Elotuzumab

1 INDICATIONS AND USAGE • EMPLICITI is indicated in combination with lenalidomide and dexamethasone for the treatment of adult patients with multiple myeloma who have received one to three prior therapies. • EMPLICITI is indicated in combination with pomalidomide and dexamethasone for the treatment of adult patients with multiple myeloma who have received at least two prior therapies including lenalidomide and a proteasome inhibitor. EMPLICITI is a SLAMF7-directed immunostimulatory antibody indicated in • combination with lenalidomide and dexamethasone for the treatment of adult patients with multiple myeloma who have received one to three prior therapies. (1) • combination with pomalidomide and dexamethasone for the treatment of adult patients with multiple myeloma who have received at least two prior therapies including lenalidomide and a proteasome inhibitor. (1)

2 DOSAGE AND ADMINISTRATION • With lenalidomide and dexamethasone: 10 mg/kg administered intravenously every week for the first two cycles and every 2 weeks thereafter until disease progression or unacceptable toxicity. (2.1) • With pomalidomide and dexamethasone: 10 mg/kg administered intravenously every week for the first two cycles and 20 mg/kg every 4 weeks thereafter until disease progression or unacceptable toxicity. (2.2) • Premedicate with dexamethasone, diphenhydramine, ranitidine and acetaminophen. (2.3) 2.1 Recommended Dosing when EMPLICITI Is Used in Combination with Lenalidomide and Dexamethasone The recommended dosage of EMPLICITI is 10 mg/kg administered intravenously every week for the first two cycles (28-day cycle) and every 2 weeks thereafter in conjunction with the recommended dosing of lenalidomide and low-dose dexamethasone as described below. Continue treatment until disease progression or unacceptable toxicity. Refer to the dexamethasone and lenalidomide prescribing information for additional information. Administer premedications before each dose of EMPLICITI [see Dosage and Administration (2.3) and Warnings and Precautions (5.1) ] . Administer dexamethasone as follows: • On days that EMPLICITI is administered, give dexamethasone 28 mg orally between 3 and 24 hours before EMPLICITI plus 8 mg intravenously between 45 and 90 minutes before EMPLICITI. • On days that EMPLICITI is not administered but a dose of dexamethasone is scheduled (Days 8 and 22 of cycle 3 and all subsequent cycles), give 40 mg orally. The recommended dosing is presented in Table 1. Table 1: Recommended Dosing Schedule of EMPLICITI in Combination with Lenalidomide and Dexamethasone Cycle 28-Day Cycles 1 and 2 28-Day Cycles 3+ * Premedicate with the following 45 to 90 minutes prior to EMPLICITI infusion: 8 mg intravenous dexamethasone, H1 blocker: diphenhydramine (25 to 50 mg orally or intravenously) or equivalent; H2 blocker: ranitidine (50 mg intravenously) or equivalent; acetaminophen (650 to 1000 mg orally). † Oral dexamethasone (28 mg) taken between 3 and 24 hours before EMPLICITI infusion. ** Intravenous dexamethasone 45-90 minutes before EMPLICITI infusion. Day of Cycle 1 8 15 22 1 8 15 22 Premedication* ✓ ✓ ✓ ✓ ✓ ✓ EMPLICITI (mg/kg) intravenously 10 10 10 10 10 10 Lenalidomide (25 mg) orally Days 1-21 Days 1-21 Dexamethasone † (mg) orally 28 28 28 28 28 40 28 40 Dexamethasone** (mg) intravenously 8 8 8 8 8 8 Day of Cycle 1 8 15 22 1 8 15 22 2.2 Recommended Dosing when EMPLICITI Is Used in Combination with Pomalidomide and Dexamethasone The recommended dosage of EMPLICITI is 10 mg/kg administered intravenously every week for the first two cycles (28-day cycle). Starting at cycle 3 (28-day cycle), administer EMPLICITI 20 mg/kg intravenously every 4 weeks. Administer EMPLICITI in conjunction with pomalidomide and low-dose dexamethasone as described below (Table 2). Continue treatment until disease progression or unacceptable toxicity. Refer to the dexamethasone and pomalidomide prescribing information for additional information. Administer