pacanalotamab (AMG 420) / Amgen, Boehringer Ingelheim - LARVOL DELTA

Safety and Efficacy of Anti-B-cell Maturation Antigen (Anti-BCMA) Bispecific Antibodies for Relapsed/Refractory Multiple Myeloma: A Systematic Review of Clinical Trials. (PubMed, Cureus) - "AMG-420, AMG-701, elranatamab, REGN5458, teclistamab (Tec), alnuctamab (ALNUC), and ABBV-383 are the seven anti-BCMA-CD3 bispecific Abs currently being assessed in clinical trials as monotherapy and in combination with immunomodulators/proteasome inhibitors against RRMM. Our analysis of the trials revealed that bispecific Abs showed efficacy in RRMM, with CRS and hematologic toxicities being the most common adverse events, mostly low-grade and manageable. Based on the promising efficacy and safety of BCMA targeting bispecific Abs, these drugs are emerging as a new therapeutic option for patients with advanced and RRMM."

Journal • Review • Hematological Disorders • Hematological Malignancies • Inflammation • Multiple Myeloma • Oncology

Pooled Analysis on Bispecific Antibody-Related Toxicities in Multiple Myeloma (ASH 2023) - "BsAb included in our study were the following: Teclistamab, Elranatamab, REGN-5458, AMG420, AMG701, CC-93269, TNB-383B, Linvoseltamab, Talquetamab, and Cevostamab. The use of BsAbs in MM has demonstrated remarkable efficacy; however, these have been linked to a unique adverse event profile. Our results showed that non-BCMA bsAb were associated less hematotoxicity (combined grade 3-4 events and hypogammaglobulinemia), whereas BCMA bsAb were associated with less CRS rates. This is important information for treatment selection and mitigation strategy development aiming to optimize patient outcomes."

Retrospective data • Anemia • Hematological Disorders • Hematological Malignancies • Infectious Disease • Leukopenia • Multiple Myeloma • Neutropenia • Oncology • Thrombocytopenia

BCMA-targeting BiTE molecule AMG 420 in relapsed or refractory multiple myeloma: a phase 1b open-label expansion study. (PubMed, Leuk Lymphoma) - P1 | "Overall response rate was 34.8%; median progression-free survival was 2.83 months; and minimal residual disease-negative complete responses were reported in 8.7% of patients. Overall, the safety profile and efficacy from AMG 420 established the proof-of-concept of T-cell engager therapy as a promising therapeutic class in multiple myeloma and BCMA as an effective target for T-cell engager therapy."

Journal • P1 data • Hematological Malignancies • Infectious Disease • Inflammation • Multiple Myeloma • Oncology • Pain • Septic Shock

Assessment of AMG 420 in Subjects With Relapsed and/or Refractory Multiple Myeloma (clinicaltrials.gov) - P1 | N=23 | Terminated | Sponsor: Amgen | Phase classification: P1b ➔ P1 | Completed ➔ Terminated; Amgen re-evaluated the portfolio and decided to discontinue clinical development activities for AMG 420.

Monotherapy • Phase classification • Trial termination • Hematological Malignancies • Multiple Myeloma • Oncology

INFECTIONS FOLLOWING BISPECIFIC ANTIBODIES IN MYELOMA: A SYSTEMATIC REVIEW AND META-ANALYSIS (EHA 2023) - "Despite promising efficacy in MM, BsAbs may come with substantial infection risk, warranting more detailed analysis of infections and immune phenotyping to guide targeted supportive care. Table – Summary of included studiesAgent Target Source Phase Enrolment (mm/yy) N Median prior lines All- Grade Infection N (%) Grade ≥3 Infection N (%) Alnuctamab (CC-93269) BCMA Wong 2022 I 03/18- 68 4 23 (34) 6 (9) ABBV-383 BCMA Voorhees 2022 I 10/22- 174 5 61/124 (50) 39/124 (22) Elranatamab BCMA Raje 2022 I 10/21- 123 5 82 (67) 43 (35) Linvoseltamab (REGN545) BCMA Bumma 2022 Ib/II 1/19- 252 5 136 (54) 73 (29) Pacanalotamab (AMG-420) BCMA Topp 2020 I 3/19 – 4/22 42 5 14 (33) 10 (24) Teclistamab BCMA Moreau 2022 I/II 09/20- 165 5 126 (77) 57 (45) Teclistamab + daratumumab BCMA + CD38 Rodriguez- Otero 2022 II 03/21- 46 5 29 (63) 8 (17) Forimtamig (RG6234) GPRC5D Carlo- Stella 2022 I 11/20- IV: 51 SC: 57 IV: 5 SC: 4 IV: 31 (61) SC: 26 (46) IV:11 (22) SC:15 (27) Talquetamab GPRC5D Chari..."

