Multiple myeloma is staged using a system called the Revised International Staging System (R-ISS), which divides the disease into three stages based on blood test results and the genetic profile of the cancer cells. Unlike many solid tumors that are staged by size and spread, myeloma staging is entirely about biology: how aggressively the cancer is behaving at a molecular level and how much damage it has already done to your body’s normal functions.
Before getting into the formal stages, it helps to know that myeloma doesn’t appear out of nowhere. It develops through precursor conditions that aren’t yet cancer, and understanding where those fit in the picture gives the staging system more context.
The Precursor Conditions Before Myeloma
Nearly all cases of multiple myeloma begin as a condition called monoclonal gammopathy of undetermined significance, or MGUS. In MGUS, a small number of abnormal plasma cells produce an unusual protein detectable in the blood, but there are no symptoms and no organ damage. Most people with MGUS never develop myeloma. The risk of progression is roughly 1% per year.
Between MGUS and active myeloma sits smoldering multiple myeloma (SMM). SMM was first defined in 1980 as having 10% or more abnormal plasma cells in the bone marrow, or a monoclonal protein level of 3 g/dL or higher, without any signs of organ damage. People with SMM have a higher risk of progressing to active myeloma than those with MGUS, but they still may go years without needing treatment. Some newer approaches involve early intervention for the highest-risk smoldering patients, though watchful monitoring remains standard for many.
Active multiple myeloma is diagnosed when organ damage or specific biomarkers cross a threshold. The International Myeloma Working Group looks for things like elevated calcium, kidney dysfunction, anemia, bone lesions, or more than one focal lesion on MRI that is at least 5 mm in size. Once you meet these criteria, staging tells you how advanced the disease is.
How the R-ISS Stages Work
The Revised International Staging System uses four factors to assign a stage:
- Beta-2 microglobulin (B2M): a protein in the blood that rises as myeloma becomes more active. Higher levels indicate greater tumor burden.
- Albumin: a protein made by the liver. Lower levels suggest the disease is having a bigger impact on overall health.
- Lactate dehydrogenase (LDH): an enzyme that increases when cells are breaking down rapidly, a sign of aggressive disease.
- Cytogenetics: the genetic profile of the cancer cells, tested through a bone marrow biopsy. Certain chromosome changes classify the cancer as high risk.
These four pieces of information together determine your stage. No imaging scans or tumor measurements factor in.
R-ISS Stage I
Stage I is the most favorable category. To qualify, all four factors must fall in the low-risk range: B2M below 3.5 mg/L, albumin at 3.5 g/dL or higher, normal LDH levels, and no high-risk genetic changes in the cancer cells. Meeting all four criteria together means the disease has a lower tumor burden and a less aggressive biology. Patients diagnosed at Stage I generally have the longest progression-free intervals and the best overall outcomes.
R-ISS Stage III
Stage III sits at the opposite end. It requires B2M of 5.5 mg/L or higher, combined with either high-risk cytogenetics, elevated LDH, or both. This combination signals a high tumor burden and aggressive disease behavior. Stage III carries the shortest expected survival times of the three groups.
R-ISS Stage II
Stage II is essentially everything that doesn’t fit Stage I or Stage III. You might have one unfavorable marker but not enough to reach Stage III, or your B2M might be moderately elevated without the accompanying genetic risk. This makes Stage II the broadest category, and outcomes within it vary considerably depending on which specific factors pushed you out of Stage I.
What Makes Cytogenetics “High Risk”
The genetic changes in your myeloma cells are one of the most important factors in staging and prognosis. The R-ISS specifically flags three abnormalities as high risk:
- Deletion of part of chromosome 17 (del(17p)): this removes a gene that normally helps suppress tumor growth.
- A swap of material between chromosomes 4 and 14 (t(4;14)): this drives more aggressive cell behavior.
- A swap between chromosomes 14 and 16 (t(14;16)): another translocation linked to worse outcomes.
These are detected through specialized testing on bone marrow samples, most commonly a technique called FISH (fluorescence in situ hybridization). Having even one of these abnormalities prevents you from being classified as Stage I and, if combined with a high B2M, places you in Stage III.
Other genetic changes also affect prognosis even though the original R-ISS doesn’t formally include them. The Mayo Clinic classification adds a swap between chromosomes 14 and 20 and a condition called hypodiploidy (where cancer cells have fewer chromosomes than normal) to the high-risk list. An extra copy of part of chromosome 1 (called 1q gain) is another marker increasingly recognized as unfavorable. When three or more of these genetic abnormalities appear together, some researchers classify the disease as “ultra-high risk,” with expected survival under two years without aggressive treatment.
A Newer Four-Tier System
Researchers have proposed a second revision called the R2-ISS that splits patients into four risk groups instead of three. This system assigns points based on the original ISS stage, the presence of del(17p), t(4;14), elevated LDH, and 1q abnormalities. The points add up to place patients into low risk (0 points), low-intermediate risk (0.5 to 1 point), intermediate-high risk (1.5 to 2.5 points), or high risk (3 to 5 points).
In the study that developed this system, about 19% of patients fell into the low-risk group, 31% into low-intermediate, 41% into intermediate-high, and roughly 9% into the highest risk tier. The four-tier model may eventually replace the current three-stage system because it separates the large, mixed Stage II group into more precise categories. For now, the original R-ISS remains the standard in most clinical settings.
The Older Durie-Salmon System
Before the R-ISS, doctors used the Durie-Salmon staging system, developed in the 1970s. It focused on physical markers of disease burden rather than molecular biology. Stage I required hemoglobin above 10 g/dL, normal calcium (below 10.5 mg/dL), and minimal bone damage. Stage III meant hemoglobin below 8.5 g/dL, calcium above 12 mg/dL, and advanced bone lesions visible on X-ray. The system also subdivided each stage by kidney function (A for normal, B for impaired).
You may still see the Durie-Salmon system referenced in older literature or in some treatment centers, but it has largely been replaced by the R-ISS. The newer system is more precise because it incorporates genetic information that better predicts how the disease will behave over time.
Survival by Stage
Survival statistics for myeloma are complicated by the fact that the main U.S. cancer database (SEER) doesn’t track patients by R-ISS stage. Instead, it groups cases into broad categories. The five-year relative survival rate for multiple myeloma overall is about 62%, based on patients diagnosed between 2015 and 2021. Solitary plasmacytoma, a localized form, has an 81% five-year survival rate.
Within the R-ISS framework, Stage I patients consistently live significantly longer than Stage III patients in clinical studies. The gap is substantial: Stage I patients in many datasets have median overall survival measured in years beyond what Stage III patients experience. But these are population-level numbers. Individual outcomes depend heavily on which treatments are used, how well the disease responds, and how many high-risk genetic features are present. Newer treatment combinations have improved survival across all stages, and the numbers continue to shift as therapies advance.
What Staging Means for Treatment
Your stage doesn’t dictate a single treatment path, but it shapes how aggressively your care team approaches the disease. Stage I patients with standard-risk genetics may do well with conventional combination therapy. Stage III patients, especially those with multiple high-risk genetic changes, are more likely to be offered intensive regimens and may be enrolled in clinical trials testing newer approaches like targeted antibodies or cellular therapies.
Staging also sets expectations for monitoring. Higher-stage disease is watched more closely after initial treatment, with more frequent blood work and imaging to catch early signs of relapse. Because myeloma is generally considered treatable but not curable, the stage at diagnosis helps both you and your care team plan for the long game: how often to check in, how quickly to adjust if something changes, and what treatment options to hold in reserve.