Biology:Serum B-cell maturation antigen

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Short description: Cleaved form of B-cell maturation antigen

Serum B-cell maturation antigen (sBCMA) is the cleaved form of B-cell maturation antigen (BCMA), found at low levels in the serum of normal patients and generally elevated in patients with multiple myeloma (MM).[1] Changes in sBCMA levels have been found to correlate with a MM patient’s clinical status in response to treatment.[2][3]

Role in biology

BCMA is a member of the tumor necrosis factor receptor family, expressed on the cell surface of maturing plasma cells and is involved in supporting normal survival of long-lived plasma cells, production of antibodies, and class switching of immunoglobulins.[4][5] In MM, BCMA promotes the proliferation and survival of MM cells and is associated with the immunosuppression which is the hallmark of MM.[6] The BCMA molecule is the receptor for APRIL (a proliferation-inducing ligand) and BAFF (B-cell activating factor, also known as BLyS).[7][8] The binding of APRIL and BAFF to the membrane bound form of BCMA stimulates B-cell proliferation and antibody production.[8] The membrane bound BCMA can be cleaved by gamma secretase, resulting in sBCMA, and released into the blood.[9]

Clinical significance

Serum BCMA is found at low levels in the serum or plasma of normal patients and is generally elevated in patients with MM.  sBCMA levels have been found to correlate with the severity of myeloma disease and shown to be predictive of response to therapy.[2][3] Progression free survival (PFS) and overall survival (OS) in MM patients have also correlated with levels of sBCMA.  Changes in sBCMA also correlate with changes in disease status among MM patients. In addition to MM, sBCMA also appears to correlate with disease progression in monoclonal gammopathy of undetermined significance (MGUS), smoldering myeloma (SMM) and in chronic lymphocytic leukemia (CLL).[10][11]

As a biomarker

When BCMA is cleaved from the cell membrane of plasma cells by gamma secretase, a ubiquitous intramembranous protease enzyme, it is solubilized in the serum, where it can accumulate and bind to various targets including BAFF and APRIL. Patients with MM generally have higher levels of sBCMA.[9] Solubilized BCMA can sequester BAFF, preventing it from signaling B cells, resulting in reduced polyclonal antibody levels in patients with MM.[12] In multiple studies, sBCMA levels have been found to correlate with the severity of myeloma. Notably, sBCMA levels are predictive of response to therapy, PFS and OS. In addition, changes in sBCMA predict changes in clinical status more rapidly than conventional markers that are used to track MM patients. For this reason, the biomarker has been used in diagnostic evaluation of myeloma and other B-cell disorders.

In therapeutics

sBCMA can bind to anti-BCMA antibodies used as therapeutics in treating MM.  It has been shown that the high levels of BCMA present in the serum of MM patients can inhibit the effectiveness of BCMA-directed therapy.[13][14] For this reason, the gamma secretase enzyme has been the target of some recent drug therapies.  These drugs aim to inhibit the action of the gamma secretase enzyme, thus both increasing the density of BCMA on the MM cell while at the same time lowering the levels of sBCMA in the blood and allowing anti-BCMA antibodies to more effectively bind to the target cells.[15][16]

In diagnostics

sBCMA has been measured and evaluated using enzyme-linked immunosorbent assays (ELISAs) in numerous investigational studies of MM related B-cell diseases.[17] Although still investigational, sBCMA appears to be a novel biomarker to track MM such as M-protein and serum Free Light Chain (FLC). All three biomarkers are generally elevated on initial evaluation of MM, tend to increase as the severity of disease increases, and decrease as patients respond to therapy.[3]  

Because levels of the biomarkers appear to correlate with disease severity, they have been used in diagnostics as a way to monitor patients’ disease and evaluate response to therapy. Preliminary investigations have indicated that sBCMA, unlike M protein or FLC, is independent of the patient’s kidney function, and may offer an advantage to monitoring those patients.[3]

Additionally, sBCMA is expressed in non-secretory MM, a subset of MM in which patients do not express high enough levels of M protein or SFLC to be accurately followed using these two biomarkers.  These patientsgenerally need to undergo bone marrow biopsies frequently to evaluate their status.  The sBCMA biomarker may offer an alternative means to evaluate this subset of patients.[3]

In related diseases

Levels of sBCMA appear to progressively increase along the spectrum of plasma cell-related disorders.  Serum BCMA is increased in patients with active MM compared with healthy controls.[3][2] Levels of sBCMA 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).[18] Among patients with MM, sBCMA levels correlated with the percentage of malignant cells,[2][3] giving rise to the concept that sBCMA may reflect a patient’s tumor burden.

