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A Closer Look at Global MGUS Disparity: One Size Does Not Fit All

Multiple myeloma, a malignant neoplasm of plasma cells, is the second most common blood cancer in the US (1) and worldwide (2), disproportionately affects Black Americans, who are twice as likely to be diagnosed with it and its precursor, monoclonal gammopathy of undetermined significance (MGUS) (3). Is this disparity related to ethnic ancestry or environmental factors?

Kara Cicero, MD

2022 AACR-Bristol Myers Squibb Cancer Disparities Fellow Kara Cicero, MD, from the Fred Hutchinson Cancer Center, and her international team observed (4) that the prevalence of conventional MGUS was similar between Eswatini, a country in Africa where 97% of the population is Black (5), and Olmsted County in Minnesota, where 97% of the population is White (6). In both areas, 3.4% of individuals older than 50 years of age had MGUS defined by detectable monoclonal protein on protein electrophoresis. As Dr. Cicero shared, “We were a bit surprised to find the prevalence of conventional MGUS to be similar between Eswatini and Olmsted County, as prior studies have repeatedly demonstrated higher rates of monoclonal gammopathies within Black compared to White populations in America. Our study elicits further questions than answers: MGUS has been thought to disproportionately affect populations of African descent, but perhaps this reflects environmental disparities rather than any differences attributed to ethnic ancestry.”

To determine the prevalence of MGUS in Eswatini, Dr. Cicero and her colleagues randomly selected 515 plasma samples from the Swaziland HIV Incidence Measurement Survey (SHIMS2) from individuals older than 35 years of age (7). MGUS cases were defined using the same criteria as those used in the Olmsted County study for reliable comparison: 1) monoclonal protein on electrophoresis, regardless of the free light chain ratio (conventional MGUS), or 2) abnormal free light chain ratio plus elevation in the appropriate free light chain (light-chain MGUS) (6, 8).

Although the prevalence of conventional MGUS was similar in Eswatini and Olmsted County, the prevalence of light-chain MGUS was more than 13 times higher in Eswatini. Given that this seemingly higher prevalence of light-chain MGUS was not associated with age or gender, the team hypothesized that this putative increase might not be due to ethnic ancestry but rather to the current definition of an “abnormal” light-chain MGUS, which is based on the Olmsted County data. The median free light chain ratio that was observed among Eswatini individuals with light-chain MGUS was 1.83, only slightly above the normal laboratory reference of 1.65. Unfortunately, the team did not have bone marrow biopsies to confirm underlying plasma cell clonality, and longitudinal follow-up for progression was not possible. These observations suggest that different populations may require different reference values for free light chain ratios to reflect clonality.

As part of their effort to identify non-genetic/ethnic factors predisposing individuals to MGUS development, Dr. Cicero’s team compared the prevalence of MGUS among HIV- positive and HIV-negative individuals. Although a higher prevalence of MGUS has been previously reported among HIV-infected patients (9), no study has prospectively analyzed the prevalence of MGUS within an HIV-positive cohort compared with an HIV-negative cohort. Although they did not find an association between MGUS and HIV status in their study, Dr. Cicero and her colleagues confirmed previous observations that MGUS was more prevalent among HIV-positive individuals not on antiretroviral therapy. However, low MGUS prevalence was not associated with lower HIV viral loads.

Highlighting the benefits of the AACR grant, Dr. Cicero shared, “AACR’s cancer disparities fellowship funded the testing of plasma samples from Eswatini’s nationally representative biorepository, without which our research project would not have been possible. Moreover, AACR’s generous support allowed for international collaboration and capacity building.”

References:

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA: A Cancer Journal for Clinicians. 2019; 69:7–34
  2. Bray F, Laversanne M, Ferlay J, Siegel RL, Soerjomataram I, Jemal A, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians. 2024; 74:229-63
  3. Waxman AJ, Mink PJ, Devesa SS, Anderson WF, Weiss BM, Kristinsson SY, et al. Racial disparities in incidence and outcome in multiple myeloma: a population-based study, Blood. 2010; 116:5501–5506
  4. Cicero KI, Dlamini X, Mavengere Y, Justman J, Nuwagaba-Biribonwoha H, Dlamini S, et al. Prevalence of monoclonal gammopathy of undetermined significance in Eswatini: a population-based study in Africa. JNCI Cancer Spectr. 2024; 8(4):pkae056
  5. Eswatini. https://www.cia.gov/the-world-factbook/static/c166966c1b8164ed4649b6f985f3b31a/WZ-summary.pdf. Accessed July 2021.
  6. Kyle RA, Therneau TM, Rajkumar SV, Larson DR, Plevak MF, Offord JR, et al. Prevalence of Monoclonal Gammopathy of Undetermined Significance. N Engl J Med 2006; 354:1362-1369
  7. Government of the Kingdom of Eswatini. Swaziland HIV Incidence Measurement Survey 2 (SHIMS2). Mbabane: Government of the Kingdom of Eswatini; 2016-2017. https://phia.icap.columbia.edu/wp-content/uploads/2019/05/SHIMS2_Final-Report_05.03.2019_forWEB.pdf. Accessed July 2021.
  8. Dispenzieri A, Katzmann JA, Kyle RA, Larson DR, Melton LJ, Colby CL, et al. Prevalence and risk of progression of light-chain monoclonal gammopathy of undetermined significance: a retrospective population-based cohort study. Lancet 2010; 375:1721-1728
  9. Bibas M, Pittalis S, Orchi N, De Carli G, Agrati C, Girardi E, et al. Prevalence of monoclonal gammopathy of undetermined significance (MGUS) at HIV diagnosis in individuals 18–40 years old: a possible HIV indicator condition. Blood Cancer Journal 2021; 11:91