DEFINITION

Plasma cell disorders are a group of neoplastic or potentially neoplastic diseases of hematopoietic cells known as plasma cells. Plasma cells are B cells that secrete immunoglobulins. The clinical manifestations of these disorders result from the uncontrolled and progressive proliferation of a plasma cell clone, the effect of normal bone marrow replacement, and the overproduction of specific proteins.

Plasma cell disorders are characterized by the secretion of monoclonal proteins or immunoglobulins (M protein or paraprotein). An abnormal M protein may be present when the total protein concentration in quantitative immunoglobulin values are within normal limits. The presence of an abnormal M protein is usually associated with:

• multiple myeloma,
• monoclonal gammopathy of undetermined significance (MGUS),
• or Waldenström's macroglobulinemia.

An M protein rarely is associated with other lymphoproliferative disorders (such as Non-Hodgkin's lymphoma) or primary amyloidosis.

Historically, an entity known as smoldering multiple myeloma has been defined, which clinically falls between MGUS and overt multiple myeloma. Smoldering multiple myeloma is generally defined as greater than 10% plasma cells in the marrow and an M serum protein of greater than 3g/dL; however, serum creatinine and calcium levels are normal. Additionally, lytic bone lesions are absent. Although smoldering myeloma inevitably evolves into overt multiple myeloma, often, there is stability over time. Frequently, the initial therapy is observation. Because of the relative infrequency of these other plasma cell disorders, this chapter will focus solely on multiple myeloma.

Multiple myeloma accounts for 7% of hematologic malignancies, with approximately 14,000 newly diagnosed cases in the United States annually.¹ The median age of diagnosis is approximately 65 years, although 2% to 4% of patients are less than 40. Males are diagnosed approximately twice as frequently as females, and multiple myeloma is more common in blacks than in the white population.

Multiple myeloma is a B cell malignancy with plasma cells phenotypically expressing CD38+, CD56+, and CD138+. Approximately 20% of myeloma cells express CD20. Overproduction of interleukin 6 (IL-6), a plasma cell growth factor; tumor necrosis factor; and IL-1 are generally seen in multiple myeloma. Deletions of p53, a tumor-suppressor gene, also have been reported in myeloma patients. Cytogenetically, deletions of chromosome 13 are not infrequent (found in approximately 15% of patients) and are associated with an adverse prognosis.

The clinical manifestations of multiple myeloma can be divided into four broad categories: plasma cell growth in bone marrow and skeletal disease, immunologic abnormalities, effect of the abnormal paraprotein, and renal failure.

Plasma Cell Growth In Bone Marrow
and Skeletal Disease
The most common presenting symptom of multiple myeloma is bone pain, usually involving the spine or chest. Diffuse osteoporosis is often seen radiographically. Characteristic myeloma changes are lytic lesions (rounded, punched-out areas of bone) found most commonly in vertebral bodies, the skull, ribs, humerus, and femur. Bone scans may or may not accurately reflect the destruction seen on radiographic films.

A solitary plasmacytoma—essentially, a solid tumor mass of plasma cells—is found in 2% of patients and is usually seen in a vertebral body. Plasmacytomas are conventionally treated with radiation therapy; however, despite this therapy, most patients ultimately progress to have more typical manifestations of multiple myeloma.

Most neurologic abnormalities associated with multiple myeloma result from direct extension of a skeletal tumor. Spinal cord compression is present in 10% of patients. Although peripheral neuropathies are uncommon in myeloma, they can be caused by amyloidosis, hyperviscosity, or both.

Anemia develops in most patients and is generally secondary to poor red blood cell production—either from marrow infiltration with plasma cells, or from kidney failure and resultant inappropriately low erythropoieten production. Rouleaux are often present on the peripheral smear, resulting from the increased number of immunoglobulins in the plasma. Mild neutropenia occurs in up to 50% of patients. Thrombocytopenia is common, either from the myelomaitself or from repeated courses of chemotherapy. Plasma cell leukemia, a condition in which plasma cells predominate among the circulating white blood cells, is typically a terminal stage of multiple myeloma and is associated with short survival.

Immunologic Abnormalities
Patients with myeloma often suffer from repeated episodes of infection, similar to that seen in patients with reduced levels of immunoglobulins. Commonly, patients exhibit a reciprocal decrease in normal immunoglobulin values in the presence of an elevated M protein. An increased incidence of both gram-positive and gram-negative organisms has been reported.

Effect of Abnormal Paraprotein
Hyperviscosity syndrome results from the presence of serum proteins with high intrinsic viscosity. This is most commonly associated with immunoglobulin M (IgM) paraprotein, but may also occur with IgG or IgA paraprotein. High viscosity interferes with efficient blood circulation of the brain, kidneys, and extremities. Headache is common, and dizziness, vertigo, and symptoms of severe ischemia may result. Peripheral neuropathy may occur secondary to occlusive changes in small vessels. High levels of M protein may interfere with coagulation factors and lead to abnormal platelet aggregation and abnormal platelet function; therefore, bruising and purpura are common.

