Serum B-cell Maturation Antigen Levels Research Articles

Early Safety Results of P-BCMA-ALLO1, a Fully Allogeneic Chimeric Antigen Receptor T-Cell (CAR-T), in Patients with Relapsed / Refractory Multiple Myeloma (RRMM)

P-BCMA-ALLO1 is an allogeneic CAR-T that targets B-cell Maturation Antigen (BCMA) and is currently being investigated for the treatment of RRMM. P-BCMA-ALLO1 cells are manufactured from healthy donor T-cells using non-viral transposon-based integration (piggyBac® DNA Delivery System) that introduces a human anti-BCMA V H-based CAR and an iCas9 safety switch. The piggyBac® DNA delivery system produces a highly enriched T stem cell memory product. The Cas-CLOVER™ Site-Specific Gene Editing System eliminates endogenous T cell receptor (TCR) expression via knockout of the TCR beta chain 1 gene to prevent graft-vs-host disease (GvHD), and the beta-2 microglobulin gene to reduce Major Histocompatibility Complex (MHC) class I expression to eliminate host-vs-graft responses. P-BCMA-ALLO1 demonstrated compelling activity in MM xenografts, providing rationale for this first-in-human phase I study. The primary objective is to assess the safety and maximum tolerated dose (MTD) of P-BCMA-ALLO1 based on dose limiting toxicity (DLT) in RRMM patients with measurable disease who have received a proteasome inhibitor (PI), immunomodulatory agent (IMiD) and anti-CD38 monoclonal antibody therapy. Key secondary objective will assess the anti-myeloma effect of P-BCMA-ALLO1. Exploratory objectives will assess CAR-T related cytokines, serum BCMA levels and cellular kinetics. The trial utilizes a standard 3 + 3 dose escalation design to test seven planned dose levels of intravenous P-BCMA-ALLO1 ranging from 0.0625 × 10 6 to 15 × 10 6 cells/kg (NCT04960579). Multiple lymphodepletion (LD) strategies and cyclic administration of P-BCMA-ALLO1 are being investigated. Repeat P-BCMA-ALLO1 administration is allowed for patients who do not achieve at least a partial response with the first dose after 4 weeks of follow up. We are currently dosing patients in arm S (Cyclophosphamide (Cy) 300 mg/m 2 + Fludarabine (Flu) 30 mg/m 2 X 3 days), arm P1 (Cy 500 mg/m 2 + Flu 30 mg/m 2 X 3 days), arm P2 (Cy 1,000 mg/m 2 + Flu 30 mg/m 2 X 3 days) and arm C (multiple P-BCMA-ALLO1 doses following Cy 300 mg/m 2 + Flu 30 mg/m 2 X 3 days). The median patient age was 73 (33, 85) years, 61% were female, and median time since MM diagnosis was 6.27 (1.48,18.95) years. Eight (35%) patients had high risk disease by cytogenetic criteria. The enrolled patients were heavily pretreated, having received median 7 (2,16) prior lines of therapy, with 30% having undergone prior BCMA targeting therapy. As of 10 Jul 2023, 24 patients received P-BCMA-ALLO1 at 4 dose levels. Twenty-two were treated in arm S, 1 each in arms P1 and P2. One patient received 0.25 X 10 6 cells/kg (cohort -1, arm S), 7 received 0.75 X 10 6 cells/kg (cohort 1, arm S), 12 received 2 X 10 6 cells/kg (cohort 2, 10 in arm S, 1 in arm P1 and 1 in arm P2), and 4 received 6 X 10 6 cells/kg (cohort 3). One of the cohort 2 patients received a second P-BCMA-ALLO1 infusion at the cohort 2 dose level following disease progression. The median time from enrollment to start of LD chemotherapy was 2 (1-8) days and from enrollment to CAR-T infusion was 7 (6-13) days. No patient needed bridging therapy between enrollment and the start of LD. Twenty-two (all in arm S) of the 24 treated patients completed DLT evaluation by data cutoff. None of the patients treated thus far had DLTs. Most common treatment emergent adverse events (TEAEs) were anemia (36%), neutropenia (36%), constipation (36%) and leukopenia (32%). Most common ≥ grade (G) 3 TEAEs were neutropenia (36%), leukopenia (32%) and anemia (23%). Most of the AEs were considered unrelated to P-BCMA-ALLO1. Three (14%) patients developed grade 1 Cytokine Release Syndrome (CRS). One (4%) patient experienced grade 1 Immune Effector Cell Associated Neurotoxicity Syndrome (ICANS), which resolved with one dose of corticosteroids. None of the patients experienced GvHD by the last follow up. P-BCMA-ALLO1 is a non-viral transposon-generated allogeneic “off-the-shelf” CAR-T that is rapidly available for administration and well tolerated in a heavily pretreated RRMM patient population with minimal CRS/ICANS risk. Updated results including safety, preliminary efficacy, and selected biomarkers will be presented at the American Society of Hematology 2023 meeting.

