iberdomide (CC-220) / BMS - LARVOL DELTA

Early intervention in smoldering multiple myeloma: A systematic review of comparative prospective trials (ASH 2025) - "Two studies were phase I/II trials, one comparing the use of dose-escalated multipeptide PVX-410 vaccine +/- lenalidomide (R) in SMM patients, and the other comparing dose-escalated anakinra +/-Lenalidomide/dexamethasone (Rd)...Two studies were phase II RCTs; one compared Rd +/- Carfilzomib (K) in 58 high-risk SMM patients, with statistically significantly higher 3-year PFS in KRd of 94% versus Rd of 40%; p<0.001, across a median follow-up period of 34 months...The second phase II RCT included 20 intermediate- and high-risk SMM patients treated with Iberdomide (I) +/- d, with ORR of 84.6% versus 80% in the Id versus I group...One phase III RCT compared zoledronic acid +/- thalidomide in a total of 68 SMM patients, with a median TTP of 2.4 versus 1.2 years, 1-year PFS of 85% versus 55%, and 1-year ORR of 37% versus no confirmed response during the median follow-up of 5.9 years... Preliminary evidence from comparative trials suggests that early treatment of..."

Clinical • Review • Hematological Malignancies • Multiple Myeloma • Smoldering Multiple Myeloma

Celmods potently inhibit m-MDSC induction by targeting IL-10 and MIF in multiple myeloma (ASH 2025) - "We have previously demonstrated that immunomodulatory drugs (IMiDs), such as lenalidomide (LEN) and pomalidomide (POM), are effective at inhibiting M-MDSC induction by decreasing CCL5 and MIF expression (Kuwahara-Ota S, Br J Haematol 2020); however, the effects of cereblon E3 ligase modulators (CELMoDs) such as iberdomide (IBER) and mezigdomide (MEZI)—which exhibit anti-tumor activity even in LEN- and POM-resistant MM—on M-MDSC induction remain unknown. These dual effects likely contribute to remodeling the tumor microenvironment toward an immune-permissive state. Collectively, our findings provide a mechanistic rationale for using CELMoDs to target MDSCs and enhance anti-tumor immunity in MM."

Myeloid-derived suppressor cells • Hematological Malignancies • Multiple Myeloma • Targeted Protein Degradation • CCL5 • CD33 • CRBN • IKZF1 • IL10 • IL6 • MIF • TNFA

Iberdomide: “IberDd achieved deep and durable responses in Phase 1/2 TNE NDMM”; Multiple myeloma (Bristol-Myers Squibb) - Virtual Investor Presentation on Hematology Programs

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

An immune-therapeutic salvage strategy for 'functional' high-risk (FHR) multiple myeloma (MM) incorporating iberdomide, isatuximab, and dexamethasone – the IBIS study amarc 20-01. (ASH 2025) - P2 | "Of 50 pts: 28%, 32%, 16%, 12% with 0, 1, 2 or 3 high-risk chromosomal abnormalitiesrespectively; 34% fulfilling IMS2025 high-risk criteria, 54% standard-risk and 12% in whom diagnosticCG/FISH were omitted, 83% received PI-IMID 1L (76% VRd, 3% VRd+chemotherapy, 7% VRd+Selinexor),10% bortezomib-cyclophosphamide-dexamethasone (VCD), 7% lenalidomide-dexamethasone (Rd), 24%ASCT; 10% 1REF to 1L and 90% relapsed after initial response to 1L, of these 72% had ³PR to 1L. In this second planned interim analysis, IB-IS-DEX was well-tolerated, achieved early diseasecontrol and demonstrated promising efficacy in FHR MM. Preliminary ctDNA genomic analyses highlight asubstantial burden of adverse biology, with frequent del(17p), MYC copy number gains, and high cTFamong pts with PD. Updates on survival will be presented at the conference."