Levels of sBCMA among patients with MM were elevated when compared with healthy controls (P<0.0001) and those with monoclonal gammopathy of undetermined significance (MGUS) (P=0.0157).[3][2] Furthermore, sBCMA levels were significantly higher among patients with smoldering multiple myeloma (SMM) and untreated active MM patients than healthy donors (P<0.0001).[3][11]

In a retrospective study of MGUS and SMM patients, the highest levels of sBCMA were observed among patients with SMM who progressed to MM, intermediate levels were seen in patients with MGUS who progressed to MM, and lowest baseline levels were found among patients with MGUS who did not progress to MM. The change in sBCMA over time was lowest in the non-progressing patients with MGUS.[11]

Sometimes, MM patients show undetectable levels of monoclonal immunoglobulin (M protein) in the serum or urine.[19] For this reason, these patients are generally monitored using bone marrow biopsies and PET CT scans.[19] It has been found, however, that sBCMA can be reliably measured in these patients, and correlates well with disease activity and changes in their PET scans and the percentage of bone marrow plasma cells during the course of disease.[3]

In response to treatment

sBCMA has been investigated among MM patients undergoing numerous treatment regiments. Changes in sBCMA levels were found to correlate with changes in an individual patient’s clinical status in response to treatment for MM.[3][2][20]

Additionally, sBCMA levels were significantly higher among patients with progressive disease than in patients with disease responsive to treatment (P=0.0038).[2] Interestingly, sBCMA levels correlated with response to treatment, independent of the type of treatment.

Among patients starting new treatment, changes in sBCMA levels from baseline to one week later (cycle 1 day 8) were found to predict PFS, with >25% increase or decrease in serum BCMA levels on cycle 1 day 8 indicating a much shorter or longer time on treatment, respectively.[21]

As predictor of progression free survival and overall survival

Serum BCMA levels have been reported to predict both PFS and overall survival (OS) in MM.[3][2][20][22][23]

In a study by Ghermezi et al., sBCMA levels were predictive of PFS and OS among patients with MM. PFS was significantly longer for patients with sBCMA levels below the median (326.4 ng/mL) versus those with levels above the median (median, 9.0 vs 3.6 months; P=0.0006). Similarly, OS was significantly longer among those with sBCMA levels below the median compared with those above (median, 155 vs 96 months; P =0.0108).[3]

MM patients with sBCMA levels above the median had significantly shorter survival compared with patients with levels below the median concentration (P=0.0014). Patients in the highest quartile showed a markedly shortened survival compared with the remainder of the patients (P=0.0003).[2]

In a prospective Phase 1 trial of sBCMA to predict clinical outcomes among patients with relapsed or refractory MM treated with lenalidomide, ruxolitinib and methylprednisolone, baseline sBCMA levels were found to be predictive of PFS. Specifically, patients with a baseline sBCMA level in the highest quartile (range, 414.7 – 1655.1 ng/mL) had a significantly shorter PFS than those in the lowest three quartiles (range, 10.3 – 318.2 ng/mL; median PFS: 1.12 vs. 6.64 months; P=0.006).[22] In the same prospective Phase 1 trial, changes in sBCMA during the first cycle study treatment accurately predicted patients later best response.[23] Notably, changes in sBCMA occurred more rapidly than changes in either M-protein or FLC.

Studies to further investigate the role of sBCMA in predicting OS and PFS are ongoing.

