ezobresib (BMS-986158) / BMS - LARVOL DELTA

MEZIGDOMIDE (MEZI) IN NOVEL COMBINATIONS FOR RELAPSED OR REFRACTORY MULTIPLE MYELOMA (RRMM): UPDATED RESULTS FROM THE CA057-003 TRIAL (EHA 2025) - P1/2 | "The CA057-003 phase 1/2 trial (NCT05372354) is evaluating all-oral, novel targeted triplet combination regimens using a MEZI + dexamethasone (DEX) (MEZId) backbone in RRMM, plus EZH2 inhibitor tazemetostat (TAZ), BET inhibitor BMS-986158, or MEK inhibitor trametinib (TRAM). MEZId combined with the novel therapeutic agents TAZ, BMS-986158, or TRAM showed promising efficacy and safety in RRMM. These results provide a rationale for further exploration of these novel all-oral combinations"

Multiple Myeloma • Neutropenia • Plasmacytoma • IKZF1

MEZIGDOMIDE (MEZI) IN NOVEL COMBINATIONS EFFECTIVELY REACTIVATES IMMUNE SYSTEM IN PATIENTS WITH RELAPSED OR REFRACTORY MULTIPLE MYELOMA (RRMM) INCLUDING THOSE AFTER T-CELL-REDIRECTING THERAPIES (EHA 2025) - P1/2 | "MEZI + dexamethasone (MEZId) in combination with novel agents, such as tazemetostat (TAZ), the bromodomain inhibitor (BETi) BMS-986158, and trametinib (TRAM) showed promising efficacy and safety in the phase 1/2 CA057-003 trial (NCT05372354) in pts with RRMM, including those post-TCRT...Last regimen included TCRT for 28 pts (BCMA CAR-T, n=8; GPRC5D CAR-T, n=6; BCMA TCE, n=3; GPRC5D TCE, n=8, BCMA TCE+GPRC5D TCE, n=2; trispecific T-cell-activating constructs, n=1), or various non-TCRT regimens for the other 28 pts... MEZId-based novel combinations lead to activation of adaptive and innate immune populations in pts with RRMM irrespective of prior TCRT exposure. Dynamics of immune changes upon tx with MEZId-based novel combinations is concordant with findings reported for the MEZId backbone. These results suggest previous exposure to TCRT and the addition of novel agents do not affect the ability of MEZI to increase activation and proliferation of NK and T cells,..."

Clinical • IO biomarker • Hematological Malignancies • Multiple Myeloma • Oncology • B3GAT1 • CCR7 • CD8 • HAVCR2 • IKZF1 • IL2RA • IL7R

Dual Inhibition of PAX3-FOXO1 in Rhabdomyosarcoma (PAS 2025) - "While RMC-6272 initially reduced PAX3-FOXO1 protein levels, a rebound effect was observed. This was matched by an upregulation of mRNA levels, suggesting transcriptional mechanisms and providing rationale to study mTORC1 and BET inhibitors in combination. The second experiment of mTORC1 and BET inhibitors together revealed that the combination of RMC-6272 followed by BMS-986158 resulted in the greatest reduction in PAX3-FOXO1 levels aside from combined treatment."

Oncology • Rhabdomyosarcoma • Sarcoma • Solid Tumor • FOXO1 • PAX3

Exploring BET inhibitors as promising agents for solitary fibrous tumor (Sarcoma-RC 2025) - "RNA-seq was performed on Illumina NovaSeq X. Results Among seven BETis tested in SFT cells, Mivebresib and BMS-986158 exhibited the lowest IC50 values (INT-SFT: 10.8 nM and 6.23 nM; IEC139: 12.5 nM and 28.8 nM) and, in contrast to other BETis, induced apoptosis at 50 nM (INT-SFT: 32% and 45.9%; IEC139: 27.5% and 34.3%)...Combining BETis with PARPi rucaparib or ATRi berzosertib showed synergistic effects, enhancing apoptotic responses and DNA damage accumulation...In vivo, Mivebresib markedly reduced tumor growth in SFT PDX models, supporting its potential as a targeted therapy. Legal entity responsible for the study The authors."

