ezobresib (BMS-986158) / BMS - LARVOL DELTA

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 (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

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

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

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

The impact of novel bet inhibitors on the treatment armamentarium of Myelofibrosis. (PubMed, Expert Opin Investig Drugs) - "We summarize preclinical evidence and clinical trial data of BET inhibitors, including pelabresib, INCB057643, BMS-986158, and other investigational agents, both as monotherapy and in combination with JAK inhibitors. However, hematologic toxicities, durability of responses, and the impact on survival and leukemic transformation remain unresolved. Biomarker-driven patient selection and rational combination strategies will be essential to optimize the clinical integration of BET inhibitors in MF."

Journal • Fibrosis • Gene Therapies • Hematological Disorders • Immunology • Myelofibrosis • Myeloproliferative Neoplasm • Oncology

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: May 2026 ➔ Aug 2028 | Trial primary completion date: May 2026 ➔ Aug 2028

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

Ex Vivo Characterization Studies Identify Candidate Therapies for the Individualized Care of NF2-Related Schwannomatosis. (PubMed, Cancers (Basel)) - "Drug sensitivity screens in 2- and 3-dimensional formats revealed cytotoxic effects of fimepinostat in primary cells; dasatinib with brigatinib was the most effective cytostatic combination. Ineffective therapies attempted in the patient were also ineffective ex vivo. These data support the idea of using the FPM workflow to improve and individualize the standard of care for severe NF2-SWN patients using surgical samples."

Journal • Preclinical • Brain Cancer • Oncology • Pediatrics • Solid Tumor

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 | N=108 ➔ 216

Enrollment change • Monotherapy • 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"

Bispecific • Breast 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

Efficacy and safety of Ruxolitinib-based combination therapy in the patients with Myelofibrosis (MF): a systematic review and meta-analysis. (PubMed, Ann Med) - "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%). For patients with prior JAK inhibitor exposure, Ruxolitinib plus Siremadlin (SVR35: 45%) showed notable activity...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."

Journal • Retrospective data • Chronic Eosinophilic Leukemia • Hematological Disorders • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • Thrombocytopenia

Progress of investigational bromodomain and extra-terminal domain inhibitors for myelofibrosis therapy. (PubMed, Expert Opin Investig Drugs) - "Trials assessing the efficacy of pelabresib, ABBV-744, INCB057643, BMS-986158, and OPN-2853 are detailed herein. Research into novel pan-and selective-BETis both as monotherapy and in combination with JAKis or other mechanism-based therapies are ongoing. Whether BETi therapy in MF will ultimately deliver substantial anti-clonal activity to modify disease biology and meaningfully impact clinical outcomes is yet to be determined."

Journal • Review • Fibrosis • Hematological Disorders • Immunology • Myelofibrosis • Myeloproliferative Neoplasm • Oncology • ABL1 • BCR

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

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

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

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