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Multiple Myeloma International Staging System (ISS)

Multiple Myeloma International Staging System (ISS) is practical tool utilized for the prognosis of multiple myeloma severity
Serum β2 microglobulin
<3.5 mg/L 0
3.5 - 5.4 mg/L 1
>5.4 mg/L 2
Serum albumin
<3.5 g/dL 0
>=3.5 g/dL 10


Measured Factor
Multiple Myeloma International Staging System
Measured Factor Disease
  • Multiple myeloma
Measured Factor Detail
Multiple Myeloma International Staging System (ISS) is used in newly diagnosed multiple myeloma patients. It is used to differentiate the patients into 3 separate prognostic groups. The calculation takes into account patient features such as level of serum albumin and β2 microglobulin.
Body System
Measured Factor Low Impact
  • Stage 1 indicates low risk; serum β2 microglobulin <3.5 mg/L and serum albumin ≥ 3.5 g/dL
Measured Factor High Impact
  • Stage 2 illustrates moderate risk; serum β2 microglobulin <3.5 mg/L, but serum albumin <3.5 g/dL or Serum β2 microglobulin 3.5 – 5.4 mg/L irrespective of the serum albumin
  • Stage 3 indicates high risk; Serum β2 microglobulin ≥5.5 mg/L

Result Interpretation

Ranges Ranges
  • Critical High: ≥5.5
Result High Conditions
  • Multiple myeloma
False Positive
  • Chronic kidney disease
  • Usage of serum FLC assay in screening panels
References: 2
Test Limitations
ISS may not discriminate between stage I and stage II patients
References: 3


Study Validation 1
This study aims to prove that there is need for a reliable, simple staging system for multiple myeloma which can be applied for patient classification and stratification internationally. 10,750 patients were gathered for Clinical and laboratory data with untreated symptomatic myeloma patients from 17 different institutions in Asia, Europe, North America. Serum beta2-microglobulin, age, platelet count, serum albumin, and serum creatinine emerged as strong predictors of survival which were used in the tree analysis. It is concluded that the new ISS is based on easy to use variables which is recommended for widespread use.
References: 4
Study Validation 2
TaqMan Low Density Arrays performed global analysis of serum mRNAs, followed by quantitative real-time PCR has been done in this study. The analyses showed that five deregulated microRNAs named miR-744, let-7d, miR-130a, let-7e, and miR-34a, relapsed and newly diagnosed the multiple myeloma in monoclonal gammopathy of undetermined significance when compared to healthy donors. Lower levels of let-7e and miR-744  were related with shorter remission of myeloma and overall survival patients. The study demonstrate that microRNAs are altered in monoclonal gammopathy and multiple myeloma and let-7e with miR-744 are associated with survival of patients with myeloma.
References: 5
Study Validation 3
The study is to assess this ISS model in patients with Waldenstrom's macroglobulinemia (WM). A total of 83 untreated patients with WM required systemic treatment and pretreatment values for both b2-microglobulin and serum albumin were available. Patients were laminated into three ISS stages based on these variables. Stage I contains albumin > or = 3.5 g/dl, b2-microglobulin < 3.5 mg/dl, stage II consist of albumin < 3.5 g/dl, b2-microglobulin < 3.5 mg/gl and stage III consists of b2-microglobulin > 5.5 mg/dl. 45% of patients were recorded with low albumin and 52% of patients with high b2-microglobulin respectively. The median overall survival (OS) was 115 months. Analysis indicated that recently proposed ISS for multiple myeloma (MM) could stratify the patients with Waldenstrom's macroglobulinemia into three unique subgroups with different survival times. International staging system, if validated in independent series, a new staging system for WM was provided.
Study Additional 1
The aim of the study is to evaluate prognostic value of ISS in newly diagnosed MM (NDMM). Clinical and laboratory data was collected from 4,445 patients with NDMM were pooled together. Investigators enrolled three groups named as revised ISS including ISS stage I, no high-risk CA, and normal LDH level ; R-ISS III, including ISS stage III and high-risk CA; and R-ISS II, including all the other possible combinations. The study concluded that R-ISS is a powerful and simple prognostic staging system. The study recommend use of ISS to stratify patients with NDMM in clinical studies.
References: 6
Study Additional 2
This study involves the comparison of symptom of patients with diagnosed MM by ISS Stage. Total 599 patients were involved for analysis. Race, Sex, heavy and light chain isotypes all were equally distributed among the ISS stages. The median age was 62 for ISS stage I, 67 for ISS stage III, 65 for stage II. Stage III patients had higher serum M-proteins, LDH, bone marrow plasma cells, circulating plasma cells, creatinine, platelets and lower hemoglobin but Stage I and II patients were similar in disease burden. Further, stage III patients had physical functioning, poorer performance status, global health, social functioning, role functioning, and increased fatigue and pain. It is Concluded that Stage I and stage II Patients had lower disease and symptom burden than Stage III.
References: 3
Study Additional 3
The aim of the study was to validate and compare the Lung Injury Score (LIS) with Berlin definition in patients with acute respiratory distress syndrome (ARDS). A total 550 ARDS patients were recruited in this validation study. Results showed that with every one point increase the probability of in-hospital death increased to 58% odds and similar pattern was seen with Berlin score. The predictive value of both the scores was also found to be similar. This study concluded that both LIS and Berlin score were correlated with increased in hospital morbidity and in hospital mortality in patients with ARDS.
References: 7


  1. Durie BG, Salmon SE. A clinical staging system for multiple myeloma. Correlation of measured myeloma cell mass with presenting clinical features, response to treatment, and survival. Cancer. 1975;36(3):842-54.
  2. Katzmann JA. Screening panels for monoclonal gammopathies: time to change. Clin Biochem Rev. 2009;30(3):105-11.
  3. Fiala MA, Slade M, Keller J, Stockerl-Goldstein K, Tomasson M, Wildes TM, et al. The Association of International Staging System (ISS) Stage with Disease and Symptom Burden in Patients with Newly Diagnosed Multiple Myeloma. Blood. 2015; 126:2115
  4. Greipp PR, San miguel J, Durie BG, Crowley JJ, Barlogie B, Bladé J, et al. International staging system for multiple myeloma. J Clin Oncol. 2005;23(15):3412-20.
  5. Tichý M, Maisnar V, Palicka V, Friedecký B, Vávrová J, Novotná H, et al. International Staging System required standardization of biochemical laboratory testing in multiple myeloma. Neoplasma. 2006;53(6):492-4.
  6. Palumbo A, Avet-loiseau H, Oliva S, et al. Revised International Staging System for Multiple Myeloma: A Report From International Myeloma Working Group. J Clin Oncol. 2015;33(26):2863-9.
  7. Dimopoulos M, Gika D, Zervas K, Kyrtsonis M, Symeonidis A, Anagnostopoulos A, et al. The international staging system for multiple myeloma is applicable in symptomatic Waldenstrom's macroglobulinemia. Leuk Lymphoma. 2004;45(9):1809-13.

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