Multiple myeloma is the most common of a group of plasma cell disorders, characterized by the expansion of monoclonal bone marrow plasma cells that produce a monoclonal immunoglobulin (m-component), present in serum and/or urine. Many multiple myeloma patients harbour an infection of Karposi Sarcoma herpes virus in their bone marrow dendritic cells.

Under normal circumstances, maturation to antibody-secreting plasma cells is controlled by the immune system. Plasma cell expansion is uncontrolled in the malignant form and is responsible for lytic bone lesions, the hallmark of these B-cell neoplasias.do B-cells develop into plasma cells?

1. Lymphoid stem cell : Enzyme Terminal transferase (TdT)

Unclassified ALL

2. Early B cells: HLA-DR

CD19,CD10,CD20,CD22

Heavy chain gene rearrangement (HCR)

Kappa and lambda R and D

Pre-B ALL

3. Intermediate B cells: Loose CD10 add CD21

Burkitt's lymphoma

4. Mature B cell: Antigen-Driven differentiation.

Multiple myeloma CD38,PCA-1

Waldenstrom's CD38

Diffuse lymphoma.Etiology:

Generally MM is believed to be caused by a multistep process. For an idiotypic immunoblobulin to be produced, it is believed that the malignant transforming event must occur in a late B cell precursor, some time after the immunoglobulin gene has been rearranged, and the idiotype determined (Palumbo, Battaglio et al. 1992; Van Ness and Billadeau 1993; Bakkus, Vanriet et al. 1994) Genetic factors probably play an important role in determining whether the early B cells of an individual are susceptible to any of the malignant transforming events the person is exposed to.rs

1. Mouse plasmacytomas:

Inbred mice develop more MGUS (Radl and Hollander 1974). The gene has not been identified.

There is no correlation between the development of spontaneous gammopathy and susceptibility to the induction of plasmacytomas by mineral oil. (Potter, Pumphery et al. 1975)

2. Racial differences:

The low incidence of MM in Japanese and Chinese populations has moved with them to Hawaii and the U.S.A.(Devesa 1991), suggesting that the incidence of the disease in these populations is determined more by genetic rather than by enviromental factors.

3. Increased risk of MM is associated with certain HLA types

A large population-based study of 46 black male MM cases (with 88 black male controls), and 85 white male MM cases (with 122 white controls ) has been done to determine whether there is any association of human leukocyte antigens of Class 1 (HLA -A,-B,-C) and Class II (HLA-DR,HLA-DQ) with the disease (Pottern, Gart et al. 1992). Black cases had significantly higher gene frequencies for Bw65, Cw2 and DRw14 than their controls, while white case had higher gene frequencies than controls for A3 and Cw2, and blanks at the DR and DQ loci. The frequency of Cw2 in the black and white controls was similar. These findings suggest that the Cw2 allele, or a gene close to the C loci, confers susceptibility to the development of MM, but does not explain the higher risk among blacks. The authors also suggest that undefined Class II antigens may play an etiologic role. New molecular techniques, using genomic DNA, may lead to the identification of these alleles.

4. Familial plasma cell neoplasia

The occurence of multiple cases of a malignancy in a family, without a clear Mendelian pattern of inheritance, suggests that the family members may be exposed to the same enviromental hazard. However, no hazardous factor has been recognized in any of the MM and WM families investigated. (Loth, Perrotta et al.1991) (Grosbios, Gueguen et al. 1986) (Bizzaro and Pasini 1990)

On the other hand, the discovery that several affected family members have inherited identical HLA haplotypes ( Blattner, Garber et al. 1980;Grosbois,Gueguen et al. 1986; Loth, Perrotta et al. 1991), suggests that the tendency to develop these B- cell neoplasms may be inherited.

iromental factors

1. Radiation:

Risk not increased ( Preston, Kusumi et al. 1994)

The epidemiology of multiple myeloma has been extensively reviewed by Riedel et al. (Riedel and Pottern 1992):

a. Socioeconomic factors, such as family size and income have not been found to be important (Johnston, Gufferman et al. 1985; McWhorter, Shatzkin et al. 1989)

b. Smoking. Negative association. (Mclaughlin et al. 1992)

c. Occupations.

Farming has demonstrated association and not. Unsure which aspect of farming.

Metal workers, rubber manufacturing.

