iberdomide

1 INDICATIONS AND USAGE ZENBEXUS is indicated, in combination with daratumumab and hyaluronidase-fihj and dexamethasone, for the treatment of adult patients with multiple myeloma who have received at least 1 prior line of therapy including a proteasome inhibitor and an immunomodulatory agent. This indication is approved under accelerated approval based on minimal residual disease (MRD)-negative complete response (CR) at any time [see Clinical Studies (14) ] . Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). ZENBEXUS is a cereblon-modulating protein degrader indicated in combination with daratumumab and hyaluronidase-fihj and dexamethasone for the treatment of adult patients with multiple myeloma who have received at least 1 prior line of therapy including a proteasome inhibitor and an immunomodulatory agent. (1) This indication is approved under accelerated approval based on minimal residual disease (MRD)-negative complete response (CR) at any time. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).

2 DOSAGE AND ADMINISTRATION • Recommended dosage: 1 mg orally once daily with or without food on Days 1 to 21 of repeated 28-day cycles until disease progression or unacceptable toxicity. (2.2) • See Full Prescribing Information for recommended ZENBEXUS dosage modifications. (2.3 , 2.4 , 2.5) 2.1 Pregnancy Testing Prior to Administration Females of reproductive potential must have negative pregnancy testing and use effective contraception methods before initiating ZENBEXUS [see Warnings and Precautions (5.1) and Use in Specific Populations (8.3) ] . 2.2 Recommended Dosage The recommended dosage of ZENBEXUS is 1 mg orally once daily with or without food [see Clinical Pharmacology (12.3) ] on Days 1 to 21 of a 28-day cycle, until disease progression or unacceptable toxicity, in combination with daratumumab and hyaluronidase-fihj and dexamethasone. 2.3 Dosage Modifications The recommended dosage modifications for adverse reactions are provided in Table 1. Table 1: Recommended Dosage Modifications for Adverse Reactions Adverse Reaction Severity Based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 5.0. Dosage Modification Refer to daratumumab and hyaluronidase-fihj and dexamethasone Prescribing Information for information about dosage modifications for daratumumab and hyaluronidase-fihj and dexamethasone. Neutropenia (Absolute neutrophil count [ANC] <500 cells/mcL) [see Warnings and Precautions (5.4) ] Grade 4 • Interrupt ZENBEXUS. • Consider initiating granulocyte colony-stimulating factor (GCSF), as appropriate. • Follow complete blood count (CBC) at least weekly. • ANC must return to ≥1,000 cells/mcL before restarting. • The dose of ZENBEXUS may be maintained if neutropenia was the only ZENBEXUS-related toxicity requiring a dose modification and GCSF treatments are continued. • If a dose reduction is clinically appropriate, decrease ZENBEXUS to 0.75 mg once daily when restarting treatment. Febrile Neutropenia (ANC <1,000 cells/mcL with a single temperature of >38.3°C [101°F] or with a sustained temperature of ≥38°C [100.4°F] for more than 1 hour) Grade 3 Thrombocytopenia (platelet count <25,000/mcL) Grade 4 • Withhold ZENBEXUS for the remainder of the cycle. • Platelet count must return to ≥50,000/mcL before restarting. • Decrease ZENBEXUS to 0.75 mg once daily when restarting treatment. Thrombocytopenia with bleeding or any requirement for a platelet transfusion Grade 3 Thromboembolism [see Warnings and Precautions (5.3) ] ≥ Grade 3 • Interrupt ZENBEXUS. • Initiate anticoagulant therapy. • Restart treatment at a decreased ZENBEXUS dose to 0.75 mg once daily when acute symptoms of thrombosis/embolism have been resolved, at the discretion of the treating physician. Other ZENBEXUS related adverse reactions [see Adverse Reactions (6.1) ] ≥ Grade 3 • Interrupt ZENBEXUS. • Restart ZENBEXUS when adverse event has resolved or improved to ≤ Grade 2. • If a dose reduction is clinically appropriate, decrease ZENBEXUS to 0.75 mg once daily when restarting treatment. 2.4 Dosage Modifications for CYP3A Inhibitors Avoid concomitant use of ZENBEXUS with strong or moderate CYP3A inhibitors. If concomitant use with strong CYP3A inhibitors is unavoidable, reduce ZENBEXUS dose to 1 mg every other day on Days 1 to 21 of a 28-day cycle [see Drug Interactions (7.1) and Clinical Pharmacology (12.3) ] . If concomitant use with moderate CYP3A inhibitors is unavoidable, reduce ZENBEXUS dose to 0.75 mg once daily on Days 1 to 21 of a 28-day cycle [see Drug Interactions (7.1) and Clinical Pharmacology (12.3) ] . If dose modification is needed due to adverse events, reduce ZENBEXUS dose to 1 mg every other day on Days 1 to 21 of a 28-day cycle. 