The emergence of b-cell maturation antigen (BCMA) targeting immunotherapy in multiple myeloma

Objective Multiple myeloma, a plasma cell neoplasm is the second most common hematological malignancy in the United States. Despite significant advances in treatment armamentarium over the last decade, multiple myeloma remains an incurable malignancy. B-cell maturation antigen (BCMA) is an antigen expressed on the surface on plasma cells that can be targeted by novel mechanisms of action including antibody-drug conjugates (ADCs), bispecific T-cell engagers, and chimeric antigen receptor (CAR) T-cell therapy. This review summarizes the clinical application and development of approved and investigational immunotherapies targeting BCMA. Data Sources A search of the PubMed database was conducted using the following search terms: BCMA, CAR T, myeloma, belantamab mafodotin, and bispecific. Ongoing clinical trials, as well as abstracts from ASH and ASCO evaluating the efficacy and safety of novel agents targeting BCMA were evaluated. Prescribing information was also reviewed. Data Summary Since the discovery of BCMA as a target for myeloma, researchers have developed antibody-drug conjugates, bispecific T-cell engagers, and CAR T-cell therapies as novel treatment modalities for myeloma patients. Belantamab mafodotin and idecabtagene vicleucel represent currently available therapies and ongoing trials have demonstrated the efficacy and safety of bispecifics and other BCMA targeting therapies. Conclusion BCMA targeting antibody drug conjugates, bispecific T-cell engagers, and CAR T-cell therapies have demonstrated clinical activity in myeloma patients and represent novel therapies in multiple myeloma treatment paradigm.

Targeting B-cell maturation antigen increases sensitivity of multiple myeloma cells to MCL-1 inhibition

Not available.

Circulating Interleukin-7 in Human Pulmonary Arterial Hypertension

Objectives: Interleukin-7 (IL-7) secures B cell maturation, regulatory T and natural killer (NK) cell survival, and homeostasis, all of which are important for beneficial immunomodulation in pulmonary arterial hypertension (PAH). However, the role and potential impact of IL-7, VEGF-C and the vascular injury markers ICAM-1, and VCAM-1 on the pathobiology and severity of PAH is unknown.Methods: EDTA blood was collected during cardiac catheterization from the superior vena cava (SVC), pulmonary artery (PA), and ascending aorta (AAO) in children with pulmonary hypertension (PH) [n = 10; 9.1 (3.9–18.5) years] and non-PH controls [n = 10; 10.5 (2.0–17.3) years]. Compartment-specific plasma concentrations of IL-7, VEGF-C, aldosterone, ICAM-1, and VCAM-1 were determined using Meso Scale Discovery's multi array technology and the LIAISON Aldosterone Assay.Results: Children with PH had approximately 50% lower IL-7 (p < 0.01) and 59% lower VEGF-C plasma levels (p < 0.001) in the SVC, PA, and AAO versus non-PH controls. IL-7 and VEGF-C concentrations negatively correlated with the pulmonary vascular resistance (PVR)/systemic vascular resistance (SVR) ratio (rho = −0.51 and r = −0.62, respectively). Central-venous IL-7 strongly positively correlated with VEGF-C (r = 0.81). Most patients had a step down in ICAM-1 and VCAM-1 plasma concentrations across the pulmonary circulation and both ICAM-1 and VCAM-1 transpulmonary gradients negatively correlated with invasive hemodynamics.Conclusion: This manuscript is the first report on decreased circulating IL-7 and VEGF-C plasma concentrations in human PAH and their inverse correlations with invasive surrogates of PAH severity. Additional and larger studies are needed to explore the role of the immune-modulatory IL-7 and VEGF-C in pediatric and adult PAH.

Early Dynamics and Depth of Response in Multiple Myeloma Patients Treated With BCMA CAR-T Cells

Chimeric antigen receptor T-cell (CAR-T) therapy targeted against B-cell maturation antigen (BCMA) in multiple myeloma (MM) has produced rapid responses but many eventually relapse. In light of this new treatment, novel predictors of progression-free survival (PFS) are needed. We performed a single institution analysis of 54 BCMA-CAR-T patients. We analyzed patient’s overall response rate (ORR) by the IMWG criteria, involved serum-free light chains (iFLC), and minimal residual disease testing by next-generation sequencing (MRD-NGS). Between patients who achieved a ≤SD and those who achieved a ≥PR, PFS differed significantly (p < 0.0001); though there was no difference between patients who achieved a ≥CR vs. VGPR/PR (p = 0.2). In contrast, patients who achieved a nonelevated iFLC at 15 days (p < 0.0001, HR = 6.8; 95% CI, 2.7–17.3) or 30 days (p < 0.001, HR = 16.7; 95% CI, 3.9–71.7) had a prolonged PFS compared with those with an elevated iFLC. Patients achieving MRD-NGS less than the detectable limit at a sensitivity of 10−6 had a better PFS than those with detectable disease at 1 month (p = 0.02) and 3 months (p = 0.02). In conclusion, achieving a nonelevated iFLC and an undetectable MRD-NGS quickly were factors that were strongly associated with improved PFS. Further studies are needed to confirm the role of these markers in MM patients receiving CAR-T therapies.

