Population-based studies on familiality and prognosis in patients with monoclonal gammopathies

Monoclonal gammopathies constitute a group of diseases which have in common an overproduction of monoclonal immunoglobulins, M-proteins. Clues to their etiology have been found in studies showing familial aggregation of these diseases. We included 2,144 patients with lymphoplasmacytic lymphoma/Waldenström s macroglobulinemia (LPL/WM) and 4,458 patients with monoclonal gammopathy of undetermined significance (MGUS), their 6,177 and 14,621 first-degree relatives respectively, and controls and their relatives. We found first-degree relatives of LPL/WM, compared to first-degree relatives of controls, to have 20-fold (95% confidence interval (CI): 4.1-98), 3.0-fold (2.0-4.4), 3.4-fold (1.7-6.6), and 5.0-fold (1.3-19) increased risks of developing LPL/WM, non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), and MGUS, respectively. First-degree relatives of MGUS patients had increased risks of MGUS (hazard ratio (HR)=2.8; 95% CI 1.4-5.6), multiple myeloma (MM) (2.9; 1.9-4.3), LPL/WM (4.0; 1.5-11), and CLL (2.0; 1.2-2.3). These findings support shared common susceptibility genes that predispose to a variety of lymphoproliferative disorders.

We included 4,259 MGUS patients and compared their survival to that of the general population by computing relative survival ratios (RSRs). One-, 5-, 10-, and 15-year RSRs were 0.98 (95% CI 0.97-0.99), 0.93 (0.91-0.95), 0.82 (0.79-0.84), and 0.70 (0.64-0.76), respectively. Younger age at MGUS diagnosis was associated with a significantly lower excess mortality compared to older age (p<0.001). The excess mortality among MGUS patients increased with longer follow-up (p<0.0001). IgM (versus IgG/A) MGUS was associated with a superior survival (p=0.038). We also compared causes of death with 16,151 matched controls and found MGUS patients to have an increased risk of dying from both malignant transformation and non-malignant causes. Our findings are of importance in the understanding and clinical management of MGUS. The underlying mechanisms of our findings may be causally related to the MGUS, but may also be explained by an underlying disease that led to the detection of MGUS.

We conducted a study including 14,381 MM patients diagnosed in Sweden 1973-2003 to define survival patterns among MM patients. One-year survival improved (p<0.001) over time in all age groups. Improvement in 5-year (p<0.001) and 10-year (p<0.001) RSR was, however restricted to patients <70 years and <60 years, respectively. High dose melphalan with subsequent autologous stem cell support, thalidomide, and a continuous improvement in supportive care measures are probably the most important factors contributing to this finding. We also assessed the impact of socioeconomic status (SES) on survival in 14,744 patients with MM. Overall, higher white-collar workers had a lower mortality than other SES groups (p<0.005). No difference was observed in the first two calendar periods. However, in 1990-1999, self-employed (HR=1.18; 1.02-1.37), blue-collar workers (1.18; 1.04-1.32), and retired (1.45; 1.16-1.80) had a higher mortality compared to higher white-collar workers. In 2000-2005, blue-collar workers had a higher mortality (1.31; 1.07-1.60) compared to higher white-collar workers. Differences in co-morbidity, management and life-style, are likely factors to explain these findings.

We assessed the risks of venous and arterial thrombosis in 19,391 MM and 5,395 MGUS patients compared to 76,415 and 20,761 matched controls. At 1, 5 and 10 years after MM diagnosis, there was an increased risk for venous thrombosis with HR=7.9 (6.5-9.6), 4.5 (4.0-5.1), and 3.9 (3.5-4.4), respectively. The corresponding HRs for arterial thrombosis were 2.0 (1.8-2.2), 1.5 (1.4-1.6), and 1.4 (1.4-1.5). At 1, 5 and 10 years after MGUS diagnosis, we found a 3.3-fold (2.2-5.0), 2.0-fold (1.6-2.5), and 2.0-fold (1.7-2.4) increased risk of venous thrombosis. The corresponding risks for arterial thrombosis were 1.4 (1.2-1.7), 1.2 (1.1-1.3), and 1.2 (1.1-1.3). IgG/IgA (but not IgM) MGUS patients had an increased risk for venous and arterial thrombosis. These findings are of relevance for future studies and for the improvement of thrombosis prophylaxis strategies.

List of scientific papers

I. Kristinsson SY, Björkholm M, Goldin LR, McMaster ML, Turesson I, Landgren O (2008). Risk of lymphoproliferative disorders among first-degree relatives of lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia patients: a population-based study in Sweden. Blood. 112(8): 3052-6. Epub 2008 Aug 13
https://pubmed.ncbi.nlm.nih.gov/18703425

II. Landgren O, Kristinsson SY, Goldin LR, Caporaso NE, Blimark C, Mellqvist UH, Wahlin A, Bjorkholm M, Turesson I (2009). Risk of plasma-cell and lymphoproliferative disorders among 14,621 first-degree relatives of 4,458 patients with monoclonal gammopathy of undetermined significance (MGUS) in Sweden. Blood. Jan 30: Epub ahead of print
https://pubmed.ncbi.nlm.nih.gov/19182202

III. Kristinsson SY, Björkholm M, Andersson TML, Eloranta S, Dickman PW, Goldin LR, Blimark C, Mellqvist UH, Wahlin A, Turesson I, Landgren O (2009). Patterns of survival and causes of death following a diagnosis of monoclonal gammopathy of undetermined significance (MGUS): A population-based study. [Manuscript]

IV. Kristinsson SY, Landgren O, Dickman PW, Derolf AR, Björkholm M (2007). Patterns of survival in multiple myeloma: a population-based study of patients diagnosed in Sweden from 1973 to 2003. J Clin Oncol. 25(15): 1993-9. Epub 2007 Apr 9
https://pubmed.ncbi.nlm.nih.gov/17420512

V. Kristinsson SY, Derolf AR, Edgren G, Dickman PW, Björkholm M (2009). Socioeconomic differences in patient survival are increasing for acute myeloid leukemia and multiple myeloma in Sweden. J Clin Oncol. 27(12): 2073-80. Epub 2009 Mar 16
https://pubmed.ncbi.nlm.nih.gov/19289627

VI. Kristinsson SY, Pfeiffer R, Björkholm M, Goldin LR, Blimark C, Mellqvist UH, Wahlin A, Turesson I, Landgren O (2009). Arterial and venous thrombosis in monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma: A population-based study. [Manuscript]