Clinical Outcomes and Serum B-Cell Maturation Antigen Levels in a Real-World Unselected Population of Newly Diagnosed Multiple Myeloma Patients.

Progression-free survival (PFS) and overall survival (OS) of newly diagnosed multiple myeloma (MM) patients have been widely published in the clinical trials setting, but data published from real-world settings are limited. We determined the survival and factors that predict outcomes among 161 unselected, newly diagnosed MM patients whose frontline therapy was started at a single clinic specializing in the treatment of this B-cell malignancy. None of these patients underwent an autologous stem cell transplantation as part of their initial therapy and the population had a high proportion (35%) of cytogenetic high-risk patients. With a median follow-up of 42.7 months, the cohort had a median PFS of 22.8 months and a median OS of 136.2 months. The 1-, 3-, and 5-year survival rates were 97.5%, 85.3%, and 76.2%, respectively. These results are considerably better than those reported from patients enrolled in clinical trials and those from countries with national registries. Age <65years predicted for a longer OS (p=0.0004). Baseline serum B-cell maturation antigen (sBCMA) levels were also assessed and showed median and mean levels of 320.3 ng/mL and 551.1 ng/mL, respectively. Furthermore, patients with baseline sBCMA levels in the lowest quartile (≤136.2 ng/mL) showed a longer PFS (p=0.0262). These results provide clinicians with a real-world understanding of the survival of unselected, newly diagnosed patients initiating therapy in a clinic specializing in the care of MM patients.

Serum B-cell maturation antigen level in multiple myeloma

Background Multiple myeloma (MM) is a malignant neoplasm of plasma cells that accumulate in the bone marrow producing excessive amounts of monoclonal immunoglobulins (Ig) and suppression of other normal polyclonal Igs, leading to bone destruction and marrow failure. B-cell maturation antigen (BCMA) is known to bind to B-cell-activating factor (BAFF) or a proliferation-inducing ligand (APRIL), leading to the activation of cell proliferation pathways and upregulation of antiapoptotic proteins, which is considered the main step in the pathogenesis of MM. Aim This study was planned to evaluate serum BCMA levels in MM patients and its clinical significance. Patients and methods This study was carried out on 40 newly diagnosed MM patients and 40 apparently healthy individuals served as the control. The two studied groups were compared as regards serum BCMA levels using the enzyme-linked immunosorbent assay technique. Results Results showed that there was a statistically significant increase in MM patients when compared with the control group, and there was a significant positive correlation between BCMA level and plasma cells in bone marrow, M protein, number of bone lesions, and beta-2 microglobulin. However there was no correlation between BCMA level and age, creatinine, and hemoglobin. Conclusion Serum BCMA level was significantly elevated in MM patients compared with healthy controls that may suggest the role of BCMA in the pathogenesis of MM. The high sensitivity of BCMA suggests that it may be a novel diagnostic marker, and its level was positively correlated with other prognostic markers. It may be used as a prognostic marker in MM patients.

Serum B-Cell maturation antigen is an independent prognostic marker in previously untreated chronic lymphocytic leukemia

B-Cell maturation antigen (BCMA) is a cell membrane receptor expressed on mature B lymphocytes, with elevated serum levels found among patients with B-cell malignancies, including chronic lymphocytic leukemia (CLL). Serum BCMA (sBCMA) levels were measured in 331 untreated, newly diagnosed CLL patients using an enzyme-linked immunosorbent assay with a polyclonal anti-BCMA antibody. Elevated sBCMA levels were found among patients with CLL compared with age- and sex-matched healthy controls and those with more active CLL based on prognostic factors. The relationships between sBCMA, time to first treatment (TTFT), overall survival (OS) and multiple prognostic factors were compared using Mann-Whitney and Kruskal-Wallis tests. The median sBCMA level in the CLL cohort (48.6 ng/mL) was significantly higher (p < 0.001) compared with those of age- and sex-matched healthy subjects (n=100; 37.8 ng/mL). Serum BCMA correlated with TTFT(hazard ratio [HR]=2.9, 95% confidence interval 2.0-4.2, p < 0.001) and OS (HR=2.5, 95% confidence interval: 1.5-4.0, p < 0.001). Multiple models were used to test the predictive effects of sBCMA, sex, CLL International Prognostic Index (CLL-IPI) and International Prognostic Score for early-stage CLL (IPS-E) on TTFT and OS. The addition of sBCMA to CLL-IPI and IPS-E improved their prognostic ability to predict TTFT and OS. Thus, sBCMA is a new promising prognostic biomarker for CLL.