CNS Disorders • Constipation • Gastroenterology • Gastrointestinal Disorder • Hematological Disorders • Hematological Malignancies • Infectious Disease • Insomnia • Multiple Myeloma • Neutropenia • Respiratory Diseases • Septic Shock • Sleep Disorder • Squamous Cell Carcinoma

Iberdomide plus daratumumab and dexamethasone (IberDd) in patients with newly diagnosed multiple myeloma by renal function: A subgroup analysis of the CC-220-MM-001 trial (ASH 2025) - P1/2 | "Introduction: Lenalidomide (LEN) plus daratumumab (DARA) and dexamethasone (DEX) is a standard-of-care treatment for transplant-ineligible (TNE) newly diagnosed multiple myeloma (NDMM). Despite the observed numerical differences in ORR and CR between RI subgroups, logisticregression analyses showed no correlation between baseline CrCl and key efficacy and safety endpoints,suggesting that RI does not impact clinical outcomes in pts with TNE NDMM treated with IberDd, and thatIBER dose modifications are not required for pts with mild to moderate RI. These data are consistent withprevious observations in pts with RRMM receiving IBER+DEX."

Clinical • Febrile Neutropenia • Infectious Disease • Lymphoma • Multiple Myeloma • Neutropenia • Plasmacytoma • Renal Disease • CRBN • IKZF1

Golseek-1: A Phase 3, double-blind, randomized study of golcadomide (GOLCA), a potential, first-in-class, oral CELMoD™ agent, + R-CHOP vs placebo + R-CHOP in patients with previously untreated, high-risk, large B-cell lymphoma (ASH 2025) - P3 | "Rituximab, cyclophosphamide, doxorubicin, vincristine,and prednisone (R-CHOP) is the standard first-line treatment for DLBCL, achieving cure rates inapproximately 60–70% of patients...GOLCA drivesthe closed, active conformation of cereblon to induce rapid and deep degradation of Ikaros and Aiolos,leading to direct cell killing (agnostic of cell of origin [COO]) and immunomodulatory activity.In the Phase 1b study CC-220-DLBCL-001, GOLCA in combination with R-CHOP demonstrated apredictable and manageable safety profile with high rates of durable responses, irrespective of COO, inpreviously untreated aggressive B-cell lymphomas (BCL), including promising activity in HR patients(Amzallag et al, ASH 2024, #579)...After a screening period of ≤4 weeks, patients will receive either GOLCA (0.4 mg) or placebo orallyonce daily for 7 consecutive days in each of 6 cycles, combined with R-CHOP every 21 days.The primary endpoint is progression-free survival (PFS) by investigator..."

Clinical • P3 data • B Cell Lymphoma • Burkitt Lymphoma • Diffuse Large B Cell Lymphoma • Epstein-Barr Virus Infections • Follicular Lymphoma • Indolent Lymphoma • Lymphoma • Non-Hodgkin’s Lymphoma • Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type • ALK • BCL2 • CRBN • IKZF1

Phase II trial of maintenance therapy with iberdomide after autologous hematopoietic cell transplant for patients with multiple myeloma previously treated with lenalidomide (ASH 2025) - P2 | "Amaintenance strategy is needed after melphalan and salvage aHCT in patients previously treated withlenalidomide. Changes in immune function over time willalso be reported. Overall, these outcomes support further investigation of iberdomide as a maintenancestrategy for patients in the salvage setting and with lenalidomide refractoriness."

Clinical • P2 data • Hematological Disorders • Hematological Malignancies • Infectious Disease • Multiple Myeloma • Neutropenia • Transplantation

Mezigdomide overcomes CRBN mutations emerging post IMiD therapy (ASH 2025) - "Here we describe thelandscape of CRBN mutations in patients post IMiD treatment and through modeling, structure,biochemical and functional assays, we probe the consequences and their potential impact to IMiD andCELMoD agent activities pre-clinically and clinically. CD138+ sorted samples from MM patients across several clinical studies from pomalidomide(POM; CC-4047), iberdomide (IBER: CC-220), and mezigdomide (MEZI; CC-92480) based regimens wereprofiled by whole genome sequencing (WGS) from patients with >2-5+ prior lines of therapy. Somatic CRBN missense mutations in MM patients who have relapsed on prior IMiD-basedtherapies are rare and not recurrent. In silico modeling through Rosetta ddG and metadynamics canpredict the potential for IMiD or CELMoD induced conformational changes associated with anopen/closed state. MEZI has the potential to overcome mutations by interacting with additional moietiesoutside of the TBD that may affect the stabilization of cereblon or..."

