Introduction

Multiple myeloma (MM) literally means “multiple tumours originating from the bone marrow.” MM is a cancer of the plasma cell. The plasma cell (PC) is one of the white blood cells responsible for immunity. They produce antibodies that help fight off infection. PCs reside in the bone marrow. In MM, they may fill up the marrow and interfere with the production of other cell types. However, one of the manifestations of MM may be plasmacytomas which are solid tumours of PCs that may form both within and outside of bones.

The plasma cell develops from a B cell originating from the bone marrow. Before a B cell matures into a plasma cell, it is stimulated by the presence of a foreign substance (i.e. antigen) to rapidly divide and produce a number of clones that mature into plasma cells. These plasma cells are identical and all produce the same antibody to bind against the antigen that was initially recognized by the B cell. Plasma cells produce thousands of antibodies every second and die off within 5 days.

MM belongs to a group of disorders that affects the plasma cell called monoclonal gammopathies. This spectrum of disorders is characterized by unregulated plasma cell division and the overproduction of a single immunoglobulin (i.e. paraprotein). Immunoglobulins are a family of proteins that are secreted from B cells and plasma cells into the blood. All antibodies are immunoglobulins, but not all immunoglobulins are antibodies. For instance, the immunoglobulins that are secreted in multiple myeloma are pathologic and are not thought to have any significant immune function. In fact, they are believed to be responsible for some of the disease findings in multiple myeloma, such as renal failure.

The median age of diagnosis of MM is 70 years. Prognosis is determined by the International Staging System that has categorized MM into three stages based on the concentration of β2-microglobulin in the blood. Patients have a median survival of 62 months for stage 1 MM, 45 months for stage 2 disease, and 29 months for stage 3 disease.*

Other conditions belonging to the spectrum of monoclonal gammopathies include monoclonal gammopathy of undetermined significance (MGUS) and asymptomatic myeloma (smouldering multiple myeloma). The International Myeloma Working Group officially defined these diseases in 2003 (see diagnostic criteria below). MGUS is an asymptomatic, benign condition of the plasma cell. Asymptomatic myeloma is essentially a more severe presentation of MGUS, still without symptoms. Both have a risk of progressing to multiple myeloma. MGUS has an annual risk of progression to MM of 1%. It is thought that at least one third of MM emerges from a pre-existing plasma cell disorder. The balance arise de novo. The rate of progression of smouldering multiple myeloma to symptomatic disease (i.e. MM) is 10% per year for the first 5 years, 5% per year for the next 5 years, and 1.5% per year thereafter.The most important predictor for the risk of progression to plasma cell malignancy is the paraprotein concentration. Six percent of those with a paraprotein concentration of 0.5 g/L will progress at ten years compared to 34% with a paraprotein concentration of 3.0 g/L. Nevertheless, it is not recommended to treat MGUS or asymptomatic myeloma, only multiple myeloma.

Signs and symptoms of MM

The most common symptoms are fatigue, bone pain, and recurrent infection. A classic group of findings are known by the acronym CRAB (hyperCalcemia, Renal insufficiency, Anemia, Bone lesions).

Diagnosis (1)

MGUS is defined as:
1.Serum paraprotein < 30 g/L, AND
2.Clonal plasma cell <10% on bone marrow biopsy, AND
3.No ROTI* or symptoms

Asymptomatic myeloma is defined as:
1.Serum paraprotein >30 g/L, AND/OR
2.Clonal plasma cell >10% on bone marrow biopsy, AND/OR
3.No ROTI* or symptoms

Multiple myeloma (symptomatic) is defined as:
1.Bone marrow clonal plasma cells or plasmacytoma
2.Presence of serum or urine paraprotein
3.Evidence of ROTI*:
a.Hypercalcemia
b.Renal insufficiency
c.Anemia
d.Bone lesions
e.Other: recurrent severe infections, amyloidosis, symptomatic hyperviscosity

* ROTI = related organ or tissue impairment.