• 93% of patients will have more than one pathological fracture and/or bone lesion.
• 70% of patients will have bone pain.
• Bleeding can occur because of thrombocytopenia and even more rarely from monoclonal protein which impacts clotting.
• As many as 30% of patients with multiple myeloma will present with hypercalcemia which can cause bone pain, nausea, thirst, and constipation.
• If the patient is presenting symptoms of weakness, back pain, numbness, or dysesthesias in their extremities a spinal cord compression should be considered.
• Severe cases of anemia can be present.
• Infections such as shingles, Pneumococcal organisms, and Haemophilus are common due to leukopenia and abnormal humoral immunity.
• Patients with a high tumor volume may present with epistaxis.
• Generalized malaise, fever, sluggish mentation, paresthesia, sensory loss, and infection can indicate hyperviscosity.
• Meningitis and carpal tunnel syndrome are both common neurologic symptoms associated with myeloma.

The standard workup for patients who are suspected of having multiple myeloma includes many components. The 2009 International Workshop created guidelines to standardize the investigative workup:

• Bone marrow biopsy and/or bone marrow aspiration
• Skeletal survey
• Standard metaphase cytogenetics
• MRI’s
• Fluorescent in situ hybridization
• Urine and serum assessment for monoclonal protein
• Serum-free light chain assay
• Serum beta (2)-microglobulin, lactate dehydrogenase, and albumin measurement
• Complete blood count looking for thrombocytopenia, anemia, leukopenia
• A complete metabolic panel of protein, albumin and globulin, creatinine, uric acid, and blood urea nitrogen levels.
• A 24-hour urine collection to quantify creatinine and Bence Jones protein clearance

Imaging

PET scans and whole body MRI’s can be used to evaluate the extent of the multiple myeloma. Using both scanning techniques is thought to be helpful in assessing the effectiveness of expensive and aggressive treatments. Currently, however, PET scans are not part of standard practices. Bone scans should not be used in evaluating multiple myeloma as more than 50% of lesions tend to be missed.

Others

Bone marrow biopsies and aspirations can be used to evaluate the extent of malignancy. Using both allows the doctor to calculate the percentage of plasma cells in the aspirate, though the biopsy tends to be more accurate.

Staging

There are currently two staging systems in use to determine the severity of multiple myeloma in patients. The Salmon-Durie System has been in use since 1975 and the International Staging System was developed in 2005 [4] [5] [6].

Salmon-Durie Staging System

Stage 1:

• Cell mass is less than 0.6 × 1012 cells/m2
• Serum calcium value less than 12 mg/dL
• Hemoglobin value greater than 10 g/dL
• Only one bone plasmatoma on radiographs or a normal bone structure with a scale of 0
• Urine light-chain M component on electrophoresis less than 4 g/24 h
• IgG value less than 5 g/dL
• IgA value less than 3 g/dL

Stage 2:

• Cell mass is 0.6-1.2 × 1012 cells/m2
• Does not meet the criteria for stage 1 or stage 3

Stage 3:

• Cell mass is greater than 1.2 × 1012 cells/m2
• Serum calcium value greater than 12 mg/dL
• Advanced lytic bone lesions (scale 3) on radiographs
• Hemoglobin value equal to 8.5 g/dL
• IgG value greater than 7 g/dL
• IgA value greater than 5 g/dL
• Urine light-chain M component on electrophoresis greater than 12 g/24 h

International Staging System

Stage 1:

• CRP ≥4.0 mg/dL
• Beta-2 microglobulin less than or equal to 3.5 g/dL and albumin ≥3.5 g/dL
• Absence of chromosome 13 deletion
• Low serum IL-6 receptor
• Plasma cell labeling index < 1%
• Long duration of initial plateau phase

Stage 2:

• Beta-2 microglobulin level ≥3.5 to < 5.5 g/dL, or
• Beta-2 microglobulin < 3.5 g/dL and albumin < 3.5 g/dL

Stage 3:

• Beta-2 microglobulin of 5.5 g/dL or more

The main options for therapy include:

• Chemotherapy and immunosuppression (melphalan, cyclophosphamide, doxorubicin, thalidomide, lenalidomide, bortezomib, carfilzomib, pomalidomide, prednisone and dexamethasone)
• Autologous stem cell transplantation
• Radiation
• Surgical care

Prognosis of multiple myeloma is determined by 2 factors - how many tumors there are and how fast they are spreading. C-reactive protein and beta-2 microglobulin are both used to predict survival.

The median survival rates are as follows:

• 54 months if both proteins are less than 6 mg/L
• 27 months when only one protein is less than 6 mg/L
• 6 months when both proteins are more than 6mg/L

Factors that led to a poor prognosis are hypercalcemia, renal impairment, tumor mass, and Bence Jones proteinemia. Patients that undergo conventional therapy have an average survival rate of 3 years. Fifty percent of patients who undergo high-dose chemotherapy with stem-cell transplantation survive for longer than 5 years [3]. The leading cause of death for patients with a myeloma is a bacterial infection.

To date an exact cause for multiple myeloma has not been identified, but various factors have been suggested [1] [2]. Since most individuals diagnosed with the disorder are in the older age group the common thought is that decreased immune system that comes with age increases the chance of developing multiple myeloma. While no evidence suggests that the disease is hereditary, it has been reported in 2 or more first degree relatives and in identical twins. Oncogenes such as c-myc have been associated with plasma cell tumors early in their development.

Individuals working with toxic chemicals such as insecticides, herbicides, heavy metals, petroleum products, and asbestos could be at an increased risk for developing multiple myeloma though the risk cannot be quantified. A correlation between multiple myeloma and radiation has been identified in examining the medical histories of Nagasaki WWII survivors, who were exposed to more than 50 Gy of radiation. Of the 109,000 survivors, 29 died of a multiple myeloma between 1950 and 1976. While a link between pre-existing inflammatory diseases and multiple myeloma has been suggested, no case-control studies have been able to support the relationship.

