Sigurdur Y. Kristinsson

International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma

This International Myeloma Working Group consensus updates the disease definition of multiple myeloma to include validated biomarkers in addition to existing requirements of attributable CRAB features (hypercalcaemia, renal failure, anaemia, and bone lesions). These changes are based on the identification of biomarkers associated with near inevitable development of CRAB features in patients who would otherwise be regarded as having smouldering multiple myeloma. A delay in application of the label of multiple myeloma and postponement of therapy could be detrimental to these patients. In addition to this change, we clarify and update the underlying laboratory and radiographic variables that fulfil the criteria for the presence of myeloma-defining CRAB features, and the histological and monoclonal protein requirements for the disease diagnosis. Finally, we provide specific metrics that new biomarkers should meet for inclusion in the disease definition. The International Myeloma Working Group recommends the implementation of these criteria in routine practice and in future clinical trials, and recommends that future studies analyse any differences in outcome that might occur as a result of the new disease definition.

Patterns of Survival in Multiple Myeloma: A Population-Based Study of Patients Diagnosed in Sweden From 1973 to 2003

PURPOSE To define patterns of survival among all multiple myeloma (MM) patients diagnosed in Sweden during a 30-year period. PATIENTS AND METHODS A total of 14,381 MM patients (7,643 males; 6,738 females) were diagnosed in Sweden from 1973 to 2003 (median age, 69.9 years; range 19 to 101 years). Patients were categorized into six age categories and four calendar periods (1973 to 1979, 1980 to 1986, 1987 to 1993, and 1994 to 2003). We computed relative survival ratios (RSRs) as measures of patient survival. RESULTS One-year survival improved (P < .001) over time in all age groups and RSRs were 0.73, 0.78, 0.80, and 0.82 for the four calendar periods; however, improvement in 5-year (P < .001) and 10-year (P < .001) RSR was restricted to patients younger than 70 years and younger than 60 years, respectively. For the first time, in analyses restricted to MM patients diagnosed at age younger than 60 years, we found a 29% (P < .001) reduced 10-year mortality in the last calendar period (1994 to 2003) compared with the preceding calendar period (1987 to 1993). Females with MM had a 3% (P = .024) lower excess mortality than males. CONCLUSION One-year MM survival has increased for all age groups during the last decades; 5-year and 10-year MM survival has increased in younger patients (younger than 60 to 70 years). High-dose melphalan with subsequent autologous stem-cell transplantation, thalidomide, and a continuous improvement in supportive care measures are probably the most important factors contributing to this finding. New effective agents with a more favorable toxicity profile are needed to improve survival further, particularly in the elderly.

Success Story of Targeted Therapy in Chronic Myeloid Leukemia: A Population-Based Study of Patients Diagnosed in Sweden From 1973 to 2008

PURPOSE Chronic myeloid leukemia (CML) management changed dramatically with the development of imatinib mesylate (IM), the first tyrosine kinase inhibitor targeting the BCR-ABL1 oncoprotein. In Sweden, the drug was approved in November 2001. We report relative survival (RS) of patients with CML diagnosed during a 36-year period. PATIENTS AND METHODS Using data from the population-based Swedish Cancer Registry and population life tables, we estimated RS for all patients diagnosed with CML from 1973 to 2008 (n = 3173; 1796 males and 1377 females; median age, 62 years). Patients were categorized into five age groups and five calendar periods, the last being 2001 to 2008. Information on use of upfront IM was collected from the Swedish CML registry. RESULTS Relative survival improved with each calendar period, with the greatest improvement between 1994-2000 and 2001-2008. Five-year cumulative relative survival ratios (95% CIs) were 0.21 (0.17 to 0.24) for patients diagnosed 1973-1979, 0.54 (0.50 to 0.58) for 1994-2000, and 0.80 (0.75 to 0.83) for 2001-2008. This improvement was confined to patients younger than 79 years of age. Five-year RSRs for patients diagnosed from 2001 to 2008 were 0.91 (95% CI, 0.85 to 0.94) and 0.25 (95% CI, 0.10 to 0.47) for patients younger than 50 and older than 79 years, respectively. Men had inferior outcome. Upfront overall use of IM increased from 40% (2002) to 84% (2006). Only 18% of patients older than 80 years of age received IM as first-line therapy. CONCLUSION This large population-based study shows a major improvement in outcome of patients with CML up to 79 years of age diagnosed from 2001 to 2008, mainly caused by an increasing use of IM. The elderly still have poorer outcome, partly because of a limited use of IM.

