LYNOZYFIC

1 INDICATIONS AND USAGE LYNOZYFIC is indicated for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least four prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody. This indication is approved under accelerated approval based on response rate and durability of response [see Clinical Studies (14) ] . Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s). LYNOZYFIC is a bispecific B-cell maturation antigen (BCMA)‑directed CD3 T-cell engager indicated for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least four prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti‑CD38 monoclonal antibody. This indication is approved under accelerated approval based on response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s). ( 1 )

2 DOSAGE AND ADMINISTRATION Premedicate to reduce the risk of CRS and infusion-related reactions (IRR). ( 2.1 , 2.3 ) Administer only as an intravenous infusion. ( 2.1 , 2.6 ) Recommended Dosage ( 2.2 ): Dosing Schedule Day Dose of LYNOZYFIC Step-Up Dosing Schedule Day 1 Step-up dose 1 5 mg Day 8 Step-up dose 2 25 mg Day 15 First treatment dose 200 mg Weekly Dosing Schedule One week after Day 15 treatment dose and once weekly from Week 4 to Week 13 for 10 treatment doses Second and subsequent treatment doses 200 mg Biweekly (Every 2 Weeks) Dosing Schedule Week 14 and every 2 weeks thereafter Subsequent treatment doses 200 mg Patients who have achieved and maintained VGPR or better at or after Week 24 and received at least 17 doses of 200 mg Every 4 Weeks Dosing Schedule At Week 24 or after and every 4 weeks thereafter Subsequent treatment doses 200 mg Patients should be hospitalized for 24 hours after administration of the first step-up dose and for 24 hours after administration of the second step-up dose. ( 2.1 ) See Full Prescribing Information for instructions on preparation and administration. ( 2.6 ) 2.1 Important Administration Instructions Administer LYNOZYFIC intravenously according to the step-up schedule to reduce the incidence and severity of cytokine release syndrome (CRS) [see Dosage and Administration (2.2) ] . Administer only as an intravenous infusion after dilution in 0.9% Sodium Chloride Injection [see Dosage and Administration (2.6) ] . Administer pretreatment medications [see Dosage and Administration (2.3) ] . LYNOZYFIC should be administered by a healthcare provider with immediate access to emergency equipment and appropriate medical support to manage severe reactions such as cytokine release syndrome (CRS), infusion-related reactions (IRR), and neurologic toxicity, including ICANS [see Warnings and Precautions (5.1 and 5.2) ] . Due to the risk of CRS and neurologic toxicity, including ICANS, patients should be hospitalized for 24 hours after administration of the first step-up dose, and for 24 hours after administration of the second step-up dose. 2.2 Recommended Dosage The recommended dosage for LYNOZYFIC is presented in Table 1. In patients who experience CRS, ICANS, or neurologic adverse reactions, refer to Tables 3, 4, and 5, respectively, for recommendations regarding administration of the next LYNOZYFIC dose. Continue treatment until disease progression or unacceptable toxicity. The recommended dosing schedule for LYNOZYFIC is provided in Table 1. The recommended dosage of LYNOZYFIC is step-up doses of 5 mg, 25 mg, and 200 mg, followed by 200 mg weekly for 10 doses, followed by 200 mg biweekly (every 2 weeks). In patients who have achieved and maintained VGPR or better at or after Week 24 and received at least 17 doses of 200 mg, decrease the dosing frequency to 200 mg every 4 weeks. Table 1: LYNOZYFIC Dosing Schedule Dosing Schedule Day Weekly doses should be at least 5 days apart. Biweekly doses should be at least 10 days apart. Every 4-week doses should be at least 24 days apart. LYNOZYFIC Dose Duration of Infusion Step-up Dosing Schedule Day 1 Step-up dose 1 5 mg 4 hours Day 8 Step-up dose 2 25 mg Day 15 First treatment dose 200 mg Weekly Dosing Schedule One week after Day 15 treatment dose and once weekly from Week 4 to Week 13 for 10 treatment doses Second and subsequent treatment doses 200 mg 1 hour for the second treatment dose, and 30 minutes for subsequent doses For patients who experienced CRS with the previous dose of LYNOZYFIC, the duration of infusion should be maintained at the duration of the previous infusion; reduce the duration of infusion sequentially in subsequent doses in patients who do not experience CRS (e.g., 4 hours, 1 hour, then 30 minutes). Biweekly (Every 2 Weeks) Dosing Schedule Week 14 and every 2 weeks thereafter Subsequent treatment doses 200 mg 30 minutes Patients who have achieved and maintained VGPR or better at or after Week 24 and received at least 17 doses of…