Oncology • Sarcoma • Solid Tumor • CCND1 • CDKN1A • NAB2 • STAT6

Identification of BET Inhibitors (BETi) Against Solitary Fibrous Tumor (SFT) Through High-Throughput Screening (HTS). (PubMed, bioRxiv) - "Consequently, combining BET inhibitors with PARP (Poly (ADP-ribose) polymerase) or ATR inhibitors significantly enhanced anti-proliferative effects in SFT cells. Taken together, our study established BET inhibitors Mivebresib and BMS-986158 as promising anti-SFT agents."

Journal • Hematological Disorders • Hematological Malignancies • Oncology • Sarcoma • Solid Tumor • NAB2 • STAT6

Targeting the interplay between replication stress (RS) induced DNA damage response (DDR) and epigenetics in children with high-risk neuroblastoma and sarcoma (LCC 2025) - "ATR inhibitor (AZD6738/Cerelasertib) combinations with epigenetic drugs causing chromatin closing: bromodomain/histone acetyltransferase (HAT) inhibitors (BI-894999, CBP30, BMS-986158), histone demethylase (KDM) inhibitors (GSK-J4), or chromatin opening: DNA methyltransferase inhibitors (OTS186935, Decitabine), histone deacetylase (HDAC) inhibitors (Panobinostat, Entinostat, Vorinostat) were tested in neuroblastoma and sarcoma cell lines. These combinations offer superior efficacy than either drug alone. Functional studies will elucidate mechanisms responsible for observed synergy, and effective combinations will be validated in vivo."

Clinical • CNS Tumor • Neuroblastoma • Oncology • Pediatrics • Rhabdomyosarcoma • Sarcoma • Solid Tumor • MYCN

Mezigdomide (MEZI) in Novel-Novel Combinations for Relapsed or Refractory Multiple Myeloma (RRMM): Preliminary Results from the CA057-003 Trial (ASH 2024) - P1/2 | "The CA057-003 phase 1/2 trial (NCT05372354) is evaluating all-oral, novel-novel targeted triplet combination regimens using a MEZI plus dexamethasone (DEX) (MEZId) backbone in patients (pts) with RRMM. The third agent in each combination intervenes on a key oncogenic pathway identified by The Myeloma Genome Project to be upregulated in RRMM : the EZH2 inhibitor tazemetostat (TAZ) for PRC2 complex dysregulation, the BET inhibitor BMS-986158 for CKS1b (located on Chr 1q) amplification, and the MEK inhibitor trametinib (TRAM) for RAS-RAF-MEK-ERK activation...These results provide a rationale for further exploration of these novel all-oral combinations. Accrual continues and updated results will be presented at the meeting."

IO biomarker • Bone Marrow Transplantation • Multiple Myeloma • Neutropenia • Plasmacytoma • CKS1B • IKZF1

Golcadomide-Mediated Degradation of Aiolos/Ikaros Synergizes with BET Inhibitors through Bidirectional Restructuring of the Directly Regulated Epigenetic Environment in DLBCL (ASH 2024) - "This agent exerts significant cell-autonomous anti-DLBCL activity in preclinical models and has demonstrated notable clinical efficacy in combination with Rituximab and R-CHOP in early clinical trials. Given the epigenetic mechanisms through which Aiolos/Ikaros derive their activity, we sought to explore combination strategies with other epigenetic agents, such as BMS-986158 (BMS-158), a selective BET inhibitor, to further enhance GOLCA's cell-autonomous activity...Conclusions : Through a genome-wide unbiased multi-omics approach, our results demonstrated that the synthetic lethal relationship between Ikaros/Aiolos and BRD4 in DLBCL depends, at least in part, on their ability to collaboratively sustain MYC expression by epigenetically stimulating the activities of its promoter and the MYC-activating enhancer. These findings suggest that combining GOLCA with a BET inhibitor may result in greater clinical efficacy through enhanced cell-autonomous activity in patients..."

