General MM

MGUS prevalence among family members of patients with MM

Monoclonal gammopathy of undetermined significance (MGUS) is a benign condition that can progress to smoldering multiple myeloma (SMM) and/or multiple myeloma (MM). It is now widely accepted that all patients with MM have had MGUS at some point before onset of the disease.

It has been previously shown that the existence of probands with either MM or MGUS is associated with increased risk of MGUS among first-degree relatives1. However, several studies addressing the correlation between familial MM/MGUS and disease prognosis, have produced contradictory findings.

Alyssa I. Clay-Gilmour from the Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, US, and collaborators, examined the prevalence of MGUS among first-degree family members of patients with MM and SMM, in an expanded cohort of probands from a previous study1. The MGUS prevalence rate was compared with that of a reference population2. Taking into account the probands’ age at disease onset, tumor, and clinical characteristics, they also studied the risk of familial MGUS among first-degree family members. The results were published in Leukemia in September 20183.

Key Data:
  • Total number of probands = 430 (MM = 400; SMM = 30)
  • Racial/ethnic groups of probands: Caucasian = 97.0%
  • Gender of probands: male = 56.0%
  • Age of probands: 50–79 years = 85.5%
  • Total number of first-degree relatives of probands = 1,179; siblings = 62.8%; children = 25.4%, parents = 11.8%
  • Gender of first-degree relatives of probands: females = 58.7%
  • Age of first-degree relatives of probands = > 40 years old
  • Total probands with a first-degree relative with MGUS = 68/430
  • Number of first-degree relatives of probands with MGUS = 75/1,179; prevalence rate (adjusted by age and gender to 2,000 US reference population) = 5.8 (95% confidence interval [CI], 4.5–7.2)
  • Prevalence rates of MGUS increased with the age of first-degree relatives (95% CI) (age category in years):
    • 40–49 = 1.9 (0.7–4.1)
    • 50–59 = 3.9 (2.0–7.0)
    • 60–69 = 7.2 (4.5–11.0)
    • 70–79 = 12.2 (7.6–18.4)
    • 80+ = 13.8 (7.7–22.7)
  • Prevalence rates of MGUS among first-degree relatives with MM/SMM vs reference population (age 50+) = 7.9 (95% CI, 6.0–9.8) vs2 (95% CI, 3.0–3.5);
  • Risk of MGUS among first-degree relatives with MM/SMM vs reference population = 2.4 fold increased risk (95% CI, 1.9–2.9)
  • Risk of MGUS in first-degree relatives similar between younger probands (< 55 years) (risk ratio [RR] = 2.6, 95% CI, 2.0–3.3) and older probands (≥ 55 years) (RR = 1.9, 95% CI, 1.2–3.1, P = 0.29)
  • Risk of MGUS in first-degree relatives with similar male probands (RR = 2.5, 95% CI, 1.4–1.9) and female probands (RR = 2.3, 95% CI, 1.0–4.3, P = 0.67)
  • Risk of MGUS in first-degree relatives not associated with isotype
  • Risk of MGUS in first-degree relatives not associated with cytogenetics (IgH translocation or trisomies)
  • Familial risk of MGUS was examined among paired members of the same family with MM and MGUS: No evidence that pairs of relatives with MM and MGUS have similar age at onset (P = 0.44), or same gender (P = 0.81), or same heavy chain type (P = 0.48)
  • No difference in overall survival (OS) between the MM probands (n = 400) with a family history of MGUS (n = 62) vs those without (n = 338) (hazard ratio [HR] = 0.93; 95% confidence interval [CI], 0.64–1.35, P = 0.7)
Conclusions

This study reveals a 2–3-fold increase in MGUS prevalence among first-degree family members of patients with MM/SMM, in agreement with previously published results. However, it does not support an association between familial MGUS and the age, gender, isotype, or cytogenetics of MM probands. Screening first-degree relatives in families with more than one member affected with MM may be an effective method to prevent disease progression.

References
  1. Vachon C.M. et al. Increased risk of monoclonal gammopathy in first-degree relatives of patients with multiple myeloma or monoclonal gammopathy of undetermined significance. Blood. 2009 Jul 23;114(4):785-90. DOI: 10.1182/blood-2008-12-192575.
  2. Kyle R.A. et al. Prevalence of monoclonal gammopathy of undetermined significance. The New England Journal of Medicine. 2006 Mar 30;354(13):1362-9.
  3. Clay-Gilmour A.I. et al. Risk of MGUS in relatives of multiple myeloma cases by clinical and tumor characteristics. Leukemia. 2018 Sep 10. DOI: 10.1038/s41375-018-0246-2. [Epub ahead of print].
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