MULTIPLE MYELOMA

Multiple myeloma is a disseminated malignancy of monoclonal plasma cells that accounts for 15% of all hematologic cancers. In 2008, an estimated 19,920 new cases will be diagnosed in the United States, and 10,690 Americans will die of this disease. Incidence rates for myeloma (5.3 in men and 3.5 in women) and mortality rates (3.7 in men and 2.5 in women) per 100,000 population have remained stable for the past decade.

Epidemiology

Gender Men are affected more frequently than women (1.4:1.0 ratio).

Age The median age at presentation is 71 years, according to most tumor registries, although the median age reported in studies is approximately 66 years.

Race The annual incidence per 100,000 population is 6.4 among white men and 4.1 among white women. Among black men and women, the frequency doubles to 12.7 and 10.0, respectively, per 100,000 population. This racial difference is not explained by socioeconomic or environmental factors and is presumably due to unknown genetic factors.

Geography There is no clear geographic distribution of multiple myeloma. In Europe, the highest rates are noted in the Nordic countries, the United Kingdom, Switzerland, and Israel. France, Germany, Austria, and Slovenia have a lower incidence, and developing countries have the lowest incidence. This higher relative incidence in more developed countries probably results from the combination of a longer life expectancy and more frequent medicalsurveillance.

Survival The 5-year survival rate for all patients treated with conventional therapy is approximately 33%. The 5-year survival rate is lower among patients ≥ age 65 (20% to 25%) than in those < age 65 (30% to 35%).

Etiology and risk factors

No predisposing factors for the development of multiple myeloma have been confirmed.

Environment Some causative factors that have been suggested include radiation exposure (radiologists and radium dial workers), occupational exposure (agricultural, chemical, metallurgical, rubber plant, pulp, wood and paper workers, and leather tanners), and chemical exposure to formaldehyde, epichlorohydrin, Agent Orange, hair dyes, paint sprays, and asbestos. None of these associations has proven to be statistically significant, and some have been contradicted by negative correlations. The initial report that survivors of the atomic bombings in Japan had an increased risk of developing myeloma has been refuted by longer follow-up.

Viruses A preliminary report in a limited number of patients noted the presence of herpesvirus 8 in the dendritic cells of patients with multiple myeloma. However, further evaluation by a number of investigators has failed to confirm this result. Patients with myeloma also do not appear to have a significant immune response against this virus.

Cytogenetics Karyotypic abnormalities in myeloma are complex, with both numeric and structural abnormalities. DNA aneuploidy is observed in more than 90% of cases, which are predominantly hyperdiploid, with less than 10% hypodiploid (which carries a poor prognosis). Recurrent nonrandom structural abnormalities have been identified and linked to the pathogenesis and prognosis of myeloma. The immunoglobulin (Ig) heavy-chain gene at 14q32 is frequently involved in translocations with partner chromosomes 4, 6, 8, 11, and 16. The location and oncogenes involved are shown in Table 1. Translocations involving chromosomes 4 and 16 as well as del17p13 (p53) have been associated with a poor prognosis. Del13q or monosomy 13 is observed in 15% to 20% of patients with conventional cytogenetics and also carries a poor prognosis across standard and high-dose therapies. Interphase fluorescence in situ hybridization (FISH) with a specific probe for chromosome 13q34 (retinoblastoma gene, Rb 1) identifies this abnormality in up to 50% of patients, with a less clear prognostic implication.

Genetic factors Although multiple myeloma is not an inherited disease, there have been numerous reports of multiple cases in the same family. However, a case-control study revealed no significant increase in the incidence among relatives of patients who had multiple myeloma, other hematologic malignancies, or other cancers.

Monoclonal gammopathy of unknown significance (MGUS) Patients with MGUS develop myeloma, macroglobulinemic lymphoma, or amyloidosis at a rate of 1% per year.

Signs and symptoms

The clinical features of multiple myeloma are variable. Findings that suggest the diagnosis include lytic bone lesions, anemia, azotemia, hypercalcemia, and recurrent infections. Approximately 30% of patients are free of symptoms and are diagnosed on routine physicals with abnormal laboratory studies including elevation of serum protein.

Bone disease Bone pain, especially from compression fractures of the vertebrae or ribs, is the most common symptom. At diagnosis, 70% of patients have lytic lesions, which are due to accelerated bone resorption. These changes are induced by factors modulating osteoclastic activity and produced by the bone marrow microenvironment and, to a lesser extent, myeloma cells. These factors include interleukin (IL)-1B, tumor necrosis factor (TNF)-α, and IL-6 as well as newly identified factors such as osteoprotogerin, TNF-related activation-induced cytokine (TRANCE), mip-1–alpha, and receptor activator of nuclear factor kappa B (RANK) ligand. DKK-1 has been described as a soluble factor produced by multiple myeloma cells inhibiting osteoblastic activity.

Anemia Normocytic, normochromic anemia is present in 60% of patients at diagnosis. It is due primarily to the decreased production of red blood cells by marrow, infiltration with plasma cells, and the suppressive effect of various cytokines. Patients with renal failure may also have decreased levels of erythropoietin, which can worsen the degree of anemia.

Hypercalcemia Among newly diagnosed patients, 20% have hypercalcemia (corrected serum calcium level > 11.5 mg/dL) secondary to progressive bone destruction, which may be exacerbated by prolonged immobility. Hypercalcemia should be suspected in patients with myeloma who have nausea, fatigue, confusion, polyuria, or constipation. It may suggest high tumor burden. It should be considered an oncologic emergency and requires prompt treatment.

Renal failure Approximately 20% of patients present with renal insufficiency and another 20% to 40% develop this complication in later phases of the disease. Light-chain cast nephropathy is the most common cause of renal failure. Additional causes include hypercalcemia, dehydration, and hyperuricemia. Less commonly, amyloidosis, light-chain deposition disease, nonsteroidal anti-inflammatory agents taken for pain control, intravenous radiographic contrast administration, and calcium stones may contribute to renal failure. More recently, bisphosphonate therapy has been associated with renal failure.