scholarly journals Expression of Myeloma Cell and Soluble B-Cell Maturation Antigen (BCMA) in Relapsed and Refractory Multiple Myeloma Patients Treated with GSK2857916 in BMA117159

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1977-1977 ◽  
Author(s):  
E.J. Dettman ◽  
Fabio Rigat ◽  
Josh Albert ◽  
Ruth Barnard ◽  
Mary Birchler ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Plasma Cells ◽  
Cell Maturation ◽  
Employment Equity ◽  
B Cell Maturation ◽  
Post Infusion ◽  
Equity Ownership ◽  
Expansion Cohort ◽  
B Cell Maturation Antigen

Abstract Introduction: B-cell maturation antigen (BCMA) is a cell surface receptor that is widely expressed on multiple myeloma (MM) cells. GSK2857916 is a humanized Fc enhanced IgG1 anti-BCMA antibody conjugated to the microtubule inhibitor monomethyl auristatin-F (MMAF). Safety and clinical efficacy of a Q3W GSK2857916 dosing schedule were assessed in relapsed/refractory MM subjects in the first time in human trial BMA117159. In the dose escalation phase, 38 subjects were treated with doses from 0.03 mg/kg up to 4.60 mg/kg, followed by an expansion cohort of 35 subjects at a dose of 3.40 mg/kg where an overall response rate (ORR) of 60% (21/35; 95% CI 42.1-76.1) by IMWG criteria was demonstrated (Trudel, et al. Blood 2017). Several novel biomarkers were followed during the BMA117159 study, including: the level of BCMA expression on MM cells and circulating soluble BCMA (sBCMA). Methods: The expression of BCMA on MM cells was measured in subjects enrolled in BMA117159 at baseline in formalin-fixed paraffin-embedded bone marrow aspirate samples using a BCMA Immunohistochemistry (IHC) assay and a dual color IHC assay with BCMA and CD138 (plasma cell marker). The antibody to detect BCMA (J6M0) uses the same CDR regions as GSK2857916. BCMA staining was quantified as a percentage positive of all cells, percentage of plasma cells as determined by morphology, or in CD138+ cells (for the dual color IHC assay). Soluble BCMA was measured in serum samples collected at pre- and post-infusion at cycle 1 using immunoassays to determine the levels of free and GSK2857916-bound sBCMA. All measurements were performed at central laboratories. Results: Among the subjects enrolled in BMA117159, the baseline BCMA expression was found specifically in plasma cells using BCMA IHC, with a median of 100% plasma cells expressing BCMA across all subjects, compared to a median of 5% of all bone marrow cells expressing BCMA. In the dose expansion cohort, no differences by response group were noted in BCMA staining with both responders (PR or better) and non-responders having 100% BCMA positivity in plasma cells. Comparable results were observed using a dual staining IHC assay for BCMA and CD138, where 95% of CD138+ cells expressed BCMA in non-responders compared with 88% in responders. Examination of circulating sBCMA in BMA117159 subjects revealed high sBCMA levels, with a baseline median concentration of free sBCMA of 58 ng/mL across all doses (n = 68; range 4 ng/mL to >1000 ng/mL). Among patients enrolled in the expansion phase, the median baseline sBCMA concentrations were higher in non-responders compared to responders (81 ng/mL, n = 12; compared to 43 ng/mL, n = 19). However, high baseline sBCMA levels were also found in responders with levels up to 262 ng/mL. To examine whether sBCMA may act as a surrogate for BCMA expression in tumor cells, the relationship between these measures was examined; however, no strong associations were observed between baseline sBCMA and BCMA IHC staining (Spearman rho = 0.27). The binding of GSK2857916 to sBCMA can be measured by comparing the post-infusion levels of free sBCMA measured 60 minutes after the start of infusion to those found at pre-infusion. It was found that the reduction in free sBCMA appeared to be related to the dose level administered, and doses above 1.92 mg/kg consistently achieved a greater than 90% reduction of free sBMCA. Conclusions: These preliminary data indicate that tumor cells from MM patients participating in BMA117159 consistently expressed the BCMA receptor at baseline, and the levels of expression did not appear to be associated with response to treatment. At higher dose levels, it was found that GSK2857916 bound a large fraction of sBCMA, and responses to GSK2857916 were observed in 60% of dose expansion subjects with either low or high baseline sBCMA. However, at present, the sample sizes are limited, and further investigations in future studies are necessary to understand the value of these biomarkers for treatment decisions. Study is funded by GlaxoSmithKline (NCT02064387); drug linker technology is licensed from Seattle Genetics; monoclonal antibody is produced using POTELLIGENT® Technology licensed from BioWa. Disclosures Dettman: GlaxoSmithKline: Employment, Equity Ownership. Rigat:GlaxoSmithKline: Employment, Equity Ownership. Albert:GlaxoSmithKline: Employment, Equity Ownership. Barnard:GlaxoSmithKline: Employment, Equity Ownership. Birchler:GlaxoSmithKline: Employment, Equity Ownership. Deghenhardt:GlaxoSmithKline: Employment, Equity Ownership. DeWall:GlaxoSmithKline: Employment, Equity Ownership. Gaye:GlaxoSmithKline: Employment, Equity Ownership. He:GlaxoSmithKline: Employment, Equity Ownership. Liu:GlaxoSmithKline: Employment, Equity Ownership. Opalinska:GlaxoSmithKline: Employment, Equity Ownership.