Various professions but just as many fail to show a correlation.

No definite cause.

d. Various exposures: benzene and petroleum. No association.

e. Chronic antigenic stimulation (CAS):

Association between rheumatoid arthritis and MM. At least two follow-up studies of patients with rheumatoid arthritis have detected a subsequent increased incidence of MM (Isomaki, Hakulinen et al. 1978; Hakulinen, Isomaki et al. 1985; Katusic, Beard et al. 1985), and an excess of RA has been detected in case- control studies of MM in New Zealand and northern Sweden (Pearce, Smith et al. 1986; Eriksson 1993 ). An examination of the frequency of autoimmune disease among first degree relatives of myeloma patients, discovered a significantly increased risk of RA, as compared to the incidence of first degree relatives of the controls (Linet, McLauglin et al. 1988). If this finding is confirmed in larger studies it will suggest that genetic factors underlie the association.

A case- control study of patients with Gaucher's Disease in Israel found that these cases have an increased risk of developing hematologic malignancies, including myeloma (Shiran, Brenner et al. 1993)

The discovery of a HIV-1-seropositive patient with myeloma, whose IgG/kappa M-protein specifically recognized the HIV-1 p24 gag antigen, suggests that the antigen- driven response to the viral infection did play a role in the pathogenesis of myeloma in this patient (Konrad, Kricka et al. 1993)Incidence and prevalence:

Myeloma increases in incidence with age. The median age at diagnosis is 68 years. It is rare under age 40. The yearly incidence is around 4 per 100 000 and remarkably similar in countries troughout the world. Males are slightly more commonly affected than females, and blacks have nearly twice the incidence of whites. In the age group over 25 the incidence is 30 per 100 000. Myeloma accounts for about 1 persent of all malignancies in whites and 2 persent in blacks; 13 persent of all hematologic cancers in whites and 33 percent in blacks.hogenesis and clinical manifestations:

Bone pain is the most common symptom in myeloma, affecting nearly 70 percent of patients. This is decreasing as routine screening is identifying asymptomatic cases on a more regular basis. The pain usually involves the back and ribs, and unlike the pain of metastatic carcinoma, which often is worse at night, the pain of myeloma is precipitated by movement. Persistent localized pain in a patient with myeloma usually signifies a pathologic fracture. The bone lesions of myeloma are caused by the proliferation of the tumor cells and the activation of osteoclasts which destroy the bone. The osteoclasts respond to osteoclast activating factors (OAF) made by the myeloma cells (OAF activity can be mediated by several cytokines, including interleukin 1, lymphotoxin, and tumor necrosis factor. Interleukin 6 is the most important in this regard.) However, production of these factors stops following administration of corticosteroids or interferon- . The bone lesions are lytic in nature and are rarely associated with osteoblastic new bone formation; therefore radioisotopic bone scanning is less useful in diagnosis than plain radiography. The bone lysis results in substantial mobilization of calcium from bone, and serious acute and chronic complications of hypercalcemia and dominate the clinical picture. Localized bone lesions may expand to the point that mass lesions may be palpated, especially on the skull, clavicles, and sternum, and the collapse of vertebrae may lead to symptoms of spinal cord compression.

The next most common problem in patients with myeloma is infection. The most common infections are pneumonias and pyelonephritis, and the most frequent pathogens are Streptococcus pneumoniae, Staphylococcus aureus, and Klebsiella pneumoniae in the lungs and Escherichia coli and other gram-negative organisms in the urinary tract. In about 25 percent of patients, recurrent infections are the presenting features, and over 75 percent of patients will have a serious infection at some time in their course. The susceptibility to infection has several contributing causes. Firstly, patients with myeloma have diffuse hypogammaglobulinemia if the M component is excluded. The hypogammaglobulinemia is related to both decreased production and increased destruction of normal antibodies. Moreover, some patients generate a population of circulating regulatory cells in response to their myeloma that can suppress normal antibody synthesis. In the case of IgG myeloma, normal IgG antibodies are broken down more rapidly than normal because the catabolic rate for IgG antibodies varies directly with the serum concentration. The large M component results in fractional catabolic rates of 8 to 16 percent instead of the normal 2 percent. These patients have very poor antibody responses, especially to polysaccharide antigens such as those on bacterial cell walls. Such responses are normally T cell-independent. Most measures of T cell function in myeloma are normal, but a subset of CD4+ cells may be decreased. Granulocyte lysozyme content is low, and granulocyte migration is not as rapid as normal in patients with myeloma, probably the result of a product of the tumor. There are also a variety of abnormalities in complement functions in myeloma patients. All these factors contribute to the immune deficiency of these patients.

