ALBERT

Description: Key Points Free light chain ratio, M-protein concentration, and immunosuppression predict progression of MGUS to lymphoid malignancies.

Description: Background. Evidence from multiply affected families, case-control and population-based registry studies implicate a role for genetic factors in multiple myeloma (MM). Previous studies based on small numbers have suggested excess risk of MGUS in relatives of MM patients. Aims of this large nationwide MGUS study were to quantify risks of developing MGUS and lymphoproliferative malignancies in first-degree relatives and to define characteristics of familial aggregation. Methods. We identified 4488 MGUS patients diagnosed in all major hematology/oncology outpatient units in Sweden (1967–2005), with linkable relatives. Using the population-based central Multigenerational Registry, we obtained 17628 frequency-matched controls and first-degree relatives of cases (n=14689) and controls (n=58698). Relatives of MGUS cases and controls were linked with hospital-based outpatient registries and the central Swedish Cancer Registry to define occurrence of MGUS and lymphoproliferative tumors. Measures of familial aggregation were calculated by a marginal survival model using relatives as the cohort. Results. Compared with controls, relative risk (RR) of MGUS was significantly increased (RR=2.84; 95% CI 1.45–5.57) in relatives of MGUS cases. Relatives of MGUS cases (vs. controls) also had excess risk of MM (RR=2.87; 95% CI 1.92–4.27), Waldenstrom’s macroglobulinemia (WM) (RR=4.94; 95% CI 1.32–18.46), and chronic lymphocytic leukemia (CLL) (RR=2.05; 95% CI 1.22–3.43). Risk-estimates were similar for various types of first-degree relatives (parents, siblings, offspring); the same was true when we estimated risks by age at MGUS of cases (above vs. below 65 yrs), and sex of relatives. Age at onset of MGUS and lymphoproliferative tumors was virtually the same for case and control relatives. There was no increased risk (RR∼1) of NHL or HL among relatives of MGUS cases. Conclusions. Among first-degree relatives of a large nationwide MGUS cohort in Sweden, we found 2- to 3-fold elevated risks of developing MGUS, MM, WM, and CLL. These results suggest the operation of shared common germ line susceptibility genes in the pathway to MGUS and certain lymphoproliferative tumors. Better characterization of early genetic lesions mediating monoclonal plasma-cell proliferation, survival, and migration in the bone marrow microenvironment will ultimately enhance our understanding of MGUS, MM, WM, and CLL pathophysiology, provide clues to etiology, and allow identification of novel molecular targets.

Description: Introduction: Certain autoimmune and infectious conditions are associated with increased risks of subtypes of non-Hodgkin lymphomas (NHL). A few prior studies suggest that chronic immune stimulation may particularly elevate risk for the NHL subtype lymphoplasmacytic lymphoma (LPL)/Waldenström’s macroglobulinemia (WM). To improve our understanding on the role of immune-related and inflammatory conditions in LPL/WM pathogenesis, we conducted a large population-based study including close to 2,500 LPL/WM patients diagnosed in Sweden and almost 10,000 matched controls. Methods: Using both the central Cancer registry and local hospital-based registries, we identified all LPL/WM patients diagnosed in Swedish hospitals 1958–2005. From the Swedish Population Registry we identified four matched controls per LPL/WM patient. Through data linkage with the central Inpatient registry, we gathered information on hospital inpatient discharges that listed autoimmune-, infectious-, and other inflammatory/allergic diseases present at least 1 year prior to LPL/WM. Using Poisson regression, we calculated rate ratios (RR) and 95% confidence intervals (CI) adjusted for categorical year of birth, date of diagnosis, gender, and county. Results: A total of 2,470 LPL/WM patients (647 LPL and 1,823 WM), and 9,698 population-based matched controls were included in the study. We found an increased risk of developing LPL/WM among individuals with a prior history of systemic sclerosis (RR=4.7; 1.4–15.3), Sjögren’s syndrome (RR=12.1; 3.3–45.0), autoimmune hemolytic anemia (AIHA) (RR=24.2; 5.4–108.2), polymyalgia rheumatica (RR=2.9; 1.6–5.2), and temporalis arteritis (RR=8.3; 2.1–33.1). We also found excess risk of LPL/WM among persons with a history of pneumonia (RR=1.4; 1.1–1.7), septicaemia (RR=2.4; 1.2–4.3), pyelonephritis (RR=1.7; 1.1–2.5), sinusitis (RR=2.7; 1.4–4.9), herpes zoster (RR=3.4; 2.0–5.6), and influenza (RR=2.9; 1.7–5.0). Importantly, when we assessed the associations by latency (time between immune-related or inflammatory conditions and LPL/WM), for most autoimmune- and infectious diseases the excess LPL/WM risk remained significant at 〉5 years latency. We found no significant increased risk for LPL/WM among individuals with prior chronic inflammatory or allergic conditions. Conclusions: In the largest investigation of risk factors for LPL/WM to date, we found a personal history of certain autoimmune and infectious diseases to be associated with excess LPL/WM risk. Immune-related conditions might act as potential LPL/WM triggers or they could represent premalignant immune disruptions preceding LPL/WM. Our results provide novel insights into the as yet unclear pathogenesis of LPL/WM.

