Multiple Myeloma - Myeloma, myelomatosis

Multiple myeloma is a form of cancer which affects plasma cells in the bone marrow. Plasma cells normally produce antibodies and are a specialised form of blood cell called B-lymphocyte. In myeloma a single cell becomes malignant and produces a very large number of identical cells (a clone). In normal circumstances, the antibody molecules present in the blood are very varied in their structure, reflecting the large number of infections they may be required to combat. In patients with myeloma very large quantities of a single type of antibody are produced. This form of antibody is called para-protein and it is present in the blood and/or urine in about 99% of cases. Normal antibody levels are almost always reduced in myeloma. This, combined with a slight reduction in the numbers of neutrophils (special type of white blood cell), leads to a susceptibility to infections which may be life-threatening

 

Introduction

Multiple Myeloma fits in the group of plasm cell disorders characterized by neoplastic proliferation of single clone of plasma cell engaged in the production of a monoclonal immunoglobulin, usually monoclonal IgG or IgA.

The growth of the tumor, which takes place in the bone marrow, its protein products and the individual response to the disorder will result in all of the organics disfunctions seen in this disease. Skeletal destruction with bone pain, anemia, hypercalcemia and renal failure are some of the features.

Epidemiology

Multiple Myeloma accounts for 1% of all malignant disease and slightly more than 10% of hematologic malignancies. The annual incidence of Multiple Myeloma is 4 per 100.000 increasing with aging. The median age of patients at the time of diagnosis is 61 years. It is more commom in men and blacks.

Etiology

The cause of Multiple Myeloma is unclear. Exposure to radiation, benzene and other organic solvents, herbicides, and insecticides may play a role. A genetic predisposition may also be involved. Some trials shows that chronic antigenic stimulation leads to a transformation of the progenitor B-cell, a fact that may explain the higher incidence of Multiple Myeloma in farmers, woodmakers and oilworkers.

Pathogenesis

In the very beginning, cell production from the bone marrow stem cell results in two lineages with lymphoid characteristics : pre- T cell and pre-B cell. The first will migrate to the Thymus where they will be differenciated into T cells. The last cells will reach the peripheral blood as " tracer limphocytes " . This kind of cell is the result of a process of differentiation not related to antigen that produces a great variety of cells which express small amounts of immunoglobulin on their surface.

These cells, at some moment of their lives, will be stimulated by antigens or cytokines from helper T cells and will migrate to lymph nodes where they initiate a clonal proliferation which results in plasmablasts that express on their surface IgM and IgA. Those cells can go in two ways: get back to the blood as helper T cells or migrate to the bone marrow.

After the activated B cells enter the bone marrow, they stop proliferating and differenciate into plasm cells, under the influence of adhesion molecules and factors such interleukin-6. They start to produce immunoglobulin and die by apoptosis after several weeks or months. What initiates this process is still unclear.

The cells in Multiple Myeloma are often immature, may have the appearance of plasmablasts and produce low amounts of clonal immunoglobulin. The cause of the failure in the process of differentiation is not clear, but chromossomial translocation and increase in the expression of oncogen Cmyc could play an important role.

The rate of cell proliferation in the beginning of Multiple Myeloma disease is very low compared to the terminal phase. The myeloma cells are aneuploid and their chromosomes have many numerical and structural abnormalites that seems to prevent the differentiation and death of these cells, which continue to proliferate and acumulate in the bone marrow. All these alterations are correlated with resistance to treatment and short survival characteristc of aggressive disease.

Chromosomial mutation may occur during the course of the disease and once identified can be useful for following the disease. Recently studies have shown that myeloma cells are not confined to bone marrow. They may be found in the blood and other tissues.

Some citokines are involved in the pathogenesis of Multiple Myeloma. Interleukin-6 is essenciatial for the survival and growth of myeloma cells, which express specific receptors for this cytokine, and also prevents spontaneous or dexamethasone induced apoptosis.

There is some evidences that interleukin-6 is produced by bone cells and stromal cells after stimulation by myeloma cells. The interleukin-6 system ( interleukin-6, soluble interleukin-6 receptor a, interleukin-1-b ) play an important role in the pathogenesis of bone lesions because it activates osteoclasts in the vicinity of myeloma cells and thus provoke bone reabsorption.

Clinical Aspects

Multiple Myeloma patients may show various clinical alterations that, almost always, are not specific for MM, making it necessary to do some specific exams to confirm the disease.

