Elotuzumab

• 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)

For injection: 300 mg or 400 mg of elotuzumab as a white to off-white lyophilized powder in a single-dose vial for reconstitution. For Injection: 300 mg or 400 mg lyophilized powder in a single-dose vial for reconstitution. (3)

None. None (4)

• Infusion reactions: Premedication is required. Interrupt EMPLICITI for Grade 2 or higher and permanently discontinue for severe infusion reaction. ( 2.3 , 2.4 , 5.1)
• Infections: Monitor for fever and other signs of infection and treat promptly. (5.2)
• Second Primary Malignancies (SPM): Higher incidences of SPM were observed in a controlled clinical trial of patients with multiple myeloma receiving EMPLICITI. (5.3)
• Hepatotoxicity: Monitor liver function and stop EMPLICITI if hepatotoxicity is suspected. (5.4)
• Interference with determination of complete response: EMPLICITI can interfere with assays used to monitor M-protein. This interference can impact the determination of complete response. (5.5)

5.1 Infusion Reactions EMPLICITI can cause infusion reactions. Infusion reactions were reported in 10% of patients treated with EMPLICITI in the ELOQUENT-2 trial and 3.3% in the ELOQUENT-3 trial. In the ELOQUENT-2 trial, all reports of infusion reaction were Grade 3 or lower. In the ELOQUENT-2 trial, Grade 3 infusion reactions occurred in 1% of patients. The most common symptoms of an infusion reaction included fever, chills, and hypertension. Bradycardia and hypotension also developed during infusions. In the ELOQUENT-2 trial, 5% of patients required interruption of the administration of EMPLICITI for a median of 25 minutes due to infusion reactions, and 1% of patients discontinued due to infusion reactions. Of the patients who experienced an infusion reaction, 70% (23/33) had them during the first dose. In the ELOQUENT-3 trial, the only infusion reaction symptom was chest discomfort (2%), which was Grade 1. All patients in the ELOQUENT-3 trial who experienced an infusion reaction had them during the first treatment cycle. Administer premedication consisting of dexamethasone, antihistamines (H1 and H2 blockers) and acetaminophen prior to EMPLICITI infusion [see Dosage and Administration (2.3) ]. Interrupt EMPLICITI infusion for Grade 2 or higher infusion reactions and institute appropriate medical management [see Dosage and Administration (2.4) ].

5.2 Infections In the ELOQUENT-2 trial (N=635), infections were reported in 81% of patients in EMPLICITI combined with lenalidomide and dexamethasone (E-Ld) arm and 74% in lenalidomide and dexamethasone (Ld). In the ELOQUENT-3 trial (N=115), infections were reported in 65% of patients in both EMPLICITI combined with pomalidomide and dexamethasone (E-Pd) arm and in pomalidomide and dexamethasone (Pd) arm. In the ELOQUENT-2 trial, Grade 3 to 4 infections were noted in 28% and 24% of E-Ld- and Ld-treated patients and in the ELOQUENT-3 trial, 13% and 22% of E-Pd- and Pd-treated patients, respectively. Discontinuations due to infections occurred in 3.5% of E-Ld-treated and 4.1% of Ld-treated patients in the ELOQUENT-2 trial and 7% of E-Pd-treated and 5% of Pd-treated patients in the ELOQUENT-3 trial. Fatal infections were reported in 2.5% and 2.2% of E-Ld- and Ld-treated patients in the ELOQUENT-2 trial and 5% and 3.6% of E-Pd- and Pd-treated patients in the ELOQUENT-3 trial. Opportunistic infections were reported in 22% of patients in the E-Ld arm and 13% of patients in the Ld arm in the ELOQUENT-2 trial and 10% of patients in the E-Pd arm and 9% of patients in the Pd arm in the ELOQUENT-3 trial. In the ELOQUENT-2 trial, fungal infections occurred in 10% of patients in the E-Ld arm and 5% of patients in the Ld arm. Herpes zoster was reported in 14% of patients treated with E-Ld and 7% of patients treated with Ld in the ELOQUENT-2 trial and 5% of patients treated with E-Pd and 1.8% of patients treated with Pd in the ELOQUENT-3 trial. Monitor patients for development of infections and treat promptly.

5.3 Second Primary Malignancies In the ELOQUENT-2 trial (N=635), invasive second primary malignancies (SPM) have been observed in 9% of patients treated with E-Ld and 6% of patients treated with Ld and in the ELOQUENT-3 trial (N=115) in 1.8% of patients treated with Pd and in none of the patients treated with E-Pd. In the ELOQUENT-2 trial, the rate of hematologic malignancies were the same between E-Ld and Ld treatment arms (1.6%). Solid tumors were reported in 3.5% and 2.2% of E-Ld- and Ld-treated patients, respectively. Skin cancer was reported in 4.4% and 2.8% of patients treated with E-Ld and Ld, respectively. Monitor patients for the development of second primary malignancies.

