Multiple Myeloma (MM) is a cancer originating in the bone marrow’s plasma cells. When these specialized white blood cells become malignant, they proliferate uncontrollably, crowding out healthy blood cells and causing damage to the bones and kidneys. Determining the extent and biological aggressiveness of the disease is achieved through staging. The most current and comprehensive method used globally to classify the disease’s prognosis is the Revised International Staging System (R-ISS). This system integrates multiple factors to provide a precise risk assessment, helping patients and physicians understand the expected behavior of the disease.
Defining the Revised International Staging System
The Revised International Staging System (R-ISS) was established in 2015 by the International Myeloma Working Group (IMWG). It improved upon the older International Staging System (ISS), which relied solely on two blood markers, by incorporating genetic and metabolic data. This revised system uses a combination of four distinct factors to sort newly diagnosed multiple myeloma patients into three prognostic stages. Integrating these variables provides a more nuanced understanding of the disease’s biological nature and overall burden.
The foundational framework of the R-ISS begins with the two serum markers from the original ISS: serum Beta-2 Microglobulin (B2M) and serum Albumin. B2M is a small protein shed by myeloma cells, and its concentration in the blood serves as a measure of the tumor burden. Conversely, serum Albumin, a protein made by the liver, is a general indicator of overall health, and lower levels are often associated with more advanced disease activity. These two markers initially divide patients into broad categories of risk.
R-ISS Stage I represents the most favorable prognostic group, requiring a B2M level less than 3.5 mg/L and an Albumin level of 3.5 g/dL or greater. Stage I patients must also have no evidence of high-risk genetic abnormalities and normal levels of Lactate Dehydrogenase (LDH). R-ISS Stage III identifies the highest-risk category. This stage is automatically conferred if the patient has a B2M level of 5.5 mg/L or higher, or if they possess specific high-risk genetic factors or high LDH levels. R-ISS Stage II encompasses all other patients who do not meet the criteria for either Stage I or Stage III, positioning them in an intermediate-risk group.
The Role of High-Risk Genetic Factors in Staging
The inclusion of cytogenetic factors is the defining feature that makes the R-ISS an improved prognostic tool. Cytogenetics refers to the study of chromosomes in myeloma cells, typically analyzed through Fluorescence In Situ Hybridization (FISH) on a bone marrow sample. Specific chromosomal abnormalities indicate a more aggressive disease form, even if serum markers suggest a lower disease burden. These genetic findings reflect the underlying malignant biology and can override favorable serum results.
The R-ISS identifies three major cytogenetic abnormalities that are considered high-risk and automatically contribute to a Stage III classification. The first is the deletion of a portion of chromosome 17, del(17p), which results in the loss of the TP53 tumor suppressor gene. The absence of this gene impairs the cell’s ability to self-destruct, leading to uncontrolled proliferation and resistance to certain therapies. The R-ISS also flags specific chromosomal translocations, which involve the exchange of genetic material between two different chromosomes.
The two key high-risk translocations are t(4;14) and t(14;16). The t(4;14) translocation places an oncogene next to an active genetic switch, leading to the overexpression of a protein that drives myeloma cell growth. Similarly, t(14;16) causes the overexpression of another gene that promotes malignant behavior. Detecting any one of these three genetic abnormalities—del(17p), t(4;14), or t(14;16)—is sufficient to place a patient into the highest-risk R-ISS Stage III category.
Another high-risk factor incorporated into the R-ISS Stage III definition is an elevated level of Lactate Dehydrogenase (LDH). LDH is an enzyme found in almost all body tissues, and high serum levels suggest a high turnover or destruction of cells, common in rapidly growing cancers. Elevated LDH indicates an aggressive disease biology and contributes to the Stage III designation alongside high-risk cytogenetics. This multi-factor approach ensures that patients with biologically aggressive disease are accurately identified.
Predicting Outcomes Based on RISS Stage
The primary purpose of the R-ISS is to provide a reliable prognosis, including expected survival and time until the disease progresses. The three distinct stages—I, II, and III—translate directly into low, intermediate, and high-risk categories, each with a statistically different expected outcome. This stratification allows for clear, evidence-based discussion regarding the likely behavior of the specific myeloma. The R-ISS classification is a powerful predictor because it combines the extent of the disease (B2M/Albumin) with its biological nature (cytogenetics/LDH).
Patients classified with R-ISS Stage I, who have favorable blood markers and no high-risk genetic factors, are considered to have standard-risk disease and the most favorable outlook. Clinical data demonstrated that this group has a 5-year overall survival (OS) rate of approximately 82%. The median progression-free survival (PFS) for Stage I patients is approximately 66 months, reflecting a prolonged period of disease control. This low-risk designation frames the expectations for a longer, more manageable clinical course.
R-ISS Stage II patients fall into the intermediate-risk category, as their results do not meet the criteria for Stage I or Stage III. This group often includes patients with intermediate levels of B2M, lower Albumin, or non-high-risk cytogenetic abnormalities. The 5-year OS rate for Stage II patients is around 62%, indicating a moderate risk of adverse outcomes. The median PFS for this intermediate group is approximately 42 months.
Patients in R-ISS Stage III face the most challenging prognosis, defined by high B2M, high LDH, or the presence of high-risk cytogenetics. The 5-year OS rate for this group is about 40%, emphasizing the aggressive nature of the disease biology. The median PFS is the shortest, averaging around 29 months. This necessitates a more urgent and aggressive treatment approach from the time of diagnosis.
How Staging Guides Treatment Strategy
The R-ISS classification plays a direct role in guiding the initial treatment strategy for newly diagnosed multiple myeloma patients. Physicians use the stage to determine the intensity of therapy required to achieve a durable remission. The fundamental distinction is made between standard-risk (R-ISS I and II) and high-risk (R-ISS III) treatment protocols.
For patients in the standard-risk categories (R-ISS I and II), treatment typically involves a combination of novel anti-myeloma agents, such as proteasome inhibitors and immunomodulatory drugs. The choice and duration of therapy may be less aggressive than for the high-risk group. The determination of eligibility and timing for an autologous stem cell transplantation (ASCT), where a patient’s own stem cells are used to rescue the bone marrow after high-dose chemotherapy, is a major decision influenced by the R-ISS stage.
Patients classified with R-ISS Stage III disease require a more intensive and aggressive treatment plan to combat resistant and rapidly proliferating myeloma cells. Treatment regimens often involve triplet or quadruplet combinations of the most potent novel agents, sometimes utilizing different drug classes simultaneously to overcome resistance. The Stage III designation may prompt the consideration of tandem (double) ASCT for eligible patients, or the immediate use of maintenance therapy to sustain remission. The staging system serves as a tool for risk-adapted therapy, ensuring treatment intensity matches the biological aggressiveness of the myeloma.