Bone lesions are very common, bone pain being the most prevalent symptom (70%). These lesions are, in most of the cases, lytic lesions caused by tumor expansion and activation of osteoclasts by myeloma cells secretion of osteoclasts activation factors (OAF). Interleukin-6 may have an important role in osteoclast activation, and so, in bone reabsortion. Because of low bone density, the occurence of pathologic fractures is common. Expansive lesions can be found through physical examination.

Because of the great bone reabsortion, another common problem is hypercalcemia that may lead to renal alterations and neurologic symptoms if not treated.

Recurrent infections is the second big problem. Pneumonia and pyelonephritis are the most frequent. The cause of these infections is the fact in MM there is a clonal production of one type of non-functioning antibody, and so, there is little production of normal antibodies. There is an alteration of neutrophils (dimished migration) and the complement system is also altered. Cellular immunity can sometimes be altered with cd4+ lymphocyte dysfunction. So, the great defect on immunity in Myeloma is in opsonization and humoral immunity. Encapsuled bacteria are the most prevalent pathogens because they need opsonization to be phagocytized by reticular-endothelial system cells.

Half of the M.M patients have renal pathology. Frank renal insufficiency is observed in 25% of them. There are various causes, including amyloid deposits, hypercalcemia, hyperuricemia and recurrent infections. Indeed, tubular damage is often seen because of the excretion of light chains that affect directly the tubular cells.

Anemia occurs in 80% of MM patients, generally, normocytic and normochromic, caused by destruction of bone marrow with invasion of MM cells and by inhibition of cell production in bone marrow by tumor factors. Granulocytopenia and thrombocytopenia are rare, but coagulation abnormalities are seen because of platelet dysfunction and/or interaction of a monoclonal component (M component) with some coagulaction factors.

Even neurologic symptoms are seen, and they have many causes.

Hypercalcemia can lead to lethargy, dizzinness and depression. Bone fractures can result in medullar compression syndrome and radicular pain. Carpal tunnel syndrome and mono and polyneuropathies can be caused by amyloid infiltration in pheripheral nerves.

Although we have seen generalized distribution of plasmocytes in the body, the tumoral expansion is restricted to the bone and bone marrow, and so, rarely leads to splenomegaly and linphadenopathy.

Diagnosis

The diagnosis of M.M is confirmed when bone marrow plasmocytosis (>10%), lytic bone lesions and monoclonal immunoglobulin in serum or urine is found. There are two variants of MM: Solitary bone plasmocytoma (one lytic lesion with no bone marrow plasmocytosis) and extramedullary plasmocytoma. Those variants are seen in younger people and are well treated with radiotherapy.

The most difficult diferential diagnosis is with monoclonal gammopathy (MG). It is more common than MM, has less than 2g/dl of M component, no Bence-Jones protein, less than 5% of plasmocytosis and doesn't show any of MM clinical manifestations. MG doesn't need treatment.

We initiate our investigation with a physical examination searching for bone lesions or masses. Radiographic images can reveal lytic bone lesions or diffuse low bone density. A hemogram can show anemia. Serum values of calcium, urea nitrogen and uric acid can be elevated. Using protein eletrophoresis we can observed a M-component in urine and/or serum.

M-component is represented by IgG in 53%, IgA in 25% and IgD in 1%. Twenty percent (20%) of the patients will show only light chains in serum and urine. Less than 1% of the patients have no detectable M-component.

There is a complex staging system in Multiple Myeloma that is actually a functional system which serves to evaluate the prognosis using various types of clinical and laboratory tests. This differs from the anatomic staging systems for solid tumors.

Staging

Treatment

Facts that should be considered in the beggining of the treatment

1. Symptons
2. Laboratorial findings
3. Physical exam findings

Treatment goals - prolonging life vs. giving a better quality of life

When we should treat?

Stage 1 with Bence Jones protein

Stage 2

Stage 3

Progressive skeletal lesions

Vertebral compression causing fractures

Recurrent infections

Increase of M-component

Associated leukemia or other alteration of bone marrow

What is the treatment?

1. Solitary Plasmacytoma

radiation therapy at doses of 4000 to 5000 cGy

70 percent of soft-tissue plasmacytomas are cured with radiation

30 percent of solitary plamacytomas of bone are cured with radiation

2. Indolent Myeloma

treatment is witheld until the onset of symptons or evidence of disease progression

3. Standard treatment of symptomatic Multiple Myeloma

Melphalan, cyclophosphamide and glucocorticoids are the most effective drugs against Multiple Myeloma. The standart treatment is still the combination of Melphalan and Predinisone.