2.5 Recommended Dosage in Patients with Renal Impairment In patients with eGFR less than 30 mL/min/1.73 m 2 not receiving dialysis, reduce ZENBEXUS dose to 0.75 mg once daily on Days 1 to 21 of a 28-day cycle. If dose modification is needed due to adverse events, reduce ZENBEXUS dose to 1 mg every other day on Days 1 to 21 of a 28-day cycle. In patients with eGFR greater than 30 mL/min/1.73 m 2 or eGFR less than 30 mL/min/1.73 m 2 receiving intermittent hemodialysis, no dose adjustment is recommended [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ] . 2.6 Administration ZENBEXUS is a hazardous drug. Follow applicable special handling and disposal procedures. 1 Take ZENBEXUS at approximately the same time each day with or without food [see Clinical Pharmacology (12.3) ] . Swallow ZENBEXUS capsules whole with water. Do not open, break, or chew the capsules. Direct contact with the capsule contents should be avoided. In case of capsule breakage, avoid raising dust during clean-up. If contact occurs, wash thoroughly with soap and water. Delayed or Missed Doses If a dose is missed and it has been less than 12 hours since the missed dose, take the missed dose as soon as possible. If it has been more than 12 hours since the missed dose, skip the missed dose. Do not double the next dose.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling. • Serious Venous and Arterial Thromboembolism [see Warnings and Precautions (5.3) ] • Neutropenia [see Warnings and Precautions (5.4) ] • Infections [see Warnings and Precautions (5.5) ] • Second Primary Malignancies [see Warnings and Precautions (5.6) ] Most common (≥20%) adverse reactions with ZENBEXUS in combination with daratumumab and hyaluronidase-fihj and dexamethasone are upper respiratory tract infection, fatigue, musculoskeletal pain, pneumonia, diarrhea, motor dysfunction, rash, sleep disorder, hypogammaglobulinemia, COVID-19, and constipation. The most common Grade 3 or 4 (≥30%) laboratory abnormalities are neutrophil count decreased, white blood cell count decreased, and lymphocyte count decreased. (6) To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety of ZENBEXUS in combination with daratumumab and hyaluronidase-fihj and dexamethasone was evaluated in EXCALIBER-RRMM, a two-stage, phase 3, randomized, multicenter open-label study in patients with relapsed or refractory multiple myeloma (RRMM) after 1 or 2 prior lines of therapy [see Clinical Studies (14) ] . Patients were randomized to receive ZENBEXUS (at 1 of 3 dose levels) in combination with daratumumab and hyaluronidase-fihj and dexamethasone or daratumumab and hyaluronidase-fihj, bortezomib and dexamethasone (DVd) in stage 1, and ZENBEXUS 1 mg in combination with daratumumab and hyaluronidase-fihj and dexamethasone (IberDd) or DVd in stage 2. The MRD Primary Analysis Group included the first 420 patients randomized to ZENBEXUS 1 mg in combination with Dd (N=207) or DVd (N=213) in stage 1 and stage 2. Safety was assessed in patients in the MRD Primary Analysis Group who received at least one dose of the study drug (IberDd: N=204; DVd: N=204). Among patients who received ZENBEXUS, 86% were exposed for 6 months or longer and 73% were exposed for greater than one year. Serious adverse reactions occurred in 58.3% of patients who received ZENBEXUS. Serious adverse reactions in ≥2% of patients included pneumonia (26%), upper respiratory tract infection (6.4%), second primary malignancy (5.9%), neutropenia (4.9%), febrile neutropenia (3.9%), COVID-19 (4.4%), and sepsis (2.9%). Fatal adverse reactions occurred in 10 patients (4.9%) who received ZENBEXUS. Sepsis (1.5%) was the only fatal drug reaction that occurred in more than 1 patient. The following fatal adverse reactions occurred in one patient each: listeria encephalitis, influenza, lung adenocarcinoma, cardiac arrest, large intestine perforation, metabolic acidosis, and respiratory failure. Permanent discontinuation of ZENBEXUS due to an adverse reaction occurred in 7.8% of patients. The most frequent adverse reaction which resulted in permanent ZENBEXUS discontinuation was neutropenia (1%). Dosage interruption of ZENBEXUS due to an adverse reaction occurred in 84% of patients. Adverse reactions which required dosage interruption in >10% of patients included neutropenia, upper respiratory tract infection, pneumonia and COVID-19. Dosage reductions of ZENBEXUS due to an adverse