5.4 Hepatotoxicity In the ELOQUENT-2 trial (N=635), elevations in liver enzymes (aspartate transaminase/alanine transaminase [AST/ALT] greater than 3 times the upper limit, total bilirubin greater than 2 times the upper limit, and alkaline phosphatase less than 2 times the upper limit) consistent with hepatotoxicity were reported in 2.5% and 0.6% of E-Ld- and Ld-treated patients. Two patients experiencing hepatotoxicity were not able to continue treatment; however, 6 out of 8 patients had resolution and were able to continue treatment. Monitor liver enzymes periodically. Stop EMPLICITI upon Grade 3 or higher elevation of liver enzymes. After return to baseline values, continuation of treatment may be considered.

5.5 Interference with Determination of Complete Response EMPLICITI is a humanized IgG kappa monoclonal antibody that can be detected on both the serum protein electrophoresis (SPEP) and immunofixation (IFE) assays used for the clinical monitoring of endogenous M-protein [see Drug Interactions (7.2) ] . This interference can impact the determination of complete response and possibly relapse from complete response in patients with IgG kappa myeloma protein.

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. […]

7.1 Drug Interactions For important drug interactions involving lenalidomide, pomalidomide and dexamethasone, refer to their respective prescribing information.

7.2 Laboratory Test Interference EMPLICITI may be detected in the SPEP and serum immunofixation assays of myeloma patients and could interfere with correct response classification. A small peak in the early gamma region on SPEP that is IgGƙ on serum immunofixation may potentially be attributed to EMPLICITI, particularly in patients whose endogenous myeloma protein is IgA, IgM, IgD, or lambda light chain restricted. This interference can impact the determination of complete response and possibly relapse from complete response in patients with IgG kappa myeloma protein [see Warnings and Precautions (5.5) ].

Pregnancy: Embryo-fetal toxicity in combination with lenalidomide and dexamethasone or pomalidomide and dexamethasone. (8.1)

8.1 Pregnancy Risk Summary There are no available data on EMPLICITI use in pregnant women to inform a drug associated risk of major birth defects and miscarriage. Animal reproduction studies have not been conducted with elotuzumab. EMPLICITI is administered in combination with lenalidomide and dexamethasone or pomalidomide and dexamethasone. Lenalidomide and pomalidomide can cause embryo-fetal harm and are contraindicated for use in pregnancy. Refer to the lenalidomide, pomalidomide and dexamethasone prescribing information for additional information. Lenalidomide and pomalidomide are only available through a REMS program. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

8.2 Lactation Risk Summary There are no data on the presence of EMPLICITI in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in the breastfed child from elotuzumab administered in combination with lenalidomide and dexamethasone or pomalidomide and dexamethasone, advise lactating women not to breastfeed during treatment with EMPLICITI. Refer to the lenalidomide, pomalidomide and dexamethasone prescribing information for additional information.

8.3 Females and Males of Reproductive Potential Pregnancy Testing Refer to the lenalidomide and pomalidomide labeling for pregnancy testing requirements prior to initiating treatment in females of reproductive potential. When EMPLICITI is used with lenalidomide or pomalidomide, there is a risk of fetal harm, including severe life-threatening human birth defects associated with lenalidomide and pomalidomide, and the need to follow requirements regarding pregnancy avoidance, including testing. Contraception Females Refer to the lenalidomide and pomalidomide labeling for contraception requirements prior to initiating treatment in females of reproductive potential. Males Lenalidomide and pomalidomide are present in the blood and semen of patients receiving the drug. Refer to the lenalidomide and pomalidomide full prescribing information for requirements regarding contraception and the prohibitions against blood and/or sperm donation due to presence and transmission in blood and/or semen and for additional information.

8.4 Pediatric Use Safety and effectiveness have not been established in pediatric patients.

8.5 Geriatric Use Of the 646 patients across treatment groups in the ELOQUENT-2 randomized trial designed to evaluate the use of EMPLICITI in combination with lenalidomide and low-dose dexamethasone in multiple myeloma, 57% were 65 years of age or older; the number of patients 65 years or older was similar between treatment groups. No overall differences in efficacy or safety were observed between patients 65 years or older and younger patients (less than 65 years of age). Of the 117 patients across treatment groups in the ELOQUENT-3 randomized trial designed to evaluate the use of EMPLICITI in combination with pomalidomide and low-dose dexamethasone in multiple myeloma, 62% were 65 years of age or older; the number of patients 65 years or older was similar between treatment groups. This study did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

Elotuzumab is a humanized IgG1 monoclonal antibody that specifically targets the SLAMF7 (Signaling Lymphocytic Activation Molecule Family member 7) protein. SLAMF7 is expressed on myeloma cells independent of cytogenetic abnormalities. SLAMF7 is also expressed on Natural Killer (NK) cells, plasma cells, and at lower levels on specific immune cell subsets of differentiated cells within the hematopoietic lineage. Elotuzumab directly activates NK cells through the SLAMF7 pathway. Elotuzumab also targets SLAMF7 on myeloma cells and interacts with Fc receptors on effector cells to mediate the killing of myeloma cells through antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). In nonclinical models, the combination of elotuzumab and lenalidomide resulted in enhanced activation of NK cells that was greater than the effects of either agent alone and increased anti-tumor activity in vitro and in vivo. Elotuzumab has also demonstrated increased anti-tumor activity when combined with pomalidomide in vivo.