Dr Benjamin Crawford( left) Haematology advanced trainee, Royal Prince Alfred Hospital, Sydney, NSW.

Professor John Gibson( right) Emeritus consultant, Institute of Haematology, Royal Prince Alfred Hospital, Sydney, NSW.

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This information was correct at the time of publication: 20 March 2026

BACKGROUND

A PARAPROTEIN is an abnormal protein

that is secreted by a clonal population( a group of cells that have been generated from a single ancestor and have the capacity for self-renewal) of immune cells( usually plasma cells, see figure 1) and is detected in the blood.

Plasma cells are defined as differentiated B-lymphocytes that are able to secrete immunoglobulins or antibodies.

While a paraprotein is the hallmark of multiple myeloma, these can also be detected in a number of conditions that range from benign to indolent or malignant. As the significance of finding a paraprotein can range from benign to aggressively malignant, the interpretation and discussion with the patient is often nuanced, and subsequent investigations and management have the potential to lead to great anxiety for both patients and clinicians.

This How to Treat reviews the origins of paraproteins, discusses the most effective screening methods to use when investigating a paraprotein, and explains the process of discerning the different conditions that can be represented by detection of a paraprotein and how these conditions are

managed. It aims to ensure the GP is familiar with the current investigations, evaluation and management of these conditions.

IMMUNOGLOBULINS

PLASMA proteins are free proteins in the blood. They serve a variety of functions, including providing oncotic pressure, participating in coagulation homeostasis, forming part of the immune system and facilitating the transportation of lipids, hormones, vitamins and minerals.

Serum albumin accounts for 55 % of plasma proteins, followed by globulins which comprise 38 %. 1 Globulins can be separated into alpha, beta and gamma globulins, the most significant of which are immunoglobulins.

Immunoglobulins( antibodies) are glycoproteins produced by plasma cells and B-lymphocytes. They share a basic common symmetric core structure and are composed of two identical heavy chains and two identical light chains( see figure 2). The variable( V) domains of the heavy and light chain form a highly specific antigen binding site and because every antibody contains two heavy and two light chains, every antibody possesses two

antigen binding sites. The exact site of antigen binding is termed the hypervariable region( part of the variable domain); these are frequently mutated sections that allow for diverse antigen recognition. The two heavy chain regions distant from the antigen binding sites form the constant( C) domain that interacts with other effector molecules and cells of the immune system and therefore mediates most of the biologic functions of antibodies.

There are five isotypes of the heavy chain IgA, IgD, IgE, IgG and IgM, with the effector functions of antibodies mediated by the heavy chain C region( see table 1). Thus, the heavy chain isotype determines the different functions of the antibodies.

There are two different light chains called kappa( κ) and lambda( λ) that are distinguished by their carboxyl-terminal constant regions. Each antibody has two identical kappa or two identical lambda light chains. Usually about 60 % of immunoglobulins have kappa light chains and 40 % have lambda light chains. 2

PARAPROTEINS

A paraprotein( also known as an M protein, monoclonal protein or

Box 1. The various forms of a paraprotein

• A heavy and light chain( a normal intact immunoglobulin structure).

• Light chain only.

• Heavy chain only.

• Misfolded immunoglobulins.

M component) is an immunoglobulin or part of an immunoglobulin that is secreted by an expanded plasma cell or B-cell clone, and that can be detected in a quantity above the background of polyclonal immunoglobulins usually present in the blood. The forms a paraprotein may take are listed in box 1.

Most paraproteins are IgG or IgA and are most commonly associated with several conditions, including monoclonal gammopathy of undetermined significance( MGUS), smouldering myeloma( SMM) and multiple myeloma( MM), see table 2. IgM paraproteins can also be associated with these conditions but are more common in lymphoplasmacytic lymphoma( also known as Waldenström macroglobulinaemia).