11 صفر 1435 هـ Medicine lec.
25/11/2013
Multiple myeloma (Kahler's disease):
It is a malignant proliferation of plasma cells. Normal plasma cells are derived from B-cells and produce immuno globulins of polyclonal type which contain both heavy and light chains. In myeloma, plasma cells produce immunoglobulin of monoclonal protein with a single heavy and light chain refered to as a paraprotein. In some cases only light chain is produced which appears in the urine as bence Jones protein urea.
Etiology:
The cause of myeloma is not known. It's frequency may increase following exposure to radiation. Chromosomal abnormality have been found in patients with myeloma such as 13 q 14 deletions, 17 P 13 deletions, 11q abnormality and translocation in (11:14) (q13:q32). It is commonly seen among farmers, wood and leather workers and those exposed to petroleum products.
Pathology:
Malignant plasma cells are present in a small number in the circulation. The majority are present in the bone marrow.
The malignant plasma cells produce cytokine which stimulate osteoclast and result in bone absorption. Example of this cytokines are osteoclast activating factor
The bone lytic lesions cause bone pain, fractures and hypercalcaemia. Marrow involvement can result in anaemia or pancytopenia. The most frequent type of myeloma is the IgG paraprotein secreting myeloma (55%) followed by IgA paraprotein secreting myeloma (21%) followed by light chain type (22%) and the others (D, E, non secretory about 2%).
Clinical features:
The incidence of myeloma is 4/ 100.000/ annum with a male:female ratio of 2:1.
The median age of diagnosis is 60-70 years.
Bone pain is the most common symptoms (70%) in a form of backache, ribs pain and this pain precipitated by movement and unlike metastatic carcinoma which become worse at night. This pain may signifies a pathologic fracture.
The bone lesions are lytic in nature and rarely associated with osteoblastic new bone formation, therefore radio isotope bone
scanning is less useful in diagnosis than is plain radiography.
Hypercalcaemia with its complication such as lethargy and thirst (anorexia, nausea, vomiting, polyuria, constipation, weakness).
Susceptibility to bacterial infection in a form of pneumonias and pyelonephritis this is due to impaired immune function (hypogammaglobulinaemia due to decrease production and increase destruction of normal antibodies).
Renal failure occur in about 25% of patients and some renal pathology in more than 50% which may be due to hypercalcaemia, amyloid deposit, hyperuricemia, recurrent infection and occasionally infiltration of the kidney by myeloma cells or tubular damage by light chains exertion.
Anaemia and tiredness due to bone marrow failure.
Headache, blurred vision, vertigo due to increased blood viscosity.
Amyloidosis and nephritic syndrome.
Bleeding due to interference with the clotting factors by the tumor products (antibodies to clotting factors, platlets dysfunction, amyloid damage of endothelium).
Mass lesions due to tumor expansion.
Notes:
Anaemia occurs in about 80% of patients. It is usually normocytic normochromic and related to the replacement of the normal marrow by expanding tumor cells and to the inhibition of haematopoiesis by factors made by the tumor. In addition mild haemolysis may contribute to the anaemia. Megaloblastic anaemia may be due to either folate or vit. B12 deficiency.
Investigations:
1-Renal function test.
2-Blood calcium and albumin for hypercalcaemia.
3-Bone lesions and fractures by x-ray, alkaline phosphatase, isotope bone scan.
4-Plasma immunoglobulins to determine the degree of immune paresis.
5- Blood counts and retics count to determine the degree of bone marrow failure.
6- Bleeding time and coagulation screen to determine the degree of haemostasis.
7-Disease activity (beta2 – microglobulin).
8- Plasma viscosity.
*The diagnosis of myeloma requires two of the following criteria:
Marrow plasmacytosis (> 10%) plus one of the followings.
Serum and/ or urinary paraprotein (M component).
3-Lytic bone lesion.