Renal failure occurs in nearly 25 percent of myeloma patients, and some renal pathology is noted in over half. There are many contributing factors. Hypercalcemia is the most common cause of renal failure. Glomerular deposits of amyloid, hyperuricemia, recurrent infections, and occasional infiltration of the kidney by myeloma cells may contribute to renal dysfunction. However, tubular damage associated with the excretion of light chains is almost always present. Normally, light chains are filtered, reabsorbed in the tubules, and catabolized. With the increase in amount of light chains presented to the tubule, the tubular cells become overloaded with these proteins, and tubular damage results either directly from light chain toxic effects or indirectly from the release of intracellular lysosomal enzymes. The earliest manifestation of this tubular damage is the adult Fanconi syndrome ( a type 2 proximal renal tubular acidosis) with increased loss of glucose, amino acids, and defects in the ability of the kidney to acidify and concentrate urine. The proteinuria is not accompanied by hypertension, and the protein is nearly all light chains. Generally, there is very little albumin in the urine because the glomerular function is usually normal. When the glomeruli are involved, the proteinuria is nonselective. Patients with myeloma also have a decreased anion gap ( i.e., sodium minus (chloride plus bicarbonate)) because the M component is cationic, resulting in retention of chloride. This is often accompanied by hyponatremia that is felt to be artificial (pseudohyponatremia) because each volume of serum has less water as a result of the increased protein.

Anemia occurs in about 80 percent of myeloma patients. It is usually normocytic and normochromic and related both to the replacement of normal marrow by expanding tumor cells and to the inhibition of hematopoiesis by factors made by the tumor. In addition, mild hemolysis may contribute to the anemia. A larger than expected fraction of patients may have megaloblastic anemia due to either folate or vitamin B12 deficiency. Granulocytopenia and thrombocytopenia are very rare. And may be seen due to the failure of antibody-coated platelets to function properly or to the intervention of the M component with clotting factors I, II,V, VII, or VIII. Raynaud's phenomenon and impaired circulation may result if the M component forms cryoglobulins, and the hyperviscosity syndromes may develop depending onn the physical properties of the M component (most common with IgM, IgG3, and IgA paraproteins). Hyperviscosity is defined on the basis of the relative viscosity of serum as compared with water.

Normal serum viscosity is 1.8 (i.e., serum is normally twice as viscous as water). Symptoms of hyperviscosity occur at a level of 5 to 6, a level usually reached at paraprotein concentrations of around 40g/L (4g/dl) for IgM, 50 g/L (5 g/dl) for IgG3, and 70 g/L (7 g/dl) for IgA.

Although this occurs in a minority of patients, they may have many cause. Hypercalcemia may produce lethargy, weakness, depression, and confusion. Hyperviscosity may lead to headache, fatigue, visual disturbances, and retinopathy. Bone damage and collapse may lead to cord compression, radicular pain, and loss of bowel and bladder control. Infiltration of peripheral nerves by amyloid can be a cause of carpal tunnel syndrome and sensorimotor mono- and polyneuropathies.

Many of the clinical features of myeloma, e.g., cord compression, pathologic fractures, hyperviscosity, sepsis, and hypercalcemia present as medical emergencies. Dispite the widespread distribution of plasma cells in the body, tumor expansion is dominantly within bone and bone marrow and, for reasons unknown, rarely cause enlargment of spleen, lymphnodes, or gut-associated lymphatic tissue.

The diagnostic triad of myeloma is marrow plasmacytosis (>10 percent), lytic bone lesions, and a serum and/or urine M component. The diagnosis may be made in the absence of bone lesions if the plasmacytosis is associated with a progressive increase in the M component over time or if extramedullary mass lesions develop. There are two important variants of myeloma, MGUS and plasmacytoma. These lesions are associated with an M component in less than 30 persent of cases, they may affect younger individuals, and both are associated with a median survival of 10 years or more. Solitary bone plasmacytoma is a single bone lesion without marrow plasmacytosis. Extramedullary plasmacytomas usually involve the submucosal lymphoid tissue of the nasopharynx or paranasal sinuses without marrow plasmacytosis. Both tumors are highly responsive to local radiation therapy. If an M component is present, it should disappear after treatment. Solitary bone plasmacytomas may recur in other bony sites or evolve into myeloma. Extramedullary plasmacytomas rarely recur or progress.