Hematological Malignancies • Multiple Myeloma • Targeted Protein Degradation • CRBN • DDB1 • IKZF1 • SDC1

Golcadomide (GOLCA), a potential, first-in-class, oral CELMoD™ agent, plus R-CHOP in patients (Pts) with previously untreated aggressive B-cell lymphoma (a-BCL): 24-month efficacy Results (ASH 2025) - P1, P3 | "GOLCA drivesthe closed, active conformation of cereblon to induce rapid and deep degradation of Ikaros and Aiolos,leading to direct cell killing (agnostic of cell of origin [COO]) and immunomodulatory activity.CC-220-DLBCL-001 (NCT04884035) is an ongoing Phase 1b, open-label, multicenter trial to assess safetyand preliminary efficacy of GOLCA+R-CHOP in previously untreated a-BCL. GOLCA+R-CHOP demonstrated a predictable and manageablesafety profile with low rates of non-hematologic AEs; addition of GOLCA to R-CHOP did not compromiseSOC delivery. These data continue to show that GOLCA 0.4mg, when added to SOC Tx, has a potential tocure more previously untreated pts with HR LBCL and support the ongoing Phase 3 trial, GOLSEEK-1, inthis population (NCT06356129)."

Clinical • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Febrile Neutropenia • Gastrointestinal Disorder • Lymphoma • Neutropenia • Non-Hodgkin’s Lymphoma • Thrombocytopenia • CRBN • IKZF1

Pomalidomide salvage in T-cell engager monotherapy failures: Real-world experience with talquetamab or elranatamab with pomalidomide combinations in heavily pretreated multiple myeloma (ASH 2025) - "al., 2023) combinations with pomalidomide (pom).Newer immunomodulatory agents such as iberdomide have been shown to induce phenotypic shifting ofthe bone marrow tumor microenvironment toward effector T and NK cells (Van Oeklen et al., 2024),providing therapeutic rationale for adding these agents to TCEs, particularly when progression isattributed to T-cell exhaustion. TCE-pom combination treatment in heavily pretreated RRMM patients, including those withprior CAR-T and pom exposure, demonstrated efficacy consistent with prior studies. ORR was 93.7% with87.5% salvage rate among TCE monotherapy-refractory patients. Safety profile showed predominantlygrade 1 CRS without ICANS."

Clinical • Monotherapy • Real-world • Real-world evidence • Hematological Disorders • Hematological Malignancies • Multiple Myeloma • Neutropenia

Trial in progress: CAR-T (idecabtagene vicleucel) in advanced myeloma plus iberdomide or usual monitoring (The Alliance A062102 CADMIUM Study) (ASH 2025) - P2 | "Background : Multiple myeloma (MM) remains incurable, though key advances such as chimeric antigenreceptor T-cells (CAR-T) and immunomodulatory agents, now evolving toward cereblon E3 ligasemodulatory drugs (CELMoDs), have substantially improved the longevity and quality of life for patients(pts)...To that end, iberdomide is an investigational CELMoD that incombination with dexamethasone has demonstrated a 30% response rate in early phase studies of tripleclass-refractory MM (Lonial et al., Lancet Haem 2022)...Enrollment data will be updated at presentation. Notably, an amendment isforthcoming which will enhance correlative studies and broaden eligibility criteria to include patients whohave received ≥2 prior lines of therapy, conforming with ide-cel's current FDA label.Study COI: BMS is supporting correlative studies.Study Support: U10CA180821, U10CA180882; BMS; U10CA180868 (NRG Oncology); http://acknowledgements.alliancefound.org"

IO biomarker • Metastases • Multiple Myeloma • Neutropenia • Targeted Protein Degradation • CRBN

Longitudinal analysis of MRD negativity and immune dynamics in patients with transplant-ineligible newly diagnosed multiple myeloma treated with iberdomide, daratumumab, and dexamethasone from the CC-220-MM-001 trial (ASH 2025) - P1/2 | "IberDd demonstrated robust activity that deepened over time and high rates of MRDnegativity at the 12-month follow-up landmark. MRD-negative CR correlated with immune changes drivenby IberDd, supporting the potential of IberDd as a broadly effective treatment option in patients with TNENDMM."

