CASE REPORT

Multiple myeloma

Irina E. Penev, PA-C; Timothy C. Evans, MD, PhD, FACP

Ms. Penev works in cardiovascular surgery at Saint Marys Hospital and at the Mayo Clinic, in Rochester, Minn. Dr. Evans is Assistant Professor of Medicine and Medical Director, medex Northwest Physician Assistant Program, University of Washington Medical Center, Seattle. The authors have indicated no relationships to disclose relating to the content of this article.

Patients with multiple myeloma may present with bone pain, renal failure, anemia, or immune deficiency. Chemotherapy alone or followed by stem cell transplantation is the treatment.

The patient was an 83-year-old white woman who was recovering from uncomplicated open abdominal cholecystectomy for cholelithiasis and chronic cholecystitis. In the evening before her scheduled release from the hospital, she developed acute renal failure with a urine output of less than 20 mL overnight. Furosemide failed to elicit diuresis. Limited plasmapheresis was employed to address a high serum protein level. Over the next week, the patient developed pneumonia and pyelonephritis, urticaria in response to the prescribed antibiotic combination, melena, anemia, and sepsis with mixed pathogens including Candida albicans.

With careful monitoring of the fluid-electrolyte balance and several rounds of plasmapheresis over the next month, the patient recovered from the infections and her kidneys resumed function. She was sent home in a relatively stable condition 2 months after her initial surgery. The episode of renal failure was attributed to stress from surgery and preoperative overuse of aspirin for body aches. These body aches were not investigated, but the cause was assumed to be osteoarthritis.

Over the next year, the patient was very fatigued, with severe hip, back, and knee pains bilaterally and recurrent Escherichia coli pyelonephritis. Urine protein electrophoresis ordered during a nephrology consultation revealed Bence Jones proteinuria. A peripheral blood smear and bone marrow biopsy confirmed the diagnosis of multiple myeloma, gamma light-chain disease. The patient was treated with a melphalan plus prednisone regimen, which she tolerated well. Despite this therapy, however, her bone pain and anemia worsened, pyelonephritis recurred, she lost appetite and strength, her kidneys failed again, and she died a little more than a year after her diagnosis.

The disease

Multiple myeloma (MM) is a monoclonal B-cell malignancy originating from lymph node follicle-center B lymphocytes, which transform into neoplastic plasma cells. They infiltrate the bone marrow and cause either multiple osteolytic lesions or diffuse bone demineralization.¹ The neoplastic plasma cells may secrete an abundance of homogeneous intact immunoglobulin (Ig)—called paraprotein or monoclonal component (M component)—found in serum. Alternatively, plasma cells may produce only Ig light chains, which are found in the urine.

MM accounts for 90% of all plasma cell cancers, 10% of all hematologic malignancies, and 1% to 2% of all malignancy-related deaths.^2,3 The overall incidence is 3 to 4 cases per 100,000 population (up to 14,400 new cases in the United States annually),^4-6 with a male-to-female ratio of 1.5:1, a mean age at diagnosis of 65 years, and median survival in the 36-month range.⁴ The incidence of MM in African-Americans is 9.5 cases per 100,000, which is significantly higher than for the general population.^5,7 For poorly understood reasons, there has been an 82% increase in the disease occurrence since 1950.⁸ Because MM is a disease of the elderly, the incidence may be anticipated to increase as the population ages. Thus, the primary care provider should actively consider this disease in clinically appropriate cases.

MM has been around for centuries. Four possible cases have been described in Native American skeletons dating from ad 200 to 1300.⁹ The first well-documented case is from 1844, in a patient whose autopsy revealed six fractures in her arms and legs, fractured ribs, and marked destruction and thinning of the bones.⁹ In a urine specimen from a patient in 1847, Henry Bence Jones discovered and described the "abundant animal matter," later named Bence Jones protein (monoclonal paraprotein light chains, excreted in urine), a hallmark of MM that is seen in 75% of patients.⁹ In 1873, J. von Rustizky introduced the term multiple myeloma to describe a patient with eight separate tumors of round, vesicle-like cells with a single peripheral nucleus.⁹

Etiology

The ultimate abnormality in malignancy is thought to be genetic. With modern cytogenetic methods, an abnormal karyotype (patterns of chromosomal translocations,^1,5,6,10,11 monosomies,¹⁰ and deletions^1,10,11) is detected in almost all patients with MM. The extent and precise role of genetic abnormalities in this disease are still to be defined.^12,13 However, certain karyotypes have been linked to poor response to chemotherapy, greatly diminished survival, and a low success rate with stem cell transplant. Additional mutations are observed in the terminal stage of illness.¹ Table 1 outlines several etiologic factors that have been implicated in MM.

