alnuctamab (CC-93269) / BMS - LARVOL DELTA

BCMA Extracellular Domain Functional Hotspots and Resistance to Variable Anti-BCMA T Cell Engagers in Multiple Myeloma (ASH 2024) - "K562 cells stably transduced to express wild type (wt) or mutant BCMA (50 clones) were screened for surface BCMA expression by flow cytometry, as well as teclistamab, elranatamab, and alnuctamab binding and cytotoxicity in cocultures with peripheral blood mononuclear cells. In summary, we herein established a dictionary of BCMA functional hotspots and characterized their differential impact on anti-BCMA TCE binding and cytotoxicity. These results will not only support the rational design of future anti-BCMA agents but also guide the clinical sequencing of anti-BCMA therapies."

IO biomarker • Hematological Malignancies • Multiple Myeloma • Oncology • TNFRSF17

Comprehensive Review of Bispecific Antibody Constructs In Multiple Myeloma: Affinities, Dosing Strategies and Future Perspectives. (PubMed, Clin Lymphoma Myeloma Leuk) - "Teclistamab, elranatamab (both BCMA × CD3), and talquetamab (GPRC5D × CD3) are approved for treating MM patients who have received at least 3 prior lines of therapy, including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody...As linvoseltamab, alnuctamab, and ABBV-383 (all BCMA × CD3), as well as forimtamig (GPRC5D × CD3) and cevostamab (FcRH5 × CD3) progress through late-stage clinical development, emerging trispecific antibodies are now available that target either 2 different MM-associated antigens or provide additional co-stimulatory signals to prevent T-cell exhaustion. Despite this plethora of therapeutic options, resistance to bsAbs is an inevitability, and the optimal positioning of these drugs within the current MM treatment landscape remains to be determined. In this review, we examine the available data on all clinically accessible bsAbs, evaluating their potential, current limitations, and..."

Journal • Review • Hematological Malignancies • Multiple Myeloma • Oncology

BCMA Mutational Screening Reveals Differential Cytotoxic Activity between T-Cell Engagers in Preclinical Co-Culture Models (ASH 2024) - "In the context of a WT expressing system, elranatamab and alnuctamab were more sensitive in inducing T-cell mediated killing in comparison to teclistamab. Finally, we identified novel mutations which can abrogate TCE activity, however most of the mutants tested in our system demonstrated sustained sensitivity to TCEs albeit the extent varied between each TCE with elranatamab and alnuctamab appearing to have broader activity compared to teclistamab."

IO biomarker • Preclinical • Hematological Disorders • Hematological Malignancies • Multiple Myeloma • Oncology

MODULE 4: Bispecific Antibodies for the Treatment of MM (ASH 2024) - "This program is supported by educational grants from GSK, Janssen Biotech Inc, administered by Janssen Scientific Affairs LLC and Karyopharm Therapeutics.Available efficacy and safety findings leading to the FDA approvals of the BCMA-directed bispecific antibodies teclistamab and elranatamab for R/R MM; optimal incorporation into management algorithms Efficacy and safety documented with investigational anti-BCMA bispecific antibodies for pretreated MM, such as linvoseltamab and alnuctamab Available efficacy and safety findings with non-BCMA-targeted bispecific antibodies for MM, such as talquetamab and cevostamab Recent FDA approval and optimal incorporation of talquetamab into disease management Spectrum, incidence and severity of CRS and other toxicities with various BCMA- and non-BCMA-directed bispecific antibodies; optimal mitigation and management strategies Rationale for and early-phase data with bispecific antibodies in combination with other systemic therapies,..."