References

  1. ↑ "Serum B-Cell Maturation Antigen (BCMA) Levels Differentiate Primary Antibody Deficiencies". The Journal of Allergy and Clinical Immunology: In Practice 8 (1): 283–291.e1. January 2020. doi:10.1016/j.jaip.2019.08.012. PMID 31430592. 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 "Serum B-cell maturation antigen is elevated in multiple myeloma and correlates with disease status and survival". British Journal of Haematology 158 (6): 727–38. September 2012. doi:10.1111/j.1365-2141.2012.09241.x. PMID 22804669. 
  3. ↑ 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 3.11 3.12 "Serum B-cell maturation antigen: a novel biomarker to predict outcomes for multiple myeloma patients". Haematologica 102 (4): 785–795. April 2017. doi:10.3324/haematol.2016.150896. PMID 28034989. 
  4. ↑ "The BCMA gene, preferentially expressed during B lymphoid maturation, is bidirectionally transcribed". Nucleic Acids Research 22 (7): 1147–54. April 1994. doi:10.1093/nar/22.7.1147. PMID 8165126. 
  5. ↑ "A new gene, BCM, on chromosome 16 is fused to the interleukin 2 gene by a t(4;16)(q26;p13) translocation in a malignant T cell lymphoma". The EMBO Journal 11 (11): 3897–904. November 1992. doi:10.1002/j.1460-2075.1992.tb05482.x. PMID 1396583. 
  6. ↑ "Expression of BCMA, TACI, and BAFF-R in multiple myeloma: a mechanism for growth and survival". Blood 103 (2): 689–94. January 2004. doi:10.1182/blood-2003-06-2043. PMID 14512299. https://ashpublications.org/blood/article/103/2/689/17829/Expression-of-BCMA-TACI-and-BAFF-R-in-multiple. 
  7. ↑ "A soluble form of B cell maturation antigen, a receptor for the tumor necrosis factor family member APRIL, inhibits tumor cell growth". The Journal of Experimental Medicine 192 (11): 1677–84. December 2000. doi:10.1084/jem.192.11.1677. PMID 11104810. 
  8. ↑ 8.0 8.1 "BAFF binds to the tumor necrosis factor receptor-like molecule B cell maturation antigen and is important for maintaining the peripheral B cell population". The Journal of Experimental Medicine 192 (1): 129–35. July 2000. doi:10.1084/jem.192.1.129. PMID 10880534. 
  9. ↑ 9.0 9.1 "γ-Secretase directly sheds the survival receptor BCMA from plasma cells". Nature Communications 6 (1): 7333. June 2015. doi:10.1038/ncomms8333. PMID 26065893. Bibcode: 2015NatCo...6.7333L. 
  10. ↑ "Plasma B-Cell Maturation Antigen Levels are Elevated and Correlate with Disease Activity in Patients with Chronic Lymphocytic Leukemia". Targeted Oncology 14 (5): 551–561. October 2019. doi:10.1007/s11523-019-00666-0. PMID 31473933. 
  11. ↑ 11.0 11.1 11.2 "Serum BCMA levels to predict outcomes for patients with MGUS and smoldering multiple myeloma (SMM).". Journal of Clinical Oncology 37 (15_suppl): 8020. 2019-05-20. doi:10.1200/JCO.2019.37.15_suppl.8020. 
  12. ↑ "Soluble B-Cell Maturation Antigen Mediates Tumor-Induced Immune Deficiency in Multiple Myeloma". Clinical Cancer Research 22 (13): 3383–97. July 2016. doi:10.1158/1078-0432.CCR-15-2224. PMID 26960399. 
  13. ↑ "Serum B-cell maturation antigen (BCMA) reduces binding of anti-BCMA antibody to multiple myeloma cells". Leukemia Research 81: 62–66. June 2019. doi:10.1016/j.leukres.2019.04.008. PMID 31035033. 
  14. ↑ "B-cell maturation antigen (BCMA) in multiple myeloma: rationale for targeting and current therapeutic approaches". Leukemia 34 (4): 985–1005. April 2020. doi:10.1038/s41375-020-0734-z. PMID 32055000. 
  15. ↑ "Gamma-secretase inhibitor enhances the cytotoxic effect of bortezomib in multiple myeloma". Cellular Oncology 34 (6): 545–51. December 2011. doi:10.1007/s13402-011-0060-6. PMID 21965140. 
  16. ↑ "Gene Expression of Gamma Secretase (GS) Complex-Related Proteins, the Enzyme That Sheds B-Cell Maturation Antigen (BCMA), Among Patients with Multiple Myeloma (MM) and Effects of the GS Inhibitor LSN424354 on Solubilized Bcma in MM and Chronic Lymphocytic Leukemia". Blood 128 (22): 5641. 2016-12-02. doi:10.1182/blood.V128.22.5641.5641. 
  17. ↑ "The Role of B-Cell Maturation Antigen in the Biology and Management of, and as a Potential Therapeutic Target in, Multiple Myeloma". Targeted Oncology 13 (1): 39–47. February 2018. doi:10.1007/s11523-017-0538-x. PMID 29230672. 
  18. ↑ "Estimating a normal reference range for serum B-cell maturation antigen levels for multiple myeloma patients". British Journal of Haematology 192 (6): 1064–1067. April 2020. doi:10.1111/bjh.16673. PMID 32321191. 
  19. ↑ 19.0 19.1 "Non-secretory multiple myeloma: from biology to clinical management". OncoTargets and Therapy 9: 7583–7590. 2016-12-15. doi:10.2147/OTT.S122241. PMID 28008276. 
  20. ↑ 20.0 20.1 "Baseline and Increases in Serum B-Cell Maturation Antigen Levels Rapidly Indicate Changes in Clinical Status Among Relapsed/Refractory Multiple Myeloma Patients Undergoing New Treatments" (in en). Blood 134 (Supplement_1): 1786. 2019-11-13. doi:10.1182/blood-2019-132012. https://ashpublications.org/blood/article/134/Supplement_1/1786/427754/Baseline-and-Increases-in-Serum-B-Cell-Maturation. 
  21. ↑ "Changes in Serum B-Cell Maturation Antigen Levels Rapidly Predict Progression Free Survival among Multiple Myeloma Patients undergoing New Treatment". Clinical Lymphoma, Myeloma & Leukemia 19 (10): e173–e174. 2019. doi:10.1016/j.clml.2019.09.290. 
  22. ↑ 22.0 22.1 "Serum b-cell maturation antigen levels to predict progression free survival and responses among relapsed or refractory multiple myeloma patients treated on the phase I IRUX trial." (in en). Journal of Clinical Oncology 36 (15_suppl): e24313. 2018-05-20. doi:10.1200/JCO.2018.36.15_suppl.e24313. 
  23. ↑ 23.0 23.1 "Baseline and Early Changes in Serum B-Cell Maturation Antigen Levels Predict Progression Free Survival and Response Status for Multiple Myeloma Patients in a Phase 1 Trial Evaluating Ruxolitinib, Lenalidomide and Methylprednisolone" (in en). Blood 132 (Supplement 1): 1894. 2018-11-29. doi:10.1182/blood-2018-99-119190. 



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