5 WARNINGS AND PRECAUTIONS Infections : Can cause serious or fatal infections. Monitor patients for signs or symptoms of infection and treat accordingly. ( 5.4 ) Neutropenia : Monitor complete blood cell counts at baseline and periodically during treatment. ( 5.5 ) Hepatotoxicity: Can cause hepatotoxicity. Monitor liver enzymes and bilirubin at baseline and during treatment as clinically indicated. ( 5.6 ) Embryo-Fetal Toxicity: May cause fetal harm. Advise females of reproductive potential of the potential risk to the fetus and to use effective contraception. ( 5.7 , 8.1 , 8.3 ) 5.1 Cytokine Release Syndrome (CRS) LYNOZYFIC can cause cytokine release syndrome (CRS), which can be serious or life-threatening. In LINKER-MM1, CRS occurred in 46% (54/117) of patients who received LYNOZYFIC at the recommended dose, with Grade 1 CRS occurring in 35% (41/117) of patients, Grade 2 in 10% (12/117), and Grade 3 in 0.9% (1/117) [see Adverse Reactions (6.1) ] . Thirty-eight percent (45/117) of patients had CRS following step-up dose 1, including 1 patient who experienced Grade 3 CRS; 8% (9/117) had an initial CRS event following a subsequent dose. Seventeen percent (19/113) of patients developed CRS after step-up dose 2, 10% (11/111) developed CRS after the first full 200 mg dose of LYNOZYFIC, and 3.6% (4/110) developed CRS after the second full dose. Recurrent CRS occurred in 20% (23/117) of patients. The median time to onset of CRS from the end of infusion was 11 (range: -1 to 184) hours after the most recent dose with a median duration of 15 (range: 1 to 76) hours. Clinical signs and symptoms of CRS included, but were not limited to pyrexia, chills, hypoxia, tachycardia, and hypotension. Administer pretreatment medications and initiate therapy according to LYNOZYFIC step-up dosing to reduce the incidence and severity of CRS [see Dosage and Administration (2.2) and Dosage and Administration (2.3) ]. Monitor patients for signs and symptoms of CRS after infusion. Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur. At the first sign of CRS, immediately evaluate patients for hospitalization, manage per current practice guidelines, and administer supportive care; withhold LYNOZYFIC until CRS resolves and modify the next dose or permanently discontinue LYNOZYFIC based on severity [see Dosage and Administration (2.5) ]. Infusion Related Reactions Infusion-related reactions (IRR) may be clinically indistinguishable from manifestations of CRS. In the patients who were treated with the recommended step-up dosing regimen and pretreatment medications [see Dosage and Administration (2.2) and Dosage and Administration (2.3) ] , the rate of IRR was 9% [11/117 including Grade 2 IRR (4.3%) and Grade 3 IRR (1.7%)]. For IRR, interrupt or slow the rate of infusion or permanently discontinue LYNOZYFIC based on severity of reaction [see Dosage and Administration (2.5) ] . LYNOZYFIC is available only through a restricted program under a REMS [see Warnings and Precautions (5.3) ] . 5.2 Neurologic Toxicity, including Immune Effector Cell-Associated Neurotoxicity Syndrome LYNOZYFIC can cause serious or life-threatening neurologic toxicity, including immune effector cell-associated neurotoxicity syndrome (ICANS) [see Adverse Reactions (6.1) ]. In LINKER-MM1, neurologic toxicity occurred in 54% of patients, with Grade 3 or 4 neurologic toxicity occurring in 8%, at the recommended dose [see Adverse Reactions (6.1) ]. Neurologic toxicities included ICANS, depressed level of consciousness, encephalopathy, and toxic encephalopathy. ICANS occurred in 8% of patients who received LYNOZYFIC with the recommended dosing regimen, including Grade 3 events in 2.6%. Most patients experienced ICANS following step-up dose 1 (5%). Two patients (1.8%) experienced initial ICANS following step-up dose 2 and one patient developed the first occurrence of ICANS following a subsequent full dose of LYNOZYFIC. Recurrent ICANS occurred in one patient.…

4 CONTRAINDICATIONS None. None. ( 4 )

7 DRUG INTERACTIONS 7.1 Effects of LYNOZYFIC on Other Drugs Certain CYP substrates Monitor for toxicity unless otherwise recommended in the Prescribing Information of certain CYP substrates where minimal changes in the concentration may lead to serious adverse reactions when used concomitantly with LYNOZYFIC. Linvoseltamab-gcpt causes the release of cytokines [see Clinical Pharmacology (12.2) ] that may suppress cytochrome P450 (CYP) enzyme activity . Concomitant use with LYNOZYFIC increases CYP substrate exposure which may increase the risk of adverse reactions related to these substrates. Increased CYP substrate exposure is more likely to occur from initiation of the LYNOZYFIC step-up dosing schedule up to 14 days after the first 200 mg dose, and during and after CRS [see Warnings and Precautions (5.1) ] .

