STAGING

 

The current staging system utilized for multiple myeloma is the International Staging system (ISS). Of note, staging systems cannot fully account for the high variability of patients' outcomes, and genetic abnormalities, such as those identified by FISH analysis, should be taken into consideration, because they are more important than staging in defining the outcomes of individual patients.

 

Durie-Salmon system (old)

 

Stage I

Patients have all of the following:
 - Hb >10.5 g/dL
 - Serum Ca <12 mg/dL
 - Low M-component
          IgG <5 g/dL
          IgA <3 g/dL
          UPEP light chain <4 g/24 hr
 - Skeletal x-ray: normal, or solitary plasmacytoma

 

Stage II

Patients not in either stage I or III

 

Stage III

Patients have any one of the following:
 - Hb <8.5 g/dL
 - Serum Ca >12 mg/dL
 - High M-component
          IgG >7 g/dL
          IgA >5 g/dL
          UPEP light chain >12 g/24 hr
 - Skeletal x-ray: >3 lytic bone lesions

 

Substage

A = serum creatinine <2 mg/dL
B = serum creatinine >2 mg/dL

 

 

 

International Staging System (ISS) (2005)

 

Stage I:   Albumin ≥ 3.5 and beta-2-microglobulin < 3.5

Stage II:  Patients not in either stage I or III

Stage III: Beta-2-microglobulin >5.5

 

The beta-2 microglobulin is the light chain component of the HLA class I antigen complex. It reflects tumor burden and renal function.
The albumin reflects the nutritional status and the presence of nephrotic-range proteinuria.

The ISS is a better staging system than the Durie-Salmon system, because of 3 reasons:
  - It is easier to determine
  - It distributes patients more uniformly across the 3 stages
  - It does not have inter-observer variability (unlike the interpretation of the skeletal survey in the DS system)

 

 

Revised ISS (R-ISS) (2015)

 

Stage I:   ISS I, normal LDH, and no high-risk CA    (5-year PFS 55%, 5-year OS 82%)

Stage II:  Patients not in either stage I or III     (5-year PFS 36%, 5-year OS 62%)

Stage III: ISS III + either high LDH or high-risk CA (5-year PFS 24%, 5-year OS 40%) 

 

High-risk chromosomal abnormalities (CA) are defined by the presence of 17p-, t(4;14), or t(14;16), as detected by FISH.
Serum LDH is considered high if greater than the upper limit of the normal range provided by the local laboratory.

The R-ISS is a better staging system than the ISS, because it takes into account not only albumin and b2m, but also LDH and CA, which are independent powerful prognostic indicators of biological aggressiveness in multiple myeloma.

 

 

 

A new staging system for multiple myeloma patients based on the Southwest Oncology Group (SWOG) experience.
Br J Haematol. 2003 Aug;122(3):441-50.
Jacobson JL, Hussein MA, Barlogie B, Durie BG, Crowley JJ; Southwest Oncology Group.

International staging system for multiple myeloma.
J Clin Oncol. 2005 May 20;23(15):3412-20.
Greipp PR, San Miguel J, Durie BG, Crowley JJ, Barlogie B, Bladé J, Boccadoro M, Child JA, Avet-Loiseau H, Kyle RA, Lahuerta JJ, Ludwig H, Morgan G, Powles R, Shimizu K, Shustik C, Sonneveld P, Tosi P, Turesson I, Westin J.
This study analyzed clinical and laboratory data from 10,750 myeloma patients, and found a reliable staging system, simpler than the old Durie-Salmon system. Patients had newly diagnosed symptomatic multiple myeloma, and they were followed at 17 institutions from several sites, including North America, Europe, and Asia. Important prognostic factors were beta-2-microglobulin, albumin, platelet count, creatinine, and age, but the combination of beta-2-microglobulin and albumin provided the simplest and most powerful risk stratification. Median survival was 62 months in stage I (b2m <3.5 and albumin > or = 3.5), 44 months in stage II (neither stage I nor III), and 29 months in stage III (b2m > or = 5.5).

International prognostic index (IPI) - a critical comparison with five multiple myeloma staging systems in the group of 270 patients treated by conventional chemotherapy.
Neoplasma. 2006;53(4):277-84.
Scudla V, Zemanova M, Minarik J, Bacovsky J, Ordeltova M, Indrak K, Budikova M, Dusek L, Farbiakova V.

Evaluation of five staging systems in 470 patients with multiple myeloma.
Haematologica. 2006 Aug;91(8):1149-50.
Mihou D, Katodritou I, Zervas K.
This study evaluates and compares 5 different staging systems in 470 patients with newly diagnosed multiple myeloma:
  - ISS (International Staging System)
  - Durie-Salmon
  - SWOG (South West Oncology Group)
  - Bataille et al.
  - Weber et al.
The ISS was the best one, because of its simplicity and high prognostic power.

