6 ADVERSE REACTIONS

The following clinically significant adverse reactions are described elsewhere in the labeling:

Infusion-related reactions [see Warnings and Precautions (5.1)] .
Neutropenia [see Warnings and Precautions (5.3)] .
Thrombocytopenia [see Warnings and Precautions (5.4)] .

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.

The safety data described below reflects exposure to DARZALEX (16 mg/kg) in 2,459 patients with multiple myeloma including 2,303 patients who received DARZALEX in combination with background regimens and 156 patients who received DARZALEX as monotherapy. In this pooled safety population, the most common adverse reactions (≥20%) were upper respiratory infection, neutropenia, infusion-related reactions, thrombocytopenia, diarrhea, constipation, anemia, peripheral sensory neuropathy, fatigue, peripheral edema, nausea, cough, pyrexia, dyspnea, and asthenia.

Newly Diagnosed Multiple Myeloma Ineligible for Autologous Stem Cell Transplant

Combination Treatment with Lenalidomide and Dexamethasone (DRd)

The safety of DARZALEX in combination with lenalidomide and dexamethasone was evaluated in MAIA [see Clinical Studies (14.1)]. Adverse reactions described in Table 7 reflect exposure to DARZALEX for a median treatment duration of 25.3 months (range: 0.1 to 40.44 months) for daratumumab-lenalidomide-dexamethasone (DRd) and of 21.3 months (range: 0.03 to 40.64 months) for lenalidomide-dexamethasone (Rd).

Serious adverse reactions with a 2% greater incidence in the DRd arm compared to the Rd arm were pneumonia (DRd 15% vs Rd 8%), bronchitis (DRd 4% vs Rd 2%) and dehydration (DRd 2% vs Rd <1%).

Table 7: Adverse Reactions Reported in ≥10% of Patients and With at Least a 5% Greater Frequency in the DRd Arm in MAIA
Body System Adverse Reaction	DRd (N=364)			Rd (N=365)
Body System Adverse Reaction	All Grades (%)	Grade 3 (%)	Grade 4 (%)	All Grades (%)	Grade 3 (%)	Grade 4 (%)
Key: D=daratumumab, Rd=lenalidomide-dexamethasone.
* Acute sinusitis, Bacterial rhinitis, Laryngitis, Metapneumovirus infection, Nasopharyngitis, Oropharyngeal candidiasis, Pharyngitis, Respiratory syncytial virus infection, Respiratory tract infection, Respiratory tract infection viral, Rhinitis, Rhinovirus infection, Sinusitis, Tonsillitis, Tracheitis, Upper respiratory tract infection, Viral pharyngitis, Viral rhinitis, Viral upper respiratory tract infection † Bronchiolitis, Bronchitis, Bronchitis viral, Respiratory syncytial virus bronchiolitis, Tracheobronchitis ‡ Atypical pneumonia, Bronchopulmonary aspergillosis, Lung infection, Pneumocystis jirovecii infection, Pneumocystis jirovecii pneumonia, Pneumonia, Pneumonia aspiration, Pneumonia pneumococcal, Pneumonia viral, Pulmonary mycosis § Infusion-related reaction includes terms determined by investigators to be related to infusion ¶ Generalized edema, Gravitational edema, Edema, Peripheral edema, Peripheral swelling # Dyspnea, Dyspnea exertional Þ Cough, Productive cough ß Blood pressure increased, Hypertension
Gastrointestinal disorders
Diarrhea	57	7	0	46	4	0
Constipation	41	1	<1	36	<1	0
Nausea	32	1	0	23	1	0
Vomiting	17	1	0	12	<1	0
Infections
Upper respiratory tract infection *	52	2	<1	36	2	<1
Bronchitis †	29	3	0	21	1	0
Pneumonia ‡	26	14	1	14	7	1
Urinary tract infection	18	2	0	10	2	0
General disorders and administration site conditions
Infusion-related reactions §	41	2	<1	0	0	0
Peripheral edema ¶	41	2	0	33	1	0
Fatigue	40	8	0	28	4	0
Asthenia	32	4	0	25	3	<1
Pyrexia	23	2	0	18	2	0
Chills	13	0	0	2	0	0
Musculoskeletal and connective tissue disorders
Back pain	34	3	<1	26	3	<1
Muscle spasms	29	1	0	22	1	0
Respiratory, thoracic and mediastinal disorders
Dyspnea #	32	3	<1	20	1	0
Cough Þ	30	<1	0	18	0	0
Nervous system disorders
Peripheral sensory neuropathy	24	1	0	15	0	0
Headache	19	1	0	11	0	0
Paresthesia	16	0	0	8	0	0
Metabolism and nutrition disorders
Decreased appetite	22	1	0	15	<1	<1
Hyperglycemia	14	6	1	8	3	1
Hypocalcemia	14	1	<1	9	1	1
Vascular disorders
Hypertension ß	13	6	<1	7	4	0