scholarly journals T Cells Genetically Modified to Express an Anti–B-Cell Maturation Antigen Chimeric Antigen Receptor Cause Remissions of Poor-Prognosis Relapsed Multiple Myeloma

2018 ◽  
Vol 36 (22) ◽  
pp. 2267-2280 ◽  
Author(s):  
Jennifer N. Brudno ◽  
Irina Maric ◽  
Steven D. Hartman ◽  
Jeremy J. Rose ◽  
Michael Wang ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
T Cells ◽  
Partial Response ◽  
B Cell ◽  
Residual Disease ◽  
Cell Maturation ◽  
B Cell Maturation ◽  
Minimal Residual ◽  
B Cell Maturation Antigen

Purpose Therapies with novel mechanisms of action are needed for multiple myeloma (MM). T cells can be genetically modified to express chimeric antigen receptors (CARs), which are artificial proteins that target T cells to antigens. B-cell maturation antigen (BCMA) is expressed by normal and malignant plasma cells but not normal essential cells. We conducted the first-in-humans clinical trial, to our knowledge, of T cells expressing a CAR targeting BCMA (CAR-BCMA). Patients and Methods Sixteen patients received 9 × 106 CAR-BCMA T cells/kg at the highest dose level of the trial; we are reporting results of these 16 patients. The patients had a median of 9.5 prior lines of MM therapy. Sixty-three percent of patients had MM refractory to the last treatment regimen before protocol enrollment. T cells were transduced with a γ-retroviral vector encoding CAR-BCMA. Patients received CAR-BCMA T cells after a conditioning chemotherapy regimen of cyclophosphamide and fludarabine. Results The overall response rate was 81%, with 63% very good partial response or complete response. Median event-free survival was 31 weeks. Responses included eradication of extensive bone marrow myeloma and resolution of soft-tissue plasmacytomas. All 11 patients who obtained an anti-MM response of partial response or better and had MM evaluable for minimal residual disease obtained bone marrow minimal residual disease–negative status. High peak blood CAR+ cell levels were associated with anti-MM responses. Cytokine-release syndrome toxicities were severe in some cases but were reversible. Blood CAR-BCMA T cells were predominantly highly differentiated CD8+ T cells 6 to 9 days after infusion. BCMA antigen loss from MM was observed. Conclusion CAR-BCMA T cells had substantial activity against heavily treated relapsed/refractory MM. Our results should encourage additional development of CAR T-cell therapies for MM.

Novel Fc-Engineered Anti-B Cell Maturation Antigen-Monomethyl Auristatin F Antibody-Drug Conjugate (GSK2857916) Induces Potent and Selective Anti-Multiple Myeloma Activity Via Enhanced Effector Function and Direct Tumor Cell Killing

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 877-877
Author(s):  
Yu-Tzu Tai ◽  
Chirag Acharya ◽  
Mike Y Zhong ◽  
Michele Cea ◽  
Antonia Cagnetta ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Lines ◽  
Cell Maturation ◽  
Antibody Drug Conjugate ◽  
Drug Conjugate ◽  
B Cell Maturation ◽  
Equity Ownership ◽  
B Cell Maturation Antigen ◽  
Antibody Drug

