Multiple Myeloma Staging: Understanding DS, ISS, and R-ISS Systems

Multiple myeloma is a complex blood cancer that affects plasma cells in the bone marrow. Accurately determining the stage of the disease is essential for guiding treatment decisions and predicting patient outcomes. Over the years, several staging systems have been developed to classify the progression of multiple myeloma based on key clinical and laboratory markers. The most widely used include the Durie-Salmon (DS) system, the International Staging System (ISS), and the more advanced Revised International Staging System (R-ISS). Each provides unique insights into disease severity and prognosis.

Durie-Salmon (DS) Staging System

The Durie-Salmon staging model, introduced in the 1970s, remains one of the earliest and historically significant frameworks for assessing multiple myeloma. This system evaluates tumor burden by analyzing three primary factors: the degree of anemia, levels of M-protein in urine, and the extent of bone damage visible on imaging studies such as X-rays. Based on these criteria, patients are classified into three stages—Stage I, Stage II, and Stage III—with higher stages indicating greater disease activity and tumor mass.

Renal Function Subgroups in DS Staging

In addition to the main stages, the DS system incorporates kidney function through subgroup classification. Patients with serum creatinine levels below 2.0 mg/dL are placed in Group A, indicating normal renal function. Those with creatinine at or above this threshold fall into Group B, signaling impaired kidney function—a critical factor linked to poorer outcomes. While the DS system offers a visual and biochemical snapshot of disease burden, it has largely been supplemented by more modern models that rely on simpler, more reproducible biomarkers.

International Staging System (ISS)

To address some limitations of the DS model, the International Staging System (ISS) was introduced in 2005. This system simplifies staging by focusing on two readily available blood markers: serum albumin and beta-2 microglobulin (β2-M). Elevated β2-M levels reflect increased tumor load and reduced kidney clearance, while low albumin often indicates more aggressive disease and systemic inflammation.

Under the ISS, patients are divided into three stages:

Stage I: Low β2-M (< 3.5 mg/L) and high albumin (≥ 3.5 g/dL)
Stage II: Values that don't meet Stage I or III criteria
Stage III: High β2-M (≥ 5.5 mg/L), indicating advanced disease

The ISS has proven highly effective in predicting survival and is now considered a global standard due to its simplicity and reliability across diverse populations.

Revised International Staging System (R-ISS)

With advances in genetic testing and molecular profiling, the R-ISS was developed in 2015 to refine prognostic accuracy even further. Building upon the foundation of the ISS, this updated model integrates additional high-risk factors:

Cytogenetic abnormalities detected by fluorescence in situ hybridization (FISH), such as del(17p), t(4;14), and t(14;16)
Lactate dehydrogenase (LDH) levels, where elevated values suggest rapid tumor turnover or extramedullary disease

How R-ISS Improves Prognostic Precision

The R-ISS combines ISS staging with these new variables to stratify patients into three distinct risk categories:

R-ISS Stage I: Favorable prognosis with low tumor burden and no high-risk markers
R-ISS Stage II: Intermediate risk, including those not meeting Stage I or III criteria
R-ISS Stage III: Highest risk, featuring elevated β2-M, high LDH, and/or adverse cytogenetics

This enhanced stratification allows oncologists to tailor therapies more effectively—opting for standard regimens in lower-risk cases or considering novel agents, stem cell transplantation, or clinical trials for high-risk patients.

In conclusion, understanding how multiple myeloma is staged empowers both clinicians and patients to make informed decisions about care. While the DS system laid the groundwork, the ISS and especially the R-ISS represent significant advancements in precision medicine, offering clearer insights into disease behavior and long-term outlook. As research continues, future staging models may incorporate immune profiles, minimal residual disease (MRD) status, and genomic sequencing for even greater personalization of treatment strategies.