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. (Blood. 2012;119(12): 2731-2737) IntroductionAfter decades of virtually no progress, multiple myeloma survival has improved significantly in the last 10 years, in younger patients even 2-to 3-fold. 1-3 Indeed, multiple myeloma has seen more remarkable progress in treatment and patient outcomes than any other cancer in the last decade. With improvements in survival, a relatively new clinical challenge that has emerged is the risk of second malignancies. This pattern of increase in second malignancies has been observed in other cancers with available curative therapies and favorable outcomes. Survivors of testicular cancer are at up to 3-fold higher risk of developing a second malignancy than the general population. 4 Survivors of Hodgkin lymphoma have more than 3 times greater risk of solid tumors. Fifteen years after diagnosis, the cumulative mortality from second malignancies exceeds cumulative mortality from Hodgkin lymphoma. 5,6 In the United States alone, the number of cancer survivors has tripled since 1971 and is growing by 2% each year; cancer survivors constitute 3.5% of the United States population. 7 Indeed, secondor higher-order cancers account for 18% of incident cancers in the United States, making them the third most common cancer diagnosis. 7 Based on the National Cancer Institute Surveillance, Epidemiology and End Results (NCI SEER) database, compared with the general population, cancer survivors have a 14% increased risk of developing a malignancy. 7 In the late 1960s, based on a restricted number of patients, an association betwee...

Large registry analysis to accurately define second malignancy rates and risks in a well-characterized cohort of 744 consecutive multiple myeloma patients followed-up for 25 years

“…SPM included hematologic and solid tumors, and in each trial their risk in the placebo group was 2%-3% versus 7%-8% in the lenalidomide group, with the differences being both statistically and clinically significant. [6][7][8][9] Some reports have also discussed the possibility that thalidomide may potentiate solid SPM, 5,10,11 suggesting an IMiD class effect associated with melphalan exposure.…”

The impact of prior malignancies on second malignancies and survival in MM patients: a population-based study

“…Smoking is a risk the factor for both cervical cancer and respiratory tract malignancies, 42 although it is not a risk factor for MM. The increased incidence of hematological malignancies, specifically acute myeloid leukemia/MDS, is well documented in MM patients, 4,6,12,13 where alkylating agents have been considered to be 1 of the main contributing factors, although a role for non-treatment-related factors has also been reported, [4][5][6]8 and the recent discovery of a genotype associated with the development of MDS in MM 22 supports a role for susceptibility genes in this development.…”

“…[1][2][3][4][5] We have previously shown in a large population-based study that the risk of developing any second malignancy is 26% higher in MM patients compared with the general population; most importantly, they had an 11-fold increased risk of developing acute myeloid leukemia and myelodysplastic syndromes (MDS) and a twofold increased risk of developing nonmelanoma skin cancer. 6 Other studies have found MM patients to have an increased risk of developing certain types of second cancers, such as melanoma, nervous system tumors, and kidney and urinary tract tumors, although mechanisms and risk factors are not well understood.…”

“…[7][8][9][10] Suggested risk factors for second malignancies include treatment-, disease-, environmental-, behavioral-, and host-related factors. 4,[11][12][13] Host-related factors include both genetic and nongenetic; reported nongenetic factors include age, male sex, and obesity. 1,8,14 Genetic factors implicated in the development of second malignancies include polymorphisms in genes encoding drug-metabolizing enzymes and DNA repair pathways.…”

Rapid Evolution of a Myelodysplastic Syndrome in a Case of Multiple-Myeloma: Therapy Related or Not?

“…The median delay between the initiation of therapy and the appearance of a secondary malignancy is of ~45 months in a compilation of 15 trials/studies/series [6]. In this review, the authors also debate on the role of genetic or behavioral factors, inherent to the patient, as well as risk factors associated with the specific characteristics of MM [8].…”