Clinical impact of discordance in serum albumin measurements on myeloma international staging system.
J Clin Oncol. 2008 Aug 20;26(24):4051-2.
Kapoor P, Snozek CL, Colby C, Larson DR, Katzmann JA, Rajkumar SV, Greipp PR.
Serum albumin level, necessary for ISS staging, can be measured either by serum protein electrophoresis or by the bromcresol assay, as part of the chemistry panel. These authors show that the two methods provide equivalent results. They recommend using the albumin level obtained by SPEP for convenience, in order to avoid missing data in clinical trials, because SPEP is always ordered at the time of diagnosis of multiple myeloma.

Incorporation of the bone marker carboxy-terminal telopeptide of type-1 collagen improves prognostic information of the International Staging System in newly diagnosed symptomatic multiple myeloma.
Leukemia. 2008 Sep;22(9):1767-72.
Jakob C, Sterz J, Liebisch P, Mieth M, Rademacher J, Goerke A, Heider U, Fleissner C, Kaiser M, von Metzler I, Müller C, Sezer O.
This study evaluated several prognostic markers for the identification of high-risk myeloma among 100 patients with newly diagnosed symptomatic multiple myeloma. Significant prognostic factors included beta2-microglobulin, albumin, transplantation, monosomy 13, and also the carboxy-terminal telopeptide of type-1 collagen (ICTP), a marker of bone resorption. After multivariate analysis, ICTP was the most powerful prognostic factor. After incorporation of ICTP in the ISS, the combined ICTP-ISS score separated 4 groups, with a 5-year overall survival rate of 95%, 64%, 46% and 22%.

Prognostic value of the serum free light chain ratio in newly diagnosed myeloma: proposed incorporation into the international staging system.
Leukemia. 2008 Oct;22(10):1933-7.
Snozek CL, Katzmann JA, Kyle RA, Dispenzieri A, Larson DR, Therneau TM, Melton LJ 3rd, Kumar S, Greipp PR, Clark RJ, Rajkumar SV.
Serum levels of free light chains were obtained at the time of diagnosis in 790 patients with multiple myeloma. The levels had prognostic significance, with inferior survival in 479 patients with a kappa/lambda ratio >32 (kappa myeloma) or <0.03 (lambda myeloma) compared with 311 patients with a kappa/lambda ratio between 0.03 and 32 ( 30 vs 39 months). The authors incorporated the abnormal kappa/lambda ratio with the ISS, for improved risk stratification.

Inter-laboratory discordance of beta-2 microglobulin results: impact on the validity of the international staging system for multiple myeloma.
Br J Haematol. 2014 Sep;166(6):951-3.
Fedele PL1, Choy KW, Doery JC, Grigoriadis G, Shortt J, Lu ZX.
In this study, 21 patient serum samples were sent to 4 different laboratories for determining the beta-2 microglobulin levels. Two laboratories used a turbidimetric method, one nephelometry, and one chemiluminescence. Interestingly, the results among the laboratories were discordant, and it resulted in a different risk stratification by the ISS staging system. The concordance of the ISS stage among the 4 laboratories was only 57%.

Revised International Staging System for Multiple Myeloma: A Report From International Myeloma Working Group.
J Clin Oncol. 2015 Sep 10;33(26):2863-9.
Palumbo A, Avet-Loiseau H, Oliva S, Lokhorst HM, Goldschmidt H, Rosinol L, Richardson P, Caltagirone S, Lahuerta JJ, Facon T, Bringhen S, Gay F, Attal M, Passera R, Spencer A, Offidani M, Kumar S, Musto P, Lonial S, Petrucci MT, Orlowski RZ, Zamagni E, Morgan G, Dimopoulos MA, Durie BG, Anderson KC, Sonneveld P, San Miguel J, Cavo M, Rajkumar SV, Moreau P.
The IMWG combined the data of 4,445 patients with newly diagnosed multiple myeloma enrolled in 11 international trials, and proposed a revised staging system for multiple myeloma (R-ISS). Median follow-up of these patients was 46 months. The revised system takes into account not only albumin and beta2-microglobulin, but also LDH and chromosomal abnormalities (CA) detected by FISH. Serum LDH was considered high if greater than the upper limit of normal range provided by the local laboratory. High-risk CA were defined by the presence of 17p-, t(4;14), or t(14;16).
The three new groups were defined as follows:
  - R-ISS   I (  871 pts): ISS I, normal LDH, and no high-risk CA    (5-year PFS 55%, 5-year OS 82%)
  - R-ISS  II (1,894 pts): Not R-ISS stage I or III                  (5-year PFS 36%, 5-year OS 62%)
  - R-ISS III (  295 pts): ISS III + either high LDH or high-risk CA (5-year PFS 24%, 5-year OS 40%)  

 

 


Giampaolo Talamo, M.D.