Abstract B cell maturation antigen (BCMA), which is highly expressed on malignant plasma cells in human multiple myeloma (MM), has not been effectively targeted with therapeutic monoclonal antibodies (mAbs). We here investigated the anti-MM activity of J6M0-mcMMAF (GSK2857916), a humanized and afucosylated anti-BCMA antibody-drug conjugate (ADC) via uncleavable linker. This novel antagonist anti-BCMA antibody shows binding against all CD138-expressing MM cell lines (n=13) and patient MM cells (n=18), confirming universal BCMA expression on the surface of myeloma cells. Real-time qRT-PCR also showed significantly upregulated BCMA mRNA in CD138+ cells purified from MM patients vs. normal donors (p < 0.03). In contrast, BCMA is undetectable in CD138-negative cells from MM patients (n=3). J6M0-mcMMAF strongly blocks cell growth and induces caspase 3-dependent apoptosis in both drug-sensitive and -resistant MM cell lines and patient CD138+ MM cells, alone and in co-culture with BMSCs. In contrast, an isotype control antibody-drug conjugate (iso-mcMMAF) had no effect on viability of ANBL6 MM cells, alone or cocultured with BMSC. J6M0-mcMMAF specifically induces cell death in CD138-positive patient MM cells but not CD138-negative cells, demonstrating the minimal bystander killing against surrounding BCMA-negative cells. J6M0-mcMMAF completely blocks colony formation of MM cell lines (n=6) via induction of G2/M arrest, followed by apoptosis. This ADC does not affect viability of BCMA-negative NK, PBMC, and BMSCs, cultured alone or together, confirming its specific targeting of BCMA-positive MM cells. J6M0-mcMMAF, which has enhanced Fc-receptor binding due to afucosylation, significantly improved autologous antibody-dependent cellular cytotoxicity (ADCC) potency and maximum MM cell lysis against MM patient cells (n=5), when compared to J6M0 with normal Fc. Such augmented ADCC and maximum patient MM cell lysis by J6M0-mcMMAFis more pronounced in the autologous setting vs. the allogenic setting where MM cells and healthy donor effectors were used. Pretreatment of PBMC effector cells with lenalidomide further increased J6M0-mcMMAF-induced ADCC against MM cells in the presence or absence of BMSC. The in vivo efficacy of J6M0-mcMMAF was evaluated in murine subcutaneous xenograft models using NCI-H929 and OPM2 cells, as well as in NK-deficient SCID-beige mice with diffuse human MM bone lesions using MM1Sluc cells. Administration of J6M0-mcMMAF at 4 mg/kg (q3d x 4, ip) completely eliminated NCI-H929 and OPM2 xenograft tumors in all mice which remained tumor-free until the termination of studies at 60 and 100 days, respectively. In the MM1Sluc bone marrow dissemination model, J6M0-mcMMAF eradicates detectable tumors after 2 doses at 0.4 mg/kg (q3d x 9, ip), which resulted in extended survival (p<0.0001) and no weight loss of mice following 120 days. J6M0 treatment, although less effective than J6M0-mcMMAF, also had significantly prolonged survival (p<0.03) and diminished tumor burden when compared with control vehicle and isotype-treated groups, indicating a potential role of macrophage-mediated phagocytosis. Indeed, J6M0-mcMMAF recruits macrophage and mediates phagocytosis of target MM cells. Taken together, our studies show that J6M0-mcMMAF potently and selectively induce direct and indirect killing of MM tumor cells both in vitro and in vivo, providing a very promising next-generation immunotherapeutic in this cancer. Disclosures: Tai: Onyx: Consultancy. Mayes:GlaxoSmithKline: Employment. Craigen:GlaxoSmithKline: Employment. Gliddon:GlaxoSmithKline: Employment. Smothers:GlaxoSmithKline: Employment. Richardson:Millenium: Consultancy; Celgene: Consultancy; Johnson & Johnson: Consultancy; Bristol-Myers Squibb: Consultancy; Novartis: Consultancy. Munshi:Celgene: Consultancy; Novartis: Consultancy; Millennium: Consultancy. Anderson:celgene: Consultancy; onyx: Consultancy; gilead: Consultancy; sanofi aventis: Consultancy; oncopep: Equity Ownership; acetylon: Equity Ownership.

scholarly journals Immunotherapeutic strategies targeting B cell maturation antigen in multiple myeloma