Annually, approximately 4 in 100,000 people are diagnosed with multiple myeloma. The condition is twice as common in African Americans, followed by Caucasians and half as common with Asian Americans. The predominant age of diagnosis is between 40 and 80 years old. The median age of diagnosis for men is 69 and for women is 71. Men are one and a half times more likely to be diagnosed with multiple myeloma than women. The malignancy is one of African American’s top 10 causes of cancer deaths.

Multiple myeloma is characterized by the rapid growth of abnormal plasma cells in more than 10% of the patient’s bone marrow. Research suggests that the bone marrow microenvironment impacts the manner in which myelomas develop tumor cells. The cells that most often become malignant in multiple myelomas are the most mature of the B-lymphocytes. This occurs when the DNA sequence is rearranged when encoding into the structure of mature immunoglobulins. During the encoding immunoglobulin A, monoclonal immunoglobulin G, and/or light chains are overproduced. This overproduction is identified through the use of urine protein electrophoresis, or serum protein electrophoresis. Multiple myelomas are often the consequence of injuries or diseases in hematologic, renal, skeletal, and nervous systems as well as general processes.

General processes

Hyperviscosity syndrome can occur with immunoglobulin A, immunoglobulin G3, and immunoglobulin G1. Sludging in the capillaries resulting in purpura, papilledema, central nervous system symptoms, retinal hemorrhage, or coronary ischemia can occur.

Hematologic processes

Neutropenia, thrombocytopenia, and anemia result from plasma cells infiltrating bone marrow which can impact clotting factors leading to defects in how it interacts with other systems.

Renal processes

Renal processes linked to multiple myeloma, are most commonly amyloidosis, direct tubular injury, or mechanisms involved in plasmacytoma. Diagnoses of hyperuricemia, hypercalcemic nephropathy, glomerulosclerosis, and light-chain nephropathy are also possible.

Skeletal processes

Wide spread skeletal destruction is caused by a rapid increase in plasma cells. Skeletal destruction is accompanied with anemia, hypercalcemia, and osteolytic lesions. When the bone is destroyed, it is replaced by tumors which can lead to spinal cord compression, pathologic fracture, and pain. A compression fracture of the vertebral body can occur.

Neurologic processes

Skeletal destruction and nerve compression can cause spinal cord compression and/or radiculopathy.

There are no guidelines for prevention of multiple myeloma.

Multiple myeloma, also known as plasma cell myeloma, myeloma, myelomatosis, and Kahler’s disease, is part of an incapacitating spectrum of malignancies including monoclonal gammopathy of unknown significance (MGUS) and plasma cell leukemia. Typically a multiple myeloma involves the skeleton and bone marrow with malignant proliferation of plasma cells. This interferes with blood cell production leading to anemia, leukopenia, and thrombocytopenia. High levels of infection are common which can lead to the overproduction of certain antibodies. This causes amyloidosis, hyperviscosity, and renal failure. There are life extending treatments, but currently no cure.

Multiple myeloma is a cancer of certain blood cells - plasma cells and it occurs in both the skeletal system and bone marrow. If you have been diagnosed with multiple myeloma then you could be experiencing any of the following symptoms: anemia, bleeding, bone pain, hypercalcemia, infection (often pneumococcal), kidney failure, malaise, neuropathies, pathologic fractures, spinal cord compression, or weakness.

There are no known causes of multiple myeloma; however, certain individuals have an increased risk of developing it. You have an increased risk of developing the condition if you are over 65, male, African American, have a family member who has been affected, or have either Monoclonal Gammopathy of Uncertain Significance (MGUS) or plasmacytoma.

If you have multiple myeloma you will through what is called induction therapy. The first stage involves chemotherapy to destroy the cancer (this will typically destroy many healthy cells too). Once you have gone through a round of chemotherapy, and if you are under the age of 70 you may have some stem cells removed and frozen through a process known as autologous stem cell transplantation. Those stem cells will be used later to lengthen your survival. Some people will receive two rounds of stem cell transplantation 6 months apart. Some patients might also do a round of radiation therapy which involves shooting a beam of radiation directly at the affected area.

Multiple myeloma treatments can cause you to feel nauseous or experience decreased immunity. Biophosphate therapy increases your risk of osteonecrosis of the jaw (exposure of the jaw bone through lesions).

1. Yiin JH, Anderson JL, Daniels RD, Seel EA, Fleming DA, Waters KM, et al. A nested case-control study of multiple myeloma risk and uranium exposure among workers at the Oak Ridge Gaseous Diffusion Plant. Radiat Res. Jun 2009;171(6):637-45.
2. Raab MS, Podar K, Breitkreutz I, Richardson PG, Anderson KC. Multiple myeloma. Lancet. Jul 25 2009;374(9686):324-39.
3. Ludwig H, Durie BG, Bolejack V, Turesson I, Kyle RA, Blade J, et al. Myeloma in patients younger than age 50 years presents with more favorable features and shows better survival: an analysis of 10 549 patients from the International Myeloma Working Group. Blood. Apr 15 2008;111(8):4039-47.
4. Dimopoulos M, Kyle R, Fermand JP, et al. Consensus recommendations for standard investigative workup: report of the International Myeloma Workshop Consensus Panel 3. Blood. May 5 2011;117(18):4701-5.
5. Durie BG, Salmon SE. A clinical staging system for multiple myeloma. Correlation of measured myeloma cell mass with presenting clinical features, response to treatment, and survival. Cancer. Sep 1975;36(3):842-54.
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