Ola Landgren

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.

Highly increased familial risks for specific lymphoma subtypes.

Studies have shown that familial risk contributes to aetiology of lymphomas. Using large population registries from Sweden, we evaluated risk of lymphoma subtypes among first‐degree relatives of 2668 follicular lymphoma (FL) patients, 2517 diffuse large B‐cell lymphoma (DLBCL) patients, and 6963 Hodgkin lymphoma (HL) patients compared to first‐degree relatives of controls. Relatives were at the highest risk for developing the same lymphoma subtype as the case. DLBCL was increased 10‐fold among relatives of DLBCL patients, FL was increased fourfold among relatives of FL patients and HL was increased fourfold among relatives of HL patients. These results imply that germline susceptibility genes are specific to lymphoma subtype.

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

Patients with multiple myeloma (MM) have an increased risk of fractures. On the basis of small numbers, patients with monoclonal gammopathy of undetermined significance (MGUS) have been reported to have an increased fracture risk. Using population-based data from Sweden, we assessed the risks of fractures in 5326 MGUS patients diagnosed from 1958 to 2006, compared with 20 161 matched controls. MGUS patients had an increased risk of any fracture at 5 (hazard ratio [HR] = 1.74; 95% confidence interval [CI], 1.58-1.92) and 10 (HR = 1.61; 95% CI, 1.49-1.74) years. The risk was significantly higher for axial (skull, vertebral/pelvis, and sternum/costae) compared with distal (arm and leg) fractures (P < .001). On the basis of 10 years of follow-up, there was an increased risk of vertebral/pelvic (HR = 2.37; 95% CI, 2.02-2.78), sternal/costae (HR = 1.93; 95% CI, 1.5-2.48), arm (HR = 1.23; 95% CI, 1.06-1.43), leg (HR = 1.40; 95% CI, 1.26-1.56), and other/multiple fractures (HR = 4.25; 95% CI, 3.29-5.51). Risks for fractures did not differ by isotype or M protein concentration at diagnosis. MGUS patients with (versus without) fractures had no excess risk of MM or Waldenström macroglobulinemia. Our results suggest that bone alterations are present in early myelomagenesis. Our findings may have implications for the development of better prophylaxis for bone disease in MGUS, and they provide novel clues on pathogenesis of MM bone disease.

Personal and family history of immune-related conditions increase the risk of plasma cell disorders: a population-based study

The associations between immune-related conditions and multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS) have previously been investigated with inconsistent results. In a large population-based study, we identified 19 112 patients with MM, 5403 patients with MGUS, 96 617 matched control subjects, and 262 931 first-degree relatives. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) for the association of MM and MGUS with immune-related conditions by use of logistic regression. A personal history of all infections combined was associated with a significantly increased risk of MM (OR = 1.2; 95% CI, 1.1-1.3), and a personal history of all conditions in the categories infections (OR = 1.6; 95% CI, 1.5-1.7), inflammatory conditions (OR = 1.4; 95% CI, 1.2-1.5), and autoimmune diseases (OR = 2.1; 95% CI, 1.9-2.4) was associated with a significantly increased risk of MGUS. Several specific immune-related conditions elevated the risk of MM and/or MGUS. A family history of autoimmune disease was associated with a significantly increased risk of MGUS (OR = 1.1; 95% CI, 1.00-1.2), but not MM. Our findings suggest that immune-related conditions and/or their treatment are of importance in the etiology of MGUS and possibly MM. The association of both personal and family history of autoimmune disease with MGUS indicates the potential for shared susceptibility for these conditions.

Patterns of survival in lymphoplasmacytic lymphoma/waldenstrom macroglobulinemia: A population-based study of 1,555 patients diagnosed in Sweden from 1980 to 2005

Clinical management of lymphoplasmacytic lymphoma (LPL)/Waldenström macroglobulinemia (WM) has changed considerably over recent years, reflected in the use of new therapeutic agents (purine analogs, monoclonal antibodies, thalidomide‐ and bortezomib‐based therapies). No population‐based studies and few randomized trials have been performed to assess survival in newly diagnosed LPL/WM. We performed a large population‐based study in Sweden including 1,555 LPL/WM patients diagnosed from 1980 to 2005. Relative survival ratios (RSRs) and excess mortality rate ratios (EMRR) were computed as measures of survival. Survival of LPL/WM patients has improved significantly (P = 0.007) over time with 5‐year RSR = 0.57 (95% confidence interval [CI] 0.46–0.68), 0.65 (0.57–0.73), 0.74 (0.68–0.80), 0.72 (0.66–0.77), and 0.78 (0.71–0.85) for patients diagnosed during the calendar periods 1980–1985, 1986–1990, 1991–1995, 1996–2000, and 2001–2005, respectively. Improvement in 1‐ and 5‐year relative survival was found in all age groups and for LPL and WM separately. Patients with WM had lower excess mortality compared to LPL (EMRR = 0.38; 95% CI 0.30–0.48). Older age at diagnosis was associated with a poorer survival (P < 0.001). Taken together, we found a significant improvement in survival in LPL/WM over time. Despite this progress, new effective agents with a more favourable toxicity profile are needed to further improve survival in LPL/WM, especially in the elderly. Am. J. Hematol. 2013.