Diffuse Large B Cell Lymphoma • Oncology • Targeted Protein Degradation • AURKA • BCL6 • BRD4 • CDKN1A • CRBN • IKZF1 • MYC • MYCN • PLK1

Study of the Bromodomain (BRD) and Extra-Terminal Domain (BET) Inhibitors BMS-986158 and BMS-986378 in Pediatric Cancer (clinicaltrials.gov) - P1 | N=41 | Completed | Sponsor: Dana-Farber Cancer Institute | Active, not recruiting ➔ Completed

Trial completion • Brain Cancer • Hematological Malignancies • Lymphoma • NUT Midline Carcinoma • Oncology • Pediatrics • Solid Tumor • BRD3 • BRD4 • MYC • MYCN

Mezigdomide (MEZI), tazemetostat (TAZ), and dexamethasone (DEX) in patients (pts) with relapsed/refractory multiple myeloma (RRMM): preliminary results from the CA057-003 trial (IMW 2024) - P1/2 | "The third agent in each combination intervenes on a key oncogenic pathway upregulated in RRMM: 1) EZH2 inhibitor TAZ for PRC2 complex dysregulation; 2) BET inhibitor BMS-986158 for CKS1B (on chromosome 1q) amplification; 3) or MEK inhibitor trametinib for RAS-RAF-MEK-ERK activation. MEZI+TAZ+DEX showed promising preliminary efficacy and safety in pts with RRMM, with no new safety concerns."

Clinical • Anemia • Hematological Malignancies • Infectious Disease • Multiple Myeloma • Neutropenia • Oncology • Plasmacytoma • Pulmonary Disease • Septic Shock • CKS1B • IKZF1

Mezigdomide plus Tazemetostat and Dexamethasone for Relapsed or Refractory Multiple Myeloma: Preliminary Results from the CA057-003 Trial (ICBMT 2024) - P1/2 | "Background/Aim : •CA057-003 (NCT05372354) is a phase 1/2 trial evaluating triplet combination regimens using a MEZI + dexamethasone (DEX) backbone, in patients with relapsed or refractory (RR)MM who are refractory to, intolerant to, or not candidates for established MM therapies •To report preliminary safety and efficacy results from the dose-finding cohort of MEZI + TAZ + DEX in the CA057-003 trial in patients with RRMM Methods : •CA057-003 is an open-label, multicenter, phase 1b/2a dose-finding and dose-expansion clinical trial evaluating MEZI + DEX in combination with TAZ, BMS-986158, or trametinib (TRAM) in patients with RRMM •In the dose-finding MEZI + TAZ + DEX cohort, patients received: —Oral MEZI, starting at a 0.3-mg dose with escalation to 0.6 mg and 1.0 mg on days 1-21 of each 28-day cycle, plus —Oral TAZ 800 mg twice daily on days 1–28, plus —Weekly oral DEX 40 mg (20 mg in patients > 75 years of age) Results : •Six (46.2%) patients continued on..."

Anemia • Hematological Disorders • Hematological Malignancies • Infectious Disease • Multiple Myeloma • Neutropenia • Oncology

Study of the Bromodomain (BRD) and Extra-Terminal Domain (BET) Inhibitors BMS-986158 and BMS-986378 in Pediatric Cancer (clinicaltrials.gov) - P1 | N=41 | Active, not recruiting | Sponsor: Dana-Farber Cancer Institute | Trial primary completion date: Jul 2024 ➔ Mar 2024

Trial primary completion date • Brain Cancer • Hematological Malignancies • Lymphoma • NUT Midline Carcinoma • Oncology • Pediatrics • Solid Tumor • BRD3 • BRD4 • MYC • MYCN

MEZIGDOMIDE (MEZI), TAZEMETOSTAT (TAZ), AND DEXAMETHASONE (DEX) IN PATIENTS (PTS) WITH RELAPSED/REFRACTORY MULTIPLE MYELOMA (RRMM): PRELIMINARY RESULTS FROM THE CA057-003 TRIAL (EHA 2024) - P1/2 | "The third agent in each combination intervenes ona** key oncogenic pathway upregulated in RRMM, as identified by The Myeloma Genome Project: 1) EZH2inhibitor TAZ for PRC2 complex dysregulation; 2) BET inhibitor BMS-986158 for CKS1b (located onchromosome 1q) amplification; 3) MEK inhibitor trametinib for RAS-RAF-MEK-ERK activation. MEZI+TAZ+DEX showed promising preliminary efficacy and safety in pts with RRMM, with no new safetyconcerns. These results provide rationale for further exploration of this novel all-oral combination. Updatedresults will be presented at the meeting."