“Real-life” data of the efficacy and safety of belantamab mafodotin in relapsed multiple myeloma—the Mayo Clinic experience

Belantamab mafodotin is a highly selective targeted therapy for multiple myeloma. It targets the B cell maturation antigen (BCMA) on plasma cells and showed promising results in several randomized clinical trials. We report the outcomes of 36 patients treated at Mayo Clinic. Our cohort received a median of eight prior lines of therapy. Six patients received belantamab in combination with other medications (pomalidomide, cyclophosphamide, thalidomide), 13 patients (36%) were 70 years or older, two patients had a creatinine of >2.5 mg/dL, and one patient was on dialysis. All three patients with renal failure received full dose belantamab. Chimeric antigen receptor (CAR-T) therapy was used prior to belantamab in seven patients and none of them responded to belantamab therapy. The overall response rate (ORR) was 33% (CR 6%, VGPR 8%, PR 19%), like the ORR reported in the DREAMM-2 trial. Keratopathy developed in 16 patients (43%), grade 1 in six patients, grade 2 in seven patients, and grade 3 in three patients. Eight percent discontinued therapy due to keratopathy. The median PFS and OS was 2 months and 6.5 months, respectively.

First report of CART treatment in AL amyloidosis and relapsed/refractory multiple myeloma

Multiple myeloma (MM) remains incurable despite the number of novel therapies that have become available in recent years. Occasionally, a patient with MM will develop an amyloid light-chain (AL) amyloidosis with organ dysfunction. Chimeric antigen receptor T-cell (CART) therapy has become a promising approach in treating hematological malignancies. Our institution has developed a second-generation B-cell maturation antigen (BCMA)–CART which is currently being tested in a clinical trial for relapsed/refractory MM.We present the first reported case, to our knowledge, of a patient with AL amyloidosis and renal involvement in the course of an MM, successfully treated with CART therapy targeting BCMA. The patient received a fractioned dose of 3×106/kg BCMA–CARTs after lymphodepletion. At 3 months from infusion, the patient had already obtained a deep hematological response with negative measurable residual disease by flow cytometry in the bone marrow. After 12 months, the patient remains in hematological stringent complete remission and has achieved an organ renal response with a decrease of 70% of proteinuria.This case suggests that concomitant AL amyloidosis in the setting of MM can benefit from CART therapy, even in patients in which predominant symptoms at the time of treating are caused by AL amyloidosis.

Belantamab Mafodotin and Relapsed/Refractory Multiple Myeloma: This Is Not Game Over

Although the therapeutic landscape for multiple myeloma (MM) has expanded, the disease always tends to relapse. In attempt to obtain deep and durable responses, each relapse requires the use of a new strategy. In recent years, new treatment options have emerged even for heavily treated patients. Novel, well-tolerated and highly effective therapies in the relapsed/refractory (RRMM) setting currently represent a real hope. Belantamab mafodotin (BLENREP™) is a first-in-class monoclonal antibody-drug conjugate (ADC) whose target is B-cell maturation antigen (BCMA) conjugated to the cytotoxic microtubule inhibitor monomethyl auristatin F (MMAF). Here, we present two cases of heavily pre-treated RRMM patients that were favorably treated with Belantamab mafodotin, obtaining at least a partial response. Treatment was well tolerated and is ongoing. This is a rare report on real life clinical use of Belantamab mafodotin outside of controlled clinical trials and provide information on efficacy and safety of this anti-myeloma new class of drugs.

An Interim Report on a Phase 1/2 Study of HPN217, a Half-Life Extended Tri-Specific T Cell Activating Construct (TriTAC ®) Targeting B Cell Maturation Antigen for the Treatment of Relapsed/Refractory Multiple Myeloma

