International Staging System (ISS) and Revised ISS (R-ISS)

In 2005, the International Myeloma Foundation (IMF) research division, the International Myeloma Working Group (IMWG), developed a new staging system. The IMWG gathered clinical and laboratory data from 17 institutions on 10,750 previously untreated symptomatic myeloma patients. These cases spanned North America, Europe, and Asia. The IMWG evaluated potential prognostic factors using various statistical techniques. The following emerged as powerful predictors of survival:

• Serum β2 microglobulin (Sβ2M): This small protein is found on most cells, including immune cells like lymphocytes. It circulates in the blood and urine. Although a nonspecific marker, high levels may signal concern for multiple myeloma, lymphoma, or kidney issues. 
• Serum albumin: Made by the liver, albumin helps keep fluid in the bloodstream and carries nutrients like vitamins and hormones. Low levels can indicate liver disease, chronic inflammation, or kidney problems. Also, it is important to understand that albumin binds to calcium. When albumin is low, the total calcium level may be higher than reported.
• Platelet count: Platelets are tiny blood cells that help clot blood and stop bleeding. Low platelet levels can occur in multiple myeloma if the bone marrow is overcrowded by plasma cells, leading to low platelet production.
• Serum creatinine: Creatinine is a waste product filtered by the kidneys. High levels can be a sign of kidney problems, including those caused by multiple myeloma. In myeloma, high calcium (hypercalcemia) and light chain levels can cause kidney issues.
• Age: Research showed that age plays a role in myeloma outcomes. Advanced age is associated with a poorer prognosis for a variety of reasons (see below).

International Staging System for Multiple Myeloma

ISS staging of multiple myeloma classifies the myeloma stage according to serum β2M and serum albumin levels. This system uses tests that can be processed at most labs, making it a simple and reproducible three-stage classification system. ISS was further validated by demonstrating its effectiveness:

• In patients in North America, Europe, and Asia.
• In patients younger and older than age 65 years.
• With standard therapy or autologous stem cell transplant (ASCT).
• In comparison with the Durie-Salmon Staging System.

ISS Stages and Criteria

The following table indicates the stages and correlating measurements according to ISS:

Revised International Staging System for Multiple Myeloma

In August 2015, the IMWG published a revision with two extra prognostic criteria. The Revised International Staging System (R-ISS) expanded the staging of multiple myeloma. It now includes specific cancer gene abnormalities (cytogenetic abnormalities) and lactate dehydrogenase levels (LDH). 

R-ISS Myeloma Stages and Criteria

These revised indicators form a more powerful prognostic index:

How Are Cytogenetic Abnormalities Tested in R-ISS?

One of the primary techniques for detecting cytogenetic abnormalities (CAs) is fluorescence in situ hybridization (FISH). Doctors take a bone marrow sample to examine chromosomes in the cancer cells. 

Pathologists use fluorescent probes, or chemical labels, to detect chromosomal differences and gene changes. The probes bind to specific DNA sequences on chromosomes so that abnormalities can be seen. Different CAs are associated with different cancers and can help provide differential diagnosis and risk stratification.

Staging and Risk Stratification

Myeloma staging and risk stratification are both important for understanding and managing myeloma, but they serve different purposes. Staging provides more information about the extent of the disease, or the myeloma burden. It is most significant at the time of diagnosis. 

Risk stratification, either standard or high, provides a likelihood of disease response to treatment and potential for disease progression. Standard risk is associated with better outcomes and accounts for approximately 75% of myeloma.

Three specific chromosome abnormalities (CAs) indicate high-risk myeloma and advanced staging. These CAs are the following:

1. Deletion of chromosome 17, or 17p-
2. Translocation of chromosomes 14 and 16, or t(14;16)
3. Translocation of chromosomes 4 and 14, or t(4;14)

Other Factors That Impact Outcomes

Myeloma staging and risk stratification are important clinical tools that can help guide treatment. However, other factors can influence a patient's prognosis and determine treatment, such as:

Age

While treatment remains similar across age groups, patients under 50 have a better prognosis. The common age range for myeloma diagnosis is between 65 and 74. The risk of developing the disease increases with age. Frailty and other illnesses (co-morbidities) may limit access to some treatment options and the ability to tolerate side effects associated with treatment. 

Kidney Function

Healthier kidneys and lower creatinine levels can improve a patient's outlook. When monoclonal immunoglobulin impairs kidney function, it becomes harder for the kidneys to remove creatinine from the blood. Increased creatinine levels can worsen prognosis and limit some treatment options.

Overall Health

General health and existing conditions, such as diabetes or heart disease, can contribute to myeloma outcomes. Doctors consider overall well-being and tolerance to treatments or medications. 

Response to Therapy

Myeloma that does not respond to treatment, even in the absence of high-risk CA, indicates a “functional” high-risk disease and is associated with poor prognosis. 

Get More Information From the International Myeloma Foundation

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