Melphalan should be given orally in a daily dose of 0.15 mg per kilogram for 7 days ( 8 to 10 mg per day ) associated with 20 mg of Predinisone 3 times daily for the same period. This therapy has to be repeated in cycles every 6 weeeks for at least 1 year. If the patient is in plateau ( stable serum and urine M-protein and no evidence of progression ), treatment should be stopped. This standart form of therapy produces objective response in 50 to 60 % of patients.

combination of other drugs including Vinca Alkaloids, Nitrosoureas, Antracyclines, the regimen of Vincristine, Doxorubicine and Dexamethasone (VAD) or VAMP (with high-dose Methylpredinisolone substituted for high dose Dexamethasone ) are effective against Myeloma but are no more effective or prolong survival more than Melphalan +Predinisone.

4. Salvage therapy and new supportive therapies

The high dose therapy with Melphalan given intravenously with autologus hematopoietic support, the addition of granulocyte-macrophage colony-stimulating factor ( GM-CSF ) and erithropoietin factor represents a significant improvement over conventional therapy and may be the treatment of choice for patients up to 65 years old. However, for many patients conventional chemotherapy continues to be the only possibility, because the median age of patients at diagnosis is about 65 years and the candidates for the treatment must have a good performance status and a normal renal function.

In patients 50 years of age or younger, allogeneic transplantation of bone marrow from an HLA-identical sibling yields encouraging results if undertaken early in the course of disease. In the future, it will possibly be the only genuinely curative therapy in Myeloma.

Interferon-a has not shown to be superior to conventional chemotherapy in previously untreated patients, but it is used as maintainence therapy for patients who have a response to initial treatment or in combination with chemotherapy, as induction therapy. It can also be helpful in prolonging remission after autologous transplants.

5. Treatment of refractory Multiple Myeloma

Almost all patients with Multiple Myeloma who respond to chemotherapy eventually relapse. The highest response rates for patients with Multiple Myeloma resistant to alkylanting agents have been with VAD ( Vincristine, Doxorubicin and Dexamethasone ) and most of his activity is from Dexamethasone.

Interferon a can be also used producing response in 10 to 20 %. When the Multiple Myeloma is at the same time refractory and/or advanced disease, cyclophosphamide ( 600 mg/m2 intravenously daily for 4 days) plus predinisone ( 100 mg daily for the same period ) followed by granulocyte-colony-stimulating factor has been helpful.

Biphosphanates, wich are potent inhibtors of bone resorption, has been shown to reduce the incidence of skeletal events, prevent hypercalcemia, alleviate bone pain and improve the patient`s quality of life , contributing to the long-term control of bone disease.

6. Managment of Complications

Hypercalcemia

- Hydratation with isotonic saline plus predinisone relieves the hypercalcemia in almost cases and prevents acute renal insufficiency
- Biphosphanates can also be helpful

Renal Insufficiency

- Increase of fluid intake
- Furosemide helps to maintain a high urine flow rate
- Allopurinol is necessary if hyperuricemia is present
- Hemodialysis is necessary in the event of symtomatic azotemia
- Plasmapheresis can be used for regaining renal function in some cases

Infection
- Renal infection must be treated promptly
- Coverage can begin with broad spectrum antibiotics pending culture results
- Prophylactic treatment and pneumococal and influenza immunozations seem not to be useful

Skeletal Lesions
- Skeletal fractures should be prevented - with exercises, calcitonin and biphosphanates
· Radiotherapy and prophylactic fixation of bones can be helpful in preventing long bone fractures

Myscellaneous complications
- Neurologic manifestations - sudden an strong pain in legs or in the back, numbness or weakness of the lower extremities or sphincter dysfunction is a medical emergency - indicating impending spinal cord compression requiring neurosurgical decompression
- Anemia - We should find the cause and then think about the treatment.
- With blood lost anemia it is not a common sense to give platelets

Prognosis

· In the first months, after the diagnosis, 15 % of the patients die. When no treatment is given Multiple Myeloma has a progressive course with a median survival of 6 months. · If it has a chronic evolution ( 2-5 years) the terminal phase is characterized by plasma cell leukemia, pancytopenia, bleeding, infections, and ultimate bone marrow failure.

Factors of Prognosis

· Age - the highest ,the worst
· Increase of these factors is associated with advanced disease: b2 microglobulin (which reflects neoplastic cell turnover and renal function), HDL, C-reactive protein ( which reflects IL-6 activity), interleukin-6
· Myeloma cells in peripheral blood and increase of those in the bone marrow
· Morphology of plama cells