Changes in Serum B-Cell Maturation Antigen Levels Rapidly Indicate Changes in Clinical Status Among Multiple Myeloma Patients Undergoing New Treatments

Introduction : B-cell maturation antigen (BCMA) is a protein that is expressed on the 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. To this end, we compared changes in levels of sBCMA with sM-protein among MM patients undergoing new treatments.Methods : Serum was obtained at least weekly during each pt's first cycle of a new therapy (C1) and the first day of their second cycle (C2D1) and at least monthly thereafter from all MM pts receiving a new Tx regimen (n=83) at a single clinic from March 2015 to July 2017. sM-protein levels were measured, and sBCMA levels were determined using an enzyme-linked immunosorbent assay (R&D Systems; Minneapolis, MN). Percentage changes in sBCMA and sM-protein throughout Tx were determined relative to levels measured at their start of treatment (C1D1). Kaplan-Meier analysis was used to assess differences in time on therapy (TOT) based on the percentage changes in sBCMA levels at cycle 1 day 8 (C1D8) and day 15 (C1D15) of the pt's new Tx. All patient samples were obtained following proper informed consent in accordance with the Declaration of Helsinki.Results : Forty-nine MM pts (IgG [n=37], IgA [n=12]) receiving 83 Tx regimens were analyzed. Regimens that resulted in a > 25% increase in sBCMA by C1D8 (n=10) had a shorter median TOT than all other regimens (n=71; median TOT: 1.73 months vs. 5.76 months; P=.0037). Regimens that showed a > 25% decrease in sBCMA levels on C1D8 (n=27) had a longer TOT (median TOT: 6.91 months) when compared with all other regimens (median TOT: 2.89 months). In contrast, sM-protein levels did not show > 25% changes at these early time points.For those patients who achieved at least a minimal response (MR) using IMWG criteria (n=30), the time to achieve at least a 25% decrease in sBCMA was much shorter (median 7 days) than the time for sM-protein (median 21 days; P=.0004). For those that progressed during the first cycle (n=5), the time to achieve at least a 25% increase in sBCMA was similarly much shorter (median 7 days) than the time for sM-protein (median 21 days).Because the half-life of IgG is long (approximately 3-4 weeks), we studied the 64 regimens among the 37 pts with IgG MM. Twenty-four (38%) achieved at least an MR. Among these pts, sBCMA levels reduced by an average of 31% on C1D8, whereas sM-protein decreased by an average of only 7.6%.The regimens that resulted in a > 25% decrease on C1D8 (n=23) had a longer TOT than regimens that did not reach this reduction (n=41; median TOT: 7.8 months vs. 2.8 months, P=.023). Those regimens with a confirmed > 25% increase in sBCMA levels (n=6) at C1D15 had a shorter TOT than those with a confirmed > 25% decrease in sBCMA levels (n=22) at C1D15 (median 0.9 months vs. 6.9 months, P <.0001), and had a shorter TOT than all other Tx regimens (n=75; median 0.9 months vs. 5.8 months, P <.0001).There were six regimens for which pts did not achieve a response during the first cycle but did so during subsequent cycles. At C1D8, sBCMA levels decreased > 25% in four pts and 24% in another pt. During the second week of therapy, sBCMA levels continued to decrease in these five pts. In contrast, sM-protein did not show a response (> 25% decrease) in any of these regimens during C1 and decreased by an average of only 9.7% and 13.3% on days 8 and 15, respectively.Conclusions: We have shown that relative changes in sBCMA levels from baseline can much more rapidly determine changes in clinical status than the standard sM-protein biomarker among MM pts starting new treatments. By C1D8, sBCMA establishes changes in clinical status whereas sM-protein takes much longer to show the effect of treatment on response status. In addition, a > 25% increase or decrease in sBCMA levels at C1D8 indicates a much shorter or longer TOT, respectively for these pts. Thus, relative changes in sBCMA levels among MM pts on new therapies allows more rapid determination of changes in their clinical status, and these early changes predict the length of time on those treatments. DisclosuresBerenson:OncoTracker, Inc.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Research Funding.