premedications before each dose of EMPLICITI [see Dosage and Administration (2.3) and Warnings and Precautions (5.1) ] . Administer dexamethasone as follows: • On days that EMPLICITI is administered, for patients 75 years or younger give dexamethasone 28 mg orally between 3 and 24 hours before EMPLICITI plus 8 mg intravenously between 45 and 90 minutes before EMPLICITI and for patients older than 75 years give dexamethasone 8 mg orally between 3 and 24 hours before EMPLICITI plus 8 mg intravenously between 45 and 90 minutes before EMPLICITI. • On days that EMPLICITI is not administered but a dose of dexamethasone is scheduled (Days 8, 15 and 22 of cycle 3 and all subsequent cycles), give 40 mg orally to patients 75 years or younger and 20 mg orally to patients older than 75 years. The recommended dosing is presented in Table 2. Table 2: Recommended Dosing Schedule of EMPLICITI in Combination with Pomalidomide and Dexamethasone Cycle 28-Day Cycles 1 and 2 28-Day Cycles 3+ * Premedicate with the following 45 to 90 minutes prior to EMPLICITI infusion: 8 mg intravenous dexamethasone, H1 blocker: diphenhydramine (25 to 50 mg orally or intravenously) or equivalent; H2 blocker: ranitidine (50 mg intravenously) or equivalent; acetaminophen (650 to 1000 mg orally). † Oral dexamethasone taken between 3 and 24 hours before EMPLICITI infusion. ** Intravenous dexamethasone 45-90 minutes before EMPLICITI infusion. Day of Cycle 1 8 15 22 1 8 15 22 Premedication* ✓ ✓ ✓ ✓ ✓ EMPLICITI (mg/kg) intravenously 10 10 10 10 20 Pomalidomide (4 mg) orally Days 1-21 Days 1-21 Dexamethasone† (mg) orally ≤75 years old 28 28 28 28 28 40 40 40 Dexamethasone† (mg) orally >75 years old 8 8 8 8 8 20 20 20 Dexamethasone** (mg) intravenously 8 8 8 8 8 2.3 Premedication Dexamethasone When EMPLICITI is used in combination with lenalidomide or pomalidomide and dexamethasone, divide dexamethasone into an oral and intravenous dose and administer as shown in Table 1 and Table 2 [see Dosage and Administration (2.1 , 2.2) ] . Other Medications In addition to dexamethasone, complete administration of the following medications 45 to 90 minutes prior to EMPLICITI infusion: • H1 blocker: diphenhydramine (25 to 50 mg orally or intravenously) or equivalent H1 blocker. • H2 blocker: ranitidine (50 mg intravenously or 150 mg orally) or equivalent H2 blocker. • Acetaminophen (650 to 1000 mg orally). 2.4 Dose Modifications If the dose of one drug in the regimen is delayed, interrupted, or discontinued, the treatment with the other drugs may continue as scheduled. However, if dexamethasone is delayed or discontinued, base the decision whether to administer EMPLICITI on clinical judgment (i.e., risk of hypersensitivity). If a Grade 2 or higher infusion reaction occurs during EMPLICITI administration, interrupt the infusion and institute appropriate medical and supportive measures. Upon resolution to Grade 1 or lower, restart EMPLICITI at 0.5 mL per minute and gradually increase at a rate of 0.5 mL per minute every 30 minutes as tolerated to the rate at which the infusion reaction occurred. Resume the escalation regimen if there is no recurrence of the infusion reaction (see Table 3 and Table 4). In patients who experience an infusion reaction, monitor vital signs every 30 minutes for 2 hours after the end of the EMPLICITI infusion. If the infusion reaction recurs, stop the EMPLICITI infusion and do not restart on that day [see Warnings and Precautions (5.1) ] . Severe infusion reactions may require permanent discontinuation of EMPLICITI therapy and emergency treatment. Dose delays and modifications for dexamethasone, pomalidomide and lenalidomide should be performed as recommended in their Prescribing Information. 