Laboratory abnormalities worsening during treatment from baseline listed in Table 8.

Table 8: Treatment-Emergent Hematology Laboratory Abnormalities in MAIA
	DRd (N=364)			Rd (N=365)
	All Grades (%)	Grade 3 (%)	Grade 4 (%)	All Grades (%)	Grade 3 (%)	Grade 4 (%)
Key: D=daratumumab, Rd=lenalidomide-dexamethasone.
Leukopenia	90	30	5	82	20	4
Neutropenia	91	39	17	77	28	11
Lymphopenia	84	41	11	75	36	6
Thrombocytopenia	67	6	3	58	7	4
Anemia	47	13	0	57	24	0

Combination Treatment with Bortezomib, Melphalan and Prednisone

The safety of DARZALEX in combination with bortezomib, melphalan and prednisone was evaluated in ALCYONE [see Clinical Studies (14.1)]. Adverse reactions described in Table 9 reflect exposure to DARZALEX for a median treatment duration of 14.7 months (range: 0 to 25.8 months) for daratumumab, bortezomib, melphalan and prednisone (D-VMP) and of 12 months (range: 0.1 to 14.9 months) for VMP.

Serious adverse reactions with at least a 2% greater incidence in the D-VMP arm compared to the VMP arm were pneumonia (D-VMP 11% vs VMP 4%), upper respiratory tract infection (D-VMP 5% vs VMP 1%), and pulmonary edema (D-VMP 2% vs VMP 0%).

Table 9: Adverse Reactions Reported in ≥10% of Patients and With at Least a 5% Greater Frequency in the D-VMP Arm in ALCYONE
Body System Adverse Reaction	D-VMP (N=346)			VMP (N=354)
Body System Adverse Reaction	All Grades (%)	Grade 3 (%)	Grade 4 (%)	All Grades (%)	Grade 3 (%)	Grade 4 (%)
Key: D=daratumumab, VMP=bortezomib-melphalan-prednisone.
* upper respiratory tract infection, bronchitis, bronchitis bacterial, epiglottitis, laryngitis, laryngitis bacterial, metapneumovirus infection, nasopharyngitis, oropharyngeal candidiasis, pharyngitis, pharyngitis streptococcal, respiratory syncytial virus infection, respiratory tract infection, respiratory tract infection viral, rhinitis, sinusitis, tonsillitis, tracheitis, tracheobronchitis, viral pharyngitis, viral rhinitis, viral upper respiratory tract infection † pneumonia, lung infection, pneumonia aspiration, pneumonia bacterial, pneumonia pneumococcal, pneumonia streptococcal, pneumonia viral, and pulmonary sepsis ‡ Infusion-related reaction includes terms determined by investigators to be related to infusion § edema peripheral, generalized edema, peripheral swelling ¶ cough, productive cough # dyspnea, dyspnea exertional Þ hypertension, blood pressure increased
Infections
Upper respiratory tract infection *	48	5	0	28	3	0
Pneumonia †	16	12	< 1	6	5	< 1
General disorders and administration site conditions
Infusion-related reactions ‡	28	4	1	0	0	0
Peripheral edema §	21	1	< 1	14	1	0
Respiratory, thoracic and mediastinal disorders
Cough ¶	16	< 1	0	8	< 1	0
Dyspnea #	13	2	1	5	1	0
Vascular disorders
Hypertension Þ	10	4	< 1	3	2	0

Laboratory abnormalities worsening during treatment from baseline listed in Table 10.

