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MULTIPLE MYELOMA AND OTHER PLASMA CELL DISORDERS

Published online October 1998

By Mohamad Hussein, M.D.

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Dr. Mohamad Hussein is a Board Certified Oncologist (specialist in the treatment of adult cancers), Staff at the Cleveland Clinic Cancer Center, and Director, Cleveland Clinic Multiple Myeloma Programs. He directs clinical trials and designs treatment programs for Chronic Leukemia's and Multiple Myeloma at the South West Oncology Group "SWOG", a national cooperative group devoted to the treatment of adult cancers. 

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MULTIPLE MYELOMA:

Multiple myeloma is a prototype of a group of conditions known as plasma cell neoplasms. Plasma cell neoplasms are a group of related disorders each of which is associated with proliferation and accumulation of immunoglobulin-secreting cells that are derived from the B-cell series of immunocytes. Monoclonal components occur in both the malignant plasma cell disorders, that is say, multiple myeloma, Waldenstrom's macroglobulinemia, solitary bone plasmacytoma, extra medullary plasmacytoma, osteosclerotic myeloma (POEMS Syndrome), amyloidosis, and heavy chain disease, as well as in the clinically unclear monoclonal gammopathy of undetermined significance/smoldering multiple myeloma.

PRESENTING SIGNS AND SYMPTOMS:

The clinical features of multiple myeloma develop from tissue damage by multiple bone tumors, complications from the monoclonal component, and an increased vulnerability to infections due to depressed normal immunoglobulin levels. These complications provide the first clues to the diagnosis and form the basis for defining the stage and prognosis. Subjective: 1) Skeletal System a) Bone pain is the most common symptom resulting from pathologic fractures. b) Compression fractures of the thoracic and lumbar vertebral bodies usually result in severe spasms and back pains. Multiple compression fractures may culminate in painless dorsal kyphosis and loss of as much as six inches of height. c) Pleuritic pain from pathologic rib and clavicular fractures is also common and is associated with marked local tenderness. d) Destruction of the proximal bones of the extremities is less frequent and distal bones of the extremities are rarely affected. e) Band-like or radicular pain should alert the clinician to impending spinal cord impression and is a serious complication representing an emergency requiring immediate diagnosis and treatment. 2) Hypercalcemia a) Nausea, confusion, polyuria and constipation are common symptoms secondary to hypercalcemia. 3) Anemia a) Easy fatigability or dyspnea on exertion is usually secondary to anemia. 4) Hyperviscosity a) When immunoglobulins are present at concentrations greater than 5 gm/dl, some IgG or IgA multiple myeloma globulin's can produce features of hyperviscosity syndrome. Lassitude, confusion, headache, transient disturbances of vision and increased bleeding tendency could be related to this syndrome. 5) Infections a) Recurrent bacterial infections are a major cause of illness and are the most common cause of death in-patients with advanced myeloma. 6) Amyloid a) Systemic amyloidosis with or without multiple myeloma could present with weakness, weight loss, ankle edema, dyspnea, paraesthesias, lightheadedness or syncope. b) Aching in the hands, particularly at night, can signify median nerve compression associated with Carpal Tunnel Syndrome, caused by amyloid infiltration of the transverse carpal ligament.

Objective findings: No specific physical abnormalities may be detected. 1) Skeletal System a) Most patients with symptomatic myeloma will have tenderness on pressure over an involved bone, kyphosis or a pathologic fracture to indicate the sight of bone lesions. b) In approximately 15% of patients, firm plasma cell tumors arise from areas of underlying bone destruction and may be palpated on the skull, sternum, clavicles and ribs, where the affected bone is close to the skin. c) Spinal examination could reveal kyphosis and on palpation, tenderness at the area of fracture or plasmacytoma, also palpation could trigger radiculopathy tha>

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COURSE OF THE DISEASE:

The median survival of multiple myeloma without any treatment is seven months. Since the introduction of chemotherapy, the median survival has improved to 36-48 months. Cure is rare in this disease. Several clinical and laboratory parameters provide important prognostic information that is extremely valuable in evaluating disease progression and different treatment regimens. Prognostic factors a) The staging system of Durie and Salmon which is based on hemoglobin, serum calcium, and monoclonal protein concentration, as well as the characteristics of the bone survey, classify patients into three stages which correlate with myeloma cell mass. b) Serum beta-2 microglobulin uncorrected for serum creatinine predicts survival remarkably well in myeloma patients. c) Karyotypic abnormalities occur in 30% of myeloma patients. Irrespective of the treatment status, patients with an abnormal karyotype have a significantly shorter median survival than those with a normal karyotype. d) The plasma cell labeling index powerfully and independently predicts survival. Also, it is a useful tool to differentiate between monoclonal gammopathy of undetermined significance and multiple myeloma. e) Other prognostic factors such as serum Interleukin-6, C-reactive protein, serum Interleukin-2, and serum IL-6 receptor appear to be other factors that could assist in predicting the course of the disease and/or response to therapy.

