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Multiple myeloma

Plasma Cell Dyscrasias

These are a group of disorders characterized by the expansion of a single clone of immunoglobulin (Ig) secreting cells and are associated with increase in levels of homogenous Ig or its fragments.
Examples of Monoclonal Gammopathies
  1. Myeloma -    
    a. Multiple myeloma   
    b. solitary plasma cytoma
  2. Waldenström’s macroglobulinemia
  3. Heavy chain disease (g, a, m)
    a. Gamma Chain (Franklin disease) – Seen in elderly resemble lymphoma.
    Franklin disease is a gamma heavy chain disease. It characterized by elevated levels of a gamma heavy chain of immunoglobulins in blood and urine.
    b. Alpha chain (Seligmann’s disease)  - It is the most common type of heavy chain disease.
    c. mu chain – Rarest form, seen in patients with CLL.
  4. Primary or immunocyte associated amyloidosis
  5. Monoclonal gammopathy of undetermined significance (benign IgG, IgA, IgD, IgM, and rarely free light chains,  biclonal gammopathies, idiopathic Bence Jones proteinuria)

Multiple Myeloma

It is a malignant neoplasm of plasma cells.
Peak age group   : 60 years and above
Light chain disease:  No serum M component; only Bence Jones proteinuria
Immunopathology: In myeloma, the transformation of B – lymphocytes to plasma cells manufacturing immunoglobulins is defective resulting in the production of abnormal monoclonal immunoglobulin. Q

Variant Forms of Myeloma

  1. Smoldering myeloma (SMM M – protein level > 3 gm/dl in the serum, > 10% atypical plasma cells in the bone marrow but no anemia, renal insufficiency or skeletal lesions). No lytic lesion, Serum Calcium is normal.
  2. Plasma cell leukemia (> 20% plasma cells in the peripheral blood and absolute plasma cell count is around 2000/mL).
  3. Nonsecretory myeloma – All features of MM except there is no M protein in serum or in urine.
  4. IgD myeloma (M – protein is smaller, and Bence – Jones proteinuria is of gamma type. Extramedullary plasmacytomas, plasma cell leukemia, and amyloidosis are common). They present with small band or no evident M-spike on serum protein electrophoresis. Higher incidence of renal insufficiency, amyloidosis and proteinuria than IgG/ IgA myeloma. Higher incidence of extramedullary involvement and inferior survival rates.
  5. Osteosclerotic myeloma (associated with the acronym POEMS – Polyneuropathy, Organomegaly, Endocrinopathy, M – protein, Skin changes)
  6. Solitary plasmacytoma


Extra Edge:  

Bence Jones Protein

  1. A Bence Jones protein is a monoclonal globulin protein found in the blood or urine. 
  2. Causes:      a. Multiple myeloma    b.  Waldenström's macroglobulinemia
  3. The proteins are immunoglobulin light chains (paraproteins) and are produced by neoplastic plasma cells. They can be kappa (most of the time) or lambda. 
  4. The light chains can be immunoglobulin fragments or single homogeneous immunoglobulins.
  5. The light chains can be detected by heating or electrophoresis of concentrated urine. Light chains precipitate when heated to 50 - 60 degrees C and redissolve at 90 -100 degrees C. 



Clinical Features of Multiple Myeloma
  1. The major feature of myeloma is the demonstration of an abnormal monoclonal protein (M protein) in the blood, urine, or both. This M protein usually consists of either one or a combi­nation of heavy chains (lgG and IgA) and light chains (K and l).
  2. Complications occur due to: Infiltration of the marrow by large numbers of plasma cells, which are usually abnormal
    1. Anaemia : normocytic and normochromic (Note: leukopenia and thrombocytopenia are rare feature)
    2. Weakness, fatigue, infection, and bleeding due to marrow failure
    3. Osteolytic lesions (Activation of osteoclast activating factor by IL-6 ) resulting from myeloma-induced bone resorption with subsequent pain (m/c symptom) and fracture. Bone involvement in MM is as follows:
      Vertebral column > ribs > Skull > Pelvis > Femur > Clavicle > Scapula
    4. Renal abnormalities due to myeloma infiltration of the kidney, hypercalcemia, toxic effects of light chains on tubules, amyloid deposition, and hyperuricemia. Urine cast is made up of light chain only (Not a complete immunoglobulin). Proteinuria can occur. (LQ 2012)  
      In MM patient may developed CRF with enlarge kidney size. Other conditions where patient may have CRF with enlarge kidney size are –
      1. Diabeties,                                  
      2. Polycystic kidney
      3. Amyloidosis                            
      4. Bilateral hydronephrosis (PGI Dec 2008)
    5. Recurrent infections due to acquired hypogammaglobulinemia and leukopenia
    6. Hypercalcemia due to myeloma-stimulated osteoclast activity. Osteoporosis can occur.
      Note: i. Metastatic calcification occurs   
      ii. Dystrophic calcifications do not occur.  
      Note: Metastatic calcification occurs but dystrophic calcifications do not occur.  (LQ 2012)
  1. Hyperviscosity due to a high concentration of the M protein which tends to aggregate can cause visual disturbance. (LQ 2012)
h. Systemic AL amyloidosis. 