Table 10: Treatment-Emergent Hematology Laboratory Abnormalities in ALCYONE
	D-VMP (N=346)			VMP (N=354)
	All Grades (%)	Grade 3 (%)	Grade 4 (%)	All Grades (%)	Grade 3 (%)	Grade 4 (%)
Key: D=daratumumab, VMP=bortezomib-melphalan-prednisone.
Thrombocytopenia	88	27	11	88	26	16
Neutropenia	86	34	10	87	32	11
Lymphopenia	85	46	12	83	44	9
Anemia	47	18	0	50	21	0

Newly Diagnosed Multiple Myeloma Eligible for Autologous Stem Cell Transplant

Combination Treatment with Bortezomib, Thalidomide and Dexamethasone (DVTd)

The safety of DARZALEX in combination with bortezomib, thalidomide and dexamethasone was evaluated in CASSIOPEIA [see Clinical Studies (14.1)]. Adverse reactions described in Table 11 reflect exposure to DARZALEX up to day 100 post-transplant. The median duration of induction/ASCT/consolidation treatment was 8.9 months (range: 7.0 to 12.0 months) for DVTd and 8.7 months (range: 6.4 to 11.5 months) for VTd.

Serious adverse reactions with a 2% greater incidence in the DVTd arm compared to the VTd arm were bronchitis (DVTd 2% vs VTd <1%) and pneumonia (DVTd 6% vs VTd 4%).

Table 11: Adverse Reactions Reported in ≥ 10% of Patients and With at Least a 5% Greater Frequency in the DVTd Arm in CASSIOPEIA
Body System Adverse Reaction	DVTd (N=536)			VTd (N=538)
Body System Adverse Reaction	All Grades (%)	Grade 3 (%)	Grade 4 (%)	All Grades (%)	Grade 3 (%)	Grade 4 (%)
Key: D=daratumumab, VTd=bortezomib-thalidomide -dexamethasone. Note: Hematology laboratory related toxicities were excluded and reported separately in the table below.
* Infusion-related reaction includes terms determined by investigators to be related to infusion † Laryngitis, Laryngitis viral, Metapneumovirus infection, Nasopharyngitis, Oropharyngeal candidiasis, Pharyngitis, Respiratory syncytial virus infection, Respiratory tract infection, Respiratory tract infection viral, Rhinitis, Rhinovirus infection, Sinusitis, Tonsillitis, Tracheitis, Upper respiratory tract infection, Viral pharyngitis, Viral rhinitis, Viral upper respiratory tract infection ‡ Bronchiolitis, Bronchitis, Bronchitis chronic, Respiratory syncytial virus bronchitis, Tracheobronchitis § Cough, Productive cough
General disorders and administration site conditions
Infusion-related reactions *	35	3	<1	0	0	0
Pyrexia	26	2	<1	21	2	0
Gastrointestinal disorders
Nausea	30	4	0	24	2	<1
Vomiting	16	2	0	10	2	0
Infections
Upper respiratory tract infection †	27	1	0	17	1	0
Bronchitis ‡	20	1	0	13	1	0
Respiratory, thoracic and mediastinal disorders
Cough §	17	0	0	9	0	0
Vascular disorders
Hypertension	10	4	0	5	2	0