Risk of lymphoproliferative disorders among first-degree relatives of lymphoplasmacytic lymphoma/Waldenström macroglobulinemia patients: a population-based study in Sweden

A role for genetic factors in the etiology of lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM) is implicated based on prior findings from multiply affected families and small case-control and cohort studies. We identified 2144 LPL/WM patients (1539 WM [72%] and 605 LPL [28%]) diagnosed in Sweden, 8279 population-based matched controls, and linkable first-degree relatives of patients (n = 6177) and controls (n = 24 609). Using a marginal survival model, we calculated relative risks and 95% confidence intervals as measures of familial aggregation. We found first-degree relatives of LPL/WM patients to have 20-fold (4.1-98.4), 3.0-fold (2.0-4.4), 3.4-fold (1.7-6.6), and 5.0-fold (1.3-18.9) increased risks of developing LPL/WM, non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), and monoclonal gammopathy of undetermined significance (MGUS), respectively. However, there was no evidence of an increased risk of developing multiple myeloma or Hodgkin lymphoma. In analyses stratified by type of first-degree relative (parent, sibling, offspring), age at diagnosis of the probands (greater or less than 70 years), and sex of the first-degree relative, we did not observe the risk estimates to be significantly different compared with the overall analyses. Our findings of highly increased risks of developing LPL/WM, NHL, CLL, and MGUS support the operation of shared susceptibility genes that predispose to LPL/WM and other lymphoproliferative disorders.

Racial disparities in incidence and outcome in multiple myeloma: a population-based study

Multiple myeloma (MM) is the most common hematologic malignancy in blacks. Some prior studies suggest inferior survival in blacks; others suggest similar survival. Using the original 9 Surveillance, Epidemiology, and End Results registries, we conducted a large-scale population-based study including 5798 black and 28 939 white MM patients diagnosed 1973-2005, followed through 2006. Age-adjusted incidence rates, disease-specific survival, and relative survival rates were calculated by race, age, and time period of diagnosis. Mean age at diagnosis was 65.8 and 69.8 years for blacks and whites, respectively (P < .001). Incidence among blacks was m twice that among whites; this disparity was greater among patients < 50 years (P = .002). Over the entire study period, disease-specific and relative survival rates were higher in blacks than whites (P < .001). For whites, 5-year relative survival rates increased significantly 1973-1993 to 1994-1998 (26.3% to 30.8%; P < .001) and 1994-1998 to 1999-2005 (30.8% to 35.0%; P = .004). Survival improvements among blacks were smaller and nonsignificant (1973-1993 to 1999-2005: 31.0% to 34.1%; P = .07). We found (1) a younger age of onset among blacks; (2) better survival in blacks 1973-2005; and (3) significant survival improvement among whites over time, with smaller, nonsignificant change seen among blacks, possibly due to unequal access to and/or disparate responsiveness to novel therapies.

Treatment-Related Risk Factors for Transformation to Acute Myeloid Leukemia and Myelodysplastic Syndromes in Myeloproliferative Neoplasms

PURPOSE Patients with myeloproliferative neoplasms (MPNs), including polycythemia vera, essential thrombocythemia, and primary myelofibrosis, have a propensity to develop acute myeloid leukemia (AML) and myelodysplastic syndromes (MDSs). Using population-based data from Sweden, we assessed the role of MPN treatment and subsequent AML/MDS risk with special focus on the leukemogenic potential of hydroxyurea (HU). METHODS On the basis of a nationwide MPN cohort (N = 11,039), we conducted a nested case-control study, including 162 patients (153 and nine with subsequent AML and MDS diagnosis, respectively) and 242 matched controls. We obtained clinical and MPN treatment data for all patients. Using logistic regression, we calculated odds ratios (ORs) as measures of AML/MDS risk. RESULTS Forty-one (25%) of 162 patients with MPNs with AML/MDS development were never exposed to alkylating agents, radioactive phosphorous (P(32)), or HU. Compared with patients with who were not exposed to HU, the ORs for 1 to 499 g, 500 to 999 g, more than 1,000 g of HU were 1.5 (95% CI, 0.6 to 2.4), 1.4 (95% CI, 0.6 to 3.4), and 1.3 (95% CI, 0.5 to 3.3), respectively, for AML/MDS development (not significant). Patients with MPNs who received P(32) greater than 1,000 MBq and alkylators greater than 1 g had a 4.6-fold (95% CI, 2.1 to 9.8; P = .002) and 3.4-fold (95% CI, 1.1 to 10.6; P = .015) increased risk of AML/MDS, respectively. Patients receiving two or more cytoreductive treatments had a 2.9-fold (95% CI, 1.4 to 5.9) increased risk of transformation. CONCLUSION The risk of AML/MDS development after MPN diagnosis was significantly associated with high exposures of P(32) and alkylators but not with HU treatment. Twenty-five percent of patients with MPNs who developed AML/MDS were not exposed to cytotoxic therapy, supporting a major role for nontreatment-related factors.

Patterns of Improved Survival in Patients With Multiple Myeloma in the Twenty-First Century: A Population-Based Study

