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Myeloma Staging Systems

Note: There is a change in Harrison 18th edition, as compare to 17th edition. In 18th edition only international staging system is mention. Durie-Salmon Staging System is not given.


Extra Edge: The Durie-Salmon staging system used previously has been found not to predict prognosis after treatment with high-dose therapy or the novel targeted therapies that have emerged. (Harrison-18th, Pg- 941)

Table - Myeloma Staging Systems (Ref. Hari. 18th ed., Pg-705)

Durie-Salmon Staging System
Stage Criteria Estimated Tumor Burden, × 1012 cells/m2
I All of the following:  
  1. Hemoglobin >100 g/L (>10 g/dL)
  2. Serum calcium <3 mmol/L (<12 mg/dL)
  3. Normal bone x-ray or solitary lesion
  4. Low M-component production
    1. IgG level <50 g/L (<5 g/dL)
    2. IgA level <30 g/L (<3 g/dL)
    3. Urine light chain <4 g/24 h
<0.6 (low)
II Fitting neither I nor III 0.6–1.20 (intermediate)
III One or more of the following:  
  1. Hemoglobin <85 g/L (<8.5 g/dL) 
  2. Serum calcium >3 mmol/L (>12 mg/dL) 
  3. Advanced lytic bone lesions
  4. High M-component production
    1. IgG level >70 g/L (>7 g/dL) 
    2. IgA level >50 g/L (>5 g/dL) 
    3. Urine light chains >12 g/24 h
>1.20 (high)
Level Stage Median Survival, Months
Sub classification based on serum creatinine levels
A < 177 mmol/L (<2 mg/dL) IA 61
B > 177 mmol/L (>2 mg/dL) IIA, B 55
  IIIA 30
  IIIB 15
International Staging System
β2M < 3.5, alb β3.5 I (28%) 62
β2M < 3.5, alb < 3.5 or β2M = 3.5–5.5 II (39%) 44
β2M > 5.5 III (33%) 29


Note: β2M, serum β2-microglobulin in mg/L; alb, serum albumin in g/dL; (#), % patients presenting at each stage.
These criteria are replaced by diagnostic criteria for multiple myeloma as below (AIIMS Nov 10)


Triad of MM
  1. BM plasmacytosis >10%
  2. Lytic lesion in the bones in X-ray
  3. Urine or plasma M components
  1. t(11:14) Most common
  2. Chromosome 13q deletion (It indicate poor prognosis)
Diagnostic criteria for multiple myeloma – (AIIMS Nov 10)
  1. Major Criteria
    1. Over 30% of cells in the bone marrow sample are plasma cells
    2. A biopsy result showing a plasma cell tumor (plasmacytoma)
    3. The monoclonal immunoglobulin (M protein) level in the blood or urine exceeds a certain amount. IgG > 3.5 g%, IgA > 2g% or > 1g/24hr of Kappa or Lambda chain on urine electro phoresis.
  2. Minor Criteria
    1. Between 10-30% of cells in the bone marrow sample are plasma cells
    2. A monoclonal immunoglobulin (M protein) level is detected but an insufficient amount is present to satisfy a major criterion
    3. Lytic lesion
    4. The amount of normal antibody (not produced by the cancer cells) in the blood is abnormally low
  3. Genetics:
    1. A variety of chromosomal alterations have been found in patients with myeloma; 13q14 deletions, 17p13 deletions, and 11q abnormalities predominate. 
    2. The most common translocations are t(11;14)(q13;q32) and t(4;14)(p16;q32), errors in switch recombination—the genetic mechanism to change antibody heavy chain isotype—participate in the transformation pathway. (Ref. Hari. 18th ed., pg - 941)
Other investigations are:
  1. Renal function tests (blood urea, creatinine, electrolytes)
  2. Blood calcium and albumin (hypercalcemia)
  3. Bone scan is normal
  4. Plasma Ig level (degree of immune paresis)
  5. Serum β2 microglobulin. It is the single best parameter to tell about poor prognosis.
  6. ESR is highly raised. 
  7. ↑ CRP & ↑ IL-6 (CRP is a surrogated marker of IL-6, which is referred as Plasma Cell growth factor)
  8. Plasma cell -
    1. Increase Acid phosphate
    2. Increase Glucuronidase
  9. Pseudohyponatremia occurs.
  10. Anion gap is less than normal.
  11. Beta–2 microglobulin level are the single most important poor prognostic factor. 
Extra Edge (Ref. Hari. 18th ed., Pg- 939)
  1. Patients with myeloma also have a decreased anion gap [i.e., Na+ – (Cl– + HCO3–)] because the M component is cationic, resulting in retention of chloride
  2. Normal relative serum viscosity is 1.8 (i.e., serum is normally almost twice as viscous as water). Symptoms of hyperviscosity occur at a level greater than 4 centipoise (cP), which is usually reached at paraprotein concentrations of 40 g/L (4 g/dL) for IgM, 50 g/L (5 g/dL) for IgG3, and 70 g/L (7 g/dL) for IgA.


