Normalization of Serum B-Cell Maturation Antigen Levels from Treatment Predicts Progression Free and Overall Survival in Multiple Myeloma Patients

Introduction: B-cell maturation antigen (BCMA) is increased in the serum (s) of multiple myeloma (MM) patients (pts). We have previously shown that baseline sBCMA levels predict outcomes for MM pts. The purpose of this study was to determine whether a decrease of sBCMA to normal levels (< 82.69 ng/mL) after initiating treatment predicts both progression free survival (PFS) and overall survival (OS) among MM pts and its relationship to clinical response status in this pt population. Methods: sBCMA levels were determined using an ELISA (R&D Systems; Minneapolis, MN) in 147 consecutive MM pts whose first treatment was in the frontline (n=87 [59%]) or salvage (n=60 [41%]) settings in a single clinic specializing in MM from February 2009 to April 2019 (observation cut-off: May 31, 2019). We determined sBCMA weekly during the first cycle and then monthly thereafter (median follow-up= 28 mo). An age-matched analysis of 206 healthy donors was used to determine a median normal sBCMA level of 37.6 ng/mL (SD 22.5 ng/mL). A reference threshold value of 82.7 ng/mL was determined using 2 SDs above the median. We defined normalization of sBCMA as a decrease in levels to < 82.7 ng/mL on two consecutive measurements. Kaplan-Meier analysis was used to compare PFS and OS among these pts and compared with responses as defined using the IMWG criteria. All pt samples were obtained following informed consent in accordance with the Declaration of Helsinki. Results: One hundred thirteen pts (77%) had a baseline sBCMA ≥ upper threshold of normal (82.7 ng/mL) with a median of 435.3 ng/mL (range, 84.5-9,153.8 ng/mL) whereas the remaining 34 pts (23%) had baseline levels below 82.7 ng/mL and were excluded from analyses in relationship to normalizing sBCMA during their treatment. sBCMA levels normalized (< 82.7 ng/mL) in over half (55%) of evaluable pts (n=62), and these pts showed a markedly longer PFS (median 33.2 mo) than pts that did not (n=51; median 4.0 mo; p<0.0001). Furthermore, those normalizing their sBCMA levels showed improved OS (p<0.0001). Among those evaluated during their frontline treatment (n=75), those who normalized (n=50) also showed a longer PFS (median 33.9 mo) than those who did not (n=25; median 12.8 mo; p<0.0001). Only 12 of 38 pts undergoing salvage treatment normalized their sBCMA, but these pts experienced both improved PFS (median 8.3 mo vs 3.1 mo; p=0.0115) and OS (p=0.0345). We also compared the PFS and OS of pts in CR to normalization of sBCMA. Pts whose sBCMA normalized (n=62) had both similar PFS (p=0.6257) and OS (p=0.7346) to those who achieved CR (n=26). Notably, every pt who achieved CR had normalized sBCMA and all pts who failed to normalize did not achieve CR (n=51). Pts who failed to normalize had shorter PFS (median 4.0 mo; n=51) than those who did not achieve CR (median 12.7 mo; n=87; p=0.0091). Among the pts who normalized sBCMA, pts who achieved CR (n=26) had similar PFS (p=0.4029) and OS (p=0.6354) to those who did not achieve CR (n=36). Conversely, among the 87 pts who did not achieve CR, pts who normalized their sBCMA (n=36) had markedly longer PFS (median 29.4 mo) than those who did not (n=51; median 4.0 mo; p<0.0001); normalizing pts also showed improved OS (p=0.0072). We examined pts whose best clinical response was ≥ MR to determine if normalization of sBCMA improved upon determination of their PFS and OS. We found that among pts who achieved PR, those who normalized sBCMA (n=26) experienced improved PFS (median 33.2 mo) than those who did not (n=18; median 12.8 mo; p=0.0173); OS was also improved in those PR pts who normalized their sBCMA (p=0.0350). Similar findings were found when analyzing those achieving MR or PR, with PFS (p=0.0006) and OS (p=0.0326) for pts who normalized (n=30) being longer than for pts who did not normalize sBCMA (n=28). Of those achieving at least an MR, both PFS (median 33.9 vs 12.8 mo; p<0.0001) and OS (p=0.0052) were longer for normalizing pts (n=59) than pts who failed to normalize (n=28). Conclusion: We have demonstrated that among MM pts starting new treatment with baseline elevated sBCMA levels, normalization of sBCMA levels (< 82.7 ng/mL) predicts markedly longer PFS and OS. Patients who achieve normalization have similar outcomes to those in CR. Additionally, our findings suggest that normalization of sBCMA predicts longer PFS and OS for pts who achieve ≥ MR. Therefore, normalization of sBCMA may be a novel approach to predict clinical outcomes for MM pts starting new treatment. Disclosures Chen: Oncotraker Inc: Equity Ownership. Swift:Bristol Mayers Squib: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Jansen: Consultancy, Honoraria. Berenson:Sanofi: Consultancy; Janssen: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Research Funding; Incyte Corporation.: Consultancy, Research Funding; OncoTracker: Equity Ownership, Other: Officer; Amgen: Consultancy, Speakers Bureau; Amag: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau.

