ezobresib (BMS-986158) / BMS - LARVOL DELTA

Efficacy and safety of ruxolitinib-based combination therapy in the patients with myelofibrosis (MF): A systematic review and meta-analysis (ASH 2025) - "Among JAK inhibitor-naïve patients, the combination of ruxolitinib with selinexor demonstrated the highest efficacy (SVR35: 92%; TSS50: 78%), followed by ruxolitinib plus BMS-986158 (SVR35: 90%). In addition, the efficacy ofthe combination of ruxolitinib with IFNα(SVR35:70%) and pelabresib (SVR35:66%; TSS50:53%) are also acceptable. For patients with prior JAK inhibitor exposure, ruxolitinib plus siremadlin (SVR35: 45%) and ruxolitinib plus selinexor (SVR35: 38%; TSS50: 33%) showed notable activity... For JAK inhibitor-naïve patients, ruxolitinib-based combination regimens demonstrated advantages over ruxolitinib monotherapy. For patients with prior JAK inhibitor exposure, the addition of combination therapy drugs may further enhance the efficacy. Personalized treatment selection remains essential, as therapeutic efficacy is significantly influenced by prior JAK inhibitor exposure."

Combination therapy • Retrospective data • Review • Chronic Eosinophilic Leukemia • Fibrosis • Hematological Disorders • Immunology • Myelofibrosis • Myeloproliferative Neoplasm • Neutropenia • Thrombocytopenia • IFNA1

Discovery of drug combinations with momelotinib to improve myelofibrosis outcomes (ASH 2025) - "The VAF screen identified numerous inhibitors of signaling pathways operating parallel to the JAK-STAT signaling pathway including SHP2 (migoprotafib), PI3K (copanlisib), MEK (cobimetinib), agents targeting BET (BMS-986158), and STAT transcriptional targets, including BCLxL (navitoclax). The hepcidin screen identified inhibitors that combined to further suppress expression of the HiBiT transgene including CDK4 (atirmociclib) and MDM2 (navtemadlin). Notably, selinexor, an XPO1 inhibitor, combined positively with momelotinib to both kill malignant cells and suppress hepcidin expression. These results highlight several promising drug combinations that could enhance outcomes for MF patients by effectively controlling anemia and halting disease progression. These discoveries provide the scientific justification to identify optimal combination regimens aimed at addressing the multifaceted challenges of myelofibrosis."

IO biomarker • Myelofibrosis • ACVR1 • BCL2L1 • BMP6 • CDK4 • JAK1

CDK4/6 inhibitors allow reduction of BET dosing in SHH medulloblastoma. (SNO 2025) - "Our results support the translation of BETi with those acting on CDK4/6 for the clinical management of children with MB."

Brain Cancer • Medulloblastoma • Solid Tumor

CDK4/6 inhibitors allow reduction of BET dosing in SHH medulloblastoma. (WFNOS 2025) - "Our results support the translation of BETi with those acting on CDK4/6 for the clinical management of children with MB."

Brain Cancer • Medulloblastoma • Solid Tumor

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

Reprogramming oncogenic mitochondria in pancreatic adenocarcinoma through BRD4 inhibition leads to programmed cell death. (PubMed, J Pharmacol Exp Ther) - "Using pharmacological and genetic BRD4 inhibition in PDA patient-derived models, we investigated the effects of BETi on mitochondrial function, mitochondrial protein complex production, ATP production, cellular respiration, autophagy/mitophagy, and murine tumor growth with BMS-986158, a BETi...SIGNIFICANCE STATEMENT: Bromo- and extraterminal domain inhibition is a novel therapeutic strategy for attacking oncogenic mitochondrial behavior in pancreatic ductal adenocarcinoma. Using this strategy in patient-derived models, this study demonstrated a series of mitochondrial-centered events in a temporal sequence leading to cell death and tumor control."

Journal • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • BRD4 • IDH1

Investigation of the Synergistic Combination of a Novel Celmod (CC-99282) and BET Inhibitors in Preclinical DLBCL (ASH 2023) - P1/2 | "Similar synergistic effects were found when combining GOLCA with JQ1, another tool compound BET inhibitor, confirming BET inhibition potentiates the anti-DLBCL effects of the CELMoD agent. BET inhibition potentiates anti-proliferative effects of GOLCA in DLBCL cells through synergistic induction of p21 and inhibition of E2F signaling. The synergetic effects of BMS-986158 and GOLCA suggest potential clinical benefits of combining lower doses of single agents to achieve better efficacy with reduced risk of adverse effects."

