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

To access publisher's full text version of this article. Please click on the hyperlink in Additional Links field.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.National Cancer Institute of the National Institutes of Healt

Clinical and genetic studies of ETV6/ABL1-positive chronic myeloid leukaemia in blast crisis treated with imatinib mesylate.

Most chronic myeloid leukaemia (CML) patients are genetically characterized by the t(9;22)(q34;q11), generating the BCR/ABL1 fusion gene. However, a few CML patients with rearrangements of 9q34 and 12p13, leading to ETV6/ABL1 chimaeras, have also been reported. Here we describe the clinical and genetic response to imatinib mesylate treatment of an ETV6/ABL1-positive CML patient diagnosed in blast crisis (BC). A chronic phase was achieved after acute myeloid leukaemia induction therapy. Then, treatment with imatinib mesylate (600 mg/d) was initiated and the effect was assessed clinically as well as genetically, including by repeated interphase fluorescence in situ hybridization studies. Until d 71 of imatinib mesylate therapy, stable improvements in the clinical and laboratory features were noted, and the frequency of ABL1-rearranged peripheral blood cells decreased from 56% to 11%. At d 92, an additional t(12;13)(p12;q13), with the 12p breakpoint proximal to ETV6, was found. The patient relapsed into BC 126 d after the start of the imatinib mesylate treatment and succumbed to the disease shortly afterwards. No mutations in the tyrosine kinase domain of ABL1 of the ETV6/ABL1 fusion were identified in the second BC. However, whereas the ETV6/ABL1 expression was seemingly the same at diagnosis and at second BC, the expression of ETV6 was markedly lower at the second BC. This decreased expression of wild-type ETV6 may have been a contributory factor for the relapse

Decrease in the incidence of total hip arthroplasties in patients with rheumatoid arthritis - results from a well defined population in south Sweden

To access publisher full text version of this article. Please click on the hyperlink in Additional Links field.INTRODUCTION: One aim of modern pharmacologic treatment in rheumatoid arthritis (RA) is to prevent joint destruction and reduce the need for surgery. Our purpose was to investigate secular trends in the incidence of primary total hip and knee arthroplasties in a well defined sample of patients with RA. METHODS: Prevalent cases with RA in 1997 and incident cases from 1997 to 2007 in a community based register in Malmö, south Sweden, were included. Based on a structured review of the medical records, patients were classified according to the 1987 ACR criteria for RA. This cohort was linked to the Swedish Hip Arthroplasty Register (through December 2006) and the Swedish Knee Arthroplasty Register (through October 2007). Patients with a registered total hip or knee arthroplasty before 1997 or before RA diagnosis were excluded. Incidence rates for the period of introduction of TNF inhibitors (1998 to 2001) were compared to the period when biologics were part of the established treatment for severe RA (2002 to 2006/2007). RESULTS: In the cohort (n = 2,164; 71% women) a primary hip arthroplasty was registered for 115 patients and a primary knee arthroplasty for 82 patients. The incidence of primary total hip arthroplasties decreased from the period 1998 to 2001 (12.6/1,000 person-years (pyr)) to 2002 to 2006 (6.6/1,000 pyr) (rate ratio (RR) 0.52; 95% confidence interval (CI) 0.35 to 0.76). There was a trend towards an increase of primary knee arthroplasties (incidence 4.8/1,000 pyr vs. 6.8/1,000 pyr; RR 1.43; 95% CI 0.89 to 2.31). CONCLUSIONS: Our investigation shows a significant decrease in the incidence of total hip arthroplasties in patients with RA after 2001. Possible explanations include a positive effect on joint damage from more aggressive pharmacological treatment.The Swedish Research Council Lund University Crafoord Foundation Swedish Rheumatism Associatio

A pooled analysis of karyotypic patterns, breakpoints and imbalances in 783 cytogenetically abnormal multiple myelomas reveals frequently involved chromosome segments as well as significant age- and sex-related differences.