 

TABLE 1 Etiologic factors implicated in multiple myeloma
Etiologic factor	Rationale for implication
Genetic predisposition	Increased incidence in first-degree relatives Increased severity and younger age at onset in successive generations High incidence in African-Americans; low incidence in China and Japan5
Ionizing radiation	Fivefold greater incidence in Hiroshima and Nagasaki survivors4 Higher susceptibility among radiologists, whose occupational radiation exposure is high12
Pesticides	Increased incidence among those exposed to dioxin, including sport fishermen near Lake Okeechobee, Fla; Black Sea fishermen; and Alaskan Native Americans8
Low socioeconomic status	Increased incidence in those with poor housing and nutrition, dangerous occupations with exposure to carcinogenic or infectious agents, stress, and poor access to health care

Clinical picture

Bone pain from lytic bone disease is a common presenting symptom in MM, occurring in more than two thirds of patients. It is usually induced by movement. Tumor growth, activated osteoclasts forming resorption lacunae, reactive myelofibrosis, and osteosclerosis all contribute to a devastating bone destruction (see Figure 1), often leading to vertebral collapse (possible reduction of height by several inches) and pathologic fractures of long bones.^1,14,15

Figures 1 and 2: Tom Chauncey, MD, Director, Marrow Transplant Unit, Veterans Administration Medical Center, Seattle, Wash. Used with permission.

Nerve compression from vertebral lesions or bone collapse often results in radiculopathy, the most common neurologic complication of MM. Extramedullary plasmacytomas, seen in 5% of patients, may cause spinal cord compression with severe back pain, weakness or paresthesias of the lower extremities, and bladder or bowel incontinence.¹⁴

Normocytic normochromic anemia and thrombocytopenia are frequent findings and result from the replacement of bone marrow hematopoietic tissue by neoplastic plasma cells.¹⁶

Up to 15% of all patients present with hypercalcemia at diagnosis.^16,17 This condition is primarily due to the release of bone-resorbing cytokines in MM. Patients may be asymptomatic or have nausea, vomiting, polydipsia, polyuria, constipation, weakness, confusion, or stupor.

Hyperviscosity syndrome may be evident occasionally, sometimes associated with blurred vision, neurologic symptoms, congestive heart failure, and spontaneous bleeding episodes. Some M components, particularly IgM, function as cryoglobulins. They can obstruct blood flow to the distal extremities, causing acrocyanosis and Raynaud's phenomenon.¹⁷

Coagulation abnormalities are often seen and result from thrombocytopenia (from MM bone marrow infiltration) and coprecipitation of cryoglobulin/coagulation factor complexes. These abnormalities may lead to GI and pulmonary hemorrhages. One study reported GI bleeding in more than 30% of their study subjects; the lung was the second most common site for hemorrhage, and lung hemorrhage was the most frequent cause of death.²

Humoral immune deficiency develops secondary to the suppression of normal B lymphocytes by neoplastic plasma cells and the increased catabolic rate of normal IgG. Susceptibility increases to a variety of infections, particularly those caused by Streptococcus pneumoniae and gram-negative organisms. The main infectious complications in MM are pneumonia and pyelonephritis.¹⁴

Renal insufficiency (plasma creatinine level greater than 1.5 mg/dL) develops in up to 50% of patients with MM. In 97% of these cases, it is caused by Bence Jones proteinuria and is related to myeloma kidney pathomorphology. Renal insufficiency may be exacerbated by concurrent fluid depletion, hypercalcemia, urinary infection, or nephrotoxic drugs.^14,18-22

Table 2 summarizes the typical clinical features of MM, depending on the type of M component.⁴

 

TABLE 2 Notable clinical features of MM depending on the type of M component
M component	Clinical features
IgG	Infectious complications; mean survival of 3-4 y
IgA	Serum hyperviscosity syndrome
IgD	Extramedullary soft tissue masses and renal disease; very aggressive course; mean survival 1 y
IgE	Affects young adult males; has leukemic phase with peripheral plasma cell count >2,000/mL; very aggressive
Light-chain	Aggressive; serum protein electrophoresis remains normal until renal involvement compromises the glomerular filtration of Bence Jones light chains
MM = multiple myeloma.