Description: We analyzed the presenting features and survival in 1689 patients with multiple myeloma aged younger than 50 years compared with 8860 patients 50 years of age and older. Of the total 10 549 patients, 7765 received conventional therapy and 2784 received high-dose therapy. Young patients were more frequently male, had more favorable features such as low International Staging System (ISS) and Durie-Salmon stage as well as less frequently adverse prognostic factors including high C-reactive protein (CRP), low hemoglobin, increased serum creatinine, and poor performance status. Survival was significantly longer in young patients (median, 5.2 years vs 3.7 years; P 〈 .001) both after conventional (median, 4.5 years vs 3.3 years; P 〈 .001) or high-dose therapy (median, 7.5 years vs 5.7 years; P = .04). The 10-year survival rate was 19% after conventional therapy and 43% after high-dose therapy in young patients, and 8% and 29%, respectively, in older patients. Multivariate analysis revealed age as an independent risk factor during conventional therapy, but not after autologous transplantation. A total of 5 of the 10 independent risk factors identified for conventional therapy were also relevant for autologous transplantation. After adjusting for normal mortality, lower ISS stage and other favorable prognostic features seem to account for the significantly longer survival of young patients with multiple myeloma with age remaining a risk factor during conventional therapy.

Description: In this double-blind, placebo-controlled study, 363 patients with untreated multiple myeloma were randomized to receive either melphalan-prednisone and thalidomide (MPT) or melphalan-prednisone and placebo (MP). The dose of melphalan was 0.25 mg/kg and prednisone was 100 mg given daily for 4 days every 6 weeks until plateau phase. The dose of thalidomide/placebo was escalated to 400 mg daily until plateau phase and thereafter reduced to 200 mg daily until progression. A total of 357 patients were analyzed. Partial response was 34% and 33%, and very good partial response or better was 23% and 7% in the MPT and MP arms, respectively (P 〈 .001). There was no significant difference in progression-free or overall survival, with median survival being 29 months in the MPT arm and 32 months in the MP arm. Most quality of life outcomes improved equally in both arms, apart from constipation, which was markedly increased in the MPT arm. Constipation, neuropathy, nonneuropathy neurologic toxicity, and skin reactions were significantly more frequent in the MPT arm. The number of thromboembolic events was equal in the 2 treatment arms. In conclusion, MPT had a significant antimyeloma effect, but this did not translate into improved survival. This trial was registered at www.clinicaltrials.gov as #NCT00218855.

