Epidemiology

Multiple myeloma is a cancer formed by malignant plasma cells. It accounts for approximately 1% of neoplastic diseases and 13% of hematologic cancers. In Western countries, the annual ageadjusted incidence is 5.6 cases per 100,000 persons. The American Cancer Society's most recent estimates for multiple myeloma in the United States are for 2012:

About 21,700 new cases will be diagnosed (12,190 in men and 9,510 in women). About 10,710 deaths are expected to occur (6,020 in men and 4,690 in women).

The median age at diagnosis is approximately 70 years; 37% of patients are younger than 65 years, 26% are between the ages of 65 and 74 years, and 37% are 75 years of age or older. Myeloma has a higher incidence in Afro-Caribbean ethnic groups than in Caucasians but there are few other distinctive epidemiological features.

Defenition

Multiple myeloma is a neoplastic plasma-cell disorder that is characterized by clonal proliferation of malignant plasma cells in the bone marrow microenvironment, monoclonal protein in the blood or urine, and associated organ dysfunction. Normal plasma cells are found in the bone marrow and are an important part of the immune system, is composed of several types of cells that work together to fight infections and other diseases. Lymphocytes (lymph cells) are the main cell type of theimmune system. There are 2 major types of lymphocytes: T cells and B cells. When plasma cells become cancerous and grow out of control, they can produce a tumor called a plasmacytoma. If there is only a single plasma cell tumor, it is called an isolated (or solitary) plasmacytoma.When there is more than one plasma cell tumor, it is called multiple myeloma.

Risk Factors

Age : The risk of multiple myeloma goes up with age. Less than 1% of cases are diagnosed in people younger than 35. Most people diagnosed with this cancer are over 65 years old. Gender : Men are slightly more likely to develop multiple myeloma than women. Race : Multiple myeloma is almost twice as common among black Americans as white Americans. Radiation : Exposure to radiation may increase the risk of multiple myeloma. At most, this accounts for a very small number of cases. Family history : Someone who has a sibling or parent with myeloma is 4 times more likely to get it than would be expected. Workplace exposures : Some studies have suggested that workers in certain petroleum-related industries may be at a higher risk. Obesity : A study by the American Cancer Society has found that being overweight or obese increases a person's risk of developing myeloma. Other cell plasma diseases : Many people with monoclonal gammopathy of undetermined significance (MGUS) or solitary plasmacytoma will eventually develop multiple myeloma.

Etiology and Pathophysiology

Abnormalities of some oncogenes (such as c-myc, N-ras and K-ras) develop early in the course of plasma cell tumors. Abnormalities in their chromosomes, chromosome number 13 are missing which make the myeloma more aggressive and resistant to treatment. Abnormally translocated chromosomes. Abnormalities in other bone marrow Cell dendritic cells release a hormone called interleukin-6 (IL-6), which stimulates normal plasma cells to grows.

Interaction between Plasma Cells and Bone Marrow in Multiple Myeloma. As part of the interaction between plasma cells and stromal cells, adhesion is mediated by cell adhesion molecules, such as vascular-cell adhesion molecule 1 (VCAM1) and integrin alpha 4 (VLA-4). This interaction increases the production of growth factors, such as interleukin- 6 and vascular endothelial growth factor (VEGF), which stimulates both plasma cells and angiogenesis. The increased osteoclast activity is due to an imbalance in the ratio between receptor activator of nuclear factor B (RANK) and osteoprotegerin (OPG) as a result of enhanced production of RANK ligand (RANKL) and reduced production of OPG. Osteoblast activity is also suppressed by the production of dickkopf homolog 1 (DKK1) by plasma cells. Moreover, plasma cells can inhibit a key transcription factor for osteoblasts, runt-related transcription factor 2, causing a reduction in differentiation from precursors to mature osteoblasts. The adhesion of plasma cells to stromal cells up-regulates many cytokines with angiogenic activity, in particular interleukin-6 and VEGF. Osteoclasts that are activated by stromal cells can also sustain angiogenesis by secreting osteopontin. Chromosomal abnormalities can cause overproduction of receptors on myeloma cells. The 1q21 amplification causes an increase in interleukin-6 receptor and consequently an increase in growth mediated by interleukin-6. CCR1 denotes chemokine receptor 1, CD40L (or CD40LG) CD40 ligand, FGFR3 fibroblast growth factor receptor 3, HGF hepatocyte growth factor, ICAM1 intercellular adhesion molecule 1, IGF1 insulin-like growth factor 1, MIP1 macrophage inflammatory protein 1 , MUC1 cell-surfaceassociated mucin 1, and NF-B nuclear factor B.