Hematological Malignancies • Multiple Myeloma • Oncology

A Study to Evaluate Alnuctamab in Combination With Mezigdomide in Participants With Relapsed and/or Refractory Multiple Myeloma (clinicaltrials.gov) - P1 | N=156 | Active, not recruiting | Sponsor: Celgene | Phase classification: P1/2 ➔ P1 | Trial primary completion date: Aug 2025 ➔ May 2025

Combination therapy • Phase classification • Trial primary completion date • Hematological Malignancies • Multiple Myeloma • Oncology

Low infection rates in patients (pts) with relapsed/refractory myeloma (RRMM) treated with alnuctamab (ALNUC) in a setting of infection reduction strategies (IRS) and less frequent dosing (IMW 2024) - P1 | "IRS included exclusion of pts with respiratory viruses and prophylaxis against bacteria (eg, levofloxacin; C1–3 and during G≥3 neutropenia), Pneumocystis (eg, trimethoprim-sulfamethoxazole; all Cs), and HSV/VZV (eg, acyclovir; all Cs). These data suggest that aggressive IRS, IRT, and reduced dosing frequency of ALNUC in later cycles contributed to successful reduction of infection rates. Additional immunologic analyses are ongoing to determine the relationship between low infection rates and the unique bivalent format/schedule of ALNUC."

Clinical • Cytomegalovirus Infection • Gastrointestinal Disorder • Hematological Disorders • Hematological Malignancies • Infectious Disease • Influenza • Multiple Myeloma • Neutropenia • Novel Coronavirus Disease • Oncology • Pneumonia • Respiratory Diseases • Septic Shock

A Study to Evaluate Alnuctamab in Combination With Mezigdomide in Participants With Relapsed and/or Refractory Multiple Myeloma (clinicaltrials.gov) - P1/2 | N=156 | Active, not recruiting | Sponsor: Celgene | Trial completion date: Feb 2032 ➔ Aug 2025 | Trial primary completion date: Feb 2032 ➔ Aug 2025

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

TRIAL IN PROGRESS: ALUMMINATE RRMM – A RANDOMIZED PHASE 3 STUDY OF ALNUCTAMAB, A BCMA-TARGETING T-CELL ENGAGER, VS STANDARD OF CARE IN PATIENTS WITH RELAPSED/REFRACTORY (RR) MULTIPLE MYELOMA (MM) (EHA 2024) - P3 | " Approximately 466 pts will be randomized 1:1 to receive SC ALNUC or investigator's choice SOC(daratumumab + pomalidomide + dexamethasone [DPd], elotuzumab + pomalidomide + dexamethasone[EPd], or carfilzomib + dexamethasone [Kd])...Key inclusion criteria include age ≥ 18 years with ECOG performance status ≤ 2 and measurable disease, 1–3prior antimyeloma LOTs including lenalidomide and an anti-CD38 mAb, progression during or after the mostrecent LOT (or failure to achieve a response), and a minimal response or better to ≥ 1 prior LOT... First enrollment is expected in March 2024."

Clinical • P3 data • Hematological Malignancies • Multiple Myeloma • Oncology

BMS axes multiple myeloma bispecific months after filing to run phase 3 trial (FierceBiotech) - "Bristol Myers Squibb has had a whiplash change of heart on its BCMA bispecific T-cell engager, halting (PDF) further development months after filing to run a phase 3 trial....BMS added a phase 3 study of the bispecific, alnuctamab, to ClinicalTrials.gov in January. At the time, the company planned to enroll 466 patients to show whether the candidate could improve progression-free survival in people with relapsed or refractory multiple myeloma. However, BMS abandoned the study within months of the initial filing....The drugmaker withdrew the study in May, on the grounds that 'business objectives have changed,' before enrolling any patients."

Trial withdrawal • Hematological Malignancies • Multiple Myeloma • Oncology

Informing the Recommended Phase III Dose of Alnuctamab, a CD3 × BCMA T-Cell Engager, Using Population Pharmacokinetics and Exposure-Response Analysis. (PubMed, Clin Pharmacol Ther) - "Logistic regression analysis for patients administered SC alnuctamab identified that increased exposure significantly increased the probability of response, although the additional benefit was minimal at exposures above 30 mg target dose. Considering the totality of exposure-response data, the clinical pharmacology assessment supported a SC RP3D of 3/6/30 mg."