2021 ◽  
Vol 8 (1) ◽  
Author(s):  
Yi Fang ◽  
Jian Hou
Keyword(s):  
Multiple Myeloma ◽  
B Cell ◽  
Plasma Cells ◽  
Residual Disease ◽  
Hematologic Malignancy ◽  
Therapeutic Strategies ◽  
Cell Maturation ◽  
B Cell Maturation ◽  
Clone Evolution ◽  
B Cell Maturation Antigen

AbstractMultiple myeloma (MM) is the second most common hematologic malignancy, and is characterized by the clonal expansion of malignant plasma cells. Despite the recent improvement in patient outcome due to the use of novel therapeutic agents and stem cell transplantation, all patients eventually relapse due to clone evolution. B cell maturation antigen (BCMA) is highly expressed in and specific for MM cells, and has been implicated in the pathogenesis as well as treatment development for MM. In this review, we will summarize representative anti-BCMA immune therapeutic strategies, including BCMA-targeted vaccines, anti-BCMA antibodies and BCMA-targeted CAR cells. Combination of different immunotherapeutic strategies of targeting BCMA, multi-target immune therapeutic strategies, and adding immune modulatory agents to normalize anti-MM immune system in minimal residual disease (MRD) negative patients, will also be discussed.

scholarly journals B-Cell Maturation Antigen (BCMA) As a Target for New Drug Development in Relapsed and/or Refractory Multiple Myeloma

2020 ◽  
Author(s):  
Hanley N. Abramson
Keyword(s):  
Multiple Myeloma ◽  
Monoclonal Antibodies ◽  
T Cell ◽  
B Cell ◽  
Plasma Cells ◽  
Cell Types ◽  
Cell Maturation ◽  
New Drug ◽  
B Cell Maturation ◽  
B Cell Maturation Antigen

During the past two decades there has been a major shift in the choice of agents to treat multiple myeloma, whether newly diagnosed or in the relapsed/refractory stage. The introduction of new drug classes, such as proteasome inhibitors, immunomodulators, and anti-CD38 and anti-SLAMF7 monoclonal antibodies, coupled with autologous stem cell transplantation, have approximately doubled the disease’s five-year survival rate. However, this positive news is tempered by the realization that these measures are not curative and patients eventually relapse and/or become resistant to the drug’s effects. Thus, there is a need to discover newer myeloma-driving molecular markers and develop innovative drugs designed to precisely regulate the actions of such putative targets. B cell maturation antigen (BCMA), which is found almost exclusively on the surfaces of malignant plasma cells to the exclusion of other cell types, including their normal counterparts, has emerged as a specific target of interest in this regard. Immunotherapeutic agents have been at the forefront of research designed to block BCMA activity. These agents encompass monoclonal antibodies, such as the drug conjugate belantamab mafodotin; bispecific T-cell engager strategies exemplified by AMG 420; and chimeric antigen receptor (CAR) T-cell therapeutics that include idecabtagene vicleucel (bb2121) and JNJ-68284528.

scholarly journals Identification Rate of Myeloma-Specific Clonotypes in Multiple Diagnostic Sample Types from Patients with Multiple Myeloma Using Next-Generation Sequencing Method

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2036-2036 ◽  
Author(s):  
Hervé Avet-Loiseau ◽  
Jill Corre ◽  
Sabrina Maheo ◽  
Jianbiao Zheng ◽  
Malek Faham ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Next Generation Sequencing ◽  
High Frequency ◽  
Plasma Cells ◽  
Employment Equity ◽  
Myeloma Cells ◽  
Sequencing Method ◽  
Equity Ownership ◽  
Generation Sequencing