COMPLICATIONS:

a) Bone destruction - Approximately 20% of patients with multiple myeloma have bone demineralization only. Radiographs of the axial skeleton, which must include both femurs, will support the diagnosis of multiple myeloma in approximately 70% of patients. 10% of patients will have a normal skeletal survey, presumably because at least 30% of bone calcium must be lost before radiographic changes are evident. Rarely, in 1.4% of patients an osteoblastic reaction is present, which is suggestive of the POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein and skin changes). b) Renal Failure - Renal failure occurs in approximately 25% of patients, more frequently in-patients with more extensive disease. Most patients with mild azotemia have no symptoms, however easy fatigability, nausea, vomiting, and confusion occur with severe renal insufficiency. Pathogenesis is multi-factorial, but more than 90% of patients with renal failure have Bence-Jones proteinuria or hypercalcemia or both. c) Infection - Recurrent bacterial infections are a major cause of illness and are the most frequent cause of death in-patients with advanced myeloma. Infections result primarily from the marked depression of production of normal immunoglobulins that occur in more than 75% of patients. Streptococcus pneumonia Hemophilus influenzae, are the most common pathogens in previously untreated myeloma patients and in non-neutropenic patients who respond to chemotherapy. However, in neutropenic patients and in those with refractory disease, staphylococcus aureus and gram-negative bacteria are the predominant organisms. Pneumococcal vaccination may be worth trying, however most multiple myeloma patients respond poorly to bacterial antigenic stimulation. Herpes zoster could be seen in-patients with multiple myeloma more commonly in those complicated by renal failure. d) Hyperviscosity syndrome - Symptoms and signs of this condition are generally not seen unless the relative serum viscosity is greater than 4.0 units (normal range 1.4-1.8) and the full blown classic syndrome is usually not observed unless the viscosity is greater than 5.0 units. The signs and symptoms include lassitude, confusion, blurred vision, dizziness, vertigo, diplopia and increase tendency to bleeding, especially oro-nasal bleeding. e) Neurologic - Thoracic or lumbo-sacral radiculopathy is the most frequent neurologic complication. Root pain results from compression of the nerve by the vertebral lesion or by the collapsed bone itself. Spinal cord or cord compression from an extradural plasma cell tumor results in back pains with radicular features, weakness or paralysis where an immediate diagnosis and treatment is necessary. Occasionally, patients with multiple myeloma experience peripheral neuropathy, which may be severe. Electromyography studies suggest that this complication occur more frequently than clinically recognized. Although the pathogenesis is unclear, the neuropathy may be caused by associated amyloidosis in some patients. Severe motor neuropathy occurs more frequently in younger patients with localized or osteosclerotic myeloma. f) Hypercalcemia - At diagnosis, one-fourth of patients have serum calcium concentrations greater than 11.5 mg/dl after correction for serum albumin. Some hypercalcemic patients may not shown bone destruction on radiographs. Nausea, confusion, polyuria and constipation are common symptoms. g) Secondary malignancies - Secondary acute leukemia develops in approximately 2% of patients who survive 2 years, which is 50-100 times more frequent than in normal individuals. Fewer than 5% of patients with multiple myeloma have acute leukemia diagnosis or acquire the disease within several months after starting chemotherapy. The frequency of solid tumors in multiple myeloma patients is no higher than in persons of similar age or sex.

LABORATORY PROCEDURES:

Changes Noted on Routine Screening Tests: Routine laboratory screening, such as CBC, SMA-16, urinalysis and chest x-ray are usually nonspecific regarding reaching a diagnosis, however are extremely helpful in pointing to specific diagnostic procedures.

a) CBC i) Anemia is present in most patients and provides a major diagnostic clue. Several factors account for anemia, such as bone marrow infiltration by plasma cells, renal failure and chronic disease. Low serum B-12 levels may occur without signs of functional B12 deficiency; however, evaluation of B12 deficiency should be sought. High levels of IgA or IgG frequently increase the plasma volume and the hematocrit may be 6 points less than the value expected from the measured red cell volume. ii) Thrombocytopenia is uncommon at the time of diagnosis and usually reflects a marked degree of bone marrow replacement by plasma cells. iii) Mild granulocytopenia occurs frequently for reasons that are unclear and usually persist throughout the clinical course. Granulocytopenia does not have any impact on the outcome of the disease. b) Immunoglobulins i) Elevated total globulins, hypoalbuminemia or overall hypoproteinemia secondary to nephrotic syndrome could be observed. c) Chemistry i) Hypercalcemia, hyperuricemia, increased serum creatinine secondary to multiple myeloma and/or renal failure. ii) Increased LDH is noted in 10-15% of patients and usually signifies a poor prognosis. iii) The serum alkaline phosphatase is usually normal but may be elevated in-patients with healing pathologic fractures or osteosclerotic lesions. iv) Proteinuria is detected in approximately 65% of patients. d) Radiological Studies i) Chest x-ray may reveal osteolytic lesions in the clavicles, scapulae or ribs, a subpleural plasmacytoma attached to a rib or a pleural effusion. ii) Cardiomegaly may be seen in-patients with cardiac amyloidosis.

