Multiple myeloma (MM) is a blood cancer characterized by the uncontrolled growth of abnormal plasma cells within the bone marrow. These cancerous cells interfere with normal blood cell production and can lead to organ damage. Multiple myeloma does have stages, which doctors use to assess the extent of the disease and its likely behavior. Staging determines the severity of the cancer, provides a standardized framework for medical communication, and guides the selection of the most effective treatment strategy.
The Evolution of Multiple Myeloma Staging Systems
The initial attempt to systematically classify MM was the Durie-Salmon Staging System, introduced in 1975. This foundational system focused on estimating the total volume of myeloma cells in the body. Staging relied on clinical markers reflecting the physical consequences of the cancer, such as anemia and bone damage.
The Durie-Salmon system measured monoclonal protein (M-protein) in the blood or urine, hemoglobin and calcium levels, and the extent of bone lesions visible on X-rays. Patients were categorized into three stages (I through III), with substages A or B based on serum creatinine levels (kidney function). However, this system had limitations because it did not account for the intrinsic biological aggressiveness of the cancer cells.
The field shifted toward a more biologically informed approach with the development of the International Staging System (ISS). The current standard is the Revised International Staging System (R-ISS), which improved the predictive accuracy of the initial ISS by incorporating genetic and metabolic factors. The R-ISS is preferred today because it includes factors known to independently affect a patient’s prognosis, moving beyond simply measuring tumor mass.
The R-ISS combines the core components of the original ISS with high-risk genetic features and a metabolic marker of disease activity. It classifies patients into three stages: Stage I (lowest risk and most favorable prognosis), Stage II (intermediate), and Stage III (most aggressive disease with the least favorable outlook). This system provides a robust assessment of disease risk, essential for modern personalized treatment planning.
Key Diagnostic Markers Used for Staging
The Revised International Staging System uses four specific laboratory inputs for classification. Two markers, Serum Beta-2 Microglobulin (B2M) and Serum Albumin, form the basis of the original ISS component. B2M is a small protein whose level is directly related to the mass of myeloma cells and kidney impairment. High levels of B2M (greater than 5.5 mg/L) indicate advanced disease and a less favorable prognosis, often leading to Stage III classification.
Serum albumin is a protein made by the liver; lower levels are associated with poorer outcomes. A normal or high albumin level (3.5 g/dL or greater) is a criterion for R-ISS Stage I disease. The combination of low B2M and high albumin suggests Stage I, while high B2M and low albumin suggest more advanced disease.
The R-ISS refines risk assessment by adding two prognostic factors. The first is the level of Lactate Dehydrogenase (LDH), an enzyme released when cells are damaged or rapidly dividing. An elevated LDH level suggests a more aggressive form of the cancer.
The second crucial addition is the assessment of specific Cytogenetic Abnormalities (CA), involving genetic testing of the myeloma cells (e.g., using FISH). The presence of certain high-risk chromosomal changes significantly worsens the prognosis. These include the deletion of part of chromosome 17 (del 17p) or translocations such as t(4;14) or t(14;16). The detection of any high-risk CA is sufficient to classify the disease as R-ISS Stage III, regardless of B2M and albumin levels, emphasizing the influence of the cancer’s underlying biology.
Prognostic Value and Treatment Implications of Staging
The R-ISS stage provides a direct correlation with a patient’s expected outcome, serving as a primary tool for prognosis. Stage I patients have the most favorable outlook, with five-year overall survival rates around 77%. Stage II patients fall into an intermediate-risk category, with survival rates typically around 53%.
Stage III identifies patients with the most aggressive disease, characterized by the highest risk factors, including elevated B2M and high-risk cytogenetics. For this group, the five-year overall survival rate can be as low as 19%. This clear distinction in expected survival guides the initial management discussion.
The assigned stage is highly influential in determining initial treatment intensity. For Stage I patients, doctors may opt for standard induction chemotherapy, sometimes followed by observation or less aggressive maintenance therapy. For Stage II and Stage III patients, high-risk features necessitate more intensive initial therapy.
This increased intensity often involves induction therapy with novel drugs, followed by high-dose chemotherapy and an autologous stem cell transplant (ASCT) for eligible patients. The stage helps determine candidacy for this aggressive approach, as ASCT benefits are pronounced in higher-risk groups. Staging is a guide, however, and a patient’s overall health, age, and personal treatment goals are always factored into the final, individualized treatment plan.