Poor prognostic factors in multiple myeloma
Stage related factors
  1. Stage III disease: High Tumor Burden
    • Hb < 8,5 g/dl
    • Hypercalcemia (Ca > 12 mg/dl)
    • Advanced Lytic bone lesions
    • High M component production
    • IgG > 7g1dl
    • IgA > 5g1dl
    • Urine light chains > 12g/24 hrs
  2. Sub classification based on serum creatinine levels
    Serum creatinine > 2 mg/dl
  3. Independent factors
    • β2 microglobulin (single most important factor)
    • ↓ Serum albumin
    • ↑ LDH
    • ↑ labeling index (%age of cells undergoing mitosis)
    • ↑ CRP or IL6
    • ↑ Hepatocyte growth factor, TGF (β) or syndecans - 1
    • Plasmo blastic morphology
  4. Genetic Abnormalities
    1. Hyperploidy
    2. Chromosome 13 deletion (and chromosome 17p deletion)
    3. t(4; 14), t(l4; 16), t(11; 4) translocation
    4. RAS & P53 mutations.
  1. Patients should be given at least 3 liters of fluid daily to preserve normal renal function. 
  2. Pamidronate 15 – 30 mg slow IV infusion helps in lowering serum calcium. 
  3. Allopurinol 300mg orally daily to prevent excessive formation of uric acid. 
  4. Chemotherapy
    Adriamycin, BCNU, cyclophosphamide and melphalan in 6 weeks pulses achieves best results. 
  5. Alpha – 2 interferon.
  6. Autologous bone marrow transplantation for resistant cases is also under evaluation
  7. Radiotherapy:
    Local irradiation for bone pain, pathological fractures and tumorous lesions. 
Newer drugs.
  1. Thalidomide
  2. Bortezomib (Proteosome inhibitor) (LQ 2012)
Recent Advances
New Drugs:
  1. Amifostine: Cancer chemotherapy produces a wide variety of side effects many of which are disabling. Amifostine is a free radical scavenger that is used to reduce such side effects. It most important therapeutic use is to act as a cytoprotective agent for treatment of alkylating agent-induced cytotoxicity. 
  2. Bortezomib: Existing therapeutic options for multiple myeloma include agents such as thalidomide, bortezomib, and lenalidomide, either used alone or in combination with standard agents, including glucocorticoids, and in conjunction with high-dose chemotherapy supported with stem cell transplantation. Bortezomib is a proteasome inhibitor.


Extra Edge:
Conditions with decreased ESR
  1. Polycythemia
  2. CHF
  3. Sickle cell anemia
  4. Afibrinogenemia
Conditions with increased ESR that need to be remembered:
  1. Multiple myeloma
  2. Anemia other than sickle cell
  3. Giant cell arteritis
  4. De Quervain thyroiditis
Other causes of Bence – Jones proteinuria
  1. Primary amyloidosis
  2. Waldenstrom’s macroglobulinemia
  3. Malignant lymphoproliferative disorders
  4. Idiopathic Bence – Jones proteinuria
Other Causes Of Paraproteins
  1. Monoclonal B gammopathy Of Uncertain Significance (MGUS)
    A paraprotein present in the blood but with no other features of myeloma.
    Age: Elderly Aetiology: Unknown
Clinical features
Patients are usually asymptomatic.
  1. Routine blood count and biochemistry are normal.
  2. The paraprotein is usually present in a small amount with no associated immune paresis. (<3 gm%)
  3. There are no lytic lesions on the bones.
  4. The bone marrow may have increased plasma cells but these are usually less than 10%.
  5. No Bence zone protein = Normal S.ca , no renal failure
  1. Usually symptomatic treatment
  2. Follow up to monitor clinical symptoms and paraprotein levels
  3. Other diseases which can develop in MGUS are lymphomas, amyloidosis, chronic lymphatic leukemia and solid tumors.
With long-term follow-up, approximately 30% of patients develop other problems; 20% develop myeloma and the remainder solid tumours.

