Epidemiology and Risk Factors

Multiple myeloma is a malignant disorder that results from a clonal proliferation of marrow plasma cells that usually results in the production of a monoclonal immunoglobulin in the serum or urine. Approximately 20,180 patients are diagnosed, and 10,650 die, annually in the U.S. with this disorder, making it the second most common hematologic malignancy in the United States.¹ The disease most commonly occurs during the seventh and eighth decades of life, is more frequent in men (1.6:1), and has an incidence in African Americans over twice as high as that noted in whites.¹

There is no undisputable risk factor for myeloma, but ionizing radiation or work in the paper, pulp, and leather tanning industries and other chemical exposures have been implicated.² Numerous reports in people with chronic exposure to low-dose ionizing radiation exist, including radiology technicians/physicians prior to routine shielding and radium watch dial painters; perhaps the best evidence was among atomic bomb survivors at Hiroshima in an initial report, but the follow-up of this report failed to confirm those initial findings.³ Similarly, benzene has been implicated, but a thorough retrospective analysis of available reports eliminated this factor as well.⁴ Hereditary factors have not previously played a prominent role as risk factors for multiple myeloma, but recent reports suggest that at least among certain populations the incidence of monoclonal gammopathy of unknown significance (MGUS)/myeloma may have a familial/genetic association.⁵

Pathology

Myeloma begins with the clonal expansion of a malignant plasma cell that is usually positive for CD38, CD138, and monoclonal cytoplasmic immunoglobulin with a clonal light chain of either kappa or lambda type. These cells typically have an eccentric nucleus within a large cytoplasm and often have an area of central clearing that corresponds to intracytoplasmic immunoglobulin. Cells of plasmacytic origin are usually negative for other markers of the B-cell lineage such as CD19 and CD20. Recent studies suggest different categories of myeloma, which may separate disease into different levels of outcome.⁶ Although a heterogeneous array of cytogenetic abnormalities have been described in patients, deletions of chromosomes 13 or 17 p, certain translocations involving chromosome 14, on which the immunoglobulin H (IgH) locus resides [t(4;14), t(14;16)], and chromosome 1 abnormalities have predicted shortened survival; [t(11;14)] has usually been associated with either an average or an improved prognosis and rarely noted to have a subgroup with poor prognosis.⁶

The abnormal clonal proliferation usually results in the production of monoclonal immunoglobulin in the serum and/or urine; IgG is secreted in approximately 60%, IgA in 20%, IgD in 2%, and IgE in less than 1%; biclonal secretion is rare. Secretion of light chain as the sole monoclonal protein is noted in 18%.⁷ Previously, 3% of patients were noted to have nonsecretory disease; this number has declined with the advent of serum free light chain (kappa, lambda free kappa:lambda) detection.

Clinical Presentation

Multiple myeloma may present with a number of characteristic features and complications such as those that result from marrow infiltration (anemia), subsequent bone destruction (lytic bone lesions, fractures, pain, and hypercalcemia) or from complications of circulating monoclonal, or reduced uninvolved immunoglobulins and/or light chains (hyperviscosity, increased infections, and renal failure).

Bone disease occurs in nearly 70% of newly diagnosed patients with multiple myeloma and results, in part, from RANKL overexpression and OPG inhibition resulting in unbridled activation of osteoclasts. Other cytokines such as interleukin-1beta (IL-1β), IL-6, and tumor necrosis factor-alpha (TNF-α) also have a role in lytic bone disease.^8,9 Progressive bone destruction results in hypercalcemia in approximately 20% of patients with newly diagnosed myeloma.

Marrow infiltration with plasma cells results in a normocytic, normochromic anemia in the majority of patients with previously untreated myeloma. Recently, up-regulation of hepcidin mRNA in myeloma patients has been noted and may play a causative role in this complication.¹⁰ In patients with high levels of circulating monoclonal serum protein, stacking of red blood cells on the peripheral blood smear, known as rouleaux formation, may occur.

