Criteria

Durie and Salmon staging system[60]

Widely used classification system, based mainly on tumor burden.

Stage I: all of the following:

  • Hemoglobin value >10 g/dL

  • Serum calcium value normal or ≤12 mg/dL

  • Bone x-ray: normal bone structure or solitary bone plasmacytoma only

  • Low M-component production rate (IgG value <5 g/dL; IgA value <3 g/dL; Bence Jones protein <4 g/24 hours)

Stage II: not stage I or III

Stage III: 1 or more of the following:

  • Hemoglobin value <8.5 g/dL

  • Serum calcium value >12 mg/dL

  • Advanced lytic bone lesions (>3)

  • High M-component production rate (IgG value >7 g/dL; IgA value >5 g/dL; Bence Jones protein >12 g/24 hours)

Patients are further subclassified into either A or B:

  • A: relatively normal renal function (serum creatinine value <2.0 mg/dL)

  • B: abnormal renal function (serum creatinine value ≥2.0 mg/dL)

International Staging System (ISS) for multiple myeloma[61]

This classification system is based on readily available laboratory parameters (i.e., serum beta2-microglobulin and albumin levels). The stages correlate with survival in the 3 subgroups:

  • Stage I: beta2-microglobulin <3.5 mg/L and albumin ≥35 g/L

  • Stage II: not stage I or III

  • Stage III: beta2-microglobulin ≥5.5 mg/L

Revised International Staging System (RISS)[4][62]

This revised classification system has been adopted by the International Myeloma Working Group. The RISS proposes three disease stages by combining the ISS with high-risk cytogenetic abnormalities or elevated lactate dehydrogenase levels:

  • Stage I: beta2-microglobulin <3.5 mg/L, albumin ≥35 g/L, no high-risk cytogenetics, and normal serum lactate dehydrogenase levels

  • Stage II: not stage I or III

  • Stage III: beta2-microglobulin ≥5.5 mg/L and high-risk cytogenetics [t(4;14), t(14;16), or del(17p)], or elevated serum lactate dehydrogenase levels

Second revision of the International Staging System (R2-ISS)[63]

The R2-ISS classification system is validated only for newly diagnosed MM. Points are assigned to the following high-risk features:

  • International Staging System (ISS) stage III: 1.5 points

  • ISS stage II: 1 point

  • Del(17p): 1 point

  • t(4;14): 1 point

  • 1q gain/amplification: 0.5 points

  • Abnormally elevated serum lactate dehydrogenase levels: 1 point

Four risk groups are determined based on the presence of high-risk features (i.e., total point score):

  • Low risk: 0 points (patient has no high-risk features)

  • Low-intermediate risk: 0.5 to 1 point (patient has one high-risk feature except ISS stage III)

  • Intermediate-high risk: 1.5 to 2.5 points (patient has any combination of high-risk features equalling 1.5 to 2.5 points)

  • High risk: 3 to 5 points (patient has any combination of high-risk features equalling 3 to 5 points)

National Comprehensive Cancer Network (NCCN): factors considered as high risk for progression/relapse[44]

Factors considered as high risk for progression/relapse for those with newly diagnosed MM:

  • Revised International Staging System (R-ISS) stage III

  • Extramedullary disease

  • Circulating plasma cells

  • Cytogenetic abnormalities, including del(1p32), t(4;14), t(14;16), t(14;20), del(17p), monosomy 17, TP53 mutation, 1q21 gain/1q21 amplification, and MYC translocation

  • High-risk gene expression profile

Factors considered as high risk for progression/relapse for those with relapsed MM:

  • Relapse within 2 years of initial therapy when transplant and maintenance are used

  • Relapse within 18 months in case of nontransplant-based treatment

  • Acquisition of 1q gain/amplification and/or del(17p)/TP53 mutation

  • Extramedullary disease at relapse

International Myeloma Working Group (IMWG) risk stratification model for smoldering multiple myeloma (SMM)[76]

This risk stratification model proposes three risk groups (incorporating three factors independently associated with progression: serum M-protein >2 g/dL; involved to uninvolved serum free light-chain ratio >20, and bone marrow plasma cells >20%):

  • Low-risk (0 factors): 2-year risk of progression of 6%

  • Intermediate-risk (1 factor): 2-year risk of progression of 18%

  • High-risk (2 or 3 factors): 2-year risk of progression of 44%

The presence of cytogenetic abnormalities, including t(4;14), t(14;16), +1q, and/or del13q, is an additional risk factor that allows for four risk groups:

  • Low-risk (0 factors): 2-year risk of progression of 6%

  • Low-intermediate risk (1 risk factor): 2-year risk of progression of 23%

  • Intermediate-risk (2 risk factors): 2-year risk of progression of 46%

  • High-risk (3 or 4 risk factors): 2-year risk of progression of 63%

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