Background B cell maturation antigen (BCMA) is a clinically validated target for multiple myeloma (MM) based on its restricted expression profile and potential functional role in promoting MM cell survival. HPN217 is a BCMA-targeting T cell engager derived from the Harpoon Tri-specific T cell Activating Construct (TriTAC ®) platform. It is a recombinant polypeptide of approximately 50 kDa, engineered to be a small globular protein to enable efficient drug diffusion and exposure in tumor tissue and have a prolonged serum half-life at the same time. It contains three humanized antibody-derived binding domains, targeting BCMA for MM cell binding, albumin for half-life extension, and CD3ε for T cell engagement, activation, and cytolytic function differentiation. Methods The ongoing Phase 1 study initially evaluates escalating doses of once weekly IV administrations of HPN217 in patients with relapsed/refractory (R/R) MM who have received at least 3 prior therapies including a proteasome inhibitor, an immunomodulatory drug, and a CD38-targeted therapy. Prior exposure to BCMA-targeting agent is permitted for this initial part of the trial. Premedication to minimize cytokine release syndrome (CRS) includes dexamethasone, diphenhydramine, acetaminophen, and a proton pump inhibitor. Primary endpoints are safety, tolerability, and determination of maximum tolerated dose (MTD) and/or recommended phase two dose (RP2D). Secondary objectives are pharmacokinetics (PK), pharmacodynamics, immunogenicity, and preliminary anti-myeloma activity. Results As of July 5, 2021, 22 patients have been treated with HPN217 in 8 individual cohorts ranging from 5 to 2150 µg/week. Patients treated received a median of 8 (range of 4 - 16) prior systemic regimens, including 5 patients who received prior BCMA-targeted belantamab mafodotin or orvacabtagene autoleucel. No dose-limiting toxicities (DLTs) have been observed and MTD has not been reached. The most common treatment-emergent adverse events (TEAEs) are hematological changes including anemia, neutropenia, and thrombocytopenia. No CRS was observed in dose cohorts receiving 5 - 270 µg/week (n=7). CRS (Grade 1, 2) was observed in 4 of 15 patients receiving ≥810 µg/week. In one patient treated at 810 µg/week, transient elevated liver transaminases (Grade 4 AST and Grade 3 ALT) was observed. A second patient in the 270 µg/week cohort also showed Grade 1 AST increase. All CRS events and liver enzyme increases resolved, and all patients were successfully re-treated with escalating doses. HPN217 demonstrated a dose proportional increase in Cmax and AUC with a median serum half-life of 74 hours (range of 38 - 197 hours), confirming half-life extension. Half-life, clearance rate, and volume of distribution were dose-independent, suggesting linear PK kinetics. Pharmacodynamic analysis shows a dose-dependent, transient increases in serum cytokines and chemokines (e.g., IL-6, IL-8, IL-10, TNFα). A transient reduction in circulating T lymphocytes accompanied by upregulation of the activation markers CD25 and CD69 were also observed. Patient response to treatment will be reported. Conclusions HPN217 represents a novel half-life extended BCMA-targeting T cell engager that can be safely administered to patients with R/R MM at a dose of up to 2150 µg weekly. TEAEs have been transient and manageable. Transient serum cytokine/chemokine increase, T cell margination and upregulation of T cell activation markers, indicate target engagement of BCMA on plasma cells and CD3 on T cells, respectively, supporting the proposed mechanism of action for HPN217. Dose escalation, including implementation of step dosing, with the goal of establishing an RP2D regimen, is ongoing. NCT04184050 Disclosures Madan: Sanofi: Consultancy, Research Funding; GSK: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Karyopharm: Research Funding, Speakers Bureau; Takeda: Speakers Bureau; BMS: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau. Cowan: Janssen: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Sanofi Aventis: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding; Secura Bio: Consultancy; Cellectar: Consultancy; Nektar: Research Funding; GSK: Consultancy; Harpoon: Research Funding. Bensinger: BMS, Janssen, Poseida, Regeneron, Trillium: Research Funding; Amgen, BMS, Janssen, Sanofi: Speakers Bureau. Hillengass: Oncotracker: Membership on an entity's Board of Directors or advisory committees; Curio Science: Speakers Bureau; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Beijing Medical Award Foundation: Speakers Bureau; Adaptive: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Skyline: Membership on an entity's Board of Directors or advisory committees; Axxess Network: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Beijing Life Oasis Public Service Center: Speakers Bureau. Leleu: Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Carsgen Therapeutics Ltd: Honoraria; Celgene: Honoraria; Gilead Sciences: Honoraria; AbbVie: Honoraria; Janssen-Cilag: Honoraria; Karyopharm Therapeutics: Honoraria; Merck: Honoraria; Mundipharma: Honoraria; Novartis: Honoraria; Oncopeptides: Honoraria; Pierre Fabre: Honoraria; Roche: Honoraria; Sanofi: Honoraria; Takeda: Honoraria, Other: Non-financial support. Lipe: Seagen Inc.: Research Funding; BMS: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; sanofi: Consultancy; GlaxoSmithKline: Consultancy; amgen: Research Funding; Cellectar: Research Funding; Karyopharm: Research Funding; Harpoon: Research Funding. Nath: Harpoon Therapeutics: Consultancy, Current equity holder in publicly-traded company. Sun: Harpoon Therapeutics: Consultancy, Current equity holder in publicly-traded company, Ended employment in the past 24 months.