Description: Abstract 743 Background There has been considerable recent focus upon the molecular classification of myeloma. However, the prognostic impact of molecular changes has mostly been assessed from small and/or incomplete studies from single institutions or groups. There has been no large scale analysis of molecular features linked to ISS stage. Methods In order to clarify the overall impact of molecular changes we undertook a collective analysis of 9,897 patients through the International Myeloma Working Group (IMWG). Within this population 2,295 patients had presence of cytogenetic abnormalities (Any CA); 1,713 hypodiploidy; 1,673 hyperdiploidy; 2,309 cytogenetic deletion 13; 3,226 deletion 13 by FISH; 1,573 FISH t(4;14); 1,486 FISH del p17; 1, 683 FISH t(11:14); and 366 FISH t(4;16). Enrolled patients had complete clinical and treatment details available including baseline standard prognostic factors, ISS stage, as well as both progression free survival (PFS) and overall survival (OS) information. Data came from 14 sites: 3 from the US and the remainder from Europe, Asia, and Latin America as for the ISS staging system analyses. Univariate and multivariate analyses were performed. Results Each of the known adverse molecular features had a negative impact upon both PFS and OS (p=002 -

Description: Background: Prophylactic bisphosphonates are used worldwide in multiple myeloma patients, and two randomised studies have shown significant effect of i.v. pamidronate 90 mg once a month (N Engl J Med 1996 Feb 22;334(8):488–931) and of oral clondronate 1600 mg daily compared to placebo (Br J Haematol 2001 Jun;113(4):1035–43). However, no larger clinical study has addressed the dose-efficacy question, which is of increasing importance in view of recent reports on the risk of renal toxicity and osteonecrosis of the jaw (ONJ). In 2000 we started a randomised double blind trial with i.v. pamidronate 30 mg versus 90 mg monthly for at least 3 years. Design: Patients with newly diagnosed symptomatic multiple myeloma were allocated to one of the two doses. Patients were stratified according to planned high dose therapy or conventional therapy and to the level of beta-2-microglobulin. Primary end-point was physical functioning at 12 months as measured by the EORTC QLQ-C30 quality of life questionnaire (QLQ), while secondary end-points were time to first objective skeletal event, cost-utility analysis, response of myeloma disease, response duration and survival, fatigue and pain determined by the QLQ. The patients were followed every third month with respect to skeletal event, toxicity and response, while the QLQ was mailed directly to the patients every third month. Skeletal x-rays were routinely performed before, and 9 and 24 months after start of pamidronate therapy. Results: 505 patients were randomised. Median age was 63,4 years (range: 35–92). Sixty percent of the patients were treated with high-dose therapy and 40 percent with melphalan-prednisone (MP) regimes. The median follow up time was 3,7 years (1.1 to 5.7 years). There was no significant difference between the two treatment arms with respect to age, proportion of high-dose treated patients, skeletal involvement, stage (both international staging system (ISS) and Durie and Salmon), or b-2-microglobulin. The initial analysis of QLQ data shows improvement of global health status, pain, fatigue and physical functioning after myeloma treatment in accordance with earlier publication (Eur J Haematol 2001 May;66(5):328–36), but no significant difference regarding the primary end-point between the two pamidronate dose groups. Time to first skeletal event was not different in the two arms. The results from the blinded review of all skeletal x-rays will be presented together with the final analysis of toxicity data (renal failure and ONJ). Conclusions:The initial analysis of the first prospective double blind trial on different doses of pamidronate as prophylactic treatment in multiple myeloma shows no significant difference between monthly infusions of 30 and 90 mg with respect to quality of life and time to first skeletal event. The final analysis will show whether the doses have any impact on the toxicity of the bisphosphonates. We recommend that the dose and type of bisphosphonate should be reconsidered in the prophylactic treatment of newly diagnosed myeloma patients. # ClinicalTrials.gov Identifier: NCT00376883