Expression of B Cell Maturation Antigen (BCMA) and Transmembrane Activator and Caml Interactor (TACI) Are Correlated and Can be Targeted at Multiple Points during the Course of Multiple Myeloma

Therapies directed to specific antigens expressed on multiple myeloma [MM] cells are desirable given the high likelihood of relapse in patients [pts] and the toxicities associated with current treatment options. BCMA and TACI are surface proteins of interest as they promote the survival and proliferation of mature plasma cells. Given that their gene expression by RT-PCR is higher in MM cells compared to normal plasma cells [PCs], and the association of increasing serum BCMA levels with disease progression, we sought to assess if similar patterns were seen on PCs measured by flow cytometry. We specifically examined changes in BCMA/TACI expression (frequency and intensity) with progression of MM, whether expression of BCMA and TACI are correlated, and if levels of their expression correlates with PC burden as determined by IHC.Flow cytometric data were collected using a validated multi-color panel used for clinical assessment of PC burden, with the addition of antibodies to BCMA and TACI, by the Flow Cytometry Clinical Laboratory at our Center. In total, 29 myeloma pts samples were analyzed, and a retrospective chart review of these individuals was performed under an IRB-approved protocol.Pts were separated into 4 sets of groups based on their number of prior lines of therapy, status of disease, prior autologous stem cell transplant [ASCT], and early relapse post-ASCT. Frequency and intensity of BCMA/ TACI expression were examined across these groups by assessing the following variables within each set of groups: % BCMA+ total PCs, % TACI+ total PCs, as well as BCMA/TACI mean fluorescence intensity (MFI). Correlation analysis was performed to assess whether BCMA expression correlated to TACI expression (n=25). To evaluate the correlation of PC burden in BM aspirate with antigen expression, correlation analysis was performed between PC burden and the BCMA/TACI expression (frequency and intensity). Statistical analysis was performed using GraphPad Prism 7 Software. Statistical tests included 1 way ANOVA (comparison of ≥3 means), student t-test (comparison of 2 means), and Pearson correlation (correlation analysis).The median patient age was 62, with 65.5% male and 34.5% female. IgG kappa (37.9%) was the most common type of MM. 17.2% were newly diagnosed, 27.6% had stable disease, 20.7% were in remission, and 39.5% had relapsed/refractory disease. A majority of pts (41.4%) received 1-3 prior lines of therapy. 51.7% underwent ASCT, 10% of which had relapsed, with 13.8% of relapses occurring ≤ 1 year post-ASCT.Four of 29 pts were excluded from data analysis due to insufficient PCs as detected by flow cytometry. ≥Four lines of therapy (n=9), relapsed/refractory disease (n=8), relapse post-ASCT (n=7), and relapse ≤ 1 year post-ASCT (n=2), were all markers of disease progression. There were no significant differences in BCMA/ TACI expression (frequency and intensity) among these groups and their counterparts, but less variability of expression was observed in newly diagnosed pts.There was a positive correlation between % BCMA+ total PCs with % TACI+ total PCs (r= 0.6051, p= 0.0014, n=25), and BCMA MFI with TACI MFI (r=0.5191, p=0.0078, n=25). A similar relationship was noted where aberrant PCs were identified (r=0.9199, p= 0.0094, n=6).Of the patients without minimal residual disease, there was a negative correlation between PCs in BM aspirate with % TACI+ total PCs(r= -0.5211, p= 0.0320, n=17). There were no significant correlations with PCs in BM aspirate and % of BCMA+ total PCs, BCMA MFI, and TACI MFI. BCMA/TACI expression was spread across a broad range for pts with ≤ 10% clonal PCs in BM aspirate, and a narrower range in pts with > 10% clonal PCs in BM aspirate.BCMA and TACI expression alone are not markers of progression of MM and should be used in conjunction with other antigens associated with progressive disease. However, the persistent and frequent expression of BCMA and TACI identified suggests that BCMA and TACI directed therapies can be used at multiple points during the course of disease. Since expression seems to be more uniform in newly diagnosed patients, patients treated at later time points may benefit from quantitative assessment of BCMA and/or TACI expression prior to receiving therapies targeting these molecules. Finally, expression of BCMA and TACI are correlated, but it remains to be seen if loss of one antigen could precipitate obligate loss of the other. DisclosuresNo relevant conflicts of interest to declare.