Preclinical • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Targeted Protein Degradation • AURKA • BRD4 • CDC45 • CDKN1A • CHEK1 • CRBN • E2F1 • IKZF1 • IL17RB • SKP2

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

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 • Multiple Myeloma • Neutropenia • Plasmacytoma • CKS1B • IKZF1

Identification of BET inhibitors (BETi) against solitary fibrous tumor (SFT) through high-throughput screening (HTS). (PubMed, Neoplasia) - "Consequently, combining BET inhibitors with PARP (Poly (ADP-ribose) polymerase) inhibitors or with ATR inhibitors significantly enhanced anti-proliferative effects in SFT cells. Taken together, this study establishes BET inhibitors Mivebresib and BMS-986158 as promising anti-SFT agents."

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

Mezigdomide (MEZI) in Novel Combinations Effectively Reactivates Immune System in Patients with Relapsed/refractory Multiple Myeloma (RRMM) Including Those After T-cell–redirecting Therapies (TCRT) (IMS 2025) - "MEZI+dexamethasone (MEZId) combined 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 in pts with RRMM, including pts post-TCRT...Last regimen included TCRT (n=28: 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 (n=28)... MEZId-based novel regimens lead to activation of adaptive and innate immune populations in pts with RRMM regardless of prior TCRT exposure. Dynamics of immune changes with MEZId-based novel regimens agree with MEZId backbone data. Results suggest prior TCRT exposure and addition of novel agents do not affect the ability of MEZI to increase activation and proliferation of NK and T cells, supporting its use in combinations for pts with prior TCRT exposure."

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

Mezigdomide (MEZI) in Novel Targeted Combinations for Relapsed/refractory Multiple Myeloma (RRMM): Updated Results from the Phase 1/2 CA057-003 Trial (IMS 2025) - P1/2 | "CA057-003 (NCT05372354) is evaluating all-oral, novel triplet regimens with a MEZI+dexamethasone (DEX) (MEZId) backbone plus EZH2 inhibitor tazemetostat (TAZ), BET inhibitor BMS-986158, or MEK inhibitor trametinib (TRAM), in RRMM. MEZId plus TAZ, BMS-986158, or TRAM showed promising efficacy and safety in RRMM, supporting further exploration of these novel all-oral combinations."

P1/2 data • Multiple Myeloma • Neutropenia • Plasmacytoma • IKZF1 • NCOA3 • TRAM1

Transcriptional Rewiring of BET Inhibitor Treated Ewing Sarcoma Cells Augments their Dependency on Focal Adhesion Kinase. (PubMed, bioRxiv) - "Combining BMS-986158 with the FAK inhibitor Defactinib had synergistic effects, reducing EwS cell proliferation, survival, and invasion in vitro, and significantly inhibited tumor outgrowth in vivo. Our studies identify BET and FAK inhibition as a rational combination therapy worthy of further investigation for EwS, and demonstrate that defining emergent mechanisms of epigenetic drug tolerance can identify new vulnerabilities that can be therapeutically targeted."

Journal • Ewing Sarcoma • Oncology • Sarcoma • Solid Tumor • FLI1

CA057-003: 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=260 | Recruiting | Sponsor: Bristol-Myers Squibb | N=160 ➔ 260

Enrollment change • Hematological Malignancies • Multiple Myeloma • Oncology

Mezigdomide (MEZI) in Novel Combinations for Relapsed or Refractory Multiple Myeloma (RRMM): Updated Results From the CA057-003 Trial (SOHO 2025) - P1/2 | "CA057-003 (NCT05372354) is a phase 1/2, multicenter, open-label trial evaluating all-oral, novel triplet combinations using a MEZI plus dexamethasone (DEX) (MEZId) backbone plus tazemetostat (TAZ), BMS-986158, or trametinib (TRAM) in RRMM. MEZId plus TAZ, BMS-986158, or TRAM showed promising efficacy and safety in RRMM."

Multiple Myeloma • Oncology • Plasmacytoma • IKZF1 • NCOA3 • TRAM1

NFE2 and PF4 as biomarkers for BET inhibition-induced thrombocytopenia in preclinical and clinical studies. (PubMed, Front Med (Lausanne)) - "The consistent downregulation of GATA1, NFE2, and PF4 transcription within hours post-BMS-986158 treatment in both preclinical and clinical studies demonstrates that BET inhibitors induce thrombocytopenia by altering GATA1 gene expression and its downstream genes, NFE2 and PF4, which regulate megakaryopoiesis and thrombopoiesis. Early detection of transcriptional changes in blood samples during treatment courses positions NFE2 and PF4 as promising biomarkers for proactively monitoring and mitigating treatment-emergent thrombocytopenia."

Journal • Preclinical • Hematological Disorders • Oncology • Thrombocytopenia • GATA1 • HEXIM1

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

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