* Two important variants of myeloma (solitary bone plasmacytroma and extramedullary plasmacytoma) are associated with an M component in fewer than 30% of cases, may affect younger individual and are associated with median survivals of 10 or more years. Solitary bone plasmacytoma is a single lytic bone lesion without marrow plasmacytosis. Solitary bone plasmacytoma may recur or evolve into myeloma. Extramedullary plasmacytoma which usually involve the lymphoid tissue of the nasopharynx or paranasal sinuses rarely recur after treatment or progress.
* Monoclonal gammopathies of uncertain significance (MGUS) are more common than myeloma occur in up to 10% over age 75. Patients usually have <10% bone marrow plasma cells, <30 gm/L (3gm/dL) of M components, no urinary bence jones protein and no anaemia or renal failure or lytic bone lesions or hypercalcaemia.
Myeloma staging system:
@Stage1: all of the following:
a- Hb>10gm/dL.
b- Serum calcium < 12mg/dL.
c- Normal bone x-ray or solitary lesion.
d- Low M component production (IgG < 5gm/dL, IgA < 3gm/dL, urine light chain < 4gm/24hours).
@Stage II fitting neither I or III.
@Stage III one or more of the following:
a- Hb < 8.5 gm/dL.
b-Serum calcium > 12 mg/dL.
c-Advanced lytic bone lesion.
d-High M.component production (IgG > 7gm/dL, IgA > 5gm/dL, urine lytic chains > 12gm/24hr.).
Treatment:
Asymptomatic patients and those with very slow progressive disease may not require therapy.All patients with stage II or III disease and stage I patients who have bence Jones proteinurea, progressive lytic bone lesions, vertebral compression fractures, recurrent infections, or rising serum M-component should receive therapy. The therapy is of two sorts:
Symptomatic supportive care including:
High fluid intake to treat renal impairement and hyperalcaemia.
Analgesia for bone pain.
Bisphosphonate for hypercalcaemia.
Allopurinol to prevent urate nephropathy.
Plasmapharesis for hyperviscosity.
Chemotherapy: intermittent pulses of an alkalating agent (melphalan, cyclophosphamide, or chlorambucil) and prednisone administered for 4-7 days every 4-6 weeks. The usual doses are as follows: melphalan, 8mg/m2 per day: cyclophosphamide 200mg/m2, chlorambucil 8mg/m2, prednisone 25-60mg/m2.
In older patients, melphalan is an effective oral therapy. In younger patients intravenous agent may improve response. Higher doses of intravenous melaphalan may produce better clinical responses which is tolerated well even in elderly. Treatment is administered until paraprotein level has stopped falling. This is termed "plateau phase" and may last for weeks or years. Successive relapses respond less well to treatment. Cyclo phosphamide may be favorable because it is less toxic to the marrow stem cells with a lower incidence of acute myelodysplastic syndrome.
Radiotherapy is effective for localized bone pain and pathological fractures and for the emergency treatment of spinal cord compression.
Transplantation: autotransplant can be used for patients under 65 years after maximum response to chemotherapy which may improve the quality of life and prolong survival.
Allogenic bone marrow transplantation should be considered in those under the age of 55 years with a sibling donar.
Bisphosphanate reduce bone pain and protect bone and may cause apoptosis of malignant plasma cells.
Thalidomide: this drug has anti-angiogenic effects against the blood vesseles suppling tumor and also has immunomodulatory effects. At low doses it has been shown to be effective against refractory myeloma and may be used in combination with dexamethasone.
Poor prognostic features at diagnosis:
Hb < 7gm/dL.
Thrombocytopenia.
Severe hypoalbuminaemia.
Intractable renal failure.
High B2-microglobulin levels.
Plasma cell leukaemia.
Note: in autologus transplantation VAD is used (3-4 months), followed by high-dose cyclophosphamide followed by GCSF "Granulocyte colony – stimulating factor" then peripheral stem cells collected then patient given melaphalan then infusion of stem cells.
* Pulsed dexamethasone and thalidomide is alternative to VAD.