Familial Monoclonal Gammopathy of Undetermined Significance, Multiple Myeloma, and Other Cancers

Kenneth Anderson, MD

2009-11-01

Dr. Anderson indicated no relevant conflicts of interest.

Landgren O, Kristinsson SY, Goldin LR, et al. Blood. 2009;114:791-95.

Vachon CM, Kyle RA, Therneau TM, et al. Blood. 2009;114:785-90.

Landgren and colleagues, from the National Cancer Institute, used population-based data in Sweden to show that first-degree relatives of patients with monoclonal gammopathy of undetermined significance (MGUS) had increased risk of MGUS, multiple myeloma (MM), Waldenström macroglobulinemia (WM), and chronic lymphocytic leukemia (CLL). Within MGUS, relatives of IgG or IgA MGUS patients had increased risk of developing MM, WM, and CLL, whereas relatives of IgM MGUS patients had an increase in only CLL. These data suggest genetic, environmental, or a combination of predisposing factors among close relatives. A second study of Vachon and coworkers, from the Mayo Clinic, used electrophoresis and immunofixation to determine whether first-degree (older than age 40) relatives of patients with MGUS or MM had an increased risk of MGUS. Compared with a reference population, an age- and sex-adjusted increased prevalence of MGUS was observed in relatives of both MGUS and MM patients, further supporting genetic and/ or environmental risk factors.

These two studies are consistent with familial or hereditary cases of MM, suggested by the very important recent studies of Lynch and colleagues. These investigators identified families with shared cancers of the prostate and pancreas, as well as acute myelogenous leukemia and myelofibrosis, in families with MGUS and MM.1 They have also described increased pancreatic cancer in association with MGUS and MM in an African-American family.2 Thus, the aggregate data are building, implicating inherited and/or genetic risk factors.

What are the implications of these findings? It is well established that MGUS is a predisposing factor for the development of MM,3 and considerable research is ongoing in the laboratory to determine whether those genetic changes within tumor cells or within the tumor microenvironment are associated with progression from MGUS to MM. Since many of the genetic changes seen in MM are already present in MGUS,4 host factors, such as cytokines, angiogenesis, or immune response, may be important. Given these increasing data that MGUS may be associated not only with MM but also with other cancers, research should now focus on genetic and molecular mechanisms within tumor cells or the host-tumor microenvironment that may be common in identified cancers besides MM. For example, comparative oncogenomic analyses of prostate cancer and MM may implicate interleukin-6 and PI3-kinase signaling in disease pathogenesis. State-of-the-art comparative genomic studies, coupled with detailed studies of tumor and host biology, should provide clues into underlying common pathogenetic mechanisms.

On a clinical level, there is recent evidence that all patients with MM have preceding MGUS.5,6 Moreover, among MGUS patients, factors such as type and quantity of monoclonal protein and abnormal ratio of Ig light chains can predict risk of progression to MM.7 Given the recent studies implicating familial and/or environmental risk factors as well as association with other cancers, there is now a great need both in clinical studies and in daily clinical practice to record a detailed family history of all cancers, as well as environmental factors (i.e., pesticide exposure) that may be implicated in pathogenesis of multiple implicated cancers. Since MGUS is common,3 it will be particularly critical to examine patient factors, including age and others, that may not only help predict if a patient may develop MM, but also if a patient may develop other cancers. At present, MGUS patients are followed expectantly without any therapeutic intervention, since the rate of progression to MM or related disorders is low. Importantly, our ability to identify those MGUS patients who are more likely to progress to MM7 has already led to clinical trials of early interventions to delay progression in this high-risk subset. Further studies to identify those patients with MGUS most likely to develop other cancers may lead to similar intervention studies in the future.

  1. Lynch HT, Watson P, Tarantolo S, et al. Phenotypic heterogeneity in multiple myeloma families. J Clin Oncol. 2005;23:685-93.
  2. Lynch HT, Ferrara K, Barlogie B, et al. Familial myeloma. N Engl J Med. 2008;359:152-57.
  3. Kyle RA, Therneau TM, Rajkumar SV, et al. Prevalence of monoclonal gammopathy of undetermined significance. N Engl J Med. 2006;354:1362-69.
  4. Davies FE, Dring AM, Li C, et al. Insights into the multistep transformation of MGUS to myeloma using microarray expression analysis. Blood. 2003;102:4504-11. 
  5. Weiss BM, Abadie J, Verma P, et al. A monoclonal gammopathy precedes multiple myeloma in most patients. Blood. 2009;113:5418-22.
  6. Landgren O, Kyle RA, Pfeiffer RM, et al. Monoclonal gammopathy of undetermined significance (MGUS) consistently precedes multiple myeloma: a prospective study. Blood. 2009;113:5412-17.
  7. Rajkumar SV, Kyle RA, Therneau TM, et al. Serum free light chain ratio is an independent risk factor for progression in monoclonal gammopathy of undetermined significance. Blood. 2005;106:812-17.

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