The most difficult differential diagnosis in patients with myeloma involves their separation from people with benign monoclonal gammopathies or (MGUS). MGUS are vastly more common than myeloma, occuring in 1 percent of the population over age 50 and in up to 10 percent over age 75. Patients with MGUS usually have fewer than 20g/L of M component, no urinary Bence Jones protein, less than 5 percent marrow plasmacytosis, and no anemia, renal failure, lytic bone lesions, or hypercalcemia. When bone marrow plasma cells are exposed to radioactive thymidine in order to quantitate dividing cells, patients with MGUS always have a labeling index of less than 1 percent and patients with myeloma always have a labeling index of more than 1 percent. Other discriminators include plasma cell acid phosphatase and -glucuronidase, both of which are low in MGUS patients and the salmon calcitonin stimulation test, which is postive only in patients with active ongoing bone destruction. Only about 11 percent of patients with MGUS go on to develop myeloma. Typically, patients with MGUS require no therapy.

The workup of patients with myeloma includes a careful physical examination searching for tender bones and masses. It is paradoxic that only a small minority of patients have an enlargment of the spleen and lymph nodes, the physiologic sites of antibody production. Chest and bone radiographs may reveal lytic lesions or diffuse osteopenia. A complete blood count with differential may reveal anemia. ESR is elevated. Very rarely patients (2 percent) may have plasma cell leukemia with more than 2000 plasma cells per microliter. This may be seen in disproportonate frequency in IgD (12 percent) and IgE (25 percent) myelomas. Serum calcium, urea nitrogen, creatine, and uric acid may be elevated. Protein electrophoresis and measurement of serum immunoglobulins are useful for detecting and characterizing M spikes, supplemented by immunoelectrophoresis, which is especially sensitive for identifying low concentrations of M components not detectable by protein electrophoresis. A 24-hour urine specimen is necessary to quantitate protein excretion, and a concentrated aliquot is used for electrophoresis and immunologic typing of any M component. Serum alkaline phosphatase is usually normal even with extensive bone involvement because of the absence of osteoblastic activity. It is also important to quantitate serum 2 microglobulin.

The serum M component will be IgG in 53 percent of patients, IgA in 25 percent, and IgD in 1 percent, and 20 percent of patients will have only light chains in serum and urine. Dipsticks for detecting proteinuria are not reliable at identifying light chains, and the heat test for detecting Bence Jones protein is falsely negative in about 50 percent of patients with light chain myeloma. Fewer than 1 percent of patients have no identifiable M component, and these are usually light chain myelomas in which renal catabolism has made them undetectable in the urine. About two-thirds of patients with serum M components also have urinary light chains. The light chain isotype may have an important impact on survival. Patients secreting lambda light chains have a significantly shorter overall survival than those secreting kappa light chains. It is not clear whether this is due to some genetically important determinant of cell proliferation or because lambda light chains are more likely to cause renal damage and form amyloid than are kappa light chains. The heavy chain isotype may have an impact on patient management as well. About half of patients with IgM paraproteins develop hyperviscosity compared with only 2 to 4 percent of patients with IgA and IgG M components. Among IgG myelomas, it is the IgG3 subclass that has the highest tendency to form both concentration- and temperature- dependent aggregates, leading to hyperviscosity and cold agglutination at lower serum concentrations.

Staging:

The staging system for patients with myeloma is a functional system for predicting survival and is based on a variety of clinical and laboratory tests.