Journal • P3 data • PK/PD data • Hematological Malignancies • Multiple Myeloma • Oncology

Comprehensive assessment of adverse event profiles associated with bispecific T cell engagers in multiple myeloma. (ASCO 2024) - "We found 23 studies which include BCMA agents: teclistamab (Tec), elranatamab, linvoseltamab, pavurutamab, and alnuctamab; and non-BCMA targets including: GPRC5D, talquetamab (Tal) and FcRH5, cevostamab, as well as combination therapies including a BiTE, specifically Tec+Tal and Tal+daratumumab (Tal+D)...More instances of CRS and CRS with Tocilizumab occurred with BCMA BiTEs vs non-BCMA BiTes, P < 0... The use of BiTEs in MM has demonstrated remarkable efficacy; however, these have been linked to a unique AE profile. Our results showed that non-BCMA were associated with less hematotoxicity (combined G3+ AEs and hypogammaglobulinemia), whereas BCMA BiTEs were associated with less CRS rates. This is important information for treatment selection and mitigation strategy development aiming to optimize patient outcomes."

Adverse events • Anemia • Hematological Disorders • Hematological Malignancies • Infectious Disease • Multiple Myeloma • Neutropenia • Oncology • Respiratory Diseases

ALUMMINATE: A Study to Evaluate Efficacy and Safety of Alnuctamab Compared to Standard of Care Regimens in Participants With Relapsed or Refractory Multiple Myeloma (RRMM) (clinicaltrials.gov) - P3 | N=0 | Withdrawn | Sponsor: Celgene | N=466 ➔ 0 | Not yet recruiting ➔ Withdrawn

Enrollment change • Trial withdrawal • Hematological Malignancies • Multiple Myeloma • Oncology

CC-93269-MM-001: Study of CC-93269, a BCMA x CD3 T Cell Engaging Antibody, in Participants With Relapsed and Refractory Multiple Myeloma (clinicaltrials.gov) - P1 | N=250 | Active, not recruiting | Sponsor: Celgene | Recruiting ➔ Active, not recruiting

Enrollment closed • Hematological Malignancies • Multiple Myeloma • Oncology

A Study to Evaluate Alnuctamab in Combination With Mezigdomide in Participants With Relapsed and/or Refractory Multiple Myeloma (clinicaltrials.gov) - P1/2 | N=156 | Active, not recruiting | Sponsor: Celgene | Recruiting ➔ Active, not recruiting

Combination therapy • Enrollment closed • Hematological Malignancies • Multiple Myeloma • Oncology

Alnuctamab: Data readout from P3 ALUMMINATE trial (NCT06232707) for 2L-4L multiple myeloma in 2025 (Bristol-Myers Squibb) - Q1 2024 Results: Data readout from P1/2 CA058-002 trial (NCT06163898) for 3L+ multiple myeloma in 2027

P1/2 data • P3 data • Hematological Malignancies • Multiple Myeloma • Oncology

A Study to Evaluate Alnuctamab in Combination With Mezigdomide in Participants With Relapsed and/or Refractory Multiple Myeloma (clinicaltrials.gov) - P1/2 | N=156 | Recruiting | Sponsor: Celgene | Not yet recruiting ➔ Recruiting | Trial primary completion date: Dec 2027 ➔ Feb 2032

Combination therapy • Enrollment open • Trial primary completion date • Hematological Malignancies • Multiple Myeloma • Oncology

ALUMMINATE: A Study to Evaluate Efficacy and Safety of Alnuctamab Compared to Standard of Care Regimens in Participants With Relapsed or Refractory Multiple Myeloma (RRMM) (clinicaltrials.gov) - P3 | N=466 | Not yet recruiting | Sponsor: Celgene

New P3 trial • Hematological Malignancies • Multiple Myeloma • Oncology

A Study to Evaluate the Safety, Effectiveness and Tolerable Dose of BMS-986393 in Novel Combinations in Participants With Relapsed and/or Refractory Multiple Myeloma (clinicaltrials.gov) - P1 | N=111 | Recruiting | Sponsor: Juno Therapeutics, Inc., a Bristol-Myers Squibb Company | Not yet recruiting ➔ Recruiting

Enrollment open • Hematological Malignancies • 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

Alnuctamab (ALNUC; BMS-986349; CC-93269), a 2+1 B-Cell Maturation Antigen (BCMA) × CD3 T-Cell Engager (TCE), Administered Subcutaneously (SC) in Patients (Pts) with Relapsed/Refractory Multiple Myeloma (RRMM): Updated Results from a Phase 1 First‑in‑Human Clinical Study (ASH 2023) - P1 | "SC ALNUC continued to demonstrate a safety profile consistent with the drug class and a low rate of severe infections. Across doses, responses were durable and deepened over time, with a high proportion of responders achieving MRD negativity. High antitumor activity was observed at target doses ≥ 30 mg and specifically at the 30-mg target dose."