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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

Blood ◽

10.1182/blood-2019-132012 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1786-1786 ◽

Cited By ~ 2

Author(s):

Sean Bujarski ◽

Kyle Udd ◽

Camilia Soof ◽

Tanya M. Spektor ◽

Tahmineh Safaie ◽

...

Keyword(s):

Multiple Myeloma ◽

Light Chain ◽

Research Funding ◽

Cell Maturation ◽

B Cell Maturation ◽

New Therapy ◽

Equity Ownership ◽

New Treatment ◽

Sm Protein ◽

B Cell Maturation Antigen

Introduction: B-cell maturation antigen (BCMA) is a protein that is expressed on malignant plasma cells from patients (pts) with multiple myeloma (MM). Our group has previously shown that MM pts have higher levels of serum (s) BCMA than healthy subjects and that sBCMA levels can be used to monitor the disease course of MM pts. Notably, we have shown that the half-life of soluble BCMA is only 24-36 hours which is much shorter than sM-protein, and its levels are independent of renal function. With the expanding therapeutic options for the treatment (Tx) of MM, there is a need for more rapid and accurate ways to assess the efficacy of new therapies. In this study, we analyzed the relationship between progression free survival (PFS) and changes in weekly levels of sBCMA, sM-protein and serum free light chain (sFLC) during the first cycle of a new treatment among relapsed/refractory (RR)MM patients. Methods: Serum was obtained weekly during each pt's first cycle of a new therapy (C1) and the first day of their second cycle (C2D1) from all RRMM pts (n = 122) at a single clinic from August 2016 to December 2018. sM-protein and sFLC levels were measured, and sBCMA levels were determined using an enzyme-linked immunosorbent assay (R&D Systems; Minneapolis, MN). Percentage changes in sBCMA, sM-protein and sFLC (difference between involved and uninvolved FLCs) throughout Tx were determined relative to levels measured at the start of treatment (C1D1). Kaplan-Meier analysis was used to assess differences in PFS based on the percentage changes from baseline in these levels at cycle 1 day 8 (C1D8), day 15 (C1D15), day 22 (C1D22), and day 29 (C2D1). All pt samples were obtained following proper informed consent in accordance with the Declaration of Helsinki. Results: The analysis involved 122 Tx in 75 RRMM pts undergoing new treatment (IgG [n = 33], IgA [n= 15], IgM [n = 1], and light chain only [n = 26]). All pts were evaluable by sBCMA (above the lower limit of detection of the assay [16 ng/mL]). Pts whose baseline sBCMA was higher than the median (217.6 ng/mL) had a significantly shorter PFS (n = 61, median PFS = 2.5 mo) than those below the median (n = 61, median = 7.3 mo, p = 0.0003). When baseline sBCMA levels were quartiled, there was an inverse relationship between sBCMA and PFS (Q1: n = 30, median = 8.0 mo; Q2: n = 31, median = 7.2 mo; Q3: n = 31, median = 3.2 mo; Q4: n = 30, median = 1.9 mo; p = 0.0002). Pts whose sBCMA increased ≥ 25% on C1D8 (n = 8) had a shorter PFS (median = 1.6 mo) than those that did not (n = 114, median = 3.9 mo, p = 0.0042). Those whose sBCMA increased ≥ 25% at any time during C1 (n = 31) also had a shorter PFS (median = 1.6 mo) than those that did not (n = 91, median = 5.2 mo, p < 0.0001). sM-protein was only evaluable by IMWG criteria (> 1.0 g/dL) in 45 (37%) of the pts and only 2 and 5 pts showed an increase of > 25% on C1D8 and anytime during cycle 1, respectively. In the remaining 77 pts who were not evaluable by sM-protein, 51 (68%) were evaluable by sFLC using IMWG criteria (> 100 mg/L difference between the involved and uninvolved FLC) and only 13 showed a > 25% increase during the first cycle. Next, we determined if changes in sBCMA could be used for pts who were not evaluable by either sM-protein or sFLC. Among pts that could not be followed by sM-protein, those with a ≥ 25% increase in sBCMA at any point in C1 (n = 18, median = 2.2 mo) had a significantly shorter PFS than those who did not (n = 59; median = 4.4 mo; p = 0.0218). Among pts that could not be followed by sFLC, those with a ≥ 25% increase in sBCMA at any point in C1 (n = 12) had a significantly shorter PFS (median = 1.6 mo) than those who did not (n = 30; median PFS = 8.7 mo; p = 0.0072). Among pts that could not be followed by either sFLC or sM-protein, a > 25% in sBCMA at any point in C1 (n = 8) showed a shorter PFS (median = 1.6 mo) than those who did not (n = 17; median = 19.3 mo; p = 0.0154). Notably, among pts whose sFLC or sM-protein were below evaluable levels, ≥ 25% increases in sFLC or sM-protein did not predict PFS. Conclusions: We have shown that serum BCMA was evaluable in all RRMM pts at the start of new therapy in contrast to the standard sM-protein and sFLC biomarkers. Baseline levels of sBCMA predict PFS in RRMM pts undergoing new therapy. Additionally, increases of sBCMA > 25% during the first cycle occur in more pts than sM-protein or sFLC, and predict for a shorter PFS. These results suggest that baseline sBCMA and monitoring its levels weekly during the first cycle of a new treatment can help improve predicting outcomes for RRMM pts. Disclosures Chen: Oncotraker Inc: Equity Ownership. Swift:Bristol Mayers Squib: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Jansen: Consultancy, Honoraria. Berenson:Sanofi: Consultancy; Amgen: Consultancy, Speakers Bureau; Amag: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; OncoTracker: Equity Ownership, Other: Officer; Bristol-Myers Squibb: Honoraria, Research Funding; Takeda: Consultancy, Speakers Bureau; Incyte Corporation.: Consultancy, Research Funding.