Stage I: All the following:

1. Hemoglobin > 100g/L

2. Serum calcium < 12mg/dL

3. Normal bone x-ray or solitary lesion.

4. Low M-component production

a. IgG level < 50 g/L

b. IgA level < 30 g/L

c. Urine light chain < 4 g/24 h

5. Estimated tumor burden < 0.6 x 10 cells/m

Stage II: Fitting neither I nor III

1. Estimated tumor burden 0.6-1.2 x 10 cells/m

Stage III: One or more of the following:

1. Hemoglobin < 85g/Ls

2. Serum calcium >12mg/dL

3. Advanced lytic bone lesions

4. High M-component production

a. IgG level > 70g/L

b. IgA level > 50g/L

c. Urine light chain > 12g/24h

5. Estimated tumor burden >1.2 x 10 cells/m

Staging based on serum Beta 2 microglobulin levels:

Stage I: level < 4ug/dL

Median survival: 43 months

Stage II: level > 4ug/dL

Median survival: 12 months

It is also felt that once the diagnosis of myeloma is firm, histologic features of atypia may also exert an influence on prognosis. Interleukin 6 may be an autocrine and/or paracrine growth factor for myeloma cells; elevated levels are associated with more aggressive disease. High labeling index and high levels of lactate dehydrogenase and thymidine kinase are also associated with poor prognosis.eatment and course:

About 10 percent of patients with myeloma will have an indolent course demonstrating only very slow progression of disease over many years. Such patients only require antitumor therapy when the serum myeloma protein rises above 50 g/L or progressive bone lesions develop. Patients with solitary bone plasmacytomas and extramedullary plasmacytomas may be expected to enjoy prolonged disease-free survival after local radiation therapy to a dose around 40 Gy. There is a low incidence of occult marrow involvement in patients with solitary bone plasmacytoma. Such patients are usually detected because their serum M component falls slowly or disappears initially only to return after a few months. These patients respond well to systemic chemotherapy.

In myeloma patients treated with systemic chemotherapy the M component lags substantially behind the symptomatic improvement, often taking 4 to 6 weeks to fall.

Aboout 15 percent of patients die within the first 3 months after diagnosis, and subsequently, the death rate is about 15 percent per year. The disease usually follows a chronic course for 2 to 5 years before developing an acute terminal phase, usually marked by the development of pancytopenia with a cellular marrow that is refratory to treatment. Widespread organ infiltration by myeloma cells occurs, and survival less than 6 months. About 46 percent of patients die in the chronic phase of the disease from progressive myeloma (16 percent), and renal failure (10 percent), sepsis (14 percent), or both (6 percent). Five percent of patients die of acute leukemia, myeloblastic or monocytic, and although it has been debated that this is related to the primary disease , it appears more likely to be the result of chronic therapy with alkylating agents. Nearly 23 percent of patients die of myocardial infarction, chronic lung disease, diabetes, or stroke, all intercurrent illnesses related more to the age of the patient group than to the tumor.

Supportive care directed at the anticipated complications of the disease may be as important as primary antitumor therapy. The hypercalcemia generally responds well to corticosteroid therapy, hydration, and natriumesis. Calcitonin may add to the inhibitory effects of steroids on bone resorption. Diphosphonates have also been shown to reduce osteoclastic bone resorption. Treatments aimed at strenghtening the skeleton, such as fluorides, calcium, and vitamin D with or without androgens, have been suggested but are not of proven efficacy. Iatrogenic worsening of renal function may be prevented by the use of allopurinol during chemotherapy to avoid urate nephropathy and by maintaining a high fluid intake to help excrete light chains and calcium. In the event of acute renal failure, plasmapheresis is approximately 10 times more effective at clearing light chains than peritoneal dialysis, and acutely reducing the protein load may result in functional improvement. Urinary tract infections should be watched for and treated early. Chronic dialysis probably should not be initiatied in patients who have failed to respond to antitumor therapy. Plasmapheresis may be the treatment of choice for hyperviscosity syndromes. Although the pneumococcus is a dreaded pathogen in myeloma patients, they do not respond to pneumococcal polysaccharide vaccines. The advent of intravenous gamma globulin preparations raises some hope that prophylactic administration may prevent some serious infections, but this has not been tested. Chronic oral antibiotic prophylaxis is probably not warranted. Patients developing neurologic symptoms in the lower extremities, severe localized back pain, or problems with bowel and bladder control may need emergency myelography and radiation therapy for palliation. Most bone lesions respond to analgesics and chemotherapy, but certain painful lesions may respond most promptly to localized radiation. The chronic anemia may respond to hematinics (iron, folate, cobalamin), and some have responded to androgens. The pathogenesis of the anemia should be established and specific therapy instituted, where possible.