8.1 Pregnancy Risk Summary Based on the mechanism of action, LYNOZYFIC may cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) ] . There are no available data on the use of LYNOZYFIC in pregnant women to evaluate for a drug associated risk. No animal reproductive or developmental toxicity studies have been conducted with LYNOZYFIC. Linvoseltamab-gcpt causes T-cell activation and cytokine release; immune activation may compromise pregnancy maintenance. In addition, based on the finding of B-cell depletion in non-pregnant animals, linvoseltamab-gcpt can cause B-cell lymphocytopenia in infants exposed to linvoseltamab-gcpt in-utero. Human immunoglobulin (IgG) is known to cross the placenta after the first trimester of pregnancy; therefore, linvoseltamab-gcpt has the potential to be transmitted from the mother to the developing fetus. Advise women of the potential risk to the fetus. LYNOZYFIC is associated with hypogammaglobulinemia, therefore, assessment of immunoglobulin levels in newborns of mothers treated with LYNOZYFIC should be considered. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Cytokine Release Syndrome [see Warnings and Precautions (5.1) ] Neurologic Toxicity, including Immune Effector Cell-Associated Neurotoxicity Syndrome [see Warnings and Precautions (5.2) ] Infections [see Warnings and Precautions (5.4) ] Neutropenia [see Warnings and Precautions (5.5) ] Hepatotoxicity [see Warnings and Precautions (5.6) ] The most common adverse reactions (≥20%) are musculoskeletal pain, cytokine release syndrome, cough, upper respiratory tract infection, diarrhea, fatigue, pneumonia, nausea, headache, and dyspnea. ( 6.1 ) The most common Grade 3 or 4 laboratory abnormalities (≥30%) are decreased lymphocyte count, decreased neutrophil count, decreased hemoglobin, and decreased white blood cell count. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Regeneron at 1-844-467-2998 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 practice. Relapsed or Refractory Multiple Myeloma The safety of LYNOZYFIC was evaluated in LINKER-MM1 [see Clinical Studies (14) ] . Patients (n=117) received LYNOZYFIC as step-up doses of 5 mg on Day 1 and 25 mg on Day 8, and the first treatment dose of 200 mg on Day 15. Patients then received 200 mg intravenously once weekly from Week 4 to Week 13, followed by 200 mg every 2 weeks from Week 14. In the Phase 2 portion of the study, patients who achieved and maintained VGPR or better at or after Week 24 and received at least 17 doses of 200 mg were able to receive every 4-week dosing. The median duration of treatment was 47 weeks (range 1, 151); 55% of patients were exposed for 9 months or longer and 36% were exposed for 1 year or longer. The median age of patients who received LYNOZYFIC was 70 years (range: 37 to 91 years); 55% were male; 71% were White, 17% were Black or African American, and 9% were Asian. Serious adverse reactions occurred in 74% of patients who received LYNOZYFIC. Serious adverse reactions that occurred in >5% of patients included cytokine release syndrome (27%), pneumonia (13%), COVID-19 (7%), and acute kidney injury (5%). Fatal adverse reactions occurred in 7% of patients, and included sepsis (3.4%), chronic kidney disease (0.9%), pneumonia (0.9%), tumor lysis syndrome (0.9%), and encephalopathy (0.9%). Permanent discontinuation of LYNOZYFIC due to adverse reactions occurred in 16% of patients. Adverse reactions leading to discontinuation that occurred in at least 2 patients included sepsis, pneumonia, and encephalopathy. Dosage interruptions or delays of LYNOZYFIC due to adverse reactions occurred in 74% of patients. Adverse reactions which required a dosage interruption or delay in >10% of patients included neutropenia (29%), upper respiratory tract infection (18%), pneumonia (15%), and COVID-19 infection (11%). The most common adverse reactions (≥20%) were musculoskeletal pain, cytokine release syndrome, cough, upper respiratory tract infection, diarrhea, fatigue, pneumonia, nausea, headache, and dyspnea. The most common Grade 3 to 4 laboratory abnormalities (≥30%) were decreased lymphocyte count, decreased neutrophil count, decreased hemoglobin, and decreased white blood cell count. Table 7 summarizes the adverse reactions in LINKER-MM1. Table 7: Adverse Reactions (≥10%) in Patients with Relapsed or Refractory Multiple Myeloma Who Received LYNOZYFIC in LINKER-MM1 Adverse Reaction LYNOZYFIC (N=117) All Grades (%) Grade 3 or 4 (%) Musculoskeletal and connective tissue disorders Musculoskeletal pain Includes other related terms. 53 3.4 Only Grade 3 adverse reactions occurred. Immune system disorders Cytokine release syndrome 46 0.9 Hypogammaglobulinemia 13 0.9 Respir…