Clinical • Anemia • Infectious Disease • Multiple Myeloma • Neutropenia • Plasmacytoma • Pulmonary Disease • CKS1B • IKZF1

CA011-023: A Study to Assess the Safety and Tolerability of BMS-986158 Alone and in Combination With Either Ruxolitinib or Fedratinib in Participants With Blood Cancer (Myelofibrosis) (clinicaltrials.gov) - P1/2 | N=216 | Active, not recruiting | Sponsor: Bristol-Myers Squibb | Trial completion date: Apr 2027 ➔ May 2026 | Trial primary completion date: Apr 2025 ➔ May 2026

Combination therapy • Monotherapy • Trial completion date • Trial primary completion date • Hematological Malignancies • Myelofibrosis • Oncology

CBP-8008: A first-in-class targeted pan-Bet protein degradation therapy using bi-specific XDC (Bi-XDC) technology for TNBC and mCRPC (AACR 2024) - "Several anticancer Bi-ligand drug conjugates including CBP-1008, CBP-1018, and CBP-1019 have been brought into various clinical stages in China and US. CBP-8008 is currently in preclinical development as a potential first-in-class pan-Bet protein degradation therapy using Bi-XDC technology for TNBC and mCRPC"

Breast Cancer • Metastatic Castration-Resistant Prostate Cancer • Oncology • Prostate Cancer • Solid Tumor • Triple Negative Breast Cancer • BRD2 • BRD3 • BRD4 • FOLR1

Transcriptional rewiring of BET inhibitor treated Ewing sarcoma cells augments their dependency on focal adhesion kinase (AACR 2024) - "We next tested BMS-986158 and the FAK-inhibitor Defactinib singly or in combination in vitro and in vivo. Thus, our studies reveal that exposure of EwS cells to BETi induces transcriptional rewiring that activates integrin and FAK signaling, restoring proliferation. This work supports further investigation of FAKi as agents that could prevent or reverse the BETi tolerant state in EwS."

Ewing Sarcoma • Oncology • Sarcoma • Solid Tumor • FLI1

Study of the Bromodomain (BRD) and Extra-Terminal Domain (BET) Inhibitors BMS-986158 and BMS-986378 in Pediatric Cancer (clinicaltrials.gov) - P1 | N=41 | Active, not recruiting | Sponsor: Dana-Farber Cancer Institute | Recruiting ➔ Active, not recruiting | N=66 ➔ 41 | Trial completion date: Jun 2025 ➔ Jul 2024

Enrollment change • Enrollment closed • Trial completion date • Brain Cancer • Hematological Malignancies • Lymphoma • NUT Midline Carcinoma • Oncology • Pediatrics • Solid Tumor • BRD3 • BRD4 • MYC • MYCN

CA011-023: A Study to Assess the Safety and Tolerability of BMS-986158 Alone and in Combination With Either Ruxolitinib or Fedratinib in Participants With Blood Cancer (Myelofibrosis) (clinicaltrials.gov) - P1/2 | N=216 | Active, not recruiting | Sponsor: Bristol-Myers Squibb | Recruiting ➔ Active, not recruiting

Combination therapy • Enrollment closed • Monotherapy • Hematological Malignancies • Myelofibrosis • Oncology

BMS-986158, a potent bromodomain and extraterminal inhibitor (BETi), as monotherapy and in combination with ruxolitinib or fedratinib, in intermediate- or high-risk myelofibrosis (MF): results from a phase 1/2 study (DKK 2024) - P1/2 | "Initial results show that BMS-986158 + RUX produced robust SVR in pts with MF, with deepening responses beyond wk 12 with continued Tx. First published: Ayala R et al. HemaSphere 2023;7[S3]:S213."

