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)].

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.