Clinical • P1 data • Anemia • Cerebral Hemorrhage • Colon Cancer • Colorectal Cancer • Cytomegalovirus Infection • Gastrointestinal Cancer • Hematological Disorders • Hematological Malignancies • Infectious Disease • Multiple Myeloma • Neutropenia • Novel Coronavirus Disease • Oncology • Respiratory Diseases • Solid Tumor • Thrombocytopenia

Mezigdomide Reverses T-Cell Exhaustion through Degradation of Aiolos/Ikaros and Reinvigoration of Cytokine Production Pathways (ASH 2023) - "Introduction: T cell exhaustion (Tex) is characterized by progressive decline in activation and proliferation and has been implicated as a major resistance mechanism of T cell immunotherapies such as BCMA directed bispecifics approved for the treatment of multiple myeloma (MM). We demonstrated here that Aiolos/Ikaros regulate and maintain T cell exhaustion. Mezi mediated degradation of both transcription factors at the same time resulted in enhanced proinflammatory cytokine expression and reduction of exhaustion associated markers, as well as enhanced Tex killing of BCMA expressing tumor cells in combination with Alnuctamab."

IO biomarker • Hematological Malignancies • Multiple Myeloma • Oncology • Targeted Protein Degradation • CD4 • CRBN • CTLA4 • CXCL1 • ENTPD1 • HAVCR2 • IKZF1 • LAG3 • PD-1 • PD-L1 • RUNX1 • RUNX2 • RUNX3 • TIGIT

Bristol Myers Squibb Announces Data at ASH 2023 from Diverse Multiple Myeloma Pipeline, Underscoring Range of Tailored Treatment Approaches to Address Unique Patient Needs (Businesswire) - P1 | N=250 | NCT03486067 | Sponsor: Celgene | "In updated results, SC alnuctamab showed durable responses with high anti-tumor activity observed at target dose of 30 mg (n=32), the dose selected for Phase 3. In the efficacy-evaluable patients treated with SC alnuctamab (n=73), the ORR was 53% across all doses and 67% at the 30 mg target dose. Median time to response was 1.2 months (range, 0.9–4.0) and responses deepened over time. Median progression-free survival (PFS) was 10.1 months (95% CI, 2.8–17.8) across all dose levels and 11.4 months (95% CI, 1.8 to not estimable) in the 30 mg target dose....A Phase 3 study of alnuctamab in patients with RRMM exposed to lenalidomide and an anti-CD38 monoclonal antibody is planned and will be initiated in the first half of 2024."

New P3 trial • P1 data • Hematological Malignancies • Multiple Myeloma • Oncology

CC-93269-MM-001: Study of CC-93269, a BCMA x CD3 T Cell Engaging Antibody, in Participants With Relapsed and Refractory Multiple Myeloma (clinicaltrials.gov) - P1 | N=250 | Recruiting | Sponsor: Celgene | Trial completion date: Aug 2027 ➔ Aug 2029

Trial completion date • Hematological Malignancies • Multiple Myeloma • Oncology

A Study to Evaluate Alnuctamab in Combination With Mezigdomide in Participants With Relapsed and/or Refractory Multiple Myeloma (clinicaltrials.gov) - P1/2 | N=156 | Not yet recruiting | Sponsor: Celgene

New P1/2 trial • Hematological Malignancies • Multiple Myeloma • Oncology

CC-93269-MM-001: Study of CC-93269, a BCMA x CD3 T Cell Engaging Antibody, in Participants With Relapsed and Refractory Multiple Myeloma (clinicaltrials.gov) - P1 | N=250 | Recruiting | Sponsor: Celgene | Trial completion date: Aug 2029 ➔ Aug 2027 | Trial primary completion date: Jun 2029 ➔ Jul 2027

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