Baseline and Changes in Serum B-Cell Maturation Antigen Levels Rapidly Indicate Changes in Clinical Status Among Patients with Relapsed/Refractory Multiple Myeloma Starting New Therapy.

B-cell maturation antigen (BCMA) is expressed on malignant plasma cells from patients with multiple myeloma (MM). These patients have higher levels of serum (s)BCMA than healthy subjects, and levels correlate with disease status. The half-life of sBCMA is only 24-36 h, and levels are independent of renal function. We determined whether baseline sBCMA values, a ≥ 25% increase, and a ≥ 50% decrease during treatment predicted progression-free survival (PFS) and overall survival (OS) among 81 patients with relapsed/refractory MM (RRMM) starting new treatments. Serum was obtained on day 22 of each patient's 28-day cycle of new therapy. Kaplan-Meier survival analysis and log-rank comparison tests were used to determine the effect of baseline sBCMA. The effect of percentage change in sBCMA was investigated using time-dependent Cox proportional hazard models. Patients with baseline sBCMA levels above the median had a shorter PFS (p=0.0077), and those in the highest quartile had a shorter PFS (p = 0.0012) and OS (p=0.0022). A ≥ 25% increase at week 4, week 8, and anytime through week 12 predicted a shorter PFS (p = 0.0011, p = 0.0005, and p < 0.0001, respectively). A ≥ 50% decrease at week 4, week 8, and anytime through week 12 predicted a longer PFS (p = 0.0045, p = 0.029, p = 0.0055, respectively). A ≥ 25% increase in sBCMA occurred before progression according to International Myeloma Working Group criteria in 67.5% of patients. Our results indicate the potential for the use of sBCMA as a new biomarker for monitoring patients with RRMM.

P0344NEFECON® (BUDESONIDE) SELECTIVELY REDUCES CIRCULATING LEVELS OF BAFF (BLYS) AND SOLUBLE BCMA AND TACI IN IGA NEPHROPATHY

Abstract Background and Aims There is increasing evidence to support a pivotal role for the gut-associated lymphoid tissue (GALT) as a major source of the poorly O-galactosylated immunoglobulin A1 (IgA1) that triggers the formation of nephritogenic immune complexes in IgA nephropathy (IgAN). Critical to the regulation of IgA synthesis in GALT are two cytokines, which regulate B-cell maturation, function and survival: BAFF (B-cell activating factor [also known as BLyS (B-lymphocyte stimulator)]) and APRIL (A PRoliferation-inducing ligand). BAFF and APRIL bind to specific cell-surface receptors: TACI (transmembrane activator and calcium modulator and cyclophilin-ligand interactor), BCMA (B-cell maturation antigen) and the BAFF receptor. Several studies have shown elevated levels of BAFF and APRIL in IgAN linked to worse clinical outcomes. The therapeutic potential of selectively targeting GALT was demonstrated in the NEFIGAN trial (NCT01738035), which assessed the safety and efficacy of a novel targeted-release formulation of budesonide (NEFECON®), designed to deliver budesonide to the GALT-rich distal ileum in patients with IgAN. The trial comprised a 6-month run-in, 9-month treatment and 3-month follow-up phase: 48 patients received NEFECON® 16 mg/day, 51 patients received NEFECON® 8 mg/day and 50 patients received placebo. The headline result of the study was that NEFECON® 16 mg/day, added to optimised renin–angiotensin system blockade, reduced proteinuria and stabilised estimated glomerular filtration rate in patients with IgAN. In this study, we aimed to determine whether NEFECON® treatment altered synthesis of the BAFF and APRIL B-cell maturation modulators. Method Serum levels of BAFF, APRIL, BCMA and TACI were measured using Luminex technology. Changes in the levels of each biomarker between randomisation (T0), end of treatment (T1) and the end of study (T2) and between treatments arms were compared using a one-way analysis of variance. Significance was set at p&amp;lt;0.05. Results A significant, dose-dependent reduction in serum BAFF levels was seen with NEFECON®, which reversed on cessation of NEFECON®. There were similar significant reductions in the levels of soluble BCMA and TACI with treatment but no effect was seen on circulating levels of APRIL. These changes were mirrored by parallel changes in soluble CD27 levels and are consistent with our previous reports describing a dose-dependent reduction in circulating IgA–IgG immune complexes, secretory IgA and galactose-deficient IgA levels with NEFECON®. Conclusion Delivering budesonide to the GALT-rich distal ileum modulates key regulators of GALT B-cell maturation in IgAN. Although the samples available are not sufficient to determine that the observed changes in serum BAFF, BCMA and TACI levels are due to a direct action on GALT, it is intriguing to note that BAFF-transgenic mice develop an IgAN-like disease, principally due to IgA overexpression in the intestinal lamina propria.

