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Multiple Myeloma

Summary

Multiple myeloma is a malignant tumor of plasma cells that causes widespread osteolytic bone damage.

The average age of the patients at diagnosis is 65 years.
The presenting symptom of multiple myeloma is usually pain. The patient may have a normocytic, normochromic anemia secondary to marrow failure and an increased ESR. Hypercalcemia may cause confusion, weakness and lethargy. Other symptoms may include cachexia, spinal cord compression and renal insufficiency. Bacterial infections are common because of a lack of normal immunoglobulin production. Monoclonal immunoglobulin is found on serum electrophoresis. Light chain subunits of immunoglobulin are called BenceJones proteins and are present in urine.
The radiological appearance of multiple myeloma is characterized by irregular lytic defects of different sizes.
Treatment of multiple myeloma consists of palliative chemotherapy or bone marrow transplant. Bisphosphonates are used to inhibit resorption of bone and subsequent hypercalcemia.
Complete Information on this Tumor
Introduction and Definition: 

Multiple myeloma is a malignant tumor of plasma cells that causes widespread osteolytic bone damage. Multiple myeloma is the most common primary tumor of bone and is found in the spine, skull, ribs, sternum and pelvis but may affect any bone with hematopoietic red marrow. There are chromosomal abnormalities that are associated with MM, such as 14q32 and deletion of chromosome 13, and these findings are more likely to be found in cases with poor outcome. Other diseases, such as solitary plasmacytoma and monoclonal gammopathy are associate with MM. Approximately 10% of patients with these diseases will eventually develop MM.

Incidence and Demographics: 
About 3 or 4 in every 100,000 people get multiple myeloma (MM), and the average age of the patients at diagnosis is 65 years. Men are slightly more likely to get MM than women. From the time of diagnosis, the average patient will survive for more than 4 years.
Symptoms and Presentation: 

The presenting symptoms of multiple myeloma are often fatigue and bone pain, but patients may have other symptoms associated with organ failure, such as kidney failure, infection, and anemia. Some patients may have asymptomatic myeloma, where the abnormal cells are present but symptoms and organ damage are not. MM patients may have a normocytic, normochromic anemia secondary to marrow failure and an increased ESR. Hypercalcemia may cause confusion, weakness and lethargy. Other symptoms may include cachexia, spinal cord compression and renal insufficiency. Bacterial infections are common because of a lack of normal immunoglobulin production.

Monoclonal immunoglobulin (Ig G)is found on serum electrophoresis and on urinalysis. Immunoglobulin (Ig) is the protein that is produced by the tumor cells. Light chain subunits of immunoglobulin are called Bence Jones proteins and are present in urine.

Initial tests include a quantitative assay for Ig, kidney function tests, serum calcium, and a beta-2 microglobulin level. Bone marrow biopsy is required to meaure the percentage of plasma cells in the bone marrow. More than 10% plasma cells is a diagnostic feature of MM.

Bone damage is common and can be severe in MM, and a large percentage of patients will develop pathologic fractures. Careful skeletal evaluation and monitoring, as well as close consultation with an orthopedic tumor specialist are recommended. Depletion of bone mineral / calcium levels can lead to severe fracture risk, but can be avoided or minimized with proper care. Bone preservation treatments should be instituted at the earliest possible moment.