Compilations of MM
In MM there is no hepatomegaly, no splenomegaly and no lymph adenopathy.
1. Hypercalcemia                 2. Spinal cord compression                3. Hyperviscosity syndrome               4.  Renal failure
Note: CHF is not a feature of MM:

Table - Clinical Features of Multiple Myeloma
Clinical Finding Underlying Cause and Pathogenetic Mechanism
Hypercalcemia, osteoporosis, pathologic fractures, lytic bone lesions, bone pain Tumor expansion, production of osteoclast activating factor by tumor cells, osteoblast inhibitory factors
Renal failure Hypercalcemia, light chain deposition, amyloidosis, urate nephropathy, drug toxicity (nonsteroidal anti-inflammatory agents, bisphosphonates), contrast dye
Easy fatigue—anemia Bone marrow infiltration, production of inhibitory factors, hemolysis, decreased red cell production, decreased erythropoietin levels
Recurrent infections Hypogammaglobulinemia, low CD4 count, decreased neutrophil migration
Neurologic symptoms Hyperviscosity, cryoglobulinemia, amyloid deposits, hypercalcemia, nerve compression, anti-neuronal antibody, POEMS syndrome, therapy-related toxicity
Nausea and vomiting Renal failure, hypercalcemia
Bleeding/clotting disorder Interference with clotting factors, antibody to clotting factors, amyloid damage of endothelium, platelet dysfunction, antibody coating of platelet, therapy-related hypercoagulable defects

Pathology of MM: 
Cells type
1. Plasma cell                                                                                              
2. Flame cell (Cell with cherry red cytoplasm)
3. Mott cell (Cells with multiple blue grape like cytoplasmic droplet) 

Inclusion body:
1. Russell body (intracytoplasmic) found in plasma cell                       
2. Dutcher body (nuclear)
3. Inclusion of fibril crystalline Rods & globular)

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, x 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
  a. IgG level <50 g/L (<5 g/dL)
  b. IgA level <30 g/L (<3 g/dL)
  c. Urine light chain <4 g/24 h
<0.6 (low)
II Fitting neither I nor III 0.6–1.20
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
a. IgG level >70 g/L (>7 g/dL)
b. IgA level >50 g/L (>5 g/dL)
c. 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
b2M < 3.5, alb ³3.5 I (28%) 62
b2M < 3.5, alb < 3.5 or b2M = 3.5–5.5 II (39%) 44
b2M > 5.5 III (33%) 29

Note: β2M, serum b2-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 08)
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 08)
  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
      iv. 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. 
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 b2 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 - a. Increase Acid phosphate        b. 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:
  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 C. Independent factors
A. 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
B. Sub classification based on serum creatinine levels
Serum creatinine> 2 mg/dl
• b2 microglobulin (single most important factor)
•  Serum albumin
•  ­LDH
• ­ labeling index (%age of cells undergoing mitosis)
• ­ CRP or IL6
• ­ Hepatocyte growth factor, TGF (b) or syndecans - 1
• Plasmo blastic morphology
D. Genetic Abnormalities
 a. Hyperploidy
 b. Chromosome 13 deletion (and chromosome 17p deletion)
 c. t(4; 14), t(l4; 16), t(11; 4) translocation
 d. 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. 
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

  1. This is a low-grade lymphoplasmacytoid lymphoma associated with an IgM paraprotein causing clinical features of hyperviscosity syndrome.
  2. It is a rare tumour occurring in the elderly.
  3. Patients classically present with features of hyperviscosity such as nosebleeds, bruising confusion and visual disturbance.
  4. Presentation may be with anaemia, systemic syndromes, splenomegaly and/or lymphadenopathy.
  5. Patients have an IgM paraprotein associated with a raised plasma viscosity.
  6. The bone marrow has a characteristic appearance, with infiltration with lymphoid cells and in addition many mast cells.
  7. No lytic lesion,  normal serum Ca, renal disease is uncommon.
  8. Waldenström’s macroglobulinemia: is also a monoclonal gammopathy and is characterized by neoplasm of lymphoplasma cytoid cells that secrete IgM
M component is only IgM and not IgG.
This is characterized clinically by
1. Lymphadenopathy                     
2. Hepatosplenomegaly                     
3. Hyperviscosity syndrome
  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 (g, a, m)
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. mm 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. Cryoglobulinemia (i.e., presence of cryoglobulins in the blood) occurs in a variety of clinically dissimilar conditions.
  4. Renal disease is associated primarily with types I and II and probably has and immune complete mediated pathophysiology.
  5. Many patients with mixed cryoglobulinemia have and underlying infection with HCV.
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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