Multiple Myeloma

Multiple myeloma is a malignancy of plasma cells — the antibody-producing cells of the bone marrow — characterised by clonal expansion of plasma cells and, in most cases, secretion of a monoclonal immunoglobulin or light chain. It is the principal plasma cell malignancy and the prototype of disorders in which a clonal protein drives disease features. Multiple myeloma is part of a continuum that includes asymptomatic precursor states.

Definition

Multiple myeloma is a neoplasm of clonal bone-marrow plasma cells, usually producing a monoclonal immunoglobulin or light chain, and associated with end-organ effects and defined diagnostic criteria distinguishing it from precursor plasma cell conditions.

Scope

This entry covers the biology of the malignant plasma cell clone, the monoclonal protein it produces, the precursor states that precede symptomatic disease, the organ effects classically summarised by the CRAB features, and the diagnostic framework defined by the International Myeloma Working Group. It is a reference description of the disease entity and not treatment guidance.

Core questions

• What defines the malignant plasma cell clone in multiple myeloma?
• How does the monoclonal protein relate to diagnosis and disease features?
• How is multiple myeloma distinguished from its precursor states?
• What organ effects characterise symptomatic disease?

Key concepts

• Clonal plasma cells
• Monoclonal protein (M-protein)
• Monoclonal gammopathy of undetermined significance
• Smouldering multiple myeloma
• CRAB features (hypercalcaemia, renal impairment, anaemia, bone lesions)
• Bone marrow microenvironment
• International Myeloma Working Group criteria

Mechanisms

Multiple myeloma develops from a clonal population of plasma cells in the bone marrow that has acquired genetic alterations conferring growth and survival advantages; the clone typically secretes a monoclonal immunoglobulin or free light chain that serves as a disease marker and can itself cause harm. The clone interacts with the bone-marrow microenvironment, promoting its own survival and disrupting normal bone remodelling. The disease arises from precursor states — monoclonal gammopathy of undetermined significance and smouldering myeloma — and progression to symptomatic disease is classically marked by the CRAB features of hypercalcaemia, renal impairment, anaemia, and bone lesions, which the International Myeloma Working Group criteria incorporate.

Clinical relevance

Multiple myeloma is the reference plasma cell malignancy and a key example of a cancer in which a secreted clonal protein and an interaction with bone help define the disease. Understanding its precursor states and defining features clarifies how it is diagnosed and classified. This entry describes the disease conceptually and is not a basis for individual diagnosis or treatment.

Epidemiology

Multiple myeloma is the major plasma cell malignancy and one of the more common hematologic cancers, occurring predominantly in older adults and more often in men. It is consistently preceded by monoclonal gammopathy of undetermined significance, a common asymptomatic condition that progresses to myeloma at a low annual rate.

History

Multiple myeloma has been recognised since the nineteenth century, with early descriptions of bone disease and the urinary light-chain protein later named after Henry Bence Jones. Twentieth-century work characterised the monoclonal protein and the plasma cell clone, and the recognition of precursor states reframed the disease as a continuum. The International Myeloma Working Group consolidated diagnostic criteria, updated in 2014 to incorporate biomarkers of malignancy.

Debates

Where to draw the line for treatable disease

The boundary between smouldering and symptomatic multiple myeloma has been redefined as biomarkers were added to the diagnostic criteria, and how to identify precursor disease that warrants reclassification remains an active question.

Key figures

• Robert A. Kyle
• S. Vincent Rajkumar
• Kenneth C. Anderson

Seminal works

• rajkumar-2014
• kyle-2004
• palumbo-2011

Frequently asked questions

What is the monoclonal protein in multiple myeloma?

It is an immunoglobulin or immunoglobulin light chain produced in excess by the clonal plasma cells. Its presence and quantity serve as a marker of the clone and, in some cases, the protein contributes directly to organ damage.

How does multiple myeloma relate to MGUS?

Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic precursor state defined by a small monoclonal protein without end-organ effects. Multiple myeloma is preceded by MGUS, which progresses to myeloma in a minority of people over time.