Staging of Multiple Myeloma

Cancer is a heterogenous disease in terms of survival. Cancer staging is a method to classify patients according to prognosis. More advanced stages are associated with a worse prognosis. Patients with a poorer prognosis need to treated more aggressive. Non-haematological cancers are stages by the TNM staging. This system relies on the size of primary tumour, number of regional nodes involved and the presence or absence of distant metastasis to stage cancers. This scheme of of things is inappropriate for haematological cancers because

1. The T Stage: Either it may be difficult to define the primary or in case of lymphoma the lymph node disease may be the primary
2. The N Stage: Lymph node are not involved except in lymphoma where they are the primary site.
3. The M Stage: Other than lymphomas haematological malignancies are “disseminated” at presentation with either the disease in the blood, as is the case with leukaemia, or in the bone marrow in case of multiple myeloma

These differences have resulted in evolution of staging/prognostic systems distinct from the TNM when one deals with haematological malignancies.

Multiple myeloma is a plasm cell neoplasm. It is characterised by a monoclonal protein in the serum and/or the urine, osteolytic lesions, anaemia, hyercalcaemia and renal failure. In the 1960s and 1970s these and other features of the disease were found to predict prognosis. Durie and Salmon in 1975 proposed the first staging system for multiple myeloma using type and amount of the monoclonal protein, haemoglobin, serum calcium and serum creatinine. They defined three stages of multiple myeloma I, II and , III. The tumour load increased as the stage increased. Each stage was further divided into substage A and B depending on the serum creatinine. The Durie-Salmon staging system is as follows:

1. Stage I (All of the below)
   1. Hemoglobin value >10 g/dL
   2. Serum calcium value normal or =12 mg/dL
   3. Bone x-ray, normal bone structure (scale 0) or solitary bone plasmacytoma only
   4. Low M-component production rate (IgG < 5 g/dL; IgA < 3 g/dL; Bence Jones protein <4 g/24 hr)
2. Stage II – Neither stage I nor stage III
3. Stage III  One or more of the following:
   1. Haemoglobin < 8.5g/dL
   2. Serum calcium > 12 mg/dL
   3. Advanced lytic bone lesions (scale 3)
   4. High M-component production rate – IgG  >7 g/dL; IgA >5 g/dL; Bence Jones protein >12 g/24 h

Durie-Salmon sub classifications (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)

This system was widely adapted but the assesment of osteolytic lesions is subjective resulting in a poor reproducibility. Several attempts to improve the system that did not gain widespread acceptance were proposed.

After the introduction of the Duris-Salmon system other prognostic factors emerged. These included serum albumin, C-reactive protein, proliferation indices for bone marrow plasma cells (flowcytometery and S-phase fraction), bone marrow plasma cells and serum β2-microglobulin levels. Serum β2-microglobulin emerged as a good predictor of prognosis. 2005 the international staging system for multiple myeloma was proposed. The ISS stage was determined by only two objectively assessable parameters, serum β2-microglobulin and serum albumin. The staging system was as follows (J Clin Oncol May 20, 2005 vol. 23 no. 15 3412-3420)

1. Stage I, Serum β2-microglobulin less than 3.5 mg/L and serum albumin ≥ 3.5 g/dL
2. Stage II, neither stage I nor III
3. Stage III, Serum β2-microglobulin ≥ 5.5 mg/L

The median survivals by stage are as follows: stage I 62months, Stage II 44 months and stage III 29 months.

Chromosomal studies, conventional karyotyping and interphase chromosomal studies using fluorescent In-situ hybridisation (FISH), identified translocations that adversely affect the out come of myeloma. These included del(17p), translocation t(4;14)(p16;q32) and translocation t(14;16)(q32;q23). In 2015 the chromosomal translocation were incorporated in the ISS and a revised system (R-ISS) was proposed (JCO.2015.61.2267)

The revised staging system is as follows

1. R-ISS I: Serum β2-microglobulin level < 3.5 mg/L and serum albumin level ≥ 3.5 g/dL), no high-risk chromosome anomalies – [del(17p) and/or t(4;14) and/or t(14;16)] and LDH level less than the upper limit of normal range.
2. R-ISS II: Nether R-ISS I nor R-ISS II
3. R-ISS III: ISS stage III (serum β2-microglobulin level > 5.5 mg/L) with either high-risk chromosomal anomalies or high LDH level

Median OS not reached R-ISS, 83 months for R-ISS II and 43 months for R-ISS III. The improved median survival for all stages in R-ISS is a reflection of the efficacy of drug therapy of myeloma.