Abstract Background: Recent reports support the prognostic importance of minimal residual disease (MRD) levels in multiple myeloma (MM) patients and suggest that novel methods for MRD assessment can play a role in the evolving MM treatment paradigm (Martinez-Lopez et al., Blood 2014). The application of next-generation sequencing (NGS)-based MRD assessment has been previously demonstrated in multiple lymphoid malignancies (Faham et al., Blood 2012; Ladetto et al., Leukemia 2013). NGS-based MRD assessment requires a diagnostic sample for initial identification of the myeloma clonotype. In order for this MRD assessment approach to be clinically practical, it must allow for analysis of a diverse set of diagnostic samples. In this study, we assessed the rate of myeloma clonotype identification in 6 sample types at diagnosis: bone marrow (BM) aspirate slides, RNA extracted from CD138+ plasma cells, methanol-fixed BM cells, BM mononuclear cells, RBC-lysed BM cells, and DNA extracted from small numbers of CD138+ plasma cells. Methods: Baseline samples were collected from 606 patients with MM. The following samples were provided at baseline: bone marrow aspirate (BMA) slides (164), RNA extracted from CD138+ plasma cells (402), methanol-fixed BM cells (30), BMA cell preparations using a Ficoll protocol (13), BMA cell preparations using an RBC lysis protocol (19), and DNA extracted from small numbers of CD138+ plasma cells (5). Samples with sufficient input DNA (>15ng) were included in the analysis, although this requirement was waived for samples from CD138+ cells. The Ficoll BMA cell preparations were divided into the mononuclear cell fraction and the lower Ficoll fraction, which is typically comprised of granulocytes and erythrocytes. Identification of myeloma clonotypes was performed using Sequenta's LymphoSIGHT™ method. Briefly, using universal primer sets, we amplified immunoglobulin heavy chain (IGH) and light chain (IGK) variable, diversity, and joining gene segments from genomic DNA. Amplified products were sequenced and analyzed using standardized algorithms for clonotype determination. Myeloma-specific clonotypes were identified for each patient based on their high-frequency (>5%) within the B-cell repertoire. Results: The NGS assay identified a high-frequency myeloma clonotype in 555/606 (92%) of patients with MM. Myeloma clonotype identification rates were 141/164 (86%) in BMA slides, 375/402 (93%) in RNA extracted from CD138+ plasma cells, 30/30 (100%) in methanol cell preparations, 13/13 (100%) in Ficoll cell preparations, 18/19 (95%) in RBC lysis cell preparations, and 5/5 (100%) using small amounts of input CD138+ DNA (approximately 5000 cells). These applicability rates are consistent with previous reports of sequencing applicability in MM patients. In thirteen patients, we investigated the potential loss of myeloma-specific clonotypes due to Ficoll cell preparation. The variation in myeloma cell loss was typically low but ranged from essentially no loss to the loss of more than 90% of the myeloma cells in the PBMC of one patient compared to the RBC lysis preparation. The myeloma cells were detected in the typically discarded lower layer of the Ficoll preparation which explained the loss. Conclusions: These results suggest that sequencing based MRD analysis is applicable in >90% of patients with MM. Multiple sample types, including archived BMA slides, can be used for identification of the myeloma clonotype. Further evaluation and optimization of sample processing methods is ongoing to enable application of the sequencing method for clinical MRD assessment in MM patients. Disclosures Zheng: Sequenta, Inc.: Employment, Equity Ownership. Faham:Sequenta, Inc.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Munshi:Celgene: Consultancy; Onyx: Consultancy; Janssen: Consultancy; Sanofi-Aventi: Consultancy; Oncopep: Consultancy, Equity Ownership, Patents & Royalties.

scholarly journals 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 ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1786-1786 ◽  
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.

Belantamab mafodotin in the treatment of relapsed or refractory multiple myeloma

2020 ◽  
Vol 16 (34) ◽  
pp. 2783-2798 ◽  
Author(s):  
Semira Sheikh ◽  
Eyal Lebel ◽  
Suzanne Trudel
Keyword(s):  
Multiple Myeloma ◽  
B Cell ◽  
Plasma Cells ◽  
Safety Data ◽  
Unmet Need ◽  
Cell Maturation ◽  
Antibody Drug Conjugate ◽  
Refractory Multiple Myeloma ◽  
B Cell Maturation ◽  
B Cell Maturation Antigen

Multiple myeloma remains an incurable disease, with a large proportion of patients in the relapsed/refractory setting often unable to achieve durable responses. Novel, well-tolerated and highly effective therapies in this patient population represent an unmet need. Preclinical studies have shown that B-cell maturation antigen is nearly exclusively expressed on normal and malignant plasma cells, thereby identifying it as a highly selective target for immunotherapeutic approaches. Belantamab mafodotin (GSK2857916, belamaf) is a first-in-class antibody–drug conjugate directed at B-cell maturation antigen and has shown promising activity in clinical trials. In this review, we provide an overview of belantamab mafodotin as a compound and present the available clinical efficacy and safety data in the treatment of relapsed/refractory multiple myeloma.