2.5 Administration Administer the entire EMPLICITI infusion with an infusion set and a sterile, nonpyrogenic, low-protein-binding filter (with a pore size of 0.2 to 1.2 micrometer) using an automated infusion pump. Initiate EMPLICITI infusion at a rate of 0.5 mL per minute for 10 mg/kg dose. The infusion rate may be increased in a stepwise fashion as described in Table 3 if no infusion reactions develop. The maximum infusion rate should not exceed 5 mL per minute. Table 3: Infusion Rate for EMPLICITI 10 mg/kg Cycle 1, Dose 1 Cycle 1, Dose 2 Cycle 1, Dose 3 and 4 and All Subsequent Cycles Time Interval Rate Time Interval Rate Rate 0-30 min 0.5 mL/min 0-30 min 3 mL/min 30-60 min 1 mL/min 30 min or more 4 mL/min 5 mL/min 60 min or more 2 mL/min - - Initiate EMPLICITI infusion rate at 3 mL per minute for 20 mg/kg dose. The infusion rate may be increased in a stepwise fashion as described in Table 4 if no infusion reactions develop. The maximum infusion rate should not exceed 5 mL per minute. Patients who have escalated to 5 mL/min at 10 mg/kg dose must decrease the rate to 3 mL/min at the first infusion at 20 mg/kg. Table 4: Infusion Rate for EMPLICITI 20 mg/kg Dose 1 Dose 2 and all subsequent doses Time Interval Rate Rate 0-30 min 3 mL/min 30 min or more 4 mL/min 5 mL/min Adjust the infusion rate following a Grade 2 or higher infusion reaction [see Dosage and Administration (2.4) ] . Do not mix EMPLICITI with, or administer as an infusion with, other medicinal products. No physical or biochemical compatibility studies have been conducted to evaluate the coadministration of EMPLICITI with other agents. 2.6 Reconstitution and Preparation Calculation of Dose • Calculate the dose (mg) and determine the number of vials needed for the 10 mg/kg and 20 mg/kg dosage based on patient weight. • Determine the volume of sterile water for injection (SWFI) needed for reconstitution as shown in Table 5. Table 5: Reconstitution Instructions for EMPLICITI Strength Amount of Sterile Water for Injection, USP Required for Reconstitution Deliverable Volume of Reconstituted EMPLICITI in the Vial Postreconstitution Concentration * After reconstitution, each vial contains overfill to allow for withdrawal of 12 mL (300 mg) and 16 mL (400 mg), respectively. 300 mg vial 13 mL 12 mL* 25 mg/mL 400 mg vial 17 mL 16 mL* 25 mg/mL Reconstitution • Aseptically reconstitute each EMPLICITI vial with a syringe of adequate size and a less than or equal to 18-gauge needle (e.g., 17-gauge). A slight back pressure may be experienced during administration of the Sterile Water for Injection, USP, which is considered normal. • Hold the vial upright and swirl the solution by rotating the vial to dissolve the lyophilized cake. Invert the vial a few times in order to dissolve any powder that may be present on top of the vial or the stopper. Avoid vigorous agitation. DO NOT SHAKE. The lyophilized powder should dissolve in less than 10 minutes. • After the remaining solids are completely dissolved, allow the reconstituted solution to stand for 5 to 10 minutes. The reconstituted preparation results in a colorless to slightly yellow, clear to slightly opalescent solution. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Discard the solution if any particulate matter or discoloration is observed. Dilution • Once the reconstitution is completed, withdraw the necessary volume for the calculated dose from each vial, up to a maximum of 16 mL from 400 mg vial and 12 mL from 300 mg vial. • Further dilute with either 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP, into an infusion bag made of polyvinyl chloride or polyolefin. The final infusion concentration should range between 1 mg/mL and 6 mg/mL. • The volume of 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP should be adjusted so as not to exceed 5 mL/kg of patient weight at any given dose of EMPLICITI. Complete the EMPLICITI infusion within 24 hours of reconstitution of the EMPLICITI lyophilized powder. If not used immediately, the infusion solution may be stored under refrigeration conditions: 2°C to 8°C (36°F-46°F) and protected from light for up to 24 hours (a maximum of 8 hours of the total 24 hours can be at room temperature, 20°C to 25°C [68°F-77°F], and room light).

