Serum B-cell maturation antigen: a novel biomarker to predict outcomes for multiple myeloma patients

Abstract

B-cell maturation antigen is expressed on plasma cells. In this study, we have identified serum B-cell maturation antigen as a novel biomarker that can monitor and predict outcomes for multiple myeloma patients. Compared to healthy donors, patients with multiple myeloma showed elevated serum B-cell maturation antigen levels (P<0.0001). Serum B-cell maturation antigen levels correlated with the proportion of plasma cells in bone marrow biopsies (Spearman's rho = 0.710; P<0.001), clinical status (complete response vs partial response, P=0.0374; complete response vs progressive disease, P<0.0001), and tracked with changes in M-protein levels. Among patients with non-secretory disease, serum B-cell maturation antigen levels correlated with bone marrow plasma cell levels and findings from positron emission tomography scans. Kaplan-Meier analysis demonstrated that serum B-cell maturation antigen levels above the median levels were predictive of a shorter progression-free survival (P=0.0006) and overall survival (P=0.0108) among multiple myeloma patients (n=243). Specifically, patients with serum B-cell maturation antigen levels above the median level at the time of starting front-line (P=0.0043) or a new salvage therapy (P=0.0044) were found to have shorter progression-free survival. Importantly, serum B-cell maturation antigen levels did not show any dependence on renal function and maintained independent significance when tested against other known prognostic markers for multiple myeloma such as age, serum β2 microglobulin, hemoglobin, and bone disease. These data identify serum B-cell maturation antigen as a new biomarker to manage multiple myeloma patients.

Figure 1.

Correlation of the proportion of plasma cells in bone marrow (BM) biopsy specimens with serum B-cell maturation antigen (sBCMA) levels in multiple myeloma (MM) patients. (A) Scatter plot showing correlation between the percentage of plasma cells in BM biopsy specimens and sBCMA levels in 57 MM patients was generated using GraphPad Prism 4. A regression line was generated using exponential growth model (Y=Start*exp [K*X]) with best-fit values (START=73.88; K=0.03404). (B) Scatter plot of Log10 transformation of sBCMA levels showing linearized correlation: Spearman correlation assessment (P<0.0001; Spearman’s rho=0.710). A regression line was generated using first order polynomial (Y=intercept +slope[X]; equation Y=0.01533[X] + 1.674; R²=0.5125.

Figure 2.

Serum B-cell maturation antigen (sBCMA) levels are elevated in multiple myeloma (MM) patients. (A) Specifically, 43 age-matched healthy donors (●) had significantly lower sBCMA levels (median 36.8 ng/mL) than 46 patients with smoldering MM (■) (median BCMA 88.9 ng/mL; P<0.0001) and 44 patients with active MM (▲) prior to any treatment (median BCMA 505.9 ng/mL; P<0.0001). (B) A threshold determination performed by ROC curve analysis indicated that the optimal threshold of sBCMA level to compare patients diagnosed as age-matched healthy donors or patients with smoldering MM (n=89) and patients diagnosed with active, untreated MM (n=44) was 107.6 ng/mL [sensitivity 93.2% (95%CI: 84%–100%); specificity 76.4% (95%CI: 67.4%–85.3%); area under curve 0.8805]. For our analysis “sensitivity” refers to the ability of sBCMA levels above a chosen threshold to be able to detect active untreated MM cases and “specificity” to sBCMA levels above a chosen threshold to identify only cases of active untreated MM above the threshold.

Figure 3.

Serum B-cell maturation antigen (sBCMA) levels correlate with changes in M-protein and serum free light chain (SFLC) levels in individual multiple myeloma (MM) patients. (A) Analysis of sBCMA (▲) versus M-protein (■) levels during the course of disease in 4 MM patients among 44 patients analyzed. (B) Analysis of sBCMA (▲) versus SFLC (■) in 2 representative MM patients during the course of their disease.

Figure 4.

Serum B-cell maturation antigen (sBCMA) levels during the course of disease among 3 patients with non-secretory disease (NSD). (A) non-secretory Patient #1977, (B) non-secretory Patient #2460 and (C) non-secretory Patient #2482. Notably, the 3 patients with NSD showed a correlation between changes in sBCMA levels and their clinical status as reflected by positron emission tomography (PET) scan and bone marrow findings during their disease course.

Figure 5.

Analysis of serum B-cell maturation antigen (sBCMA) levels and multiple myeloma (MM) patients’ response to treatment and clinical status. sBCMA levels correlated with patients’ clinical status at the time of its determination. Specifically, (A) patients with complete response (CR) (●) had significantly lower sBCMA levels (median 38.6 ng/mL) than those with partial response (PR) or minor response (MR) (■) (median 99.7 ng/mL; P=0.0045) and non-responsive disease (ND) (▲), including those with either stable or progressive disease (PD) (median 195.3 ng/mL; P<0.0001). (B) Using International Myeloma Working Group (IMWG) criteria, patients with CR (●) had significantly lower sBCMA levels (median 38.6 ng/mL) than those with PR (▲; P=0.0374; median 81.7 mg/mL), less than PR (MR+SD; o; P=0.0002; median 100.6 mg/mL) and PD (□; P<0.0001; median 301.4 mg/mL). Total number of patients=164; *P versus CR.

Figure 6.

Correlation of serum B-cell maturation antigen (sBCMA) levels with progression-free survival (PFS) in multiple myeloma (MM) patients. MM patients were assessed according to their sBCMA levels being above or below the median level (left) or in the top quartile or bottom three quartiles (right). Kaplan-Meier analysis was performed to analyze PFS of 184 MM patients before start of a new treatment (A) with a baseline sBCMA level above or below the median level of 326.4 ng/mL (left) and for those with levels in the lowest three quartiles (range 14.3–970.9 ng/mL) or the highest quartile (≥ 971.0 ng/mL) (right). (B) Progression-free survival (PFS) of 38 MM patients before starting their front-line treatment according to whether their baseline sBCMA was above or below the median level of 430.5 ng/mL (left) and for those with levels in the lowest three quartiles (range 17.8–861.7 ng/mL) or highest quartile (≥ 861.8 ng/mL) (right). (C) PFS of 146 MM patients from time of starting a new salvage therapy according to whether their baseline sBCMA was above or below the median level of 281.9 ng/mL (left) and for those in the lowest three quartiles (range 14.3–962.3 ng/mL) or highest quartile (≥ 962.4 ng/mL) (right). (D) Among 99 MM patients who had a sBCMA determination just prior to starting a new treatment and achieved at least a minor response (MR), PFS was determined from the time of determination of their baseline sBCMA according to whether it was above or below a median of 261.7 ng/mL (left) and for those in the lowest three quartiles (range 17.8–852.1 ng/mL) or highest quartile (>852.2 ng/mL) (right).

Figure 7.

Correlation of serum B-cell maturation antigen (sBCMA) levels with overall survival (OS) in 243 multiple myeloma (MM) patients. MM patients were assessed according to their sBCMA levels being above or below the median (A), or in the highest quartile compared with the bottom three quartiles (B). Kaplan-Meier analysis showed that OS was longer among patients with BCMA below the median (136.2 ng/mL), and was shorter in the highest quartile (> 470.1 ng/mL) compared with the other three quartiles (range 14.4–470.0 ng/mL).