotein excretion from the clonal plasma cells or B-cells. The light chains can be secreted into the urine and when detected in the urine by electrophoresis are called Bence-Jones proteins( see figure 3). Intact whole immunoglobulins can also be secreted into the urine and detected.
© 2008 Terese Winslow LLC, U. S. Govt. has certain rights
|
INVESTIGATION FOR A PARAPROTEIN
FOLLOWING detection of a paraprotein
|
, the next step is to assess its |
potential significance, in particular |
looking for evidence of MM or a B-cell |
neoplasm that requires treatment. |
Paraprotein levels greater than 15g / L, |
or those that are increasing on serial |
measurement, are associated with |
neoplasms and require investigation. |
While the presenting features of |
MM are sometimes non-specific, the |
presence of constitutional symptoms, |
including weight loss, night sweats |
and fevers, should raise suspicion. Bony pain is a common symptom in |
Figure 1. Blood cell development. |
MM, and bony lesions identified on |
imaging, crush fractures in younger patients and pathological fractures should prompt investigation. |
|
Ag binding |
Anaemia occurs in about 70 % of |
|
|
|
|
new cases of MM and is typically normocytic |
|
|
|
|
, although it can occasionally be macrocytic. 3 In the presence of an anaemia of unknown origin( normal |
|
|
|
|
B12, folate and iron studies, no blood |
|
|
|
|
loss, no haemolysis and no other clear |
|
|
|
|
cause), investigate for a paraprotein. |
|
|
|
|
Renal impairment with no clear |
|
|
|
|
cause should also prompt suspicion. The impairment can occur rapidly or over a period of months, and exclusion of a paraprotein is indicated if there are no clear pre-renal, renal or |
Fab |
-SS- |
-SS- |
Light chain |
post-renal causes identified. |
|
|
|
|
Hypercalcaemia is a frequent complication |
|
|
|
|
of symptomatic MM with |
|
|
|
|
|
paraprotein exclusion included in the work up of hypercalcaemia. Typically, the parathyroid hormone is appropriately suppressed and the vitamin D levels are normal.
Key laboratory investigations are the demonstration of paraprotein with serum protein electrophoresis( SPE), immunofixation( IEPG) and an analysis of serum free light chains.
|
Fc |
-SS--SS- |
Disulfide bridge
Heavy chain
Hypervariable regions
|
Serum protein electrophoresis
The patient’ s serum is applied to a buffered agarose gel matrix and an electrical charge is applied to this matrix. The serum proteins then separate into bands according to electrical charge, with albumin closest to the cathode and the globulins sifted into four major groups( see figure 4).
The paraprotein is usually detected in the gamma globulin region and can be seen above the noise of the background immunoglobulins. Quantification of the paraprotein is then achieved using densitometry on the spike shown on the EPG. This involves passing the gel through a densitometer that optically analyses the density
Figure 2. Structure of an antibody demonstrating both the constant and variable regions.
of the gel and thus the proteins at that level. This is commonly analysed and interpreted on SPE, which allows for easy visual representation of the peaks of different proteins and visual identification of the paraprotein.
Immunofixation
While SPE can detect an abnormal protein suggestive of a paraprotein, in order to confirm clonality and the type of paraprotein, immunofixation is required. Serum is prepared using the same method as for SPE and is then mixed with antibodies specific for the heavy and light chains of immunoglobulins.
These antibodies will highlight discrete bands that correspond to the same bands seen on the SPE confirming the paraproteins heavy and light chain type( see figure 5).
Variable regions Constant regions
Serum free light chains
The serum free light chain assays target epitopes on the kappa and lambda light chains that are usually obscured when in the conformation of an intact immunoglobulin. This assay allows detection of light chains that are free in the serum( or urine) and are present in more than 80 % of cases of myeloma. 4
A ratio of kappa / lambda is also commonly provided and an abnormal
Fab = fragment antibody, Fc = fragment constant
ratio is part of the interpretation of the finding of an elevated light chain. Lambda light chains are dimeric( composed of two identical simpler molecules) and their renal clearance is slower compared with kappa light chains and so the median ratio is 0.6. However, the rates of light chain production are not always equal and so reference ranges are wider. Importantly, a small proportion of cases of MM do not