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described in detail in other sections of the label: • Infusion reaction [see Warnings and Precautions (5.1) ] . • Infections [see Warnings and Precautions (5.2) ] . • Second Primary Malignancies [ see Warnings and Precautions (5.3) ] . • Hepatotoxicity [see Warnings and Precautions (5.4) ] . • Interference with determination of complete response [see Warnings and Precautions (5.5) ] . Most common adverse reactions (20% or higher) • with lenalidomide and dexamethasone are fatigue, diarrhea, pyrexia, constipation, cough, peripheral neuropathy, nasopharyngitis, upper respiratory tract infection, decreased appetite, pneumonia. (6.1) • with pomalidomide and dexamethasone are constipation and hyperglycemia. (6.1) 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 practice. EMPLICITI in Combination with Lenalidomide and Dexamethasone [ELOQUENT-2] The safety data described in this section are based on the ELOQUENT-2 study, a randomized, open-label clinical trial in patients with previously treated multiple myeloma. In ELOQUENT-2, EMPLICITI 10 mg/kg was administered with lenalidomide and dexamethasone [see Clinical Studies (14) ] . For adverse reaction evaluation, EMPLICITI combined with lenalidomide and dexamethasone was compared with lenalidomide and dexamethasone alone. The mean age of the population was 66 years and 57% of patients were 65 years of age or older. Sixty percent (60%) of the population were male, 84% were white, 10% were Asian, and 4% were black. The Eastern Cooperative Oncology Group (ECOG) performance status was 0 in 47%, 1 in 44%, and 2 in 9% of patients. These data reflect exposure of 318 patients to EMPLICITI and 317 to control with a median number of cycles of 19 for EMPLICITI and 14 for control. Serious adverse reactions were reported in 65% of patients treated on the EMPLICITI arm and 57% for patients treated on the control arm. The most frequent serious adverse reactions in the EMPLICITI arm compared to the control arm were: pneumonia (15% vs. 11%), pyrexia (7% vs. 5%), respiratory tract infection (3.1% vs. 1.3%), anemia (2.8% vs. 1.9%), pulmonary embolism (3.1% vs. 2.5%), and acute renal failure (2.5% vs. 1.9%). The proportion of patients who discontinued any component of the treatment regimen due to adverse reactions as listed below was similar for both treatment arms; 6.0% for patients treated on the EMPLICITI arm and 6.3% for patients treated on the control. Adverse reactions occurring at a frequency of 10% or higher in the EMPLICITI arm and 5% or higher than the lenalidomide and dexamethasone arm for the randomized trial in multiple myeloma are presented in Table 6. Table 6: ELOQUENT-2: Adverse Reactions with a 10% or Higher Incidence for EMPLICITI-Treated Patients and a 5% or Higher Incidence than Lenalidomide and Dexamethasone-Treated Patients [All Grades] EMPLICITI + Lenalidomide and Dexamethasone N=318 Lenalidomide and Dexamethasone N=317 Primary Term All Grades Grade 3/4 All Grades Grade 3/4 * The term fatigue is a grouping of the following terms: fatigue and asthenia. † The term cough is a grouping of the following terms: cough, productive cough, and upper airway cough. ‡ The term peripheral neuropathy is a grouping of the following terms: peripheral neuropathy, axonal neuropathy, peripheral motor neuropathy, peripheral sensory neuropathy, and polyneuropathy. § The term pneumonia is a grouping of the following terms: pneumonia, atypical pneumonia, bronchopneumonia, lobar pneumonia, bacterial pneumonia, fungal pneumonia, pneumonia influenza, and pneumococcal pneumonia. Fatigue* 62 13 52 12 Diarrhea 47 5.0 36 4.1 Pyrexia 37 2.5 25 2.8 Constipation 36 1.3 27 0.3 Cough † 34 0.3 19 0 Peripheral Neuropathy ‡ 27 3.8 21 2.2 Nasopharyngitis 25 0 19 0 Upper Respiratory Tract Infection 23 0.6 17 1.3 Decreased Appetite 21 1.6 13 1.3 Pneumonia § 20 14 14 9 Pain in Extremities 16 0.9 10 0.3 Headache 15 0.3 8 0.3 Vomiting 14 0.3 9 0.9 Weight Decreased 14 1.3 6 0 Lymphopenia 13 9 7 3.2 Cataracts 12 6 6 2.8 Oropharyngeal Pain 10 0 4 0 Laboratory abnormalities worsening from baseline and occurring at a frequency of 10% or higher in the EMPLICITI group and 5% or higher than the lenalidomide and dexamethasone group (criteria met for all Grades or Grade 3/4) for ELOQUENT-2 are presented in Table 7. Table 7: ELOQUENT-2: Laboratory Abnormalities Worsening from Baseline and with a 10% or Higher Incidence for EMPLICITI-Treated Patients and a 5% Higher Incidence than