Response to splenectomy is durable after a certain point in time in adult patients with chronic immune thrombocytopenic purpura

Abstract:u2002 Splenectomy may lead to a good response in 60–80% of adult patients with corticosteroid refractory idiopathic thrombocytopenic purpura (ITP) but, the long‐term response to splenectomy still remains less well defined. We assessed the long‐term efficacy and safety of splenectomy in adult patients with chronic ITP. A cohort of 59 splenectomised ITP patients (M/Fu2003=u200325/34; median age 39u2003yr; range 14–75) were followed up for a median of 18u2003yr (range 2–32). No life‐threatening surgical complications were observed. The overall response rate was 78% with 59% complete remission (CR) and 19% partial remission (PR). CR and PR patients were younger than non‐responding patients at time of diagnosis (median age: 36u2003yr vs 48u2003yr, Pu2003=u20030.03) and at splenectomy (median age: 38u2003yr vs 51u2003yr, Pu2003=u20030.02). Among the 46 responding patients, eventually 17 had relapse. No disease progression occurred after 12.1 and 7.3u2003yr for patients in CR or PR, respectively. One case of fatal septicaemia was recorded. We conclude that splenctomy is an effective and safe treatment in adult patients with chronic ITP failing to respond to corticosteroid treatment and importantly, our findings support the view that response to splenectomy is durable after a certain point in time.

Familial aggregation of lymphoplasmacytic lymphoma/Waldenström macroglobulinemia with solid tumors and myeloid malignancies.

Lymphoplasmacytic lymphoma (LPL)/Waldenström macroglobulinemia (WM) is a B-cell disorder resulting from the accumulation, predominantly in the bone marrow, of clonally related lymphoplasmacytic cells. LPL/WM is a very rare disease, with an incidence rate of 3–4 cases per million people per year.Currently, the causes of LPL/WM are poorly understood; however, there are emerging data to support a role for immune-related factors in the pathogenesis of LPL/WM. In addition, data show that genetic factors are of importance in the etiology of LPL/WM. In this paper, we will review the current knowledge about familiality of LPL/WM and provide novel data on solid tumors and myeloid malignancies in first-degree relatives of LPL/WM patients.

Hypercoagulability in multiple myeloma and its precursor state, monoclonal gammopathy of undetermined significance.

Patients with multiple myeloma are at an increased risk of venous thromboembolism (VTE), especially when treated with the immunomodulatory drugs, thalidomide and lenalidomide, in combination with dexamethasone and/or chemotherapy. Several studies have shown that patients with multiple myeloma precursor disease (monoclonal gammopathy of undetermined significance [MGUS]) also have a higher risk of thrombosis compared to the general population. The underlying mechanisms for the hypercoagulable state are not completely understood. In this review, we discuss risk factors for thrombosis in multiple myeloma, as well as prophylactic strategies, the evidence for thrombosis among patients with MGUS, and proposed mechanisms for the hypercoagulability.

Improved Survival in Younger Patients with Multiple Myeloma: A Population-Based Study from Malmo, Sweden

Minimal residual disease (MRD) assessment is considered investigational in multiple myeloma (MM). We report a prospective analysis of the prognostic importance of MRD detection by multiparameter flow cytometry (MFC) in 295 newly diagnosed MM patients uniformly treated in the GEM2000 protocol (VBMCP/VBAD induction plus ASCT). MRD status by MFC was determined at day 100 post-ASCT. Progression-free survival (PFS; median, 71 months vs. 37 months; P < .0001) and overall survival (OS; median, not reached vs. 89 months; P = .002) were longer in patients who were MRD-negative versus MRD-positive at day 100 post-ASCT. Interestingly, in the 147 patients who achieved immunofixation (IFx) negative complete response post-ASCT, the 5-year PFS rate was 62% in MRD-negative patients (n = 94) versus 30% in MRD-positive patients (n = 53; P < .0001), with OS at 5-year 87% versus 59% (P = .009). Moreover, in a small group of patients (n = 44) who achieved IFx-negative complete response prior to ASCT, PFS was longer in patients MRD-negative versus MRD-positive at day 100 post-ASCT (median NR vs. 36 months; P = .04). Only MRD status by MFC at day 100 postASCT and FISH cytogenetics were identified as independent prognostic factors for PFS, and only MRD status by MFC and age were identified for OS. Finally, a subgroup of 157 patients in which MRD information was available both preand post-ASCT, cases MRD-positive both preand post-transplantation (n = 93) had the worst prognosis; patients who were MRD-positive preASCT but improved to MRD-negative post-ASCT (n = 48) had an intermediate prognosis, and patients who were MRD-negative both preand post-transplantation (n = 16) had the best prognosis. The 5-year PFS and OS rates in these three prognostic subgroups were 25%, 57%, and 80%, respectively (P = .0001), and 59%, 78%, and 100%, respectively (P = .06). Our findings demonstrate the clinical importance of MRD evaluation by MFC. This type of analysis may contribute to the design of patient-specific maintenance treatment approaches, as well as the evaluation of the potential benefits of consolidation therapies.