Renal Failure
Proteinuria is present in 90% of patients with multiple myeloma, and abnormal light chains (Bence Jones protein) are found in 80% of patients. At diagnosis, the creatinine level is elevated in 50% of patients. Proximal tubules are increasingly damaged by the large protein load, and large obstructing casts frequently form within the tubules. The combination of interstitial fibrosis and hyaline casts surrounded by epithelial cells or multinucleate giant cells constitutes myeloma kidney. Additionally, hypercalcemia and hypercalciuria as well as hyperuricemia contribute to kidney damage.

DIAGNOSIS

One set of criteria for the diagnosis of multiple myeloma include the presence of plasma cells comprising greater than 10% of bone marrow cells or a plasmacytoma; plus either serum M protein greater than 3g/dL; urinary M protein; or osteolytic bone lesions.

Although conventional therapy cannot cure multiple myeloma, it can effect a temporary remission. Patients presenting with symptomatic skeletal lesions are initially treated with radiation therapy. Radiation therapy is also indicated for plasmacytomas that may impair the function of vital structures.

Systemic therapy is required to control the clinical manifestations of myeloma. Most investigators believe that an initial course of systemic therapy is indicated, which is generally followed by autologous stem cell transplantation. No single chemotherapeutic protocol clearly has been shown to be optimal; the historical standard regimen is a combination of melphalan and prednisone, which results in a response rate of approximately 60% to 70%. Another popular regimen, infusional vincristine, doxorubicin, and dexamethasone (VAD), is generally well tolerated. Recent clinical trials have demonstrated that the combination of thalidomide and dexamethasone yields a 77% response rate.^2,3 The National Comprehensive Cancer Network (NCCN) has delineated guidelines for the approach to the treatment of multiple myeloma at: http://www.nccn.org/physician_gls/f_guidelines.html.

Autologous stem cell transplantation generally consists of a collection of the patient's peripheral blood progenitor cells following stimulation by granulocyte colony-stimulating factor (G-CSF), with or without chemotherapy. The patient is then given either high-dose chemotherapy or chemotherapy with total body radiation therapy. Most investigators now use melphalan (150 mg/m² to 200 mg/m²) as the high-dose preparative regimen of choice.

One randomized trial that compared autologous transplantation to chemotherapy found that 5-year event-free survival (28% versus 10%) and overall survival rates (52% versus 12%) were significantly higher in the transplant group.⁴ Another trial conducted at a single treatment center studied more than 1,000 patients who were either newly diagnosed or had limited prior treatment. For patients presenting with a low beta₂-microglobulin level and without a chromosome 13 deletion, the data showed that up to 50% of patients achieved complete remission with sustained responses for 10 years.⁵

Although most investigators believe that autologous transplantation improves survival and event-free survival, ultimately, most patients will relapse. Efforts to reduce risk of relapse after autologous transplantation has lead to many novel therapies, including nonmyeloablative allogeneic transplantation, which attempts to generate a graft-versus-tumor effect and may be used in the older population typically affected by multiple myeloma.

Bisphosphonates are an important therapeutic tool for patients with myeloma⁶ because they demonstrate anti-bone resorptive activity and possess antitumor mechanisms, resulting in reduced bone pain. Bisphosphonates inhibit bone resorption and decrease IL-6 production in the bone marrow microenvironment, which suggests that they may have an anti-myeloma effect. Pamidronate and zoledronic acid normalize tumor-induced hypercalcemia and may minimize other complications of myeloma.

Thalidomide also has been used with efficsuccessfully in the treatment of multiple myeloma.² Although the mechanism of action is unclear (though may be related to a reduction in bone microvessel density or as a cytokine antagonist), thalidomide has been reported to yield a 40% to 50% response rate in patients with refractory disease. The most common toxicities of the agent are sedation and constipation. Thalidomide is contraindicated in pregnancy because it is highly teratogenic.

Historically, the median survival in multiple myeloma is approximately 3 years. Patients with a low beta₂-microglobulin level tend to have a better prognosis. More recently, the presence of a chromosome 13 deletion has been shown to have a significant negative impact on outcome. Prognosis is generally best with IgM disease and worse with IgG disease. An elevated lactate dehydrogenase level is associated with a grim prognosis.

1. Jemal A, Murray T, Samuels A, Ghafoor A, Ward E, Thun MJ. Cancer Statistics 2003. CA A Cancer Journal for Clinicians. 2003;53:5-26.
   
   
2. Singhal S, Mehta J, Desikan R, et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med. 1999;341:1565-71.
   
   
3. Rajkumar SV, Hayman S, Fonseca R, et al. Thalidomide plus dexamethasone (Thal/Dex) and thalidomide alone (Thal) as first-line therapy for newly diagnosed myeloma (MM). Blood. 2000;96:168a. [abstract 722]
   
   
4. Attal M, Harousseau JL, Stoppa AM, et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Francais du Myelome. N Engl J Med. 1996;335:91-97.
   
   
5. Barlogie B, Jagannath S, Desikan KR, et al. Total therapy with tandem transplants for newly diagnosed multiple myeloma. Blood. 1999;93:55-65.
   
   
6. Kyle RA. The role of bisphosphonates in multiple myeloma. Ann Intern Med. 2000;132:734-736.
   

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