reaction occurred in 29% of patients. Adverse reactions which required dose reductions in >2% of patients included neutropenia, fatigue, pneumonia, and sensory neuropathy. The most common adverse reactions (≥20%) were upper respiratory tract infection, fatigue, musculoskeletal pain, pneumonia, diarrhea, motor dysfunction, rash, sleep disorder, hypogammaglobulinemia, COVID-19, and constipation. The most common Grade 3 to 4 laboratory abnormalities (≥30%) were decreased neutrophils, decreased white blood cells, and decreased lymphocytes. Tables 2 and 3 summarize adverse reactions and laboratory abnormalities, respectively, in the EXCALIBER-RRMM study. Table 2: Adverse Reactions (≥10%) in Patients Who Received ZENBEXUS in Combination with Daratumumab and Hyaluronidase-fihj and Dexamethasone in EXCALIBER-RRMM Adverse reactions were graded according to NCI CTCAE Version 5.0. Adverse Reaction ZENBEXUS + Daratumumab and Hyaluronidase-fihj + Dexamethasone (IberDd) (n=204) Daratumumab and Hyaluronidase-fihj + Bortezomib + Dexamethasone (DVd) (n=204) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Infections and infestations Upper respiratory tract infection Upper respiratory tract infection includes nasopharyngitis, pharyngitis, respiratory tract infection, sinusitis, and other related terms. 54 Includes fatal adverse reaction: IberDd (n=1). 6 52 6 Pneumonia Pneumonia includes atypical pneumonia, bacterial pneumonia, lower respiratory tract infection, lung consolidation, viral pneumonia and other related terms. 34 25 17 10 COVID-19 Includes other related terms. 23 3.9 16 2.9 General disorders and administration site conditions Fatigue 36 3.4 33 2.5 Edema 17 0.5 24 1 Pyrexia 14 1 15 1 Musculoskeletal and connective tissue disorders Musculoskeletal pain 35 1.5 33 2.9 Bone pain 11 1 13 0.5 Gastrointestinal disorders Diarrhea 33 4.9 36 6 Constipation 20 0 22 1 Nausea 14 0.5 6 0 Nervous system disorders Motor dysfunction Motor dysfunction includes ataxia, balance disorder, gait disturbance, muscle contracture, muscle spasms, muscular weakness, myopathy, paralysis, peripheral motor neuropathy and other related terms. 26 1.5 17 2.5 Sensory neuropathy Sensory neuropathy includes anosmia, hypoesthesia, mononeuropathy, neuralgia, paresthesia, peripheral neuropathy, peripheral sensory neuropathy, polyneuropathy, radiculopathy and other related terms. 19 4.4 53 6 Dizziness 11 0 9 0.5 Skin and subcutaneous tissue disorders Rash 26 1 15 0.5 Psychiatric disorders Sleep disorder Sleep disorder includes insomnia, restless legs syndrome, sleep disorder and other related terms. 25 2.9 28 1.5 Immune system disorders Hypogammaglobulinemia Hypogammaglobulinemia includes hypogammaglobulinemia, hypoglobulinemia, and other related terms. 24 1 12 0.5 Respiratory, thoracic and mediastinal disorders Cough 18 0.5 14 0.5 Dyspnea 10 0 9 1 Renal and urinary disorders Renal impairment 11 3.4 8 3.9 Vascular disorders Hemorrhage Hemorrhage includes epistaxis, gastrointestinal hemorrhage, hematuria, injection site hemorrhage, rectal hemorrhage, subarachnoid hemorrhage, subdural hematoma and other related terms. 10 1.5 9 2 Clinically relevant adverse reactions in <10% of patients who received ZENBEXUS (in combination with daratumumab and hyaluronidase-fihj and dexamethasone) included: • Venous thromboembolic event (includes retinal vein occlusion, pulmonary embolism, deep vein thrombosis, embolism venous, post thrombotic syndrome, superficial vein thrombosis, and thrombophlebitis). • Arterial thromboembolic event (includes myocardial infarction, stress cardiomyopathy, ischemic stroke, lacunar infarction, peripheral arterial occlusive disease). • Second primary malignancy • Febrile neutropenia • Sepsis • Hepatotoxicity Table 3: Select Laboratory Abnormalities (≥30%) That Worsened from Baseline The denominator used to calculate the rate varied from 201 to 204 for both IberDd and DVd arms based on the number of patients with a baseline value and at least one post-treatment value. in Patients Who Received ZENBEXUS in EXCALIBER-RRMM Laboratory Abnormality ZENBEXUS + Daratumumab and hyaluronidase-fihj + Dexamethasone (IberDd) Daratumumab and hyaluronidase-fihj + Bortezomib + Dexamethasone (DVd) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Hematology Neutrophil count decreased 97 77 48 11 White blood cell count decreased 95 69 64 18 Lymphocytes count decreased 91 62 81 51 Platelet count decreased 62 9 92 46 Hemoglobin decreased 58 6 63 6 Chemistry Blood calcium decreased 44 2 28 1 Blood alkaline phosphatase increased 33 0.5 26 0.5