Nearly one half of patients will develop renal failure at some time during the course of their disease. Cast nephropathy of the distal tubule is the most common cause of this complication, but hypercalcemia, dehydration, hyperuricemia, and concomitant conditions such as amyloidosis and light or heavy chain deposition diseases may also be contributing factors.¹¹

Frequent bacterial infections may also be noted in patients with myeloma due to suppression of uninvolved immunoglobulins, decreased antibody response, and impaired opsonization among other abnormalities reflective of the impaired immune response in patients with multiple myeloma.^12,13

Although the diagnosis of myeloma by fixed criteria may be difficult, the International Myeloma Working Group (IMWG) proposed a simple system based on the presence of 10% or greater clonal marrow plasma cells and/or the presence of a serum monoclonal protein 3.0 g/dL or greater.¹⁴ The same group developed the “CRAB” (HyperCalcemia, Renal Failure, Anemia, Bone lesions) criteria to determine whether there has been end-organ damage that would classify a patient as having symptomatic disease that would require initiation of treatment.¹⁴ These criteria include elevated serum Calcium (≥11.5 mg/dL), Renal insufficiency (creatinine > 2 mg/dL), Anemia (>2 g/dL below the lower limit of normal or < 10 g/dL), Bone lesions (lytic disease or osteoporosis with compression fractures), or other complications (hyperviscosity, amyloidosis, and light chain deposition diseases). Patients without any of these complications are considered asymptomatic and may be observed, without treatment, with frequent follow-up until progression to symptomatic disease.

It is important to distinguish multiple myeloma from related plasma cell dyscrasias such as MGUS and solitary bone plasmacytoma (SBP) or extramedullary plasmacytoma (EMP). The diagnosis of MGUS relies on the presence of fewer than 10% marrow clonal plasma cells and a monoclonal serum protein of less than 3 g/dL in a patient who has no evidence of end-organ/tissue damage, including anemia, hypercalcemia, renal failure, or lytic bone lesions attributable to myeloma and no evidence of a B-cell proliferative disorder.¹⁴ SBP or EBP is diagnosed when a single lesion of biopsy-proven clonal plasma cells is detected without evidence of other disease including negative magnetic resonance imaging (MRI) of the spine and bone marrow examination; it is particularly important to identify these patients because 35% to 65% may be curable when given radiation therapy with curative intent.¹⁵

Staging

Numerous factors have been suggested to determine the prognosis of patients with myeloma. In the 1970s, Durie and Salmon¹⁶ proposed a staging system based on the degree of anemia, level of paraprotein, presence or absence of hypercalcemia, lytic lesions, and renal insufficiency that subsequently became the standard staging system for myeloma for several decades (Table 28-1). Although this system was predictive of the degree of myeloma tumor mass, several components were imprecise, such as extent of bone lesions and the inclusion of factors such as anemia, hypercalcemia, and renal function, which may be affected by factors other than myeloma infiltration. Subsequently, multiple new prognostic factors emerged including plasma cell hypodiploidy, C-reactive protein, lactate dehydrogenase, labeling index, cytogenetic abnormalities, and beta-2 microglobulin (β₂M).

Table 28-1 Durie-Salmon Staging System for Multiple Myeloma

In 2005, Greipp and coworkers¹⁷ proposed the International Staging System (ISS) that separated patients into three stages based on the level of serum albumin and β₂M. The data from 10,750 patients were analyzed by univariate and multivariate analysis; the system was designed using half the data set and validated in the other half of the population (Table 28-2). This system effectively identified a group of patients with a relatively short median survival of 29 months (β₂M ≥ 5.5 mg/L, stage III), another with longer median survival of 62 months (β₂M < 3.5 mg/L and albumin > 3.5 g/dL, stage III), as well as a group with intermediate survival (stage II). Although some patients in the data set may have received thalidomide, the impact on survival of bortezomib, lenalidomide, and multiple combinations utilizing both of these drugs will likely lead to improved median survivals for one or more stages defined by the ISS; the Greek Myeloma Study Group also confirmed the validity of the ISS in the era of novel agents.¹⁸ The ISS has subsequently become a standard staging system for patients with myeloma.

Table 28-2 International Staging System for Multiple Myeloma

Although the Durie-Salmon system and ISS effectively separate patients into different survival categories, the impact of chromosomal abnormalities on prognosis is significant, and some have even suggested a molecular classification of myeloma.⁶ Certain translocations involving chromosome 14 [t(4;14), t(14;16)] and deletion of chromosome 13 have previously predicted a poor prognosis, but treatment with bortezomib appears to overcome the prognostic impact of these abnormalities; the same data with lenalidomide are premature and need to be validated over time.^6,19,20 Deletion of chromosome 17p remains prognostic even in the era of novel agents; other considerations include the poor prognosis of chromosome 1 abnormalities and the possibility of an improved prognosis with t(11;14).⁶ Although no staging system based on chromosomal abnormalities has been specifically agreed upon, the aforementioned considerations are essential for the determination of prognosis and appropriate treatment decisions.