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

Serum B-cell maturation antigen (sBCMA) is a novel biomarker for B-cell malignancies. A normal reference range (<82·59ng/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 (<82·59ng/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 (≥82·59ng/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 0·9months) was faster than time to CR (5·0months; 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.

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 (&lt; 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&amp;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 &lt; 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 (&lt; 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&lt;0.0001). Furthermore, those normalizing their sBCMA levels showed improved OS (p&lt;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&lt;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&lt;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&lt;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 (&lt; 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.

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

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

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

We have previously shown that MM patients (pts) have higher levels of serum (s) BCMA than healthy subjects and these levels can be used to monitor the course of disease of MM pts. There is a need for more rapid and accurate ways to assess the efficacy of therapy (Tx) for these pts. Thus, we compared changes in levels of sBCMA, sM-protein and SFLC among MM patients undergoing new treatments.

Serum BCMA levels to predict outcomes for patients with MGUS and smoldering multiple myeloma (SMM).

8020 Background: BCMA (B-cell maturation antigen) is a TNF receptor family member found on normal and malignant B-cells, including multiple myeloma (MM). It plays a role in proliferation and antiapoptotic pathways. Levels of serum (s)BMCA are elevated in patients (pts) with plasma cell disorders (PCD) and increase with each stage of disease: healthy donor&lt; MGUS&lt;SMM&lt; active untreated MM. The purpose of this study was to test whether sBCMA levels predict progression of MGUS or SMM to MM. Methods: There were 3 cohorts in this retrospective study: MGUS progressing to MM (n=42); MGUS not progressing to MM (n=49); SMM progressing to MM (n=32). sBCMA levels were measured using an ELISA-based assay with a polyclonal anti-BCMA antibody from R&amp;D Systems (Minneapolis, MN). The Kruskal-Wallis analysis was used to assess differences. The relationships between sBCMA and both time to progression and overall survival were also assessed using Cox proportional hazard models. Results: The highest values of sBCMA were seen among pts with more advanced PCD (Table). The lowest baseline levels were seen in pts with MGUS who did not progress; the change of sBCMA over time was lowest in the MGUS non-progressors. ROC analysis identified a cutoff of 74.4 ng/mL to be predictive of progression at 5 years. This cut-point was associated with a risk ratio of progression of 5.8 (95%CI 3.2, 11.3) for all comers, a risk ratio of death for all comers of 2.5 (95%CI 1.5, 4.2), and a risk ratio of death for MGUS pts of 3.3 (95%CI 1.9, 5.7). Conclusions: Serum BCMA levels were predictive of diagnosis, progression and death among pts with MGUS or SMM. Limitations of the current study are that only a minority of pts had baseline bone marrow exams or serum FLCs to place sBCMA risk in the context of other previously described risk factors. Serum FLC is now being determined on all patients. [Table: see text]

Serum B-cell maturation antigen (BCMA) reduces binding of anti-BCMA antibody to multiple myeloma cells

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.