Signs and symptoms

Bone problems Low blood counts : anemia, leukopenia,thrombocytopenia. High blood calcium (hypercalcemia) : This can cause dehydration and even kidney failure, can also cause severe constipation and loss of appetite. Nervous system symptoms : collapse and press on spinal nerves severe pain, numbness, and/or muscle weakness. The abnormal proteins produced by myeloma cells can be toxic to the nerves. Large amounts of myeloma protein can cause hyperviscosity. It can slow blood flow to the brain and cause confusion, dizziness, and stroke-like symptoms. Kidney problems : mainly as a result of direct tubular damage from excess protein load, dehydration, hypercalcemia, and the use of nephrotoxic medications. Infections : Pneumonia is a common and serious infection seen in myeloma patients.

Diagnosis

Blood counts Quantitative immunoglobulins Electrophoresis is a test to measure the total amount of immunoglobulin in the blood and find any abnormal immunoglobulin. Free lights chain Beta-2 microglobulin Blood chemistry test : BUN and creatinine, albumin, calcium and other electrolytes Bone marrow biopsy : immunohistochemistry and flow cytometry, and chromosome analyses, including karyotype and fluorescent in situ hybridization (FISH) Imaging studies : bone x-ray, CT-Scan, MRI.

Diagnosis of multiple myeloma requires either: A plasma cell tumor (proven by biopsy) OR At least 10% of the cells in the bone marrow be plasma cells. AND one of the following: M protein over a certain level in the blood (3g/dL) OR M protein in the urine over a certain level (1g/dL) OR Holes in bones due to tumor growth are found on imaging studies.

Staging systems for multiple myeloma

Stage I Durie-Salmon Criteria All of the following: Hb > 10 gr/dl Serum calcium normal or 12 mg/dl Bone x-ray, normal bone structure or solitary bone plasmacytoma only Low M-component production rate IgG value < 5 gr/dl IgA value < 3gr/dl Bence Jones protein < 4g/24h Neither stage I nor stage III One of the following: Hb > 8.5 gr/dl Serum calcium normal or > 12 mg/dl Advance lytic bone lesions High M-component production rate IgG value > 7 gr/dl IgA value > 5 gr/dl Bence Jones protein > 12g/24h ISS Criteria Serum beta-2 microglobulin <3.5 mg/L Serum albumin 3.5g/dl

II III

Neither stage I nor stage III Serum beta-2 microglobulin <3.5 mg/L

Treatment
Traditional chemo : melphalan, vincristine, cyclophosphamide, carmustine, and doxorubicin (and liposomal doxorubicin). Corticosteroids : dexamethasone and prednisone Immunomodulating agents : thalidomide, lenalidomide. Proteasome inhibitor, work by stopping enzyme complexes (proteasomes) in cells from breaking down proteins important for keeping cell division under control. (Bortezomib, Carfilzomib) Biphosphonates : can help bones stay strong by slowing down this process (pamidronate, zoledronic acid) Radiation therapy Surgery

emergency surgery : spinal cord compression causes paralysis, severe muscle

weakness, or numbness elective surgery : may be needed to prevent fractures

Biologic therapy : Biologic therapy uses proteins that are normally found in the body to fight disease (interferon and erythropoietin) Stem cell transplant

Autologous stem cell transplant : this type of transplant

uses the patient's own blood-forming stem cells. Allogenic stem cell transplant : For this type of transplant, the stem cells come from someone else.

Plasmapheresis is helpful when certain myeloma proteins build up, thicken the blood, and interfere with circulation (called hyperviscosity).

Prognosis

International Staging System Stage

Median Survival

Stage I Stage II Stage III

62 months 44 months 29 months

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