Multiple Myeloma
Multiple myeloma is a disseminated malignancy of monoclonal plasma cells that accounts for 15% of all hematologic cancers. In 2011, an estimated 20,520 new cases will be diagnosed in the United States, and 10,610 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, although median survivial is now improving to between 5 to 7 years.
Epidemiology
Gender
Men are affected more frequently than women (1.4:1 ratio).
Age
The median age of diagnosis is 70 years, with 75% of diagnosed patients over the age of 55.
Race
The annual incidence per 100,000 population is 6.5 among white men and 4.1 among white women. Among black men and women, the frequency doubles to 13.7 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, Italy, 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 medical surveillance, although other factors may be involved.
Survival
The relative survival rate measures the survival of cancer patients in comparison to the general population to estimate the effect of the cancer in question. The overall 5-year relative survival rate for multiple myeloma was 40.9% for 1975-2003, with a notable improvement observed since 2000 when novel drugs became available.
Etiology and risk factors
No predisposing factors for the development of multiple myeloma have been confirmed, although possible contributing causes include certain toxic exposures and potential underlying genetic vulnerability.
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(Drug information on 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.
Cytogenetics
Karyotypic abnormalities in myeloma are complex, with both numeric and structural abnormalities. DNA aneuploidy is observed in more than 90%; these are predominantly hyperdiploid, with less than 10% being hypodiploid, and the latter carries a poor prognosis. Cytogenetic abnormalities can be biologically classifed as hyperdiploid or non-hyperdiploid often associated with translocations. The immunoglobulin 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, 14, and 16 as well as del17p13 (TP53) have been associated with a poor prognosis. Gene expression profiling, now commercially available, identifies 15% of patients with a potential high-risk genetic signature. Multiple myeloma presents with multiple subclones at diagnosis, which have been shown to appear and disappear with treatment over the course of the disease and accounts for ultimate failure to eradicate the disease. Such studies may ultimately help tailor therapy in the near future and so better characterize the phenomenon of clonal heterogeneity.
The location and oncogenes involved in multiple myeloma
Genetic factors
Multiple myeloma is not an inherited disease, but there have been numerous reports of multiple cases in the same family. However, a case-control study revealed no significant increase in its incidence among relatives of patients who had multiple myeloma, other hematologic malignancies, or other cancers, although this remains an area of active investigation.
Pathophysiology
Interactions between multiple myeloma cells and their microenvironment (the extracellular matrix and the bone marrow stroma), allow multiple myeloma cells to survive, grow, migrate, and resist apoptosis induced by traditional chemotherapies. These effects are partially mediated through adhesion-mediated signalling and partly through various cytokines, including IL-6, vascular endothelial growth factor, insulin-like growth factor 1 (IGF-1), and tumor necrosis factor (TNF)-α. The molecular signals mediating the proliferative effects include the RAS/RAF/mitogen activated protein kinase (MAPK) pathway, whereas the P13 kinase (P13K/AKT) pathway provides cell survival and drug resistance signals. Improved understanding of these interactions and the molecular mechanisms mediating them has allowed the evaluation of novel therapies that directly target multiple myeloma cells as well as act on the bone marrow microenvironment, and other milieu, including cortical bone.
Monoclonal gammopathy of unknown significance (MGUS)
Patients with MGUS develop myeloma, lymphoma, or amyloidosis at a rate of 1% per year. Recent studies indicate that the diagnosis of symptomatic multiple myeloma is always preceded by monoclonal gammopathy for 2 or more years.