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

Background: B-cell maturation antigen (BCMA) is highly expressed on malignant plasma cells from patients with multiple myeloma (MM). We have previously shown that serum (s) BCMA levels are elevated among MM patients, and baseline levels predict both progression free and overall survival in an unselected MM population. The half-life of soluble BCMA is much shorter (approximately 24-hours) than sM-protein (3-4 weeks). As a result, we have monitored sBCMA and sM-protein levels weekly among unselected MM patients starting any new therapy in our clinic. We have previously reported that this biomarker much more quickly determines changes in their clinical status than conventional biomarkers. In this study, we determined whether both baseline and changes in sBCMA levels during cycle 1 can predict progression-free survival (PFS) and best response among patients enrolled on the IRUX 1504 phase 1 trial evaluating ruxolitinib, lenalidomide and methylprednisolone for relapsed or refractory (RR) MM patients.Methods: Serum (s) was obtained weekly during the first cycle (C1) and first day of the second cycle (C2D1) and monthly thereafter from patients enrolled on the IRux 1504 trial from February 2017 to July 2018. sM-protein levels were assessed using standard protein electropheresis, and sBCMA levels were determined using an ELISA (R&D Systems; Minneapolis, MN). Kaplan-Meier analysis was used to assess differences in PFS based on baseline sBCMA levels and the percentage (%) change in sBCMA from baseline to C1D8. We also determined the relationship between changes in sBCMA on C1D8 and best response as determined using International Myeloma Working Group criteria. All patient samples were obtained following proper informed consent in accordance with the Declaration of Helsinki.Results: Twenty-eight MM patients (IgG [n=13], IgA [n=5], free light chain only [n=10]), were evaluated. However, one patient progressed before reaching C1D8; and, thus, could not be included in analysis evaluating the relationship between changes at C1D8 and best response. Patients with a baseline sBCMA value 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).Moreover, the percentage change in sBCMA during the first week of study treatment accurately predicted their best response. Specifically, all patients that experienced ≥ 50% decrease in sBCMA on C1D8 achieved ≥ partial response; and, furthermore, all of those that experienced a ≥25% decrease in sBCMA on C1D8 achieved at least a minimal response. In contrast, all patients that experienced ≥ 25% increase during the first week showed either only disease that was stable or progressed within two study treatment cycles. Additionally, no patient that experienced any increase in sBCMA on C1D8 achieved any response better than stable disease. These results were not seen with sM-protein, as no patient with evaluable sM-protein levels at baseline showed a ≥ 25% change on C1D8. Patients that showed any increase in sBCMA on C1D8 (n=6) had a significantly shorter PFS than those whose sBCMA decreased on C1D8 (n=21, PFS = 1.4 vs 5.1 months, P = 0.0212).Conclusion: This study represents the first prospective clinical trial in which sBCMA has been studied as a biomarker to predict clinical outcomes. In this phase 1 trial evaluating ruxolitinib, lenalidomide and steroids for RRMM patients, we have shown that baseline sBCMA levels predict PFS. Moreover, percentage changes in the levels of sBCMA unlike sM-protein during the first week of study treatment were highly predictive of these patient's best responses achieved and their PFS. Thus, baseline sBCMA levels and changes in its levels during the first week of treatment may predict outcomes for MM patients faster than conventional biomarkers. DisclosuresSoof:OncoTracker: Employment. Li:OncoTracker: Equity Ownership. Wang:OncoTracker: Equity Ownership. Sanchez:OncoTracker: Equity Ownership. Chen:OncoTracker: Equity Ownership. Berenson:OncoTracker: Employment, Equity Ownership.

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.

e24313Background: B-cell maturation antigen (BCMA) is expressed on plasma cells among patients (pts) with multiple myeloma (MM). We have previously shown that the half-life of soluble BCMA is much ...

Abstract P1-02-10: Reduced serum B-cell maturation antigen levels predict poor outcome in metastatic breast cancer patients in a phase 3 randomized 2nd-line hormone therapy trial

Abstract Background: B-cell maturation antigen (BCMA) is a member of the tumor necrosis factor receptor family and has two ligands, B-cell activating factor (BAFF) and a proliferation inducing ligand (APRIL). These ligands activate cell proliferation and inhibit apoptosis of normal and malignant B-cells including in multiple myeloma (MM) cell lines. Berenson et al have recently reported that circulating BCMA levels are elevated in B-cell malignancies and can be used to monitor disease and predict PFS and OS for patients with MM, Waldenstroms's macroglobulinemia and chronic lymphocytic leukemia (CLL). On the other hand, recent studies have shown that serum BCMA levels are very low among patients with MM in complete remission with low antibody levels and those with primary immune deficiencies specifically those with combined variable immune deficiency and X-linked agammaglobulinemia. Studies of the potential role of serum BCMA for patients with solid tumors has not been evaluated to date. Methods: The pretreatment serum from 139 patients with hormone receptor-positive metastatic breast cancer who were enrolled in a phase 3 randomized clinical trial of second-line hormone therapy was evaluated using an ELISA for BCMA. The BCMA ELISA was from R&amp;D Systems (Minneapolis, MN). Serum BCMA was correlated with TTP using categorical serum BCMA cutpoints. Results: Pretreatment serum BCMA levels had a median of 55.61 ng/ml, an interquartile range of 34.20 and 78.79 ng/ml, and full range from 3.99 to 1193.26 ng/ml. In univariate analysis for TTP, reduced serum BCMA correlated with shorter TTP at the following dichotomous cutpoints: 15 ng/ml [HR=2.60, p=0.064, n=6 (4.3%) of patients below cutpoint]; 20 ng/ml [HR=2.88, p=0.005, n=10 (7.2%) of patients below cutpoint]; 25 ng/ml [HR=2.16, p=0.023, n=13 (9.4%) of patients below cutpoint]; and 30 ng/ml [HR=1.77, p=0.016, n=27 (19.4%) of patients below the cutpoint]. Conclusions: In a phase 3 randomized clinical trial of second-line hormone therapy among patients with hormone receptor-positive metastatic breast cancer, reduced pretreatment serum BCMA was associated with shorter TTP. This may be due to the association of reduced serum BCMA with immune deficiency; and, thus, lead to shorter TTP among patients with metastatic breast cancer. Evaluation of serum BCMA as a new biomarker to predict outcomes for breast cancer and other solid tumor patients deserves further study. Citation Format: Ali SM, Leitzel K, Li M, Udd K, Wang J, Sanchez E, Chen H, Berenson J, Lipton A. Reduced serum B-cell maturation antigen levels predict poor outcome in metastatic breast cancer patients in a phase 3 randomized 2nd-line hormone therapy trial [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-02-10.