Description: Introduction The Swedish Myeloma Registry (SMR) is a prospective observational registry designed to document real-world management and outcomes in newly diagnosed myeloma, with the purpose to improve the quality of the management of patients in Sweden. Population-based registries may provide complementary information on the management of patients to that of clinical intervention trials. With high representation and excellent data quality we can present valuable information in a whole population and reduce the impact of selection on outcome and reduce the subsequent problem with extrapolating data from clinical intervention studies on non-study populations. Methods The registry comprises web-reported data on all patients diagnosed with myeloma, plasmocytoma, and plasma cell leukemia from 2008 in Sweden, at time of diagnosis and after one year of follow-up. Coverage is analyzed through the compulsory Swedish Cancer Registry. Survival is achieved from the Swedish Tax Agency. Missing data are actively requested. This first report contains data on patients diagnosed between 2008 and 2011 with follow-up after one year on patients with symptomatic disease 2008-2010, with a follow-up through the end of 2012. Analyses of incidence, patient characteristics at baseline, proportion of patients given intensive treatment, obtaining very good partial remission (VGPR) and overall survival (OS) were estimated. Results Clinical data at baseline was available for 2494 patients (96% coverage)and 1- year follow-up data on 1427 patients (90% of all symptomatic cases initially reported), from 70 different centers in Sweden. The age adjusted incidence was 6.5 myeloma cases per 100 000 inhabitants and year. The median age was 70 years for men, and 73 years for women (34% younger than 66 years). At diagnosis, 76% were reported as symptomatic myeloma, 18% as smouldering myeloma, 5% plasmocytoma and 1% plasma cell leukemia. IgG-myeloma was most common (59%), followed by IgA (21%), Bence-Jones (13%), non-secretory (4%), IgD and IgM both less than 1%. Among symptomatic myeloma (n=1910), 76% had osteolytic lesions or compression fractures at diagnosis. Anemia (defined as hemoglobin levels below 10 g/dl) was seen in 33%, impaired kidney function (s-creatinin levels above 173 mmol/l) in 18%, and hypercalcemia in 21% at the time of diagnosis. In patients were ISS was available, 23%, 45% and 32% were in stage I, II, and III, respectively. Previous MGUS was known in 13 % of patients. Overall, 81 % of patients 65 years or younger received autologous stem cell transplantation (ASCT) and 4% of the elderly population. In the patients aged 65 years and younger, 63% of patients received one of the newer drugs in the first year of treatment, for the patients 66 to 80 years the number was 56%, and 25% of patients above 80 years. Throughout the study period, an increase in VGPR-rate on initial treatment was observed, more pronounced in younger patients (65 years, the VGPR-rate increased from 17 to 27%. After a median of follow-up time of three years, OS was 63%. There was a significant difference in absolute and relative survival between younger and older patients. In symptomatic myeloma, patients 65 years or younger had an expected 3-year survival of 76% and in patients 66 years and above it was 50% (Figure). The relative 3-year survival for patients with asymptomatic patients was 81%. Discussion SMR is an instrument for increased quality in the management of plasma cell neoplasms in Sweden. This first report from the registry shows very high coverage and good adherence to guidelines in all regions of Sweden, both in diagnostics and treatment. A great effort is made to make the SMR complete and to present population-based data on management and outcome in Sweden. Longer follow-up is needed to address the question of the impact of new treatment options on the survival. The registry gives a great opportunity to perform population-based research of high quality based on the acceptance of the registry among treating physicians. Disclosures: Turesson: Celgene Corp: Honoraria.

Description: Abstract 4053 Background: Based on clinical case reports and small hospital-based patient series, monoclonal gammopathy of undetermined significance (MGUS) has been reported to increase morbidity due to bacterial infections; however, no comprehensive evaluation has been conducted. Patients and methods: Using population-based data from Sweden, we assessed the risks of viral and bacterial infections (reported to the Patient-Registry) in 5,326 MGUS patients diagnosed 1958–2006, compared to 20,161 matched population-based controls. We fit Cox proportional hazard models to estimate hazard ratios (HRs) as measures of risk. Results: At 5 years of follow-up MGUS patients had a 2.1-fold (95% confidence interval (CI) 2.1–2.3) increased risk of developing any infection compared to controls; at 10 years of follow-up, the risk was very similar (HR=2.2; 95% CI 2.0–2.3). MGUS patients had a 2.2-fold (95% CI 2.0–2.4) and 2.1-fold (95% CI 2.0–2.3) increased risk of developing bacterial infections at 5 and 10 years, respectively. A significantly increased risk (P