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

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4393-4393
Author(s):  
Scott Kristian Jew ◽  
Tiffany Chang ◽  
Sean Elliott Bujarski ◽  
Camilia Soof ◽  
Haiming Chen ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
B Cell ◽  
Clinical Response ◽  
Research Funding ◽  
Cell Maturation ◽  
B Cell Maturation ◽  
Equity Ownership ◽  
New Treatment ◽  
B Cell Maturation Antigen

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.

Constitutive B-Cell Maturation Antigen (BCMA) Activation In Human Multiple Myeloma Cells Promotes Myeloma Cell Growth and Survival In The Bone Marrow Microenvironment Via Upregulated MCL-1 and NFκB Signaling

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 681-681
Author(s):  
Yu-Tzu Tai ◽  
Chirag Acharya ◽  
Mike Y Zhong ◽  
Michele Cea ◽  
Antonia Cagnetta ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Growth ◽  
B Cell ◽  
Board Of Directors ◽  
Cell Maturation ◽  
Therapeutic Window ◽  
Advisory Committees ◽  
B Cell Maturation ◽  
Equity Ownership ◽  
B Cell Maturation Antigen

Abstract B cell maturation antigen (BCMA), a member of the tumor necrosis factor receptor superfamily (TNFRSF17), is selectively induced during plasma cell (PC) differentiation and is commonly expressed at high levels in malignant PCs. Using real time RT-PCR, we here first showed that BCMA mRNA was upregulated in CD138+ PCs from MM patients compared to normal healthy donors (p<0.04), consistent with high and restrictive BCMA expression in PCs but not normal tissues by gene expression profiling and immunohistochemistry (IHC) in a recent report (Clin Cancer Res 2013;19:2048-60). As a specific MM antigen, BCMA is universally expressed on the MM cell surface, confirmed by CD38+BCMA+ dual immunofluorescence staining. We next found that plasmacytoid dendritic cells (pDC), which support MM cell growth, survival, and drug resistance in the bone marrow (BM) microenvironment, have detectable BCMA mRNA at significantly (9-50-fold) lower levels than CD138+ plasma PCs (p<0.005 for each paired sample) from either MM patients or normal donors. Interestingly, as seen in CD138+ PCs, BCMA transcript is considerably elevated in pDC from MM patients vs. normal donors (p<0.03). In contrast, BCMA is hardly detectable in CD138-negative cells from BM aspirates of MM patients. We further define molecular mechanisms of BCMA activation in MM cells. Overexpression of BCMA in multiple MM cell lines (RPMI8226. MM1S, MM1R) by BCMA-expression vector significantly upregulates MCL-1 expression and MIP-1a, as well as NFkB p65 DNA binding activity. Conversely, BCMA siRNA blocked NFkB signaling and expression of anti-apoptotic proteins, leading to decreased MM cell viability. Importantly, stimulation of MM cells by APRIL, which is a cognate ligand for BCMA and mainly secreted by osteoclasts in the BM milieu, activated the canonical NFκB and PI3K/AKT pathways. APRIL also induces pro-survival/anti-apoptotic targets (BCL2A1, NFκB1, NFκB2) and chemotactic/osteoclast activating factors (MIP-1α and MIP1β) in a dose-dependent manner. Angiogenesis and adhesion/chemoattractant factors (IL-8, CXCL10, RANTES, MDC/ccl22) were also significantly induced upon APRIL stimulation. Conversely, BCMA-Fc protein inhibited APRIL to bind BCMA and inhibit secretion of APRIL-induced chemokines, indicating specific response of engagement of BCMA by APRIL in BCMA-expressing MM cells. Finally, APRIL induced adhesion and migration of MM cells whereas BCMA-Fc blocked APRIL-induced responses. Together, our results established active APRIL/BCMA signaling in MM in the BM microenvironment, thus providing a niche for MM disease progression. Moreover, these results strongly support rapid bench to bedside translation of the novel antagonistic anti-BCMA antibody drug conjugate (abstract #56099) to treat MM patients with a likely favorable therapeutic window. Disclosures: Tai: Onyx: Consultancy. Richardson:Millennium: Membership on an entity’s Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity’s Board of Directors or advisory committees; Novartis: Membership on an entity’s Board of Directors or advisory committees. Anderson:celgene: Consultancy; onyx: Consultancy; gilead: Consultancy; sanofi aventis: Consultancy; oncopep: Equity Ownership; acetylon: Equity Ownership.

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