X-Ray Appearance and Advanced Imaging Findings: 
The radiological appearance of multiple myeloma is characterized by irregular lytic defects of different sizes. These lytic areas are often described as "punched out" and have no periosteal reaction. Erosion begins intramedullarly and progresses through the cortex. MRI is useful for delineating spinal lesions. Lesions are hypointense to normal marrow on T1, and hyperintense on T2 images. MRi may be used in place of bone scan to stage the entire skeleton, and is more accurate than bone scan. MRI is useful in evaluation the response to treatment. PET-CT and MRI are both used to fully characterize the extent of disease. Bone scan can fail to have increased uptake in 25% of patients suggesting a plain film skeletal survey should always be done.
Laboratory Findings: 
On gross examination, the marrow space has been replaced by a diffuse gelatinous red brown tissue. Tumor nodules of approximately 1 cm in size may be present.
Differential Diagnosis: 
ewing sarcoma, lymphoma, leukemia, acute infection, LCH. Biopsy is not required if the results of the serum protein electrophoresis confirm the diagnosis of MM.
Preferred Biopsy Technique for this Tumor: 
in cases where strong support for the diagnosis exists, FNA is sufficient.
Histopathology findings: 
Microscopically, multiple myeloma is composed of sheets of plasma cells. The degree of cytologic atypia of these cells has no prognostic value. The osteolytic lesions are caused by increased osteoclastic resorption that is stimulated by cytokines released by-the plasma cells.
Treatment Options for this Tumor: 
Treatment of multiple myeloma consists of induction chemotherapy followed by stem cell transplantation for those who will benefit from it. Stem cell transplant increases survival time, but does not cure MM. Initial multi-agent chemotherapy is given prior to stem cell transplant, and numerous reversible side effects are common. Up to 90% of patients respond to initial treatments. Older patients, patients in poor condition, or those with multiple comorbidities are given melphalan and prednisone, radiation as needed, and other chemotherapy as tolerated. Thalidomide is also useful. Bisphosphonates are used to inhibit resorption of bone and subsequent hypercalcemia. Orthopedic surgeons are an essential part of the treatment team in multiple myeloma. The orthopedic surgeon may be required to evaluate a painful bone lesion for possible pathologic fracture risk. The orthopedic surgeon must make the appropriate decision between operative and non-operative treatment modalities. Please see separate sections on this website for guidelines for the evaluation of pathologic fracture risk. Multiple myeloma patients who are being prepared for stem cell transplant deserve special consideration. Bone lesions in high risk areas may be considered for aggressive surgical treatment. If pathologic fracture occurs during the stem cell transplantation process, long delays in treatment and associated morbidity are more likely to occur. Orthopedic surgeons may be the first position to encounter the painful bone lesion in patients with undiagnosed multiple myeloma. Prior to surgical stabilization of these lesions, medical stabilization should be accomplished to minimize the potential for surgical complications. Patients with multiple myeloma have an increased risk of postoperative deep venous thrombosis and should be managed accordingly. Surgical stabilization of lesions can be accomplished using multiple techniques according to the location and extent of the tumor, the condition and prognosis of the patient, and the surgeons preferences. Since the average survival after diagnosis of patients with multiple myeloma is four years, robust and durable methods of surgical reconstruction should be employed, especially in weight-bearing sites. Spinal lesions are common, and spinal compression fractures may occur. Percutaneous vertebral plastic techniques have been proven to be effective. Bulky spinal disease and spinal disease where cord compression is present or imminent may be managed with radiation in many cases. Spinal decompression surgery may be required and is effective in improving quality of life and neurologic function. Radiation therapy is typically used to limit progression of early bone lesions and for palliative pain relief.
Preferred Margin for this Tumor: 
No surgical margin is defined for this tumor, resection is not a goal.
Outcomes of Treatment and Prognosis: 
Following diagnosis, the average patient will survive proximately 50 months. Stem cell transplantation has been shown to improve disease-free survival by two or three years. Multiple competing treatment programs exist, and there is a lack of consensus as to which is the best. Patients are encouraged to enroll in clinical trials which will help determine the best treatment.
Special and Unusual Features: 
The malignant cells stimulate increased osteoclastic activity, and osteoblastic activity is decreased. Alkaline phosphatase and osteocalcin levels are correspondingly low. The RANKL osteoprotegerin pathway is the primary mediator of myeloma bone disease. (JAASO 2001 see below) Nuclear factor-kappa B ligand (RANKL)and other osteoclastic mediators are increased and osteoprotegerin production is suppressed.
Suggested Reading and Reference: 
J Am Acad Orthop Surg. 2011 Jul;19(7):410-9. Multiple myeloma: diagnosis and orthopaedic implications. Scharschmidt TJ, Lindsey JD, Becker PS, Conrad EU. Mankin, Henry, Metabolic Bone Dlsease, Instructional Course Lectures, 44:3-29, 1995. Bulloughs, Peter, Orthopaedic Patholoev (third edition), Times Mirror International Publishers Limited, London, 1997. Cotran, Robbins and Kumar, Robbins Pathologic Basis for Disease, W.B. Saunders, Co., 1994. Huvos, Andrew, Bone Tumors: DiaXnosis, Treatment and Prognosis, W.B. Saunders, Co., 1991. Wundry, GR and T. Yoneda, Facilitation and suppression of bone metastasis, Clinical Orthopaedics and Related Research, 321:34-44, March, 1995. JAAOS Vol 19 No 7 July, 2011 p 410 - 419 7/15/2011