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

British Journal of Haematology ◽

10.1111/bjh.16752 ◽

2020 ◽

Cited By ~ 3

Author(s):

Scott Jew ◽

Tiffany Chang ◽

Sean Bujarski ◽

Camilia Soof ◽

Haiming Chen ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

B Cell ◽

Cell Maturation ◽

B Cell Maturation ◽

B Cell Maturation Antigen

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Changes in Serum B-Cell Maturation Antigen Levels Rapidly Predict Progression Free Survival among Multiple Myeloma Patients undergoing New Treatment

Clinical Lymphoma Myeloma & Leukemia ◽

10.1016/j.clml.2019.09.290 ◽

2019 ◽

Vol 19 (10) ◽

pp. e173-e174

Author(s):

Sean Bujarski ◽

Kyle Udd ◽

Camilia Soof ◽

Haiming Chen ◽

Tanya Spektor ◽

...

Keyword(s):

Multiple Myeloma ◽

B Cell ◽

Progression Free Survival ◽

Cell Maturation ◽

Free Survival ◽

B Cell Maturation ◽

New Treatment ◽

B Cell Maturation Antigen

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Normalization of Serum B-cell Maturation Antigen Levels Predicts Progression Free and Overall Survival in Multiple Myeloma Patients Starting Treatment

Clinical Lymphoma Myeloma & Leukemia ◽

10.1016/j.clml.2019.09.291 ◽

2019 ◽

Vol 19 (10) ◽

pp. e174

Author(s):

Scott Jew ◽

Tiffany Chang ◽

Sean Bujarski ◽

Camilia Soof ◽

Haiming Chen ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

B Cell ◽

Cell Maturation ◽

B Cell Maturation ◽

B Cell Maturation Antigen

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Changes in Serum B-Cell Maturation Antigen Levels Are a More Rapid Indicator of Therapeutic Response or Disease Progression for Patients with Multiple Myeloma

Blood ◽

10.1182/blood.v128.22.5654.5654 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5654-5654

Author(s):

Kyle Udd ◽

Haiming Chen ◽

Mingjie Li ◽

Camilia M Soof ◽

Christian Casas ◽

...

Keyword(s):