Lenalidomide and Dexamethasone-Treated Patients [Criteria met for All Grades or Grade 3/4] EMPLICITI + Lenalidomide and Dexamethasone N=318 Lenalidomide and Dexamethasone N=317 Laboratory Parameter All Grades Grade 3/4 All Grades Grade 3/4 Hematology Lymphopenia 99 77 98 49 Leukopenia 91 32 88 26 Thrombocytopenia 84 19 78 20 Liver and Renal Function Tests Hypoalbuminemia 73 3.9 66 2.3 Elevated Alkaline Phosphatase 39 1.3 30 0 Chemistry Hyperglycemia 89 17 85 10 Hypocalcemia 78 11 77 4.7 Low Bicarbonate 63 0.4 45 0 Hyperkalemia 32 7 22 1.6 Vital sign abnormalities were assessed by treatment arm for the randomized trial in multiple myeloma and are presented in Table 8. Percentages are based on patients who had at least one vital sign abnormality any time during the course of study. Table 8: ELOQUENT-2 Vital Sign Abnormalities EMPLICITI + Lenalidomide and Dexamethasone N=318 Lenalidomide and Dexamethasone N=317 Vital Sign Parameter % % Systolic Blood Pressure ≥160 mmHg 33 21 Diastolic Blood Pressure ≥100 mmHg 17 12 Systolic Blood Pressure <90 mmHg 29 8 Heart Rate ≥100 bpm 48 30 Heart Rate <60 bpm 66 31 EMPLICITI in Combination with Pomalidomide and Dexamethasone [ELOQUENT-3] The safety data described in this section are based on ELOQUENT-3, a randomized, open-label clinical trial in patients with previously treated multiple myeloma. In ELOQUENT-3, EMPLICITI 10 mg/kg and 20 mg/kg was administered with pomalidomide and dexamethasone [see Clinical Studies (14) ] . For adverse reaction evaluation, EMPLICITI combined with pomalidomide and dexamethasone was compared with pomalidomide and dexamethasone alone. The mean age of the population was 66 years and 63% of patients were 65 years of age or older. Fifty-seven percent of the population were male, 78% were white, 20% were Asian, and none were black. The ECOG performance status was 0 in 43%, 1 in 46%, and 2 in 10% of patients. These data reflect exposure of 60 patients to EMPLICITI and 55 to control with a median number of cycles of 9 for EMPLICITI and 5 for control. Serious adverse reactions were reported in 70% of patients treated on the EMPLICITI arm and 60% for patients treated on the control arm. The most frequent serious adverse reactions in the EMPLICITI arm compared to the control arm were: pneumonia (13% vs. 11%) and respiratory tract infection (7% vs. 3.6%). The proportion of patients who discontinued any component of the treatment regimen due to adverse reactions were 5% of the patients in the EMPLICITI arm and 1.8% of the patients in the control arm. Adverse reactions occurring at a frequency of 10% or higher in the EMPLICITI arm and 5% or higher than the pomalidomide and dexamethasone arm for the randomized trial in multiple myeloma are presented in Table 9. Table 9: ELOQUENT-3: Adverse Reactions with a 10% or Higher Incidence for EMPLICITI-Treated Patients and a 5% or Higher Incidence than Pomalidomide and Dexamethasone-Treated Patients [All Grades] EMPLICITI + Pomalidomide and Dexamethasone N=60 Pomalidomide and Dexamethasone N=55 Adverse Reaction All Grades Grade 3/4 All Grades Grade 3/4 * The term pneumonia is grouping of the following terms: pneumonia, atypical pneumonia, lower respiratory tract infection, pneumoccocal sepsis, pneumonia bacterial, pneumonia influenza. Constipation 22 1.7 11 0 Hyperglycemia 20 8 15 7 Pneumonia* 18 10 13 11 Diarrhea 18 0 9 0 Respiratory Tract Infection 17 0 9 1.8 Bone Pain 15 3.3 9 0 Dyspnea 15 3.3 7 1.8 Muscle Spasms 13 0 5 0 Edema Peripheral 13 0 7 0 Lymphopenia 10 8 1.8 1.8 Other clinically important adverse reactions reported in patients treated with EMPLICITI that did not meet the criteria for inclusion in Table 6 and 9 but occurred at a frequency of 5% or greater in the EMPLICITI group and at a frequency at least twice the control rate for the randomized trial in multiple myeloma are listed below: General disorders and administration site conditions: chest pain, night sweats Immune system disorders: hypersensitivity Nervous system disorders: hypoesthesia Psychiatric disorders: mood altered Laboratory abnormalities worsening from baseline and occurring at a frequency of 10% or higher in ELOQUENT-3 in the EMPLICITI group and 5% or higher than the pomalidomide and dexamethasone group (criteria met for all Grades or Grade 3/4) for the randomized trial in multiple myeloma are presented in Table 10. Table 10: ELOQUENT-3: Laboratory Abnormalities Worsening from Baseline and with a 10% or Higher Incidence for EMPLICITI-Treated Patients