Clinical • Minimal residual disease • Hematological Malignancies • Multiple Myeloma • Transplantation • CCR7 • CD8 • CRBN • ICOS • IL2RA • IL7R • ISG20

A phase 2 trial of iberdomide, carfilzomib, daratumumab and dexamethasone quadruplet therapy for relapsed/refractory multiple myeloma: The rekindle study (ASH 2025) - P2 | "In this context, Iberdomide is a potent cereblon E3 ligase modulator (CELMoD)with demonstrated activity in IMiD-resistant disease (Lonial et al., Lancet Haematology. This quadruplet reinduction strategy adds another treatment alternative in the early relapsesetting (i.e., following lenalidomide resistance; 1-3 prior lines) where parenteral (SC or IV) T-cellredirecting therapies are gaining increased prominence. IberKDd is safe with a manageable toxicityprofile, and it affords the opportunity for de-escalation to oral monotherapy; decreasing the burden ofcontinuous parenteral therapy which is common in this setting of MM."

P2 data • Cardiovascular • Febrile Neutropenia • Hematological Disorders • Hematological Malignancies • Infectious Disease • Leukopenia • Multiple Myeloma • Myocardial Infarction • Neutropenia • Respiratory Diseases • Targeted Protein Degradation • Thrombocytopenia • CRBN

Interim analysis of efficacy and safety for ALLG MM25 (Viber-M): A phase I b/II study of venetoclax, iberdomide and dexamethasone for patients in first or second relapse of multiple myeloma with t(11; 14) (ASH 2025) - "Given the high attrition rates in patient numbers at each relapse,prioritising effective treatments early in the disease course is vital.In the era of lenalidomide (Len)-based induction and maintenance, there is need for a Len-free regimenat relapse. Iberdomide (Iber) is a potent oral cereblon E3 ligase modulator (CELMoD)...G3/4 TEAEs were reported in 11 patients (55%), with neutropenia being the most common(45%); 12 patients (60%) required filgrastim support...As of data cutoff, 44 of 50 patients have been enrolled. The planned interim analysis was conducted forthe first 20 patients (median age 65 years; range 41-83) following completion of three treatment cycles.Of these, 12 (60%) underwent planned dose escalation over three cycles, and 8 (40%) over two cycles. Themajority (75%) had one prior LOT."

Clinical • Febrile Neutropenia • Hematological Malignancies • Infectious Disease • Lymphoma • Multiple Myeloma • Neutropenia • Targeted Protein Degradation • Thrombocytopenia • CRBN

Iberdomide maintenance after autologous stem-cell transplantation in newly diagnosed multiple myeloma: An update from the phase 2 EMN26 trial (ASH 2025) - P2 | "All pts received a PI/IMiD-containing induction regimen, which also includeddaratumumab in 53% of pts. These data support the investigation of iberdomide versus lenalidomide maintenance inthe ongoing phase 3 registrational EXCALIBER Maintenance trial. The dose of 0.75 mg iberdomide waschosen as the recommended maintenance dose for further evaluation, based on comparable efficacywith superior tolerability, compared to higher doses of iberdomide."

Clinical • P2 data • Cardiovascular • Hematological Disorders • Hematological Malignancies • Infectious Disease • Multiple Myeloma • Neutropenia • Thrombocytopenia • Transplantation • Venous Thromboembolism

Safety and efficacy of elranatamab in combination with iberdomide in patients with relapsed or refractory multiple myeloma: Results from the phase 1b MagnetisMM-30 trial (ASH 2025) - P1, P2 | "The study continuesenrolling and will explore ELRA + IBER in a larger group of pts with RRMM. Results from a longer follow-up will be presented."

Clinical • Combination therapy • P1 data • Anorexia • Febrile Neutropenia • Hematological Disorders • Hematological Malignancies • Infectious Disease • Multiple Myeloma • Neutropenia • Thrombocytopenia

fss25-105: Myeloma Myth Busters: Investigating the Now, Soon, and Future Clinical Implications of CELMoDs (ASH 2025) - "Through a unique "Two Truths and a Myth" gameshow format, expert faculty will unpack key mechanistic differences between CELMoDs and IMiDs, review pivotal trial data for iberdomide and mezigdomide, and discuss the clinical implications of MRD-negative complete response as a surrogate endpoint. Participate in dynamic faculty Q&A sessions and real-world patient case challenges that highlight how CELMoDs may be integrated into near-future treatment paradigms and clinical trials. Prepare for the next wave of innovation in MM care."