Retrospective data • Review • Hematological Disorders • Hematological Malignancies • Infectious Disease • Multiple Myeloma • Neutropenia • Oncology

[VIRTUAL] Novel Therapies for the Treatment of Patients with Relapsed/Refractory Multiple Myeloma: A Review of Clinical Trials (ASH 2020) - P1, P1/2, P1b, P1b/2a, P2, P3 | " We summarized the interim results from ongoing clinical trials evaluating treatment of RRMM under following newer categories of drugs: In a phase 1b/IIa trial (NCT02773030, N=51) evaluating the efficacy of a novel immunomodulators, iberdomide CC-220 + dexamethasone (Dex) yielded an overall response rate (ORR) of 31%, clinical benefit (CB) was seen in 51% of the patients, and disease control (DC) in 88% of the patients and it was well tolerated by RRMM patients. There are other ongoing clinical trials evaluating the efficacy of Avadomide (CC-122), CC-92480 in RRMM. In a phase I/II trial (NCT01897714, N=45), melphalan-flufenamide (melflufan) + Dex yielded an ORR of 31%, it was well tolerated with 49% CB. Phase III OCEAN trial (NCT03151811, N=450) is currently ongoing to compare melflufen + Dex vs. pomalidomide (Pom) + Dex...The interim results from a phase I/II trial (NCT03314181, N=104) of Ven + daratumumab (Dara) + Dex showed ORR of 96%..."

Clinical • Hematological Malignancies • Immune Modulation • Inflammation • Multiple Myeloma • Oncology • Plasmacytoma

[VIRTUAL] Safety and Efficacy of Anti-Bcma CAR-T Cells for Relapsed/Refractory Multiple Myeloma: A Systematic Review of Literature (ASH 2020) - "An ORR of 100% with 64% stringent CR (sCR) and 36% VGPR was reported with novel anti-BCMA CART cells (CT103A)...BCMA targeting agent, JNJ-4528, showed ORR of 91%, including 4sCR, 2CR, 10MRD, and 7VGPR. CAR-T- bb2121 demonstrated ORR of 85%, sCR 36%, CR 9%, VGPR 57%, and MRD negativity of 100% (among 16 responsive pts). GSK2857916, a BCMA targeting CAR-T cells yielded ORR of 60% in both clinical trials...reported ORR of 31% along with 5 ≥CR and 5 MRD negative status in 42 pts treated with Bi T-cells Engager BiTE® Ab BCMA targeting antigen (AMG420)...The most common adverse effects exhibited were grade 1-3 hematologic (cytopenia) and cytokine release syndrome (CRS) (mostly reversible with tocilizumab). Initial data from ongoing clinical trials using BCMA targeting CAR-T therapy have yielded promising results both in terms of improved outcome and tolerable toxicity profiles. Although two phase 3 trails are ongoing, additional data is warranted to further ensure the..."

CAR T-Cell Therapy • Clinical • IO Biomarker • Review • Hematological Disorders • Hematological Malignancies • Multiple Myeloma • Oncology • CD38

Efficacy and safety of cilta-cel in patients with progressive multiple myeloma after exposure to BCMA-targeting bispecific antibody treatment (IMW 2022) - P2 | "Of the patients who received cilta-cel, 3 had prior teclistamab, and 1 each had prior AMG 420, AMG 701, PF06863135, and WVT078. Cilta-cel induced favorable responses, DOR, and PFS in heavily pretreated MM patients with prior anti-BCMA BsAb exposure. These initial results may inform treatment plans, including sequencing and washout periods between agents targeting BCMA."

Clinical • CNS Disorders • Gastroenterology • Gastrointestinal Disorder • Hematological Disorders • Hematological Malignancies • Immune Modulation • Immunology • Infectious Disease • Inflammation • Movement Disorders • Multiple Myeloma • Novel Coronavirus Disease • Oncology • Parkinson's Disease • Pneumonia • Respiratory Diseases • Subarachnoid Hemorrhage

Leveraging a physiologically-based quantitative translational modeling platform for designing B cell maturation antigen-targeting bispecific T cell engagers for treatment of multiple myeloma. (PubMed, PLoS Comput Biol) - "The biodistribution of TCEs was verified by positron emission tomography imaging of [89Zr]AMG211 (a carcinoembryonic antigen-targeting TCE) in patients. The final model simulations indicated that the number of immune synapses is similar (~55/tumor cell) between two distinct clinical stage B cell maturation antigen (BCMA)-targeting TCEs, PF-06863135 in an IgG format and AMG420 in a BiTE format, at their respective efficacious doses in multiple myeloma patients. This result demonstrates the applicability of the developed computational modeling framework to molecular design optimization and clinical benchmarking for TCEs, thus suggesting that this framework can be applied to other targets to provide a quantitative means to facilitate model-informed best-in-class TCE discovery and development."