and a 5% Higher Incidence than Pomalidomide and Dexamethasone-Treated Patients [Criteria met for All Grades or Grade 3/4] EMPLICITI + Pomalidomide and Dexamethasone N=60 Pomalidomide and Dexamethasone N=55 Laboratory Parameter All Grades Grade 3/4 All Grades Grade 3/4 Hematology Lymphopenia 98 70 91 35 Leukopenia 80 52 87 35 Thrombocytopenia 78 17 73 20 Liver and Renal Function Tests Hypoalbuminemia 65 1.7 56 1.8 Chemistry Hypocalcemia 58 3.3 40 1.8 Hyperglycemia 40 3.3 25 1.8 Hyponatremia 40 5 18 0 Hypokalemia 23 5 16 3.6 Vital sign abnormalities were assessed by treatment arm for the randomized trial in multiple myeloma and are presented in Table 11. Percentages are based on all treated patients Table 11: ELOQUENT-3: Vital Sign Abnormalities EMPLICITI + Pomalidomide and Dexamethasone N=60 Pomalidomide and Dexamethasone N=55 Vital Sign Parameter % % Systolic Blood Pressure ≥160 mmHg 18 13 Diastolic Blood Pressure ≥100 mmHg 8 4.0 Systolic Blood Pressure <90 mmHg 7 7 Heart Rate ≥100 bpm 23 24 Heart Rate <60 bpm 43 22 6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity to EMPLICITI. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to EMPLICITI in the studies described below with the incidences of antibodies in other studies or to other products may be misleading. Of 390 patients across four clinical studies including ELOQUENT-2 and in 53 patients in the ELOQUENT-3 trial, who were treated with EMPLICITI and evaluable for the presence of anti-product antibodies, 72 patients (18.5%) in the four clinical trials and 19 patients (36%) in the ELOQUENT-3 trial tested positive for treatment-emergent anti-product antibodies by an electrochemiluminescent (ECL) assay. In 63 (88%) of the 72 patients in the four clinical trials, anti-product antibodies occurred within the first 2 months of the initiation of EMPLICITI treatment and resolved by 2 to 4 months in 49 (78%) patients. In the ELOQUENT-3 trial, in all 19 patients, anti-product antibodies occurred within the first 2 months of the initiation of EMPLICITI treatment and were resolved by 2 to 3 months in 18 (95%) patients. Neutralizing antibodies post-treatment were detected in 19 of 299 patients in the four clinical trials and 2 of 53 patients in the ELOQUENT-3 trial who were evaluable for the presence of neutralizing antibodies.

12.3 Pharmacokinetics Elotuzumab exhibits nonlinear pharmacokinetics (PK) resulting in greater than proportional increases in area under the concentration-time curve (AUC) indicative of target-mediated clearance. The administration of the recommended 10 mg/kg EMPLICITI regimen with lenalidomide and dexamethasone is predicted to result in geometric mean (CV%) steady-state trough concentrations of 194 μg/mL (52%). The administration of the recommended EMPLICITI regimen with pomalidomide and dexamethasone is predicted to result in geometric mean (CV%) steady-state trough concentrations of 124 μg/mL (59%). Elimination The clearance of elotuzumab in combination with lenalidomide and dexamethasone decreased from a geometric mean (CV%) of 17.5 (21.2%) to 5.8 (31%) mL/day/kg with an increase in dose from 0.5 (i.e., 0.05 times the recommended dosage) to 20 mg/kg (i.e., 2 times the recommended dosage). When elotuzumab is administered with lenalidomide and dexamethasone, approximately 97% of the maximum steady-state concentration is predicted to be eliminated with a geometric mean (CV%) of 82.4 (48%) days. When elotuzumab is administered with pomalidomide and dexamethasone, approximately 97% of the maximum steady-state concentration is predicted to be eliminated with a geometric mean (CV%) of 78 (42%) days. Specific Populations Clinically significant differences were not observed in the PK of elotuzumab based on age (37 to 88 years), sex, race, baseline lactate dehydrogenase, albumin, renal impairment (creatinine clearance (CLcr) 15 to 89 mL/min), end-stage renal disease (CLcr <15 mL/min) with or without hemodialysis, mild hepatic impairment (total bilirubin ≤ upper limit of normal (ULN) and aspartate transaminase (AST) > ULN OR total bilirubin 1 to 1.5 times the ULN and AST any value), and coadministration with lenalidomide/dexamethasone or pomalidomide/dexamethasone. The PK of elotuzumab in patients with moderate (total bilirubin > 1.5 to 3 times the ULN and AST any value) to severe (total bilirubin > 3 times the ULN and AST any value) hepatic impairment is unknown. The clearance of elotuzumab increased with increasing body weight supporting a weight-based dose.