Combination therapy • Monotherapy • P1/2 data • Anemia • Cardiovascular • Hematological Disorders • Hypertension • Myelofibrosis • Neutropenia • Thrombocytopenia • JAK2

A Study to Evaluate Safety, Drug Levels and Effectiveness of CC-92480 (BMS-986348) in Combination With Other Treatments in Participants With Relapsed or Refractory Multiple Myeloma (clinicaltrials.gov) - P1/2 | N=220 | Recruiting | Sponsor: Bristol-Myers Squibb | Phase classification: P1b/2a ➔ P1/2

Combination therapy • Phase classification • Hematological Malignancies • Multiple Myeloma • Oncology

BMS-986158 With JAKi Shows a Manageable Safety Profile in Myelofibrosis (Targeted Oncology) - P1b/2 | N=216 | NCT04817007 | Sponsor: Bristol-Myers Squibb | "The combination of BMS-986158...with a Janus kinase (JAK) inhibitor, either ruxolitinib (Jakafi) or fedratinib (Inrebic), was manageable in regard to safety when used for the treatment of patients with intermediate- or high-risk myelofibrosis...A total of 23 patients were treated as of September 2, 2022...Safety findings showed that any grade treatment-related adverse events (TRAEs) were observed in 9 (82%) and 9 (75%) patients in parts 1A and 1B of the study, and grade 3/4 TRAEs included thrombocytopenia (n = 5, 45%), neutropenia, hypertension, and anemia...Among all evaluable patients in part 1A, SVR was observed at week 12. These responses continued to deepen at week 24....Based on these findings, the trial will conduct a dose-expansion phase using the recommended phase 2 dose of BMS-986158 and ruxolitinib (part 2A) or BMS-986158 with or without fedratinib (part 2B)."

P1/2 data • Trial status • Myelofibrosis

BET inhibitors combined with JAK inhibitors well-tolerated with myelofibrosis (Healio) - P1b/2 | N=216 | NCT04817007 | Sponsor: Bristol-Myers Squibb | "The BET inhibitor BMS986158 has continued to be well tolerated in combination with ruxolitinib and fedratinib in patients with intermediate- or high-risk myelofibrosis, according to a study presented at ASH Annual Meeting....The study noted 'early and deep' spleen volume reduction in both sets of patients, with most patients remaining on treatment at the time of reporting. Al-Ali reported that any treatment related adverse effects were 'mostly low-grade and transient,' with thrombocytopenia specifically appearing in only manageable levels."

P1/2 data • Hematological Malignancies • Myelofibrosis • Oncology

Modulation of Biomarkers By BET Inhibitor, BMS-986158, Including JAK2 Variant Allele Frequency (VAF), Bone Marrow (BM) Fibrosis, and Reversal of Abnormal Cytokine Production in Intermediate- or High-Risk Myelofibrosis (MF) (ASH 2023) - P1/2 | "In combination with Janus kinase inhibitors (JAKi), ruxolitinib (RUX) or fedratinib (FED), BET inhibitors (BETi) have been shown to reduce inflammatory signals and disease burden in preclinical models of MF. 2023) were observed as expected. Conclusions Preliminary data suggest combination treatment with BMS-986158 and JAKi in MF may modulate JAK2 VAF, BM microenvironment, circulatory cytokines, and other SF, providing evidence of early disease modifying potential of these drug combinations."

Biomarker • IO biomarker • Fibrosis • Immunology • Myelofibrosis • Oncology • CD27 • CD34 • CEACAM8 • DKK1 • IL1R1 • JAK2 • LEP • TIMP3 • TNFA

BMS-986158, a Potent BET Inhibitor, in Combination with Ruxolitinib or Fedratinib in Patients (pts) with Intermediate- or High-Risk Myelofibrosis (MF): Updated Results from a Phase 1/2 Study (ASH 2023) - P1/2 | "The reductions observed in JAK2 VAF provide promising preliminary data of potential disease modification. Dose expansion with BMS-986158+RUX in 1L MF has opened and is actively enrolling patients."

Clinical • Combination therapy • P1/2 data • Anemia • Cardiovascular • Hematological Disorders • Hepatology • Herpes Zoster • Hypertension • Leukopenia • Myelofibrosis • Neutropenia • Thrombocytopenia • Varicella Zoster • CD34 • JAK2

CA011-023: A Study to Assess the Safety and Tolerability of BMS-986158 Alone and in Combination With Either Ruxolitinib or Fedratinib in Participants With Blood Cancer (Myelofibrosis) (clinicaltrials.gov) - P1/2 | N=216 | Recruiting | Sponsor: Bristol-Myers Squibb | Phase classification: P1b/2 ➔ P1/2

Combination therapy • Monotherapy • Phase classification • Hematological Malignancies • Myelofibrosis • Oncology