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

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.

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

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. [Display omitted] DisclosuresEtessami:Oncotracker: Employment. Berenson:OncoTracker: Employment, Equity Ownership.

Serum Levels of B-Cell Maturation Antigen Are Elevated in Waldenström's Macroglobulinemia Patients and Correlate with Disease Status and Conventional M-Protein and IgM Levels

Background: Waldenström's macroglobulinemia (WM) is an incurable B-cell lymphoplasmacytic lymphoma. B-cell maturation antigen (BCMA) serves as one of the receptors for B-cell activating factor (BAFF) or a proliferation-inducing ligand (APRIL), which are members of the tumor necrosis factor (TNF) family that can induce activation of NF-κB and promote survival of B cells, including neoplastic B cells. We previously showed that serum BCMA levels are elevated in multiple myeloma (MM) patients, and correlated with disease status and overall survival (OS). In this study, we sought to determine whether BCMA levels are elevated in the serum of WM patients, track with conventional WM tumor markers, and correlate with disease status and OS.Methods: Data was obtained on a total of 67 WM patients who received treatment in one of two clinics that specialize in the treatment of WM. Serum BCMA levels were determined with a polyclonal anti-BCMA antibody using an ELISA (R&D Systems, Minneapolis, MN). Mann-Whitney analysis was used to measure differences in serum BCMA levels between WM patients and healthy subjects as well as the clinical status of WM patients. Using Kaplan-Meier analysis, OS (median follow up 5.1 years) in WM patients was measured from the time of the first assessment of serum BCMA levels in each patient. In addition, serum BCMA levels were compared to serum M-protein and IgM levels in 12 patients, serially, during their individual courses of treatment.Results: We compared serum BCMA levels for all 67 patients, including 27 untreated WM patients to healthy subjects (n = 76). Serum BCMA levels were markedly elevated in all WM patients (median 79.53 ng/mL), including those who were untreated (median 82.72 ng/mL) versus healthy subjects (median 6.32 ng/mL, p < 0.0001 for both comparisons). Serum BCMA values were compared to both serum M-protein and IgM levels in 12 WM patients during their disease course. Serum BCMA levels consistently correlated with changes in both of these established WM serum markers during their course of disease. Serum BCMA levels of WM patients also correlated with patient disease status at the time of sample collection. Specifically, serum from patients achieving > partial response (PR, n = 12) showed significantly lower levels of BCMA than samples from patients with either stable disease (SD, n = 8, p = 0.030) or progressive disease (PD, n = 21, p = 0.0004). OS (median 12.5 years) was determined among patients in the highest serum BCMA quartile (n=16; quartile range 128.91-812.48 ng/mL) and compared to levels in the lower three quartiles (n = 48; range 20.13-128.85 ng/mL). Notably, OS was shorter among patients in the top quartile compared to those in the other three quartiles (p = 0.02).Conclusions: This is the first study to demonstrate that serum BCMA levels are elevated in Waldenström's macroglobulinemia patients. Importantly, serum BCMA levels correlated with both serum IgM and M-protein levels, as well as tracked with these established WM biomarkers for individual patients during their course of disease. Additionally, patients with levels of BCMA in the highest quartile exhibited shorter OS. Thus, serum BCMA represents a new serum biomarker to predict outcome and monitor patients with Waldenström's macroglobulinemia. DisclosuresNo relevant conflicts of interest to declare.