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Multiple Myeloma                                                                                                                                                  

Basic lab:  

1. CBC, serum calcium & creatinine, serum protein electrophoresis or immunoglobulin electrohphoresis,
   UA, 24-hr urine protein & immunoglobulin electrophoresis, 24-hr urine Bence-Jones protein collection.  
2. Bone marrow biopsy & aspiration if IgG>2.5 g/dL or IgA>1.5 g/dL or IgM>3 g/dL.  
3. Skeletal x-ray survey for lytic lesions.

MM is uncommon in persons younger than 40 years; the incidence increases rapidly after age 50, equally in men and women.  
MM is characterized by

• an accumulation of plasma cells in the bone marrow >10%
• the overproduction of a monoclonal immunoglobulin. The frequency of the various immunoglobulin types of MM parallels the serum concentrations of those Igs: IgG in 60% to 70%, IgA in 20%, and light chain in only 15%; few cases of IgD and IgE have been reported, and approximately 1% of patients are nonsecretors.
  The plasma cell disorders are characterized by the secretion of electrophoretically and immunologically homogeneous (monoclonal) proteins. Each monoclonal protein (M-protein, myeloma protein, or paraprotein) consists of two heavy (H) polypeptide chains of the same class and subclass and two light (L) polypeptide chains of the same type. The heavy polypeptide chains are IgG, IgA, IgM, IgD, and IgE. The light-chain types are kappa (kappa) and lambda (lambda). A monoclonal protein (M-protein) is usually seen as a narrow peak (like a church spire) in the densitometer tracing.
• depressed levels of normal residual immunoglobulins.
• Bence Jones proteins (urinary light chains) are detected in the urine with antisera against light chains but without an anti-heavy-chain component.    

CLINICAL MANIFESTATIONS OF MULTIPLE MYELOMA

• Skeletal involvement: pain, reduced height, pathologic fractures, hypercalcemia
• Anemia: due mainly to decreased erythropoiesis; produces weakness and fatigue
• Renal insufficiency: mainly due to "myeloma kidney" from light chains or hypercalcemia; rarely from amyloidosis
• Recurrent infections: respiratory and urinary tract infections or septicemia due to gram-positive or gram-negative organisms
• Bleeding diathesis: from thrombocytopenia or coating of platelets with M-protein
• Amyloidosis: develops in 10 to 15%
• Extramedullary plasmacytomas: occur late in the disease
• Cryoglobulinemia type I: rarely symptomatic

Diagnostic Criteria for Various Gammopathies

Multiple Myeloma (MM)

The diagnosis of MM requires at least one of the following major criteria:
- plasmacytoma;
- bone marrow with at least 30% plasma cells; and
- M protein on serum electrophoresis showing levels of IgG >3.5 g/dl, IgA >2.0 g/dl, or
- urine light-chain (Bence-Jones protein) excretion > 1 g/24 hr.
One or more of the following minor criteria are also required:
- bone marrow plasmacytosis greater than 10%;
- M protein in serum or urine but less than the levels listed above under major criteria;
- lytic bone lesions; and decreased residual immunoglobulins.

Differentiation of MGUS from Multiple Myeloma and Macroglobulinemia

Differentiation of the patient with benign monoclonal gammopathy from one in whom multiple myeloma, macroglobulinemia, or a related disorder eventually develops is very difficult when the M-protein is first recognized. The size of the M-protein is of some help--levels greater than 3 grams per deciliter usually indicate overt multiple myeloma or macroglobulinemia, but some exceptions, such as smoldering multiple myeloma (SMM), exist. Levels of immunoglobulin classes not associated with the M-protein (normal polyclonal or background immunoglobulins) are almost always reduced in multiple myeloma or Waldenstrom's macroglobulinemia, but a reduction may also occur in benign monoclonal gammopathy. The association of a monoclonal light chain (Bence Jones proteinuria) with a serum monoclonal gammopathy suggests multiple myeloma or macroglobulinemia, but in many patients with small amounts of monoclonal light chain in the urine, the M-protein in the serum remains stable for many years. The presence of more than 10% plasma cells in the bone marrow suggests multiple myeloma, but some patients with more plasma cells have remained stable for long periods. The presence of osteolytic lesions strongly suggests multiple myeloma, but metastatic carcinoma may produce lytic lesions as well as plasmacytosis and may be associated with an unrelated monoclonal gammopathy.

