The International Staging System (ISS) and the revised (R)-ISS
Introduced in 2005, the International Staging System (ISS) also involves three stages (I-III), defined by the levels of two specific factors, beta-2 microglobulin and albumin, found in blood. In 2015, the ISS was updated to include chromosomal abnormalities and lactate dehydrogenase levels. This enables better stratification of newly diagnosed patients with respect to their prognosis and forms the most commonly used staging system for myeloma today: the Revised International Staging System (R-ISS). The R-ISS staging calculator provides a quick method of staging patients in clinic.
These measurements and their significance are described in more detail in the next section and the revised stages are summarised in Table 1.
Table 1: The International Staging System (ISS), revised ISS (R-ISS) and R2-ISS
| Stage/Group | ISS | R-ISS | R2-ISS |
|---|---|---|---|
| I | β2M < 3.5mg/L and serum albumin ≥ 3.5 g/dL | β2M < 3.5mg/L and serum albumin ≥ 3.5g/dL and no high-risk cytogenetics [t(4;14), t(14;16), or del(17p)] and normal LDH | Low-risk: 0 points* Not ISS stage II or IIINormal LDHDel(17p), t(4;14), 1q+ not detected |
| II | Not ISS stage I or III | Not R-ISS stage I or III | Low-intermediate risk: 0.5-1 points* ISS stage II orElevated LDH orDel(17p) or t(4;14) or 1q+ detected |
| III | β2M ≥ 5.5 mg/L | β2M ≥ 5.5 mg/L and elevated LDH or high-risk cytogenetics [t(4;14), t(14;16), or del(17p)] | Intermediate-high risk: 1.5-2.5 points* Any combination of high-risk features* which equals a score of 1.5-2.5 |
| IV | N/A | N/A | High-risk: 3-5 points* Any combination of high-risk features* which equals a score of 3-5 |
*R2-ISS is an additive scoring system based on the following: ISS II (1pt), ISS III (1.5pts), del(17p) (1pt), elevated LDH (1pt), t(4;14) (1pt), 1q+ (0.5pts)
The R-ISS is a more robust prognostic tool compared to ISS and provides patients with a more accurate prognosis. More recently, a second revision of the R-ISS, the R2-ISS, has been issued to incorporate revised cytogenetic risk factors and to take into account that R-ISS stage II patients can vary greatly in their prognosis. This splits the intermediate risk group into two: low-intermediate and high-intermediate (Table 1).
Staging information and the presence or absence of prognostic factors can be used to risk stratify patients and predict outcomes. However, healthcare professionals must recognise that these prognostic systems can lack accuracy for individual patients, and some patients will do better or worse than expected from their R-ISS stage. For example, some of the more common chromosomal translocations have been shown not always to represent more aggressive myeloma as they can be found in individuals with MGUS.
In theory, staging could also be used to inform treatment decisions, and this is becoming increasingly significant for those patients with high-risk disease. However, this must be viewed in the context of health technology assessment (HTA) guidance, which can stipulate the treatment pathways and options for patients. At present, the R-ISS is not recommended for determining treatment except within a clinical trial setting where it may provide a useful framework for testing new treatment strategies.
The communication of this sensitive information can often be challenging, with nurses often being asked by patients and their families to discuss issues arising from staging and prognostic conversations they may have had with medical staff. Listening to the patient and taking cues from them about their understanding helps guide the conversation and allows nurses to navigate the fine line between their hope, expectations, and fears.
The main prognostic factors important for staging and risk stratification will be discussed in the following sections.
Further reading
Beta-2 microglobulin
Beta-2 microglobulin (β2M) is a protein that is present on the surface of white blood cells. In myeloma, β2M is increased in proportion to the number of myeloma cells and therefore is regarded as the best single indicator of tumour burden in myeloma. High levels of β2M can also be a sign of kidney damage and therefore can be raised in someone with pre-existing kidney problems such as chronic kidney disease (CKD).
