DEFINITION

Plasma cell disorders are a heterogeneous group of diseases characterized by a clonal population of B cells (plasma cells) that produce a monoclonal protein (M protein, or paraprotein). 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 monoclonal proteins. Multiple myeloma is a plasma cell dyscrasia characterized by destructive lytic bone lesions, a plasma cell infiltrate in the bone marrow, and a monoclonal protein in the serum or urine.¹

INCIDENCE AND RISK FACTORS

Multiple myeloma was diagnosed in an estimated 19,900 patients in 2008, and about 10,700 patients died of the disease in the same year. Multiple myeloma is a cancer of older adults, with a median age at diagnosis of approximately 65 years. Men and African Americans have twice the incidence of multiple myeloma as women and whites, respectively. Specific genetic disorders and environmental exposures have not been clearly linked to the risk of multiple myeloma, with the possible exception of exposure to ionizing radiation.

PATHOPHYSIOLOGY AND NATURAL HISTORY

Multiple myeloma is a neoplasm of malignant plasma cells phenotypically expressing CD38, CD56, and CD138. In addition, approximately 20% of malignant plasma cells express CD20. Overproduction of interleukin-6 (IL-6), an autocrine and paracrine plasma cell growth factor, is believed to be central to the pathogenesis of multiple myeloma. Alterations in other cytokines and signaling molecules such as tumor necrosis factor α (TNF-α), interleukin 1 (IL-1), vascular endothelial growth factor (VEGF), transforming growth factor β (TGF-β), and receptor activator of NF-κB (RANK) play key roles in the pathogenesis of multiple myeloma (Fig. 1). The interactions between malignant plasma cells and bone marrow stromal cells and osteoclasts are central to the pathogenesis and development of bone lesions and stimulation of bone marrow angiogenesis (Fig. 2).

Figure 1 Role of bone marrow stromal cells in the pathogenesis of multiple myeloma.

The interaction of malignant plasma cell and bone marrow stromal cells results in the generation of angiogenic cytokines (VEGF and bFGF) and paracrine myeloma growth factors (IL-6, TNF-α, and IL-1β). bFGF, basic fibroblast growth factor; IL-6, interleukin-6; TNF-α, tumor necrosis factor α; VEGF, vascular endothelial growth factor.

Figure 2 Bone marrow angiogenesis in multiple myeloma.

A, Normal bone marrow (CD34 stain). B, Bone marrow from a patient with multiple myeloma. New blood vessel formation is noted (CD34 stain).

(Courtesy of Dr. Mohamad Hussein.)

A number of cytogenetic abnormalities in the malignant plasma cell clone have been described. These include deletions of chromosome 13 (in about 30% of patients), chromosome 17 deletions, and translocations involving the immunoglobulin heavy chain. As a general rule, cytogenetic abnormalities presage an adverse outcome.

The natural history of multiple myeloma is one of progressive bone destruction, refractory cytopenias, and end-organ damage in the form of renal and cardiac dysfunction. Deficits in the humoral immune system, long-term corticosteroid therapy, and progressive leukopenia from bone marrow replacement place patients at increased risk for frequent infectious complications, usually with encapsulated microorganisms.

SIGNS AND SYMPTOMS

The clinical manifestations of multiple myeloma can be divided into three categories: plasma cell growth in bone marrow and skeletal disease, immunologic abnormalities, and effects of abnormal paraprotein.

Plasma Cell Growth in Bone Marrow and Skeletal Disease

The most common manifesting symptom of multiple myeloma is bone pain, usually involving the spine or chest. Although most back pain often results from bone marrow replacement, discrete lytic lesions, or vertebral compression fractures, spinal cord compression must always be considered and ruled out, especially when back pain is not well explained by routine x-rays. Diffuse osteoporosis is often noted radiographically. Characteristic lesions of multiple myeloma are lytic lesions (rounded, punched-out areas of bone) found most commonly in vertebral bodies, the skull, ribs, humerus, and femur (Fig. 3). Lytic lesions are not usually located in the distal extremities. Bone scans might not accurately reflect the destruction seen on plain radiographic films. Accordingly, skeletal surveys are used in the initial evaluation and follow-up of patients with multiple myeloma. Hypercalcemia in patients with multiple myeloma is secondary to bone turnover and is treated with bisphosphonate therapy, which is also useful for treating pain from lytic lesions and in skeleton-related events and may have an antimyeloma effect.²

Figure 3 Lytic skeletal lesions in patients with multiple myeloma.