PURPOSE Randomized multiple myeloma (MM) studies show improved response rates and better progression-free survival for newer therapies. However, a less pronounced effect has been found for overall survival (OS). Using population-based data including detailed treatment information for individual patients, we assessed survival patterns for all patients diagnosed with MM in Malmö, Sweden from 1950 to 2005. PATIENTS AND METHODS We identified 773 patients with MM (48% males). On the basis of the age limit used for treatment with high-dose melphalan with autologous stem-cell support (HDM-ASCT; < or = 65 years old) in Sweden, we constructed Kaplan-Meier curves and used the Breslow generalized Wilcoxon test to evaluate OS patterns (diagnosed in six calendar periods) for patients 65 years old or younger and patients older than 65 years. Results Including all age groups, patients diagnosed from 1960 to 1969 had a better survival than patients diagnosed from 1950 to 1959. In subsequent 10-year calendar periods, median OS increased from 24.3 to 56.3 months (P = .036) in patients < or = 65 years old. In contrast, OS did not improve among patients older than age 65 years (21.2 to 26.7 months, P = .7). CONCLUSION With the establishment of HDM-ASCT as the standard therapy for younger patients with MM, OS has improved significantly for this age group in the general MM population. With novel therapies being commonly used at disease progression, presumably it becomes increasingly difficult to confirm survival differences between defined induction, consolidation, and maintenance therapies in the future. Consequently, in the era of novel MM therapies, population-based studies will serve as a necessary complement to randomized trials.

Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM): novel biological insights and development of early treatment strategies.

Monoclonal gammopathy of unknown significance (MGUS) and smoldering multiple myeloma (SMM) are asymptomatic plasma cell dyscrasias, with a propensity to progress to symptomatic MM. In recent years there have been improvements in risk stratification models (involving molecular markers) of both disorders, which have led to better understanding of the biology and probability of progression of MGUS and SMM. In the context of numerous molecular events and heterogeneous risk of progression, developing individualized risk profiles for patients with MGUS and SMM represents an ongoing challenge that has to be addressed by prospective clinical monitoring and extensive correlative science. In this review we discuss the current standard of care of patients with MGUS and SMM, the use of risk models, including flow cytometry and free-light chain analyses, for predicting risk of progression. Emerging evidence from molecular studies on MGUS and SMM, involving cytogenetics, gene-expression profiling, and microRNA as well as molecular imaging is described. Finally, future directions for improving individualized management of MGUS and SMM patients, as well as the potential for developing early treatment strategies designed to delay and prevent development of MM are discussed.

Chronic Immune Stimulation Might Act As a Trigger for the Development of Acute Myeloid Leukemia or Myelodysplastic Syndromes

PURPOSE Patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) often present with infections, but there are little data to assess whether a personal history of selected infections may act as pathogenic triggers. To additionally expand our knowledge on the role of immune stimulation in the causation of AML and MDS, we have conducted a large, population-based study to evaluate the risk of AML and MDS associated with a prior history of a broad range of infections or autoimmune diseases. PATIENTS AND METHODS By using population-based central registries in Sweden, we included 9,219 patients with AML, 1,662 patients with MDS, and 42,878 matched controls. We used logistic regression to calculate odds ratios (ORs) and 95% CIs for the association of AML or MDS with infectious and/or autoimmune diseases. RESULTS Overall, a history of any infectious disease was associated with a significantly increased risk of both AML (OR, 1.3; 95% CI, 1.2 to 1.4) and MDS (OR, 1.3; 95% CI, 1.1 to 1.5). These associations were significant even when we limited infections to those occurring 3 or more years before AML/MDS. A previous history of any autoimmune disease was associated with a 1.7-fold (95% CI, 1.5 to 1.9) increased risk for AML and 2.1-fold (95% CI, 1.7 to 2.6) increased risk for MDS. A large range of conditions were each significantly associated with AML and MDS. CONCLUSION Our novel findings indicate that chronic immune stimulation acts as a trigger for AML/MDS development. The underlying mechanisms may also be due to a common genetic predisposition or an effect of treatment for infections/autoimmune conditions.

Risk of plasma cell and lymphoproliferative disorders among 14621 first-degree relatives of 4458 patients with monoclonal gammopathy of undetermined significance in Sweden

Familial clustering of the precursor condition, monoclonal gammopathy of undetermined significance (MGUS) has been observed in case reports and in smaller studies. Using population-based data from Sweden, we identified 4458 MGUS patients, 17505 population-based controls, and first-degree relatives of patients (n = 14621) and controls (n = 58387) with the aim to assess risk of MGUS and lymphoproliferative malignancies among first-degree relatives of MGUS patients. Compared with relatives of controls, relatives of MGUS patients had increased risk of MGUS (relative risk [RR] = 2.8; 1.4-5.6), multiple myeloma (MM; RR = 2.9; 1.9-4.3), lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (LPL/WM; RR = 4.0; 1.5-11), and chronic lymphocytic leukemia (CLL; RR = 2.0; 1.2-2.3). Relatives of patients with IgG/IgA MGUS had a 4.0-fold (1.7-9.2), 2.9-fold (1.7-4.9), and 20-fold (2.3-170) elevated risk of developing MGUS, MM, and LPL/WM, respectively. Relatives of IgM MGUS patients had 5.0-fold (1.1-23) increased CLL risk and nonsignificant excess MM and LPL/WM risks. The results were very similar when we assessed risk by type of first-degree relative, age at MGUS (above/below 65 years), or sex. Risk of non-Hodgkin lymphoma or Hodgkin lymphoma was not increased among MGUS relatives. Among first-degree relatives of a nationwide MGUS cohort, we found elevated risks of MGUS, MM, LPL/WM, and CLL, supporting a role for germline susceptibility genes, shared environmental influences, or an interaction between both.