Key Takeaways

• Established the normal range for sBCMA among healthy subjects that are age-matched to the myeloma population and show no relationship to sex, age or race.

Abstract

The serum B‐cell maturation antigen (sBCMA) has been identified as a novel serum biomarker for patients with multiple myeloma. However, no study has yet established a reference range for sBCMA levels. Its levels were determined in 196 healthy subjects and showed a right‐tailed distribution with a median value of 37·51 ng/ml with a standard deviation of 22·54 ng/ml (range 18·78–180·39 ng/ml). Partitioning of subgroup reference ranges was considered but determined to be irrelevant. A non‐parametric method using the median ± 2 standard deviations suggests using a universal reference interval of <82·59 ng/ml.

Key Takeaways

• Demonstrated that sBCMA levels are elevated among patients with plasma cell dyscrasias with active myeloma having the highest values.
• Baseline sBCMA levels predict progression free and overall survival.
• Changes in sBCMA correlate with changes in patient clinical status.

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.

Key Takeaway

• Blocking JAK signaling with ruxolitinib reduces the levels of tumor-stimulating M2 macrophages in myeloma bone marrow.

Abstract

Monocytes polarize into pro‐inflammatory macrophage‐1 (M1) or alternative macrophage‐2 (M2) states with distinct phenotypes and physiological functions. M2 cells promote tumour growth and metastasis whereas M1 macrophages show anti‐tumour effects. We found that M2 cells were increased whereas M1 cells were decreased in bone marrow (BM) from multiple myeloma (MM) patients with progressive disease (PD) compared to those in complete remission (CR). Gene expression of Tribbles homolog 1 (TRIB1) protein kinase, an inducer of M2 polarization, was increased in BM from MM patients with PD compared to those in CR. Ruxolitinib (RUX) is an inhibitor of the Janus kinase family of protein tyrosine kinases (JAKs) and is effective for treating patients with myeloproliferative disorders. RUX markedly reduces both M2 polarization and TRIB1 gene expression in MM both in vitro and in vivo in human MM xenografts in severe combined immunodeficient mice. RUX also downregulates the expression of CXCL12, CXCR4, MUC1, and CD44 in MM cells and monocytes co‐cultured with MM tumour cells; overexpression of these genes is associated with resistance of MM cells to the immunomodulatory agent lenalidomide. These results provide the rationale for evaluation of JAK inhibitors, including MM BM in combination with lenalidomide, for the treatment of MM patients.

Key Takeaway

• Circulating BCMA levels are elevated in CLL patients and its levels predict both time to first treatment and overall survival. Its levels also correlate with the patient’s clinical status.

Abstract

Background

Chronic lymphocytic leukemia (CLL) is a malignancy of late B cells. In another late B-cell malignancy (multiple myeloma), levels of solubilized B-cell maturation antigen (sBCMA) are elevated and predict outcomes.

Objective

We sought to evaluate sBCMA as a possible prognostic factor and monitoring tool for patients with CLL.

Patients and Methods

Using an enzyme-linked immunosorbent assay (ELISA), we assessed plasma (p) levels of BCMA in 171 CLL patients and compared them with levels in healthy individuals.

Results

pBCMA levels were significantly higher among patients with CLL than those from healthy donors (p < 0.0001). Among patients with aggressive disease, pBCMA was elevated compared with patients with indolent disease (p < 0.001). Those with an initial pBCMA level in the highest quartile had a shorter time to first treatment compared with CLL patients with pBCMA levels in the lowest three quartiles (p < 0.0001). Among those in the highest quartile (pBCMA > 110.9 ng/mL), overall survival was shorter than those in the lowest three quartiles (p = 0.0007). Finally, among those patients who underwent serial pBCMA testing, changes in these levels correlated with changes in their clinical status.

Conclusions

Together, our findings show that pBCMA is a promising new prognostic and predictive indicator for patients with CLL.

Key Takeaways

• Demonstrated that sBCMA levels in myeloma patients are at high enough levels in most patients to prevent antibodies targeting BCMA from attaching to myeloma tumor cells.
• Elevated sBCMA levels may limit the efficacy of BCMA-targeted therapeutic approaches.

Abstract

B-cell maturation antigen (BCMA), a tumor necrosis factor receptor (TNFR) family member, is selectively expressed on terminally differentiated B-lymphocytes including multiple myeloma (MM) tumor cells. We sought to determine whether circulating (c)BCMA in MM serum interferes with antiBCMA antibody binding to MM cells. An enzyme-linked immunosorbent assay (ELISA) was used to determine serum (s) BCMA levels among 379 samples from patients with relapsed/refractory MM (RRMM). Furthermore, flow cytometric and immunofluorescent studies were used to examine if concentrations of BCMA in patients’ serum were high enough to interfere with the binding of anti-BCMA antibody to MM tumor cells. We have shown that BCMA is elevated in the serum from MM patients and that the median concentration of sBCMA from RRMM patients was 176 ng/mL (n = 379). Additionally, there was a consistent decrease in the binding of anti-BCMA antibody to MM tumor cells with sBCMA level ≥156 ng/mL. Together, these results demonstrate that circulating BCMA levels in most RRMM patients are high enough to interfere with anti-BCMA antibody binding to MM tumor cells and may interfere with BCMA-targeted immune-based therapies.

Key Takeaway

• This is the first report showing that BCMA is present in serum and that it is elevated in myeloma patients. It also reports that levels are associated with the patient’s clinical status and survival.

Abstract

Although TNFRSF 17 (also designated as B‐cell maturation antigen (BCMA)) is expressed on tumour cells in B ‐cell malignancies, it has not been found in serum. The present study found that BCMA concentrations were higher in the supernatants of cultured bone marrow mononuclear cells from multiple myeloma (MM ) patients than in healthy subjects. Serum BCMA levels were measured in samples from MM patients (n  = 209), monoclonal gammopathy of undetermined significance (MGUS ) individuals (n  = 23) and age‐matched controls (n  = 40). BCMA was detected in the serum of untreated MM patients (n  = 50) and levels were higher than in MGUS patients (P  =  0·0157) and healthy subjects (P  <  0·0001). Serum BCMA levels were higher among patients with progressive disease (n  = 80) compared to those with responsive disease (n  = 79; P  =  0·0038). Among all MM patients, overall survival was shorter among patients whose serum BCMA levels were above the median (P  =  0·001). We also demonstrated that sera from mice with human MM xenografts contained human BCMA , and levels correlated with the change in tumour volume in response to melphalan or cyclophosphamide with bortezomib. These results suggest that serum BCMA levels may be a new biomarker for monitoring disease status and overall survival of MM patients.