A, Skull of a patient with multiple myeloma demonstrating lytic lesions. B, Proximal humerus of a patient with multiple myeloma displaying multiple lytic lesions.

(Courtesy of Dr. Mohamad Hussein.)

Anemia is present in most patients at diagnosis and during follow-up. Anemia in multiple myeloma is multifactorial and is secondary to bone marrow replacement by malignant plasma cells, chronic inflammation, relative erythropoietin deficiency, and vitamin deficiency. Recombinant human erythropoietin may be effective for the treatment of anemia in multiple myeloma.³ Mild neutropenia and mild thrombocytopenia are common, but severe cytopenias are uncommon at diagnosis. Plasma cell leukemia, a condition in which plasma cells account for more than 20% of peripheral leukocytes, is typically a terminal stage of multiple myeloma and is associated with short survival.

DIAGNOSIS

Multiple myeloma should be suspected in older adults presenting with back pain, constitutional symptoms (sweats, weight loss), and elevated total protein levels. In addition, unexplained renal dysfunction, anemia, or pathologic fracture should prompt evaluation for this diagnosis.

Diagnostic criteria for multiple myeloma from the International Myeloma Workshop rely on a combination of criteria (Table 1).⁴ Evidence of end-organ damage (hypercalcemia, renal insufficiency, anemia, lytic bone lesions) is required for the diagnosis of symptomatic multiple myeloma. These criteria diverge from historical diagnostic criteria, which relied on the monoclonal protein concentration and the amount of bone marrow plasma cell infiltrate. These changes stem from the observation that 40% of patients with multiple myeloma have a serum M protein level lower than 30 g/L. Similarly, 5% of patients with multiple myeloma have less than 10% bone marrow plasmacytosis. The difficulty of the present diagnostic system rests in determining whether end-organ dysfunction is related to the monoclonal gammopathy. Often, this requires the exclusion of other causes of end-organ damage.

Table 1 Differential Diagnosis and Diagnostic Criteria for Multiple Myeloma and Monoclonal Gammopathy of Undetermined Significance (MGUS)*

* Related organ and tissue impairment:

The differential diagnosis of a patient with a monoclonal protein includes monoclonal gammopathy of undetermined significance (MGUS), amyloidosis, light chain deposition disease, solitary plasmacytomas of bone or extramedullary plasmacytoma, Waldenström’s macroglobulinemia, lymphoproliferative disorders (e.g., chronic lymphocytic leukemia), and rheumatologic autoimmune conditions. In addition, patients with metastatic carcinoma occasionally have a monoclonal gammopathy. The metastatic carcinoma is often well characterized when the monoclonal protein is identified, and a search for a metastatic carcinoma usually is not recommended.

STAGING

The staging evaluation of patients with multiple myeloma should include diagnostic tests as well as prognostic tests. Box 1 details the recommended staging work-up of patients with multiple myeloma. The Durie and Salmon staging system for multiple myeloma dates back to 1975 and, although still widely used, is cumbersome in clinical practice (Table 2).¹ The Southwest Oncology Group has proposed a different staging system for multiple myeloma that relies only on serum β₂-microglobulin and serum albumin levels (Table 3).⁵ In addition, the latter staging system affords excellent prognostication.

Table 2 Durie and Salmon Staging System for Multiple Myeloma*

Stage	Criteria
I	All the following: 1 Hemoglobin >10 g/dL 2 Serum calcium value normal (≤12 mg/dL) 3 On radiograph, normal bone structure or solitary bone plasmacytoma only 4 Low M component production rates a IgG <5 g/dL b IgA <3 g/dL c Urine light chain M component on electrophoresis < 4 g/24 h
II	Fitting neither stage I nor stage III
III	One or more of the following: 1 Hemoglobin <8.5 g/dL Only gold members can continue reading. Log In or Register to continue Share this: Click to share on Twitter (Opens in new window) Click to share on Facebook (Opens in new window) Like this: Like Loading... Related Related posts: Anaphylaxis Sleep-Disordered Breathing Nontuberculous Mycobacterial Disorders Systemic Scleroderma Stay updated, free articles. Join our Telegram channel Join Tags: Current Clinical Medicine Expert Consult Jul 18, 2017 | Posted by admin in GENERAL SURGERY | Comments Off on Multiple Myeloma Full access? Get Clinical Tree Get Clinical Tree app for offline access Get Clinical Tree app for offline access %d