Clinical evaluation

On physical examination, pallor (the most common physical finding) and a palpable liver (20%) and spleen (5%) may be found. Weight loss can be evident. Late in the course of the disease, extramedullary plasmacytomas can manifest as large, purplish, subcutaneous masses.^14-16

The initial laboratory assessment often reveals anemia, an elevated erythrocyte sedimentation rate, hypercalcemia, hyperuricemia, and a serum or urine M component. Creatinine is elevated in 50% of patients, sometimes to the level of renal failure. Bence Jones proteinuria cannot be detected with urinary dipstick testing (which detects only albumin), but it can be demonstrated with sulfosalicylic acid testing (which detects all proteins).¹⁴

Screening protein electrophoresis and confirmatory immunofixation of serum and 24-hour urine specimens can provide quantitative assessment of the M component. Immunoelectrophoresis may also be used but is not as sensitive. Twenty-four-hour urine protein electrophoresis and immunofixation provide identification of nephrotoxic concentrations of urinary light chains. Follow-up should be performed as shown in Table 3.²³

 

TABLE 3 Follow-up for patients with multiple myeloma
Clinical symptoms	SPEP M component	Other tests needed	Repeat SPEP
No	<1.5 g/dL	None	Annually
No	1.5-2.5 g/dL	UPEP Urine immunofixation	In 3-6 mo and, if disease is stable, annually
Yes or No	>2.5 g/dL	Metastatic bone survey 24-h UPEP + immunofixation Bone marrow aspirate/biopsy Serum b2-microglobulin C-reactive protein	If other tests normal, in 2-3 mo
Yes	In all cases	UPEP Urine immunofixation
Key: SPEP, serum protein electrophoresis; UPEP, urinary protein electrophoresis.

The peripheral smear may show stacked and clumped erythrocytes (rouleaux). Plasmacytosis is seen only rarely; but in 80% of cases of active MM, circulating monoclonal plasma cells can be detected with an immunoassay technique.²⁴

Bone marrow examination is required to diagnose MM. Of all nucleated cells seen on the sample, more than 10% must be plasma cells (see Figure 2).¹⁴ Immunoperoxidase staining can identify monoclonal immunoglobulin in cell cytoplasm, eliminating a diagnosis of reactive plasmacytosis caused by autoimmune, malignant, and infectious diseases.

Click here to view full-size graphic

Baseline radiographic studies of the skull, spine, pelvis, humeri, and femora should be performed early and repeated every 6 months.

Diagnostic criteria, differential diagnosis, and staging

For the diagnosis of MM, three simultaneous findings are required:^16,24

• The bone marrow biopsy shows more than 10% plasma cells, neoplastic plasma cell aggregates, or plasmacytoma

• The M component is greater than 3 g/dL in serum or greater than 150 mg/dL in urine, or bone lytic lesions are found, or diffuse demineralization (involving mainly flat bones such as the skull, spine, and ribs) is found

• The clinical presentation is typical of MM.

The primary considerations in the differential diagnosis should be monoclonal gammopathy of undetermined significance (MGUS), smoldering myeloma, amyloidosis, and metastatic carcinoma.^16,24

Several systems are available for staging MM. The Durie-Salmon system is based on tumor cell mass but lacks precision in determining the prognosis. A simpler system utilizes serum concentrations of albumin and ß₂-microglobulin.²⁴

Therapy and prognosis

Asymptomatic patients should not be started on chemotherapy because some of them will remain stable over time. When progressive disease is evident, chemotherapy should be initiated.

For many years, standard treatment for MM was chemotherapy with melphalan (Alkeran) and prednisone. In recent years, for patients younger than 70 years, autologous hematopoietic stem cell transplantation following chemotherapy with vincristine (Oncovin, Vincasar PFS, Vincrex), Adriamycin (doxorubicin), and dexamethasone (VAD) is an important option that should be seriously considered.²⁵ It does not cure MM, probably because the infused peripheral blood stem cells are contaminated by neoplastic plasma cells. But stem cell transpant does prolong survival by approximately 1 year in comparison with melphalan and prednisone.²⁶ Exposure to alkylating agents (melphalan) is contraindicated if transplantation is contemplated. Additional advantages of VAD followed by stem cell transplantation are that it induces a rapid response and can be used in the presence of renal insufficiency.

For patients older than 70 years, for whom autologous transplantation is not indicated, the recommended therapy remains melphalan and prednisone in 7-day courses, repeated every 6 weeks, until a plateau of stable serum and urine M-protein levels and no evidence of progression is reached. The minimum treatment is three courses, and sometimes therapy is given for 1 year or more. An initial response is achieved in 50% to 60% of cases, but complete remission is rare and occurs only 5% of the time.¹⁰ An objective response to chemotherapy is defined as clinical improvement combined with a 50% decrease in the M-protein level. A number of studies have demonstrated that results with this regimen in patients older than 70 years are as good as those obtained with more aggressive treatment regimens.