IO biomarker • Journal • Hematological Disorders • Hematological Malignancies • Multiple Myeloma • Oncology • CEACAM5

Assessment of AMG 420 in Subjects With Relapsed and/or Refractory Multiple Myeloma (clinicaltrials.gov) - P1b | N=23 | Completed | Sponsor: Amgen | Active, not recruiting ➔ Completed

Monotherapy • Trial completion • Hematological Malignancies • Multiple Myeloma • Oncology

Bispecific T-Cell Engager Antibodies in Multiple Myeloma- a Systematic Review of Phase 1 Clinical Trials (ASH 2021) - "(n= 40) stated an overall response rate (ORR) of 65% among patients receiving subcutaneous (SQ) teclistamab with a median of five prior therapies, 30% and 58% of the responders had a complete response (CR) and very good partial response (VGPR), respectively. A similar ORR of 63% was reported in 28 patients with a median of 5.5 prior therapies receiving SQ talquetamab by Berdeja et al. Cohen et al reported an ORR of 51.7% in patients receiving IV BFCR4350A at doses ≥3.6/20mg (Partial response (PR):17.2% and CR: 10.3%). SQ elranatamab achieved an ORR of 75% in 17 patients who received doses ≥215 μg/kg...evaluated REGN5458 monotherapy with dose escalation from 3 to 96 mg among 45 patients and reported an ORR of 60% at the highest dose levels. ORR of 31% was reported in 42 patients receiving IV BI836909/AMG 420 by Topp et al... The early clinical data of Bispecific T-Cell Engager therapy in heavily pretreated RRMM patients shows promising results regarding its efficacy and..."

Clinical • P1 data • Review • Anemia • Hematological Malignancies • Infectious Disease • Inflammation • Multiple Myeloma • Neutropenia

Assessment of AMG 420 in Subjects With Relapsed and/or Refractory Multiple Myeloma (clinicaltrials.gov) - P1b; N=23; Active, not recruiting; Sponsor: Amgen; Trial completion date: Feb 2025 ➔ Jun 2022; Trial primary completion date: Feb 2022 ➔ Jun 2022

Trial completion date • Trial primary completion date • Hematological Malignancies • Multiple Myeloma • Oncology

[VIRTUAL] Outcome of BCMA Bite (AMG420) Therapy in Relapse and Refractory Multiple Myeloma (RRMM) Patients (ASH 2020) - P1 | "Despite this small numbers and reporting of single institutional experience these results are encouraging in light of recent long term data of BCMA CAR-T therapy reporting on a PFS of less than 12 months. The data warrante further investigation of -BCMA targeted BiAB’s as a treatment modality in RRMM patients."

Clinical • Hematological Malignancies • Infectious Disease • Multiple Myeloma • Oncology • Respiratory Diseases

Evaluation of AMG 420, an anti-BCMA bispecific T-cell engager (BiTE) immunotherapy, in R/R multiple myeloma (MM) patients: Updated results of a first-in-human (FIH) phase I dose escalation study. (ASCO 2019) - P1; "In this FIH study of AMG 420, a BiTE vs BCMA, in R/R MM, there was a 70% response rate (7/10) with 5 out of 7 responders achieving a sCR at 400 µg/d, a recommended dose for further investigation. Clinical trial information: NCT02514239"

Clinical • P1 data • Hematological Malignancies • Leukemia • Multiple Myeloma • Oncology

Treatment with AMG 420, an Anti-B-Cell Maturation Antigen (BCMA) Bispecific T-Cell Engager (BiTE®) Antibody Construct, Induces Minimal Residual Disease (MRD) Negative Complete Responses in Relapsed and/or Refractory (R/R) Multiple Myeloma (MM) Patients: Results of a First-in-Human (FIH) Phase I Dose Escalation Study (ASH 2018) - P1; "During dose escalation, all 3 patients dosed with 400 µg/d had MRD-negative CRs, with 2 more responders in the dose confirmation cohort to date; 3 patients at lower doses also attained CRs. No major toxicities were observed up to 400 µg/d, which is a recommended dose for further investigation; DLTs at 800 µg/d were CRS and PPN."

Clinical • P1 data • Residual disease • Biosimilar • Brain Cancer • Cardiovascular • Gene Therapies • Heart Failure • Hematological Disorders • Hematological Malignancies • Hypertension • Immune Modulation • Immunology • Inflammation • Leukemia • Multiple Myeloma • Oncology • Pain • Renal Disease

EVALUATION OF AMG 420, AN ANTI-BCMA BISPECIFIC T-CELL ENGAGER (BITE®) IMMUNOTHERAPY, IN R/R MULTIPLE MYELOMA (MM) PATIENTS: UPDATED RESULTS OF A FIRST-IN-HUMAN (FIH) PHASE 1 DOSE ESCALATION STUDY (EHA 2019) - P1; "Overall, there were 13/42 responders (6 sCRs, 3 CRs, 2 VGPRs, 2 PRs). Median time to any response was 1 month, with 9 of 13 patients responding in the first cycle. Conclusion In this FIH study of AMG 420, a BiTE® vs BCMA, in R/R MM, there was a 70% response rate (7/10) with 5 out of 7 responders achieving a sCR at 400 µg/d, a recommended dose for further investigation."