Waldenstrom’s Macroglobulinemia (Ref. Hari. 18th ed., Pg- 942)

  1. Waldenström’s macroglobulinemia: is also a monoclonal gammopathy and is characterized by neoplasm of lymphoplasma cytoid cells that secrete IgM
  2. M component is only IgM and not IgG.
  3. This is a low-grade lymphoplasmacytoid lymphoma associated with an IgM paraprotein causing clinical features of hyperviscosity syndrome.
  4. It is a rare tumour occurring in the elderly.
  5. Patients classically present with features of hyperviscosity such as nosebleeds, bruising confusion and visual disturbance.
  6. Presentation may be with anaemia, systemic syndromes, splenomegaly and/or lymphadenopathy.
  7. Patients have an IgM paraprotein associated with a raised plasma viscosity.
  8. The bone marrow has a characteristic appearance, with infiltration with lymphoid cells and in addition many mast cells.
  9. No lytic lesion, normal serum Ca, renal disease is uncommon.
  10. This is characterized clinically by
    1. Lymphadenopathy
    2. Hepatosplenomegaly
    3. Hyperviscosity syndrome
Management (Ref. Hari. 18th ed., Pg - 943)
  1. Server hyperviscosity – plasmapheresis
  2. Anaemia - blood transfusion.
  3. Fludarabine, Chlorambucil
  4. Fludarabine, cladribine, bortezomib, bendamustine, lenalidomide, Rituximab,
  5. Autologous stem cell transplantation
Heavy chain disease (γ, α, μ) (Ref. Hari. 18th, ed., Pg- 944)
Franklin disease is a gamma heavy chain disease. It characterized by elevated levels of a specific heavy chain of immunoglobulins in blood or urine.
  1. Gamma Chain (Franklin disease) – Seen in elderly resemble lymphoma.
  2. Alpha chain (Seligmann’s disease) It is the most common example.
  3. mμ chain – Rarest form, seen in patients with CLL.
Comparison of MGUS, indolent myeloma (IMM) and smoldering myeloma (SMM).
  MGUS SMM IMM Multiple myeloma
Plasma cell (BM) <10% 10-30% >30% >30%
M-component IgG<3.5, IgG>3.5, IgG 3.5-7, IgG >3.5/dl;
  IgA<2 IgA>2 IgA 2-5 IgA >2g/dl
Lytic bone lesion None None ≤3 Present
- Anemia
- Renal insufficiency
- Hypercalcemia
None None None Present

IgM Myeloma

  1. A malignancy of lymphoplasmacytoid cells that secreted IgM. In contrast to myeloma, the disease was associated with lymphadenopathy and hepatosplenomegaly, but the major clinical manifestation was the hyperviscosity syndrome.
  2. The disease resembles the related diseases chronic lymphocytic leukemia, myeloma, and lymphocytic lymphoma. It originates from a post–germinal center B cell that has undergone somatic mutations and antigenic selection in the lymphoid follicle and has the characteristics of an IgM-bearing memory B cell.
  3. Waldenström's macroglobulinemia and IgM myeloma follow a similar clinical course, but therapeutic options are different.
  4. The diagnosis of IgM myeloma is usually reserved for patients with lytic bone lesions and predominant infiltration with CD138+ plasma cells in the bone marrow.
  5. Such patients are at greater risk of pathologic fractures than patients with Waldenström's macroglobulinemia.
  6. IgM in some patients with macroglobulinemia may have specificity for myelin-associated glycoprotein (MAG), a protein that has been associated with demyelinating disease of the peripheral nervous system and may be lost earlier and to a greater extent than the better known myelin basic protein in patients with multiple sclerosis.
Cryoglobulins and cryoglobulinemia
  1. Cryoglobulins are proteins that precipitate at low temperatures and dissolve on rewarming.
  2. Three types of cryoglobulins may be defined.
  3. Many patients with mixed cryoglobulinemia have and underlying infection with Hepatitis C virus.
Table - Cryoglobulins and Cryoglobulinemia
  Type Clinical Features
1. Monoclonal cryoglobulins Associated with hematologic malignancies
Heavy proteinuria, hematuria, and, occasionally, anuria
Histologic lesion: usually is a membranoproliferative glomerulonephritis
2. Mixed cryoglobulins that include a monoclonal component with antibody activity against polyclonal IgG Associated with a syndrome of immune-complex vasculitis; approximately 50% of patients have renal disease
Wide spectrum of clinical signs that vary greatly in severity
Hypertension, azotemia, and anuria, which are poor prognostic signs
Endocapillary proliferation and mesangial prominence (common pathologic features)
3. Mixed cryoglobulins in which both components are polyclonal May be associated with a variety of other diseases, with or without renal disease, including SLE, hepatitis B or C, and systemic infections

  1. in idiopathic cases is not standardized.
  2. Immunosuppressive and steroids are occasionally effective.
  3. Encouraging results have been obtained with plasmapheresis, particularly in patients with mixed cryoglobulinemia. Antiretroviral therapy may be effective in patients with HCV-caused mixed cryoglobulinemia.

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