Table 12: Treatment-Emergent Hematology Laboratory Abnormalities in CASSIOPEIA
	DVTd (N=536)			VTd (N=538)
	All Grades (%)	Grade 3 (%)	Grade 4 (%)	All Grades (%)	Grade 3 (%)	Grade 4 (%)
Key: D=daratumumab, VTd=bortezomib-thalidomide -dexamethasone.
Lymphopenia	95	44	15	91	37	10
Leukopenia	82	14	10	57	6	9
Thrombocytopenia	81	9	5	58	8	3
Neutropenia	63	19	14	41	10	9
Anemia	36	4	0	35	5	0

Relapsed/Refractory Multiple Myeloma

Combination Treatment with Lenalidomide and Dexamethasone

The safety of DARZALEX in combination with lenalidomide and dexamethasone was evaluated in POLLUX [see Clinical Studies (14.2)]. Adverse reactions described in Table 13 reflect exposure to DARZALEX for a median treatment duration of 13.1 months (range: 0 to 20.7 months) for daratumumab-lenalidomide-dexamethasone (DRd) and of 12.3 months (range: 0.2 to 20.1 months) for lenalidomide-dexamethasone (Rd).

Serious adverse reactions occurred in 49% of patients in the DRd arm compared with 42% in the Rd arm. Serious adverse reactions with at least a 2% greater incidence in the DRd arm compared to the Rd arm were pneumonia (DRd 12% vs Rd 10%), upper respiratory tract infection (DRd 7% vs Rd 4%), influenza and pyrexia (DRd 3% vs Rd 1% for each).

Adverse reactions resulted in discontinuations for 7% (n=19) of patients in the DRd arm versus 8% (n=22) in the Rd arm.

Table 13: Adverse Reactions Reported in ≥ 10% of Patients and With at Least a 5% Greater Frequency in the DRd Arm in POLLUX
Adverse Reaction	DRd (N=283)			Rd (N=281)
Adverse Reaction	All Grades (%)	Grade 3 (%)	Grade 4 (%)	All Grades (%)	Grade 3 (%)	Grade 4 (%)
Key: D=daratumumab, Rd=lenalidomide-dexamethasone.
* upper respiratory tract infection, bronchitis, sinusitis, respiratory tract infection viral, rhinitis, pharyngitis, respiratory tract infection, metapneumovirus infection, tracheobronchitis, viral upper respiratory tract infection, laryngitis, respiratory syncytial virus infection, staphylococcal pharyngitis, tonsillitis, viral pharyngitis, acute sinusitis, nasopharyngitis, bronchiolitis, bronchitis viral, pharyngitis streptococcal, tracheitis, upper respiratory tract infection bacterial, bronchitis bacterial, epiglottitis, laryngitis viral, oropharyngeal candidiasis, respiratory moniliasis, viral rhinitis, acute tonsillitis, rhinovirus infection † Infusion-related reaction includes terms determined by investigators to be related to infusion ‡ cough, productive cough, allergic cough § dyspnea, dyspnea exertional
Infections
Upper respiratory tract infection *	65	6	< 1	51	4	0
General disorders and administration site conditions
Infusion-related reactions †	48	5	0	0	0	0
Fatigue	35	6	< 1	28	2	0
Pyrexia	20	2	0	11	1	0
Gastrointestinal disorders
Diarrhea	43	5	0	25	3	0
Nausea	24	1	0	14	0	0
Vomiting	17	1	0	5	1	0
Respiratory, thoracic and mediastinal disorders
Cough ‡	30	0	0	15	0	0
Dyspnea §	21	3	< 1	12	1	0
Musculoskeletal and connective tissue disorders
Muscle spasms	26	1	0	19	2	0
Nervous system disorders
Headache	13	0	0	7	0	0

Laboratory abnormalities worsening during treatment from baseline listed in Table 14.