LABORATORY

• Anemia is present in 70% of the patients at the time of diagnosis. Nearly all patients will develop anemia as the disease progresses.
• Peripheral blood smear - rouleaux formation
• Serum protein electrophoresis - usually shows a spike or a localized band (M spike in approximately 80% of patients). Of these, 50% are IgG protein, 20% IgA, and 17% free monoclonal light chains (Bence Jones protein).
• Urine electrophoresis - positive about 70% of the time for light chains, but inconsistencies hinder diagnosis
• Hypercalcemia
• Decreased platelets
• Elevated sedimentation rate
• Elevated creatinine and BUN

• Major Criteria for Multiple Myeloma:
  1. Monoclonal protein spike on electrophoresis: IgG>3.5 g/dL or IgA>2 g/dL or Bence Jones proteinuria >1 g/24 hr
  2. Bone marrow plasma cells at least > 10%
  3. Lytic bony lesions
• Possible Associated Features:
  • Cytopenias as frequent anemia, renal failure,  & hypercalcemia (in 10-20% of MM patients).
  • Signs and symptoms of hyperviscosity, such as shortness of breath, confusion, and chest pain, are uncommon in patients with IgG MM but may occur at extremely high serum protein concentrations. Hyperviscosity occurs more often in patients with IgA MM because of greater polymerization of the paraprotein.
• Ancillary investigations:
  • Commonly used: Levels of other immunoglobulins, serum beta2-microglobulin
  • Investigational: plasma cell labeling index, serum Interleukin-6 levels, cytogenetics or oncogene studies, etc.

Treatment of Multiple Myeloma

Indications for therapy include the development of significant anemia, hypercalcemia, or renal insufficiency; the occurrence of lytic bone lesions; and the finding of extramedullary plasmacytomas.

• Radiation Therapy:
  Palliative radiation in a dose of 20 to 30 Gy should be limited to patients who have multiple myeloma with disabling pain and a well-defined focal process that has not responded to chemotherapy.  Analgesics in combination with chemotherapy usually can control the pain.
• Autologous Stem Cell or Bone Marrow Transplantation for patients younger than 70 years old  
  - the median survival was longer with transplantation than with chemotherapy.
• Chemotherapy:
  Chemotherapy is the preferred initial treatment for overt, symptomatic multiple myeloma in patients older than 70 years or in younger patients in whom transplantation is not feasible.
  The oral administration of melphalan and prednisone produces objective response in 50 to 60% of patients.
  Melphalan 0.15 mg/kg /day for 7 days (8-10 mg/day), with prednisone 20 mg three times daily for the same 7 days.
  The chemotherapy course is repeated every 6 weeks for at least 3 courses, and usually is for one year.

Almost all patients with multiple myeloma will eventually relapse.

Treatment for Refractory Multiple Myeloma:

VBAP (vincristine, carmustine [BCNU], doxorubicin [Adriamycin]) on day 1 and prednisone daily for 5 days every 3 to 4 weeks benefits 30% of patients. It is well tolerated. If the patient's leukocyte and platelet levels are satisfactory, cyclophosphamide, 600 mg/m2 /day intravenously for 4 days (days 1-4), plus prednisone, 50 mg twice a day for the same 4-day period, followed by granulocyte colony-stimulating factor, has been helpful in patients with refractory advanced disease.

Thalidomide given orally at a dose of 200 mg/d for 2 weeks, then increased by 200 mg/d every 2 weeks, up to a maximal dose of 800 mg/d. Four (25%) achieved a partial response to therapy, with a greater than 50% reduction in the serum or urine M protein level. Responses lasted 2, 4+, 8, and 10+ months. Major adverse effects included constipation, sedation, rash, and peripheral neuropathy. CONCLUSION: Thalidomide is an active agent in the treatment of patients with advanced myeloma. (Mayo Clin Proc 2000 Sep;75(9):897-901)

Multiple myeloma has a progressive course, and the median survival is approximately 3 years.