The cytogenetic features (ploidy, complexity, breakpoints, imbalances) were ascertained in 783 abnormal multiple myeloma (MM) cases to identify frequently involved chromosomal regions as well as a possible impact of age/sex. The series included MM patients from the Mitelman Database of Chromosome Aberrations in Cancer and from our own laboratory. Hyperdiploidy was most common, followed by hypodiploidy, pseudodiploidy and tri-/tetraploidy. Most cases were complex, with a median of eight changes per patient. The distribution of modal numbers differed between younger and older patients, but was not related to sex. No sex- or age-related differences regarding the number of anomalies were found. The most frequent genomic breakpoints were 14q32, 11q13, 1q10, 8q24, 1p11, 1q21, 22q11, 1p13, 1q11, 19q13, 1p22, 6q21 and 17p11. Breaks in 1p13, 6q21 and 11q13 were more common in the younger age group. The most frequent imbalances were + 9, - 13, + 15, + 19, + 11 and - Y. Trisomy 11 and monosomy 16 were more common among men, while -X was more frequent among women. Loss of Y as the sole change and + 5 were more common in elderly patients, and - 14 was more frequent in the younger age group. The present findings strongly suggest that some karyotypic features of MM are influenced by endogenous and/or exogenous factors

History of autoimmune disease is associated with impaired survival in multiple myeloma and monoclonal gammopathy of undetermined significance: a population-based study

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked FilesMultiple myeloma (MM) is a plasma cell disorder preceded by monoclonal gammopathy of undetermined significance (MGUS). Incidence of MM and MGUS is higher among patients with autoimmune disease. The aim of this study was to determine whether a history of autoimmunity has an impact on survival in MM and MGUS. Using high-quality national Swedish registries, we identified 8367 patients with MM, 18,768 patients with MGUS, and 110,251 matched control subjects, and obtained information on previous autoimmune disease in patients and controls. Cox regression was used to calculate hazard ratios (HRs) for overall survival with 95 % confidence intervals (CIs). In patients with MM and a prior autoimmune disease, the risk of death was significantly increased, HR = 1.2 (95 % CI 1.2-1.3) compared to MM patients with no history of autoimmunity. In MGUS patients, a prior autoimmune disease was associated with a significantly 1.4-fold elevated risk of death (95 % CI 1.3-1.4). When analyzing different types of autoimmune diseases, a history of ulcerative colitis had a stronger impact on survival in MM than in controls. Our findings that a history of autoimmune disease has a negative impact on survival in MM and MGUS could be due to shared underlying common genetic factors, or that patients with a history of autoimmunity develop more severe cases of MM and MGUS, or cumulative comorbidity in the individual. Our results suggest that more attention should be paid to comorbidity as a prognostic factor in MGUS and MM, and underlines the need for studies aimed at tailoring therapy according to comorbidity.Swedish Blodcancerfonden Swedish Cancer Society Stockholm County Council Karolinska Institutet Karolinska Institutet Foundations University of Iceland Icelandic Centre for Research (RANNIS) Landspitali University Hospita

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

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked FilesIn the present study, we aimed to evaluate 2 hypotheses. First, we hypothesize that prior malignancy is a proxy for genetic susceptibility that could be a risk factor for subsequent malignancy development in multiple myeloma (MM) patients. Second, we hypothesize that survival after MM is influenced by a prior malignancy. All patients diagnosed with MM from 1 January 1973 to 31 December 2010 were identified from the Swedish Cancer Register. Cox regression model was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) where prior malignancy was compared in MM patients who developed a subsequent malignancy and MM patients who did not. In another Cox regression model, survival was compared in MM patients with and without a prior malignancy diagnosis. A total of 19 791 patients were diagnosed with MM. Patients with a prior malignancy diagnosis had a significantly increased risk of developing a subsequent malignancy compared with MM patients without (HR 1.42, 95% CI 1.23-1.65, P 1 prior malignancy reduces survival even further.Asrun Einarsdottir Foundation in Iceland Blodcancerfonden Swedish Cancer Society Stockholm County Council Karolinska Institutet Foundation University of Iceland Research Fund Icelandic Centre for Research Landspitali University Hospital Research Fund Marie Curie Career Integration Grant Memorial Sloan Kettering Cancer Center Core Grant by the National Cancer Institute, National Institutes of Healt

Monoclonal gammopathy of undetermined significance and risk of lymphoid and myeloid malignancies: 728 cases followed up to 30 years in Sweden.