Table 14: Treatment-Emergent Hematology Laboratory Abnormalities in POLLUX
	DRd (N=283)			Rd (N=281)
	All Grades (%)	Grade 3 (%)	Grade 4 (%)	All Grades (%)	Grade 3 (%)	Grade 4 (%)
Key: D=daratumumab, Rd=lenalidomide-dexamethasone.
Lymphopenia	95	42	10	87	32	6
Neutropenia	92	36	17	87	32	8
Thrombocytopenia	73	7	6	67	10	5
Anemia	52	13	0	57	19	0

Combination Treatment with Bortezomib and Dexamethasone

The safety of DARZALEX in combination with bortezomib and dexamethasone was evaluated in CASTOR [see Clinical Studies (14.2)]. Adverse reactions described in Table 15 reflect exposure to DARZALEX for a median treatment duration of 6.5 months (range: 0 to 14.8 months) for daratumumab-bortezomib-dexamethasone (DVd) and of 5.2 months (range: 0.2 to 8.0 months) for bortezomib-dexamethasone (Vd) arm.

Serious adverse reactions occurred in 42% of patients in the DVd arm compared with 34% in the Vd arm. Serious adverse reactions with at least a 2% greater incidence in the DVd arm compared to the Vd arm were upper respiratory tract infection (DVd 5% vs Vd 2%), diarrhea and atrial fibrillation (DVd 2% vs Vd 0% for each).

Adverse reactions resulted in discontinuations for 7% (n=18) of patients in the DVd arm versus 9% (n=22) in the Vd arm.

Table 15: Adverse Reactions Reported in ≥10% of Patients and With at Least a 5% Greater Frequency in the DVd Arm CASTOR
Adverse Reaction	DVd (N=243)			Vd (N=237)
Adverse Reaction	All Grades (%)	Grade 3 (%)	Grade 4 (%)	All Grades (%)	Grade 3 (%)	Grade 4 (%)
Key: D=daratumumab, Vd=bortezomib-dexamethasone.
* Infusion-related reaction includes terms determined by investigators to be related to infusion † edema peripheral, edema, generalized edema, peripheral swelling ‡ upper respiratory tract infection, bronchitis, sinusitis, respiratory tract infection viral, rhinitis, pharyngitis, respiratory tract infection, metapneumovirus infection, tracheobronchitis, viral upper respiratory tract infection, laryngitis, respiratory syncytial virus infection, staphylococcal pharyngitis, tonsillitis, viral pharyngitis, acute sinusitis, nasopharyngitis, bronchiolitis, bronchitis viral, pharyngitis streptococcal, tracheitis, upper respiratory tract infection bacterial, bronchitis bacterial, epiglottitis, laryngitis viral, oropharyngeal candidiasis, respiratory moniliasis, viral rhinitis, acute tonsillitis, rhinovirus infection § cough, productive cough, allergic cough ¶ dyspnea, dyspnea exertional
Nervous system disorders
Peripheral sensory neuropathy	47	5	0	38	6	< 1
General disorders and administration site conditions
Infusion-related reactions *	45	9	0	0	0	0
Peripheral edema †	22	1	0	13	0	0
Pyrexia	16	1	0	11	1	0
Infections
Upper respiratory tract infection ‡	44	6	0	30	3	< 1
Gastrointestinal disorders
Diarrhea	32	3	< 1	22	1	0
Vomiting	11	0	0	4	0	0
Respiratory, thoracic and mediastinal disorders
Cough §	27	0	0	14	0	0
Dyspnea ¶	21	4	0	11	1	0

Laboratory abnormalities worsening during treatment are listed in Table 16.

