Bone Marrow Immunophenotypic Analysis Allows the Identification of High Risk of Progression and Immune Condition-Related Monoclonal Gammopathy of Undetermined Significance.

Monoclonal gammopathy of undetermined significance (MGUS) progresses to plasma cell dyscrasia, mainly multiple myeloma (MM), at a rate of approximately 1% per year. Moreover, recent studies have shown that MM is nearly always preceded by MGUS, encouraging investigators to find better predictors for MM development in order to implement strategies to prevent or delay progression. In addition, a high prevalence of MGUS has been noted in a series of patients with immune disorders or chronic infections. Multiparameter flow cytometry allows the identification and quantification of both monoclonal and polyclonal plasma cells. This study analyses the relationship between monoclonal and polyclonal bone marrow plasma cells (BMPC), studied by means of flow cytometry, and its association with either immune or infectious disorders, or the development of MM in newly diagnosed MGUS patients.

We conducted a retrospective cohort study to analyse the prognostic value of the aberrant (CD38⁺⁺ CD138⁺ CD19^– CD45^weak) to normal (CD38⁺⁺ CD138⁺ CD19⁺ CD45⁺) phenotype bone marrow plasma cells ratio (A/N ratio) and another 13 variables at baseline for the development of a plasma cell dyscrasia. We also performed a cross-sectional study to evaluate the association of those variables at baseline with the presence of a chronic immune response disorder. In each patient, the following variables were examined: age, sex, hemoglobin, serum creatinine, serum calcium, B₂-Microglobulin, type and size of the serum monoclonal component (MC), isotype of the MC immunoglobulin, presence of urine MC, quantification of serum immunoglobulin levels, erythrocyte sedimentation rate, BMPC percentage and presence of atypical plasma cells on light microscopy, and aberrant and normal phenotype BMPC percentages. The effect of variables on progression was calculated using a Cox proportional hazards regression model. To identify variables at baseline associated with immune or chronic infectious disorders. a series of univariate and multivariate analyses was fitted using a binary logistic regression strategy.

Between March 1997 and April 2008, flow cytometry analysis on bone-marrow samples was performed on 322 patients with newly diagnosed MGUS. Median patient age was 71 years (interquartile range (IQR) 63-78 years) with a slightly male predominance (51%). Median follow-up was 46 months (IQR 23-58 months). During the period of observation, in 23 (7.1%) patients a transformation was registered into: MM (n=22), and primary amyloidosis (n=1). A total of 24 (7.4%) patients had a diagnosis of autoimmune disorder, and 18 (5.6%) patients of a chronic infection. Multivariate analysis for progression to MM revealed an increased A/N ratio as the main independent prognostic variable. In addition, our study found a significant association between a reduced A/N ratio and the diagnosis of a chronic immune response related condition. Using receiver-operating characteristic analysis we created an A/N ratio range from 4 to 0.20. Values of 4 or higher define a group of MGUS patients at high risk of progression (OR, 10.7; 95% confidence interval 4.2-39), whereas A/N ratio values of 0.20 or lower are associated with immune disorders or chronic infections (OR, 20.9; 95% confidence interval 8.5-51.1). A total of 282 patients had an A/N ratio below 4, and 42 had values equal to or above the cut-off. Patients with an A/N ratio ≥ 4 had a cumulative probability of transformation of 35% at 5 years, compared with 3% for those with an A/N ratio < 4.

Extreme values of the A/N ratio at diagnosis seem to be related with two different conditions: high risk MGUS, likely to progress to MM, and immune condition related MGUS. Our findings further support the routine use of phenotypic characterization of bone marrow plasma cells in patients with MGUS at diagnosis.

No relevant conflicts of interest to declare.