Clinical • P1 data • Gene Therapies • Hematological Disorders • Hematological Malignancies • Immunology • Leukemia • Multiple Myeloma • Oncology • Pain

BCMA-targeted BiTEs for multiple myeloma (YouTube) - "Niels van de Donk...gives an overview of the use of B-cell maturation antigen (BCMA)-targeted T-cell redirectors, and discusses how these fit into the treatment landscape for myeloma....Finally, Prof. van de Donk discusses the role of chimeric antigen receptor T-cell (CAR-T) therapies for the treatment of myeloma, highlighting pros and cons in comparison to BiTEs."

Interview • Video

Cases from the Community: Investigators Discuss Emerging Research and Actual Patients with Multiple Myeloma (Research To Practice) - "MODULE 1: Up-Front Management of Newly Diagnosed Multiple Myeloma (NDMM)....MODULE 4: Novel Agents and Strategies Under Investigation."

CME

[VIRTUAL] Recent updates on bispecific T-cell engager (BiTE) antibodies in relapsed and refractory multiple myeloma. (ASCO 2021) - "reported ORR of 39% in 49 pts treated with REGN5458 an anti BCMA and CD3 BiTE antibody...al reported an ORR of 73% with Teclistamab at 1500µg/kg SC...reported ORR of 83% in 9 pts treated with 9mg of AMG 701...reported an ORR of 80% among 15 RRMM pts treated with TNB-383B at the dose of 40-60mg IV every 3 weeks . Topp et al reported an ORR of 70% among 10 pts treated with AMG420/BI-836909 at MTD of 400µg/d . Chari et al reported results of Talquetamab which targets GPRC5D which showed an ORR of 66% in 55 evaluable pts...Cohen et al reported results on BFCR4350A, an anti FcRH5 BiTE which showed an ORR of 53% at dose ≥3.6/20mg Q3W...Most of the CRS cases were grade 1-2 and resolved either by themselves or required treatment with tocilizumab and steroids... The most recent data on BiTE antibodies in RRMM has shown promising results with good tolerability . However, the trials are ongoing and a longer follow up is needed."

Hematological Disorders • Hematological Malignancies • Inflammation • Multiple Myeloma • Oncology

AMG 420 and AMG 701 in R/R myeloma (YouTube) - "Hermann Einsele, MD...discusses the use of the bispecific T-cell engagers (BiTEs), AMG 420 and AMG 701, for the treatment of multiple myeloma....This interview took place during the 7th World Congress on Controversies in Multiple Myeloma (COMy), 2021."

Interview • Video

COMy 2020 | The benefits of bispecific antibodies for treating multiple myeloma (VJHemOnc) - "Luciano Costa, MD, PhD, UAB School of Medicine, Birmingham, AL, discusses the emergence of bispecific antibodies to treat multiple myeloma. Bispecific antibodies work in a similar way to CAR T-cells to destroy tumors, however, they do not have the same constraints as CAR T-cells....This interview took place during the Controversies in Multiple Myeloma (COMy) 2020 Virtual World Congress."

Interview • Video

AMG420 (International Myeloma Society)

Live event

Novel immunotherapies for myeloma treatment (YouTube) - "Hermann Einsele, MD, FRCP...discusses the use of novel immunotherapies for the treatment of multiple myeloma. Prof. Einsele highlights data from the Phase Ib trial (NCT03836053) of AMG 420, which demonstrated promising efficacy results, and gives a broad overview of other bispecific T-cell engagers (BiTEs) which are being developed for the treatment of multiple myeloma."

Video

BiTEs for the treatment of multiple myeloma (YouTube) - "Hermann Einsele, MD, FRCP...gives an overview of his presentation at EMN 2021 on the use of bispecific T-cell engagers (BiTEs) for the treatment of multiple myeloma. Prof. Einsele outlines how BiTEs can be used to tackle challenges associated with a lack of antitumor reactive T-cells in patients with multiple myeloma....Finally, he outlines the use of the CD3 and GPRC5D-targeting BiTE, talquetamab, and cevostamab, which targets FcRH5 and CD3 for myeloma treatment."

Video

Expert Selections From ASH 2020: Multiple Myeloma (Clinical Care Options) - "In this commentary, Shaji K. Kumar, MD, and Sagar Lonial, MD, share insights on selected abstracts from ASH 2020 about multiple myeloma (MM) and how these data are poised to affect clinical practice."