Smoldering Myeloma

• Major Criteria:
  • Meets myeloma criteria except minimal or no bony lesions, no compression fractures
• Possible Associated Features:
  • Usually asymptomatic; no anemia, hypercalcemia or renal failure
• Ancillary investigations:  Requires peiodic follow-up testing

MGUS (Monoclonal Gammopathy of Undetermined Significance)

• Major Criteria:
  1. Monoclonal protein spike on electrophoresis: IgG<3.5 g/dL, IgA<2 g/dL; Bence Jones proteinuria <1 g/24 hr
  2. Bone marrow plasma cells <10%
  3. No lytic bony lesions & Other immunoglobulins normal
• Possible Associated Features:
  • Should be asymptomatiac; no anemia, hypercalcemia, or renal failure.  NO underlying disease associated with paraproteinemia (eg. lymphoma, amyloidosis)
• Ancillary investigations:  Related to level of paraproteinemia present & Requires periodic follow-up testing.
• It occurs in about 1% of the general population and 3% of normal persons older than 70 years; IgG is most commonly increased. Features of MM that distinguish it from MGUS include greater concentrations of serum and urine M proteins, increased percentage of bone marrow plasma cells, higher plasma cell label-ing index, the presence of lytic bone lesions, and the presence of circulating plasma cells in the peripheral blood. After prolonged follow-up, four groups of patients with MGUS can be identified:
  (1) those with a contained monoclonal gammopathy (19%);
  (2) those whose serum immunoglobulin level increases to more than 3 g/dl but do not require any therapy (10%); (3) those who die without multiple myeloma or another related disease developing (47%); and
  (4) those in whom myeloma, amyloidosis, macroglobulinemia, or another lymphoproliferative disorder develops (24%, two thirds of which are myeloma). Progression to a malignancy occurs at 8 to 10 years. Unfortunately, there are no laboratory studies that reliably predict which patients with MGUS will progress to MM.

Biclonal Gammopathies

• Biclonal gammopathies occur in 2 to 3% of patients with monoclonal gammopathies.
• Biclonal gammopathy of undetermined significance accounts for about two thirds of patients. The remainder have multiple myeloma, macroglobulinemia, or other lymphoproliferative diseases. Triclonal gammopathies may also occur.

Solitary Plasmacytoma

• Major Criteria:
  • Biopsy-proven monoclonal plasma cell tumore; absence of other major criteria
• Possible Associated Features:  Frequently symptomatic (eg, bone pain, fractures)
• Ancillary investigations:  Requires periodic follow-up testing.  Serum or urine paraprotein should disappear after local Rx.

Waldenstrom's Macroglobulinemia

• Monoclonal IgM paraprotein with IgM > 3 g/dL
• Waldenstrom's macroglobulinemia, characterized by an IgM gammopathy, lymphadenopathy, and hepatosplenomegaly, was formerly included with these disorders but is now more appropriately classified as a lymphoplasmacytoid, indolent non-Hodgkin's lymphoma

Amyloidosis

• is characterized by the deposition of amyloid fibrils in various tissues.
  Amyloidosis may occur either
  secondary to a chronic inflammatory condition (amyloid A, or AA) or as a
  primary condition (amyloid light chain-related, or AL) in the setting of a B cell malignancy.  In AL, the fibrils are made up of fragments of light chains of immunoglobulins, with a clonal proliferation of bone marrow plasma cells, and Bence Jones proteinuria is present.  
• The diagnosis is made by a biopsy of the affected organ or a urine sample stained with Congo red.

Idiopathic Bence Jones Proteinuria  

• Bence Jones proteinuria is a recognized feature of multiple myeloma, primary amyloidosis, Waldenstrom's macroglobulinemia, and other malignant lymphoproliferative disorders. A benign Bence Jones proteinuria may also occur. Patients have been documented to have a stable serum level of M-protein and Bence Jones proteinuria for more than 15 years without developing multiple myeloma or related disorders.

REF:

Multiple Myeloma 1999 Update  
      - presented 12-3-1999 prior to the 41st American Society of Hematology Annual Meeting in New Orleans, Louisiana.
Multiple Myeloma Update March 2000 - Medscape
Postgraduate Med 8/1999;106:135 - Malcolm Brigden
SAM 1999
Dambro: Griffith's 5-Minute Clinical Consult, 1999 ed.
Goldman: Cecil Textbook of Medicine, 21st Ed., 2000

Multiple Myeloma: How Far Have We Come?    
Kenneth C. Anderson - Mayo Clinic Proceedings January 2003 Volume 78 Number 1

Current Therapy for Multiple Myeloma
S. Vincent Rajkumar - Mayo Clinic Proceedings August 2002 Volume 77 Number 8

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