Regardless of which regimen is used initially, relapse almost always eventually occurs. If this happens after the plateau state has been reached, the initial chemotherapy regimen should be reinstituted although the response in general is shorter and poorer.¹⁷

More aggressive chemotherapeutic regimens have been tried; some have produced a high initial response but contradictory results for overall patient survival.¹⁷ Interferon alpha has been shown to inhibit the growth of some myeloma cell lines in vitro, but only a small survival benefit of 4 months in vivo has been found.¹⁷

The prognosis in MM depends on two major factors: renal function and the total body tumor burden. Criteria for high burden include extensive lytic bone lesions, hemoglobin less than 8.5 g/dL, serum calcium greater than 12 mg/dL, M component greater than 5 gm/dL, and high lactate dehydrogenase or ß2-microglobulin.⁴ Renal failure is commonly seen in patients with a high tumor mass.¹⁹

One challenging aspect of managing MM is treating the numerous complications of the disease. Approaches to these complications are given in Table 4.^17,27 MM remains incurable. Biphasic in course, it starts with an initial chronic, stable phase and progresses to an accelerated, preterminal phase. Patients survive an average of 6 months if the disease is untreated. Chemotherapy prolongs survival to 3 years (8.6 months in the presence of renal failure).¹⁹ The cause of death is usually infection, renal failure, or, in some studies, lung hemorrhage.² The 5-year survival rate has not changed much over the past 20 years.³

 

TABLE 4 Treatment modalities for common complications of multiple myeloma
Complication	Treatment
Hypercalcemia	Hydration, prednisone, and bisphosphonates Encourage activity to avoid osteopenia
Renal insufficiency	Hydration Plasmapheresis Hemodialysis or peritoneal dialysis for end-stage renal disease
Hyperviscosity	Plasmapheresis
Infection (>30% mortality; risk especially increased in the first 2 mo of chemotherapy)	Trimethoprim/sulfamethoxazole prophylaxis probably beneficial Pneumococcal and influenza vaccines indicated for all patients
Bone pain	Analgesics Chemotherapy Local radiation for uncontrolled debilitating pain
Lytic skeletal lesions (pathologic fractures, spinal cord compression)	Bisphosphonates
Symptomatic anemia	Erythropoietin

New therapeutic approaches

Research efforts now are concentrated on achieving a better understanding of the biology of MM and finding new therapeutic approaches based on that understanding. The interplay between neoplastic plasma cells, bone marrow stroma, cell-cell contact, and cytokine production results in a local environment that supports the growth and maintenance of MM neoplastic plasma cells.²⁸

Monoclonal antibodies that specifically block interleukin (IL)-6 have been developed. IL-6 is a major apoptosis prevention factor, which compromises the attempts for apoptosis induction with corticosteroid therapy.^3,5,28

Antiangiogenic agents are being investigated to target angiogenic cytokines. This approach can potentially offset the MM-cell proliferation provided for by the bone marrow vascularization. The immunomodulator thalidomide has demonstrated antitumor activity via this mechanism and is being studied with appropriate caution related to its association with birth defects.^1,2,5

Immune therapy approaches include the following:³

• Donor lymphocyte infusions after relapse in patients who have received allogenic transplants

• Trials to clone the gene for the idiotypic protein characteristics in individual patients and to modify the gene to include loci for major histocompatibility complex class I antigens (this approach could render myeloma cells with potentially strong immunogenic features for the patient's T cells)

• Attempts to fuse myeloma cells with dendritic cells, thus rendering the entire myeloma cell as an antigenic stimulus (trial vaccines with such fused cells have protected test animals from subsequent tumor challenge)

• Attempts to find suitable antigens for vaccines to stimulate immune response against myeloma cells. Recently, sperm protein 17 (Sp17), a cancer-testis antigen, was identified in 26% of patients with MM.²⁹ Normal Sp17 tissue expression is limited to the spermatozoal acrosome. Sp17 is highly immunogenic in vivo (Sp17 autoantibodies commonly develop after vasectomy). These features make it a safe T-cell target and an ideal candidate for immunotherapy. Extensive work is under way to develop an Sp17 vaccine for MM.²⁹

The steady growth in knowledge about the disease biology of MM makes researchers optimistic in their efforts to find a cure.

Acknowledgment

The authors wish to thank Keren H. Wick, PhD, for invaluable technical and editorial support.

 

KEY POINTS in this article Multiple myeloma accounts for 10% of all hematologic malignancies and 1% to 2% of all malignancy-related deaths. It is becoming increasingly common in older people, and the incidence is significantly higher in African-Americans. Factors that have been implicated in the development of multiple myeloma include genetics, ionizing radiation, pesticides, and low socioeconomic status. Presenting symptoms include bone pain, radiculopathy, anemia, thrombocytopenia, hypercalcemia, hyperviscosity, coagulation abnormalities, immune deficiency, and renal insufficiency. Treatment consists of chemotherapy alone or, for patients younger than 70 years, chemotherapy followed by autologous hematopoietic stem cell transplantation. Autologous transplantation prolongs survival by about 1 year.

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Irina Penev. Case Report: Multiple myeloma. JAAPA September 2004;17:33-38.

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