Multiple Myeloma ◽

B Cell ◽

Disease Progression ◽

Cell Maturation ◽

M Protein ◽

Protein Levels ◽

B Cell Maturation ◽

New Therapy ◽

New Treatment ◽

B Cell Maturation Antigen

Abstract Introduction: B-cell maturation antigen (BCMA) is a protein found on the surface of malignant plasma cells from multiple myeloma (MM) patients (pts). We have previously shown that MM pts show higher serum (s) levels of BCMA than healthy subjects and that these levels predict outcomes and can be used to monitor the disease course of these pts. We have recently shown that the half-life of solubilized BCMA is much shorter (1 day) than the conventional serum marker, monoclonal (M) immunoglobulin (21-28 days; Sanchez et al. Clin Can Res 2016). Given the increasing number of therapeutic options for treating MM pts, it becomes of increasing importance to have more rapid ways to assess the efficacy of therapies. We compared changes in serum BCMA to M-protein levels among MM patients receiving new treatments. Methods: Serum BCMA and M-protein levels were determined from all MM pts showing a measurable serum M-protein beginning any new therapy at a single clinic from March 2015 to July 2016. Samples were obtained during each visit (at least weekly) throughout the first cycle of new therapy (C1 D1) and the first day of their second cycle (C2 D1). Analysis of sBCMA levels was determined using an enzyme-linked immunosorbent assay (ELISA; R&D Systems, Minneapolis, MN). All sBCMA samples for each individual pt were measured using a single ELISA plate. All serum M-protein measurements were completed in the same clinical laboratory. Percentage changes in sBCMA and serum M-protein levels during treatment were determined relative to the level from the blood draw obtained just prior to the initiation of a new therapy. All patient samples were obtained following proper informed consent in accordance with the Declaration of Helsinki. Results: Twenty MM pts (IgG [n=16] and IgA [n=4]), were studied in frontline (n=5) and salvage (n=15) settings. Eleven (55%) pts responded to treatment (1 complete response [CR], 5 partial response [PR] and 5 minimal response [MR]) whereas 7 and 2 pts showed stable disease (SD) and progressive disease (PD), respectively. Changes from baseline (C1 D1) for samples taken during the remainder of C1 and C2 D1 showed sBCMA levels changed more quickly than serum M-protein among responding and progressing pts (Table 1). A 30 - 43% reduction in relative sBCMA levels by the end of the second week of treatment predicted subsequent achievement of an MR for 3 pts. By C1 D15, serum M-protein levels in these pts only decreased by an average of only 11% (range, 3% - 23%). In all 5 pts who achieved PR, sBCMA decreased >30% (range, 31% - 57%) by C1 D8 whereas serum M-protein only decreased by an average of 5% (range, -15% - +15%). A decrease of >43% (range, 43% - 69%) by C1D15 correlated with an eventual PR (n=5) in all 5 pts who subsequently achieved a PR. During that same time, serum M-protein levels varied by an average of only 26% (range, 16% - 36%). In the patient who achieved a CR, the drop in sBCMA was more marked than serum M-protein and was 20% on C1 D8 and 78% on C1 D15 whereas serum M-protein only decreased by 12% and 61% on C1 D8 and C1 D15, respectively. An increase in sBCMA of >30% by C1 D8 indicated disease progression (n=2) in both pts who developed PD at the end of C1. For pts who only showed SD during C1, sBCMA levels only varied <1% on C1 D8. Over this same time period, serum M-protein changed by an average of 3%. In other pts who achieved SD during C1, mid-cycle changes in the levels of sBCMA resulting in >30% increases relative to the sample obtained one week prior (n=3) correctly predicted disease progression during the following cycle in all of these pts. Conclusions: In this study, we have shown that serum BCMA levels more quickly and markedly change than conventional M-protein levels among MM pts receiving any new treatment. Specifically, relative changes in sBCMA levels >30% during the first week of a new treatment correlate with eventual changes in the clinical status of these pts. Thus, frequent assessment of serum BCMA levels during the first month of any new treatment may be helpful to make more rapid decisions as to whether it will ultimately provide benefit to individual MM pts. Disclosures Etessami: Oncotracker: Employment. Berenson:OncoTracker: Employment, Equity Ownership.

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B-cell maturation antigen (BCMA) in multiple myeloma: the new frontier of targeted therapies

Therapeutic Advances in Hematology ◽

10.1177/2040620721989585 ◽

2021 ◽

Vol 12 ◽

pp. 204062072198958

Author(s):

Larysa Sanchez ◽

Alexandra Dardac ◽

Deepu Madduri ◽

Shambavi Richard ◽

Joshua Richter

Keyword(s):

Multiple Myeloma ◽

T Cell ◽

B Cell ◽

Targeted Therapies ◽

Safety Data ◽

Cell Maturation ◽

Treatment Modalities ◽

Cell Therapies ◽

B Cell Maturation ◽

B Cell Maturation Antigen

Outcomes of patients with multiple myeloma (MM) who become refractory to standard therapies are particularly poor and novel agents are greatly needed to improve outcomes in such patients. B-cell maturation antigen (BCMA) has become an important therapeutic target in MM with three modalities of treatment in development including antibody–drug conjugates (ADCs), bispecific T-cell engagers (BITEs), and chimeric antigen receptor (CAR) T-cell therapies. Early clinical trials of anti-BCMA immunotherapeutics have demonstrated extremely promising results in heavily pretreated patients with relapsed/refractory MM (RRMM). Recently, belantamab mafodotin was the first anti-BCMA therapy to obtain approval in relapsed/refractory MM. This review summarizes the most updated efficacy and safety data from clinical studies of BCMA-targeted therapies with a focus on ADCs and BITEs. Additionally, important differences among the BCMA-targeted treatment modalities and their clinical implications are discussed.

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