To access publisher's full text version of this article. Please click on the hyperlink in Additional Links field.In 728 Swedish cases of monoclonal gammopathy of undetermined significance (MGUS), followed up to 30 years (median, 10 years), we estimated the cumulative risk of hematologic disorders originating from lymphoid and myeloid lineages. Using Cox regression models, we examined associations of demographic and laboratory factors with progression and determined the discriminatory power of 3 prediction models for progression. Eighty-four MGUS cases developed a lymphoid disorder, representing a cumulative risk of 15.4%. Multiple myeloma (MM) occurred in 53 patients, and the 30-year cumulative risk was 10.6%; an ∼0.5% annual risk. Three factors were significantly associated with progression: abnormal free light-chain (FLC) ratio (1.65), M-protein concentration (≥1.5 g/dL), and reduction of 1 or 2 noninvolved immunoglobulin isotype levels (immunoparesis). A prediction model with separate effects for these 3 factors and the M-protein isotype had higher discriminatory power than other models, although the differences were not statistically significant. The 30-year cumulative risk for myeloid malignancies was 1.5 g/dL, factors previously considered by Mayo Clinic researchers, are predictors for MM progression and suggests that separate consideration of immunoparesis and the Mayo Clinic risk factors could improve identification of MGUS patients at high risk for progression

Multiple myeloma and infections: a population-based study on 9253 multiple myeloma patients.

Infections are a major cause of morbidity and mortality in patients with multiple myeloma. To estimate the risk of bacterial and viral infections in multiple myeloma patients, we used population-based data from Sweden to identify all multiple myeloma patients (n=9 253) diagnosed from 1988 to 2004 with follow-up to 2007 and 34 931 matched controls. Cox proportional hazard models were used to estimate the risk of infections. Overall, multiple myeloma patients had a 7-fold (hazard ratio =7.1; 95% confidence interval = 6.8-7.4) risk of developing any infection compared to matched controls. The increased risk of developing a bacterial infection was 7-fold (7.1; 6.8-7.4), and for viral infections 10-fold (10.0; 8.9-11.4). Multiple myeloma patients diagnosed in the more recent calendar periods had significantly higher risk of infections compared to controls (p<0.001). At one year of follow-up, infection was the underlying cause in 22% of deaths in multiple myeloma patients. Mortality due to infections remained constant during the study period. Our findings confirm that infections represent a major threat to multiple myeloma patients. The effect on infectious complications due to novel drugs introduced in the treatment of multiple myeloma needs to be established and trials on prophylactic measures are needed

Monoclonal gammopathy of undetermined significance and risk of infections: a population-based study.

To access publisher full text version of this article. Please click on the hyperlink in Additional Links field.No comprehensive evaluation has been made to assess the risk of viral and bacterial infections among patients with monoclonal gammopathy of undetermined significance. Using population-based data from Sweden, we estimated risk of infections among 5,326 monoclonal gammopathy of undetermined significance patients compared to 20,161 matched controls. Patients with monoclonal gammopathy of undetermined significance had a 2-fold increased risk (P<0.05) of developing any infection at 5- and 10-year follow up. More specifically, patients with monoclonal gammopathy of undetermined significance had an increased risk (P<0.05) of bacterial (pneumonia, osteomyelitis, septicemia, pyelonephritis, cellulitis, endocarditis, and meningitis), and viral (influenza and herpes zoster) infections. Patients with monoclonal gammopathy of undetermined significance with M-protein concentrations over 2.5 g/dL at diagnosis had highest risks of infections. However, the risk was also increased (P<0.05) among those with concentrations below 0.5 g/dL. Patients with monoclonal gammopathy of undetermined significance who developed infections had no excess risk of developing multiple myeloma, Waldenström macroglobulinemia or related malignancy. Our findings provide novel insights into the mechanisms behind infections in patients with plasma cell dyscrasias, and may have clinical implications.Stockholm County Council Karolinska Institutet Cancer Society in Stockholm NIH, NC