Clinical • Hematological Malignancies • Multiple Myeloma

Data from part 1 of the phase 1b MagnetisMM-30 trial (NCT06215118), presented at the 2025 ASH Annual Meeting, showed that the combination of elranatamab-bcmm (Elrexfio) and iberdomide (CC-220) produced early responses with a safety profile consistent with the known toxicities of each drug in patients with relapsed or refractory multiple myeloma (Targeted Oncology) - "At a median follow-up of 7.8 months (range, 0.7-11.3), the doublet induced an objective response rate (ORR) of 95.5% (95% CI, 77.2%-99.9%) in all evaluable patients (n = 22), which included a complete response (CR) or better rate of 45.5% and a very good partial response (VGPR) or better rate of 77.3%. Moreover, responses occurred early, with a median time to response of 1.4 months (range, 0.5-2.7)."

P1 data • Multiple Myeloma

The Combination of the Novel Trifunctional BCMA NK Cell Engager SAR445514 with IMiDs and Celmods Enhances Cytotoxicity Against Multiple Myeloma Cells As Compared to Single Agents (ASH 2024) - P1/2 | "When SAR'514 was combined with either pomalidomide, iberdomide or mezigdomide, a higher cytotoxic activity was observed as compared to single agent pomalidomide (p=0.1197) and significantly higher as compared to single agent iberdomide (p=0.0035) or mezigdomide (p=0.0026). SAR'514 shows the highest potency in combination with mezigdomide.Conclusion : In summary, these results demonstrate that the combinations of SAR'514 with pomalidomide IMiD or iberdomide and mezigdomide CELMoDs potentiate MM tumor cell killing in vitro and provide consistent support for the evaluation of this combination in patients with multiple myeloma."

Hematological Malignancies • Multiple Myeloma • Oncology • FCGR3A

Bristol Myers Squibb Data at ASH 2025 Showcase Potential of Hematology Pipeline and Build Momentum for Next Generation Portfolio (Businesswire) - "Data from the company’s targeted protein degradation and cell therapy research platforms, as well as other hematology programs, will highlight development across key disease areas including multiple myeloma, lymphomas and myeloid diseases."

Clinical data • Diffuse Large B Cell Lymphoma • Follicular Lymphoma • Large B Cell Lymphoma • Multiple Myeloma • Non-Hodgkin’s Lymphoma • Transplantation

CDK4/6 Inhibition Reverses MEIS2 Inhibition of CRL4CRBN By Both Disrupting MEIS2-CRBN Association and Opposing Regulation of MEIS2 and CRBN Synthesis That Enhances IMiD Therapy in Multiple Myeloma (ASH 2024) - "The immunomodulatory drugs (IMiDs) lenalidomide (Len) and pomalidomide (Pom) are standard of care for multiple myeloma (MM)...Indeed, induction of prolonged early G1 arrest by CDK4/6 inhibition with palbociclib 1) enhanced Len and Pom killing in model MM cell lines; 2) reduced the MEIS2 protein by transcriptional repression and increased the CRBN protein by post-transcriptional regulation in cooperation with Len; 3) this led a > 5 fold reduction in the MEIS2/CRBN protein ratio, exacerbated loss of IKZF1/3 and IRF4, and enhanced apoptosis (caspase- cleavage)...In this study, we provide the first evidence that CDK4/6 inhibition reverses MEIS2 inhibition of CRBN that has a potential to enhance the clinical response to IMiD. The prospect that through cell cycle control CDK4/6 inhibition may also enhance the anti-MM activity of CELMoDs, the newly developed IMiDs such as iberdomide, in relapsed-refractory setting is exciting and warrants future investigation."

