Plasma cell dyscrasias are heterogeneous disorders arising from the proliferation of a monoclonal population of plasma cells. Some of these disorders can present serendipitously as benign processes that can be observed; others are highly aggressive and require immediate intervention. The most common plasma cell dyscrasia is monoclonal gammopathy of undetermined significance (MGUS), a benign condition that can be observed. Related disorders include smoldering multiple myeloma (SMM), multiple myeloma (MM), solitary plasmacytoma of the bone, extramedullary plasmacytoma, Waldenström macroglobulinemia (WM), primary amyloid light-chain (AL) amyloidosis, heavy-chain disease, POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome, and the recently recognized TEMPI (telangiectasias, elevated erythropoietin and erythrocytosis, monoclonal gammopathy, perinephric fluid collection, and intrapulmonary shunting) syndrome. The spectrum of MGUS, SMM, and MM represents a natural progression of the same disease. This chapter focuses on the etiology, genetics, biology, diagnosis, clinical features, and current therapy of MM and other plasma cell disorders.
Major recent discoveries have changed the way we understand, diagnose, and treat plasma cell dyscrasias. The initial sequencing of the myeloma genome and single-cell genetic analysis paved the way for the concept of intraclonal heterogeneity and Darwinian selection of clones. Increasingly sensitive diagnostic and monitoring techniques allow for more accurate diagnosis, minimal residual disease monitoring, and detection of early relapse. New diagnostic criteria for MM have been implemented, and the introduction of novel classes of agents such as immunomodulatory drugs and proteasome inhibitors has led to improved overall survival. Additionally, immunotherapy using monoclonal antibodies against different myeloma targets has shown promising activity in clinical trials. Major advances have also occurred in WM as a highly recurrent single point mutation of the MYD88 gene has been identified, and new treatments that abrogate this highly active pathway are already in use. Finally, a new paraneoplastic syndrome, the TEMPI syndrome, has been identified and described.
Multiple myeloma is a malignant proliferation of plasma cells. In virtually all cases, myeloma cells (as well as their precursors MGUS and SMM) secrete immunoglobulins. Usually, myeloma cells secrete immunoglobulin (Ig) G (60%); other types are less common (IgA 20%, IgD 2%, IgE <0.1%, biclonal <1%). Light chain–only secretion is noted in 18%; <5% of patients do not secrete a heavy- or light-chain immunoglobulin (nonsecretory MM).
Epidemiology and Risk Factors
In 2014, approximately 24,000 people were diagnosed with MM in the United States, and 11,090 died from the disease. The median age at diagnosis is 69 years. The incidence is highest in the age range of 65 to 74 years (27.7%), followed by the 75- to 84 year-old range (24.7%). The annual age-adjusted incidence of the disease per 100,000 population is 7.2 among white men and 4.3 among white women. Among African Americans, the frequency doubles to 14.8 in men and 10.5 in women. There is also a difference in mortality by racial group. The annual age-adjusted mortality rate per 100,000 is 4.0 and 2.5 in white men and women, respectively, and 7.7 and 5.3 in African American men and women, respectively. The ...