Diagnostic procedures and Tests:

When plasma cell dyscrasia is suspected the following tests should be performed to confirm the diagnosis, detect complications, assist in the staging of the disease and establish baseline values for following the treatment progress. 1) Myeloma Proteins: Serum and urine protein electrophoresis demonstrate a peak or localized band in 80% of patients, hypo-gammaglobulinemia in 10% and no apparent abnormalities in the remainder. In multiple myeloma patients with hypogammaglobulinemia almost always these patients have a monoclonal light chain protein in the urine. Immunoelectrophoresis and immune fixation are rather expensive, however are very sensitive when compared to protein electrophoresis which could miss up to 15% of monoclonal gammopathies. In 99% of the cases, a monoclonal protein in the serum or the urine or both is detected and in 1% of the patients no monoclonal protein is noted indicating nonsecretory multiple myeloma which is secondary to a defect in the synthesis or assembly of the light or heavy chains. 2) Bone Marrow Aspirate and Biopsy: This procedure is helpful in evaluating the different etiologies for the cytopenias and is also crucial for the diagnosis of multiple myeloma as well as evaluating cell morphology and >

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3) Urinalysis: Proteinuria is detected in approximately 65% of patients. The recognition of light chain protein (Bence-Jones protein) depends on the demonstration of the monoclonal light chain by immune electrophoresis or immune fixation. 24 hour urine collection for protein quantitation supplemented by urine protein electrophoresis is essential for following response to therapy. 4) Radiologic Procedures: A complete bone survey is an essential part of the evaluation of monoclonal gammopathies. The skeletal survey should include the complete spine, long bones of the arms and legs, skull, ribs, and pelvis. The order listed is the order of frequency of involvement. Approximately 20% of patients will have bone demineralization alone. Radiographs of the axial skeleton, which must include bone femurs, will support the diagnosis of multiple myeloma in approximately 70% of the patients. Punched out lesions are best seen on lateral skull radiographs. 10% of the patients will have a normal skeletal survey at the time of diagnosis. a) Computed Tomography and Magnetic Resonance Imaging; May detect bone destruction more sensitively and especially useful in detecting the extent of extra medullary soft tissue lesions. MRI of the lumbar spine and pelvis may detect more advanced disease that may require chemotherapy, primarily in-patients with an apparently localized plasmacytoma or with asymptomatic indolent multiple myeloma.

DIFFERENTIAL DIAGNOSIS:

Lytic bone lesions could be related to metastatic carcinoma, connective tissue diseases, chronic infections or lymphoma. Patients with multiple myeloma must be differentiated from those with monoclonal gammopathy of undetermined significance and smoldering multiple myeloma. Asymptomatic patients with an M-component of less than 3 gm/dl, fewer than 10% b>

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MULTIPLE MYELOMA VARIANCE:

This will be discussed in another issue

THERAPY FOR MULTIPLE MYELOMA MM remains a disease for which cure is a rarity. Most patients succumb to their disease within 36-48 months from the time of diagnosis. Limitations of effective therapy for MM are primarily associated with the low cell proliferation rate and multi-drug resistance. Therapy for multiple myeloma includes induction, maintenance, and supportive aspects. The induction portion of the treatment aims at reducing the tumor volume, and achieving a plateau phase. The standard maintenance approach is no treatment. Different drugs, and treatment modalities as bone marrow transplantation has been entertained, and used with out a significant impact on the disease free or the overall survival. Supportive care in multiple myeloma has advanced significantly over the past few years. Growth factor support with erythropoeitin replacement, GM-CSF for stimulating the WBC is a safe and effective method to decrease or prevent the occurrence or the severity of neutropenia. Cell component support, has improved with a better chances at a transfusion match with lower complication rates. The different regimens used in the induction portion of the disease are overall comparable. The difference between the regimens is mainly related to the toxicity profile, as well as the quickness of response, and the ability of the combination to reverse some of the combination side effects.

Over the past 5 years, there has been a substantial advancement in our understanding of the biology and pathogenesis of multiple myeloma. We can reasonably hope that improvements in treatment will follow our increased knowledge of this disease.