Second malignancies after multiple myeloma: from 1960s to 2010s

Abstract

Based on small numbers, recent reports from 3 randomized trials have consistently demonstrated more hematologic malignancies in patients treated with lenalidomide as maintenance (vs placebo). This fact has prompted concern and highlighted the association between multiple myeloma and second malignancies. Furthermore, an excess of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) after multiple myeloma has been known for over 4 decades. Most prior studies have been restricted because of small numbers of patients, inadequate follow-up, and limitations of ascertainment of second malignancies. Although the underlying biologic mechanisms of AML/MDS after multiple myeloma are unknown, treatment-related factors are presumed to be responsible. Recently, an excess risk of AML/MDS was found among 5652 patients with IgG/IgA (but not IgM) monoclonal gammopathy of undetermined significance, supporting a role for disease-related factors. Furthermore, there is evidence to suggest that polymorphisms in germline genes may contribute to a person's susceptibility to subsequent cancers, whereas the potential influence of environmental and behavioral factors remains poorly understood. This review discusses current knowledge regarding second malignancies after multiple myeloma and gives future directions for efforts designed to characterize underlying biologic mechanisms, with the goal to maximize survival and minimize the risk for second malignancies for individual patients.

Figure 1

Proposed model of second malignancies after multiple myeloma. Examples for the categories include the following: (1) alkylating agents, immunomodulatory agents, autologous stem cell transplant, and radiation; (2) molecular subtypes of disease, biclonal disease, and bone marrow microenvironment; (3) polymorphisms in germline genes (eg, drug-metabolizing genes, erythropoietin promoter gene), chronic antigenic stimulation, and genetic susceptibility with other malignancies; (4) occupation, pesticides, and chlorinated solvents; and (5) tobacco, obesity, alcohol, and diet.

Figure 2

Cumulative incidence of developing a second cancer and cumulative probability of death because of competing causes, after multiple myeloma. Data, which are based on 33 229 patients who received a diagnosis of multiple myeloma between 1973 and 2008 in the United States, are from the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute. Reprinted from Landgren et al with permission.