Hematological Malignancies • Lymphoma • Multiple Myeloma • Oncology • Targeted Protein Degradation • CCNA2 • CDK2 • CRBN • E2F1 • IKZF1 • IKZF3 • IRF4

Investigating the Functional Impact of CRBN Mutations on Response to IMiD/Celmod Agents in Myeloma (ASH 2023) - "Introduction Immunomodulatory drugs (IMiDs) have revolutionized the treatment of myeloma (MM), with lenalidomide (Len) and pomalidomide (Pom) approved and novel cereblon E3 ligase modulators (CELMoDs, e.g. iberdomide, Iber and mezigdomide, Mezi) in clinical trials...These mutations included all those located in the Lon protease-like domain (p.D50H, p.A143V, p.L190F, p.R283K) and two within the thalidomide binding domain but not close to the tri-tryptophan binding pocket nor neo-substrate binding area (p.A347V and p.W415G)(fig.1b)...Discussion These data highlight key differences in the functional impact of different CRBN missense mutations that have been previously identified in patients. These results may have important implications for the interpretation of CRBN sequencing results from patients for future therapy decisions, particularly differentiating those who may, despite relapsing on IMiDs with CRBN mutations, have the potential to still benefit from the use of..."

Hematological Malignancies • Multiple Myeloma • Oncology • Targeted Protein Degradation • CRBN • IKZF1 • IRF4

Early Intervention with Celmods, but Not Imids, Prevents Relapse to Forimtamig Driven By GPRC5D-Negative Myeloma Cells (ASH 2023) - "To evaluate if cereblon modulation represents a strategy to improve PFS, we combined fixed-duration forimtamig with either pomalidomide (pom) or iberdomide (iber) at C1 day 1 (C1D1). Taken together, our data suggest that combination with CELMoDs but not IMIDs can prevent relapse to forimtamig driven by GPRC5D negative tumor cells. We confirm timing of intervention with CELMoDs to have an significant impact on PFS and cytokine release and suggest a broad therapeutic window using low dose forimtamig and intermittent dosing of iberdomide or mezigdomide."

IO biomarker • Hematological Malignancies • Multiple Myeloma • Oncology • CCL3 • CRBN • CXCL8 • GPRC5D • IFNG • IL2 • TNFA

Role of Ras-Related C3 Botulinus Toxin Substrate 1 in p53-Related Proliferation and Drug Sensitivity in Multiple Myeloma (ASH 2024) - "In KMS11/Tet-on p53, KMS26/Tet-on p53, and MM.1S cells, cotreatment with Nutlin-3 and 1A-116 did not increase p53, p21, or Mdm2 protein expression...KMS11 and KMS26 cell survival at 72 h after treatment declined when CRBN modulators lenalidomide, pomalidomide, and iberdomide were combined with the Rac1 inhibitor 1A-116 (25µM) compared with CRBN modulator treatment alone. In contrast, Rac1 inhibitor showed no additive effect on cell survival after 24 h of bortezomib treatment in HMCLs...High RAC1 mRNA expression in intramedullary plasma cells of patients with NDMM is associated with worse prognosis. Our research provides new insights for development of novel therapies targeting the Rac1 pathway to improve MM patient prognosis, including patients with p53 dysfunction."

Hematological Malignancies • Lymphoma • Monoclonal Gammopathy • Multiple Myeloma • Oncology • ANXA5 • CDC42 • CDKN1A • CRBN • MDM2 • RHOA • SDC1

EZH2 Inhibition Overcomes Immunomodulatory Drug (IMiD) Resistance in Multiple Myeloma Cell Lines in a Cereblon Pathway Dependent Manner (ASH 2023) - "Following concentration/duration optimisation, cell lines were treated with EZH2i (Tazemetostat) 0.25-1µM or DMSO control for 5 days alone, and then in combination with IMiD (Lenalidomide, Len, 0-20 µM, Pomalidomide, Pom, 0-8 µM) or CELMoD (Iberdomide, CC-220, 0-2 µM and Mezigdomide, CC-92480, 0-0.1uM) for a further 5 days. Conclusions Our results suggest that combining EZH2i with IMiDs/CELMoDs can overcome resistance to these agents in MM cell line models, with synergy that is CRBN-dependent. By examining the key components of the CRBN pathway we identified that EZH2i reduced H3K27me3 and increased Ikaros and Aiolos association at the IRF4 promoter, suggesting a possible re-coupling of Ikaros/Aiolos to IRF4 expression, which may be responsible for reinstating IMiD/CELMoD activity, driving the synergistic effect seen."

Immunomodulating • Preclinical • Hematological Malignancies • Multiple Myeloma • Oncology • Targeted Protein Degradation • ANXA5 • CRBN • EZH2 • IKZF1 • IRF4