Normalization of serum B‐cell maturation antigen levels predicts overall survival among multiple myeloma patients starting treatment.

Jew S et al. BJH. 22 May 2020 online publication ahead of print. doi: 10.1111/bjh.16752

Key Takeaways and Abstract

Key Takeaways

  • Established that baseline levels of sBCMA that are below the upper limits of normal (82.6 ng/mL) at the start of new therapy are associated with improved survival
  • Reduction of sBCMA into the normal range following the start of new treatment predict for improved progression-free and overall survival.


Serum B‐cell maturation antigen (sBCMA) is a novel biomarker for B‐cell malignancies. A normal reference range (<82·59 ng/ml) has been recently established but the impact of achieving normal levels to outcomes for patients receiving treatment for B‐cell malignancies has not been studied. We first found that among multiple myeloma (MM) patients starting a new treatment, those who begin treatment within normal sBCMA limits (<82·59 ng/ml) have improved progression‐free survival (PFS; P  = 0·0398) and overall survival (OS; P  = 0·0217) than those who do not. Furthermore, among patients who begin treatment with elevated (≥82·59 ng/ml) sBCMA levels, we assessed the relationship of a decrease in sBCMA to the normal range to OS and found that those who normalize sBCMA demonstrated improved OS (P  = 0·0078). Normalizing patients also experienced a markedly improved overall response rate (P  < 0·0001). Moreover, all patients who achieved complete remission (CR) showed normalization of sBCMA, and time to normalization (median 0·9 months) was faster than time to CR (5·0 months; P  = 0·0036) for these patients. These results suggest that normalization of sBCMA may be an accurate predictor of OS for MM patients during treatment and predict for a higher likelihood of response.

Estimating a normal reference range for serum B‐cell maturation antigen levels for multiple myeloma patients.

Jew S et al. BJH 22 April 2020 online publication ahead of print. doi: 10.1111/bjh.16673

Key Takeaways and Abstract

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.


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.

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

Ghermezi M et al. Haematologica. 2017 Apr; 102(4): 785–795. doi: 10.3324/haematol.2016.150896

Key Takeaways and Abstract

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.


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.

A Phase I study of ruxolitinib, lenalidomide, and steroids for patients with relapsed/refractory multiple myeloma.

Berenson JR et al. Clin Cancer Res 2020 May 15;26(10):2346-2353. doi: 10.1158/1078-0432.CCR-19-1899

Key Takeaways and Abstract

Key Takeaways

  • The first clinical trial to show that the JAK inhibitor ruxolitinib is clinically active in multiple myeloma.
  • The combination of ruxolitinib, lenalidomide and steroids produce responses among patients who are resistant to lenalidomide and steroids.


Purpose: This Phase I trial evaluated the safety and efficacy of a novel, all-oral combination consisting of the JAK 1/2 inhibitor ruxolitinib (RUX), lenalidomide (LEN) and steroids for treating relapsed/refractory multiple myeloma patients. Many newer drugs have been evaluated together and in combination with older agents for these patients but the responses to these regimens including those containing immunomodulatory agents are transient; and, thus, new therapeutic approaches to help overcome resistance to immunomodulatory agents are needed. Experimental Design: A traditional 3+3 dose-escalation design was used to enroll subjects in four cohorts with a planned total enrollment of 28 patients. Subjects received ruxolitinib (RUX) twice daily, lenalidomide (LEN) daily on days 1‑21 of a 28-day cycle and methylprednisolone (MP) orally every other day. Primary endpoints were safety, clinical benefit rate (CBR) and overall response rate (ORR). Results: Twenty-eight patients were enrolled. The median age was 67 years and received a median of 6 prior treatments including LEN and steroids to which 93% were refractory. No DLTs occurred. The CBR and ORR were 46% and 38%, respectively. All 12 responding pts were refractory to LEN. G3 or G4 AEs included anemia (18%), thrombocytopenia (14%) and lymphopenia (14%). Most common SAEs included sepsis (11%) and pneumonia (11%). Conclusions: This study provides the basis for studying the addition of JAK inhibitors to improve the efficacy of immunomodulatory agents with steroids for treating myeloma patients but perhaps can also be expanded for treating other cancer patients that are refractory to this class of drugs.

      JAK1/2 pathway inhibition suppresses M2 polarization and overcomes resistance of myeloma to lenalidomide by reducing TRIB1, MUC1, CD44, CXCL12, and CXCR4 expression.

      Chen H et al. Brit J Haematol. 188(2):283-294 (2020). doi: 10.1111/bjh.16158

      Key Takeaways and Abstract

      Key Takeaway

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


      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.

      Plasma B-Cell maturation antigen levels are elevated and correlate with disease activity in patients with chronic lymphocytic leukemia.

      Udd K et al. Targeted Oncology. 14(5):551-561 (2019). doi: 10.1007/s11523-019-00666-0

      Key Takeaways and Abstract

      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.



      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.


      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.


      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.


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

      Serum BCMA reduces binding of anti-BCMA antibody to multiple myeloma cells.

      Chen H, et al. Leukemia Res. 81:62-66 (2019). doi: 10.1016/j.leukres.2019.04.008

      Key Takeaways and Abstract

      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.


      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.

      Serum B-cell maturation antigen is elevated in multiple myeloma and correlates with disease status and survival.

      Sanchez et al. Br J Haematol. 2012 Sep;158(6):727-38.
      doi: 10.1111/j.1365-2141.2012.09241.x

      Key Takeaways and Summary

      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.


      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.


      sBCMA Test Overview for Healthcare Practitioners

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      sBCMA: a Biomarker for Multiple Myeloma 

      BCMA or B-cell maturation antigen is a novel marker for multiple myeloma which will improve the speed at which changes in clinical status can be determined, and is also a good prognostic marker. The benefits of this marker therefore allow patients to move quickly away from a regimen that isn’t working, or begin with less treatment.

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