The normal value for serum β2M is <2 mg/L in blood, although this value may vary slightly between laboratories.
There is no strict cut-off to separate patients with a favourable or less favourable prognosis. Historically, studies have used different levels to categorise patients; however, following an International Myeloma Working Group (IMWG) review of almost 12,000 patients, it was determined that:
- β2M < 3.5 mg/L is associated with a favourable prognosis (provided albumin level is normal) – Stage I disease
- β2M ≥ 5.5 mg/L is associated with a less favourable prognosis – Stage III disease
Albumin
Albumin is a protein made by the liver that makes up more than half of the total protein in blood. In myeloma, chemical messengers (cytokines) produced by myeloma cells suppress albumin production. Therefore, a lower level of albumin indicates greater myeloma activity and is associated with a less favourable prognosis.
Like β2M, there is no strict cut-off point to separate patients with a favourable or less favourable prognosis but under the IMWG recommendations, an albumin level < 35g/l is associated with a poorer prognosis.
Cytogenetic factors
Cytogenetic factors are of prognostic importance in myeloma because chromosomal abnormalities are a key feature in the development and progression of the disease. They play a large role in the risk stratification of patients, guiding prognosis and in some cases, treatment decisions.
Nearly all myeloma patients have chromosomal abnormalities which involve structural changes that may include loss or gain of part or whole chromosomes and/or mismatching of parts of chromosomes (translocations). These chromosomal changes appear to dictate the nature and the biology of the myeloma. Certain abnormalities appear to have an impact on survival and therefore are of potential prognostic significance. FISH (fluorescence in situ hybridization) analysis has become the technique of choice to detect specific chromosomal abnormalities. Using this method, 80-90% of patients show chromosomal abnormalities in samples taken from their bone marrow.
Chromosomal abnormalities associated with poorer prognosis include deletions of parts of chromosome 17 (del 17), translocations between chromosomes 4 and 14 (t(4;14)), between chromosomes 14 and 16 (t(14;16)) and between 14 and 20 (t(14;20)) and gains in 1q21. Patients with such chromosomal abnormalities are defined as “high risk” and it is recommended that they are included in the minimal panel for testing when staging myeloma patients, as defined by the R-ISS and summarised in Table 1. When detected in patients with smouldering myeloma, specific cytogenetic abnormalities can act as predictors of progression to active myeloma e.g. del(17p) has a high-risk of progression, with a median time of 2 years. In those already with active myeloma, this high-risk classification corresponds to a low median overall survival of 3 years.
The cytogenetic markers outlined in the R-ISS are the most widely accepted markers of prognosis, however others e.g. from the Mayo Clinic may also be considered as shown in Table 2.
| Risk group | % newly diagnosed patients with this abnormality | Prognosis (active myeloma) |
|---|---|---|
| Standard risk | 60% | |
| Trisomies t(11;14) t(6;14) | Good prognosis, standard-risk MM, median OS 7–10 years | |
| High risk | 40% | |
| t(4;14) | Intermediate-risk MM, median OS 5 years | |
| t(14;16) | High-risk MM, median OS 3 years | |
| t(14;20) | High-risk MM, median OS 3 years | |
| Del(17p) | High-risk MM, median OS 3 years | |
| Gain(1q) | Intermediate-risk MM, median OS 5 years |
*Double-hit myeloma: any 2 high risk factors. Triple-hit myeloma: any 3 or more high risk factors.
Lactate dehydrogenase
Lactate dehydrogenase(LDH) is an enzyme found in most cells of the body. Usually, the concentration in the blood is low, because it stays contained within the tissues’ cells. When cells are damaged or destroyed however, they release LDH into the bloodstream, causing blood levels to rise. It can be elevated in a number of conditions, including cancer and heart disease.
In myeloma, LDH level is an indicator of tumour cell burden. Although LDH testing methods and normal ranges differ, in general a high level of LDH is associated with a less favourable prognosis.