Table 16: Treatment-Emergent Hematology Laboratory Abnormalities in CASTOR
	DVd (N=243)			Vd (N=237)
	All Grades (%)	Grade 3 (%)	Grade 4 (%)	All Grades (%)	Grade 3 (%)	Grade 4 (%)
Key: D=daratumumab, Vd=bortezomib-dexamethasone.
Thrombocytopenia	90	28	19	85	22	13
Lymphopenia	89	41	7	81	24	3
Neutropenia	58	12	3	40	5	< 1
Anemia	48	13	0	56	14	0

Combination Treatment with Twice-Weekly (20/56 mg/m 2) Carfilzomib and Dexamethasone

The safety of DARZALEX in combination with twice weekly carfilzomib and dexamethasone was evaluated in CANDOR [see Clinical Studies (14.2)] . Adverse reactions described in Table 17 reflect exposure to DARZALEX for a median treatment duration of 16.1 months (range: 0.1 to 23.7 months) for the daratumumab-carfilzomib-dexamethasone (DKd) group and median treatment duration of 9.3 months (range: 0.1 to 22.4 months) for the carfilzomib-dexamethasone group (Kd).

Serious adverse reactions occurred in 56% of patients who received DARZALEX in combination with Kd and 46% of patients who received Kd. The most frequent serious adverse reactions reported in the DKd arm as compared with the Kd arm were pneumonia (DKd 14% vs Kd 9%), pyrexia (DKd 4.2% vs Kd 2.0%), influenza (DKd 3.9% vs Kd 1.3%), sepsis (DKd 3.9% vs Kd 1.3%), anemia (DKd 2.3% vs Kd 0.7%), bronchitis (DKd 1.9% vs Kd 0%), and diarrhea (DKd 1.6% vs Kd 0%). Fatal adverse reactions within 30 days of the last dose of any study treatment occurred in 10% of 308 patients who received DARZALEX in combination with Kd versus 5% of 153 patients who received Kd. The most frequent fatal adverse reaction was infection (4.5% vs 2.6%).

Permanent discontinuation of DARZALEX due to an adverse reaction occurred in 9% of patients. Adverse reactions (>1%) which resulted in permanent discontinuation of DARZALEX included pneumonia.

Infusion-related reactions that occurred on the day of administration of any DARZALEX dose or on the next day occurred in 18% of patients and that occurred on the day of administration of the first DARZALEX dose or the next day occurred in 12%.

Table 17: Adverse Reactions (≥15%) in Patients Who Received DARZALEX in Combination with Carfilzomib and Dexamethasone (DKd) in CANDOR
Adverse Reaction	DKd (N=308)		Kd (N=153)
	All Grades	Grades 3 or 4	All Grades	Grades 3 or 4
	(%)	(%)	(%)	(%)
Key: D=daratumumab; Kd=carfilzomib-dexamethasone.
* The incidence of infusion related reactions is based on a group of symptoms (including hypertension, pyrexia, rash, myalgia, hypotension, blood pressure increased, urticaria, acute kidney injury, bronchospasm, face edema, hypersensitivity, rash, syncope, wheezing, eye pruritus, eyelid edema, renal failure, swelling face) related to infusion reactions which occurred within 1 day after DKd or Kd administration. † Fatigue includes fatigue and asthenia. ‡ Respiratory tract infection includes respiratory tract infection, lower respiratory tract infection, upper respiratory tract infection and viral upper respiratory tract infection. § Includes fatal adverse reactions. ¶ Thrombocytopenia includes platelet count decreased and thrombocytopenia. # Anemia includes anemia, hematocrit decreased and hemoglobin decreased. Þ Cough includes productive cough and cough.
General Disorders and Administration Site Conditions
Infusion-related reactions *	41	12	28	5
Fatigue †	32	11	28	8
Pyrexia	20	1.9	15	0.7
Infections
Respiratory tract infection ‡	40 §	7	29	3.3
Pneumonia	18 §	13	12	9
Bronchitis	17	2.6	12	1.3
Blood and lymphatic system disorders
Thrombocytopenia ¶	37	25	30	16
Anemia #	33	17	31	14
Gastrointestinal disorders
Diarrhea	32	3.9	14	0.7
Nausea	18	0	13	0.7
Vascular Disorders
Hypertension	31	18	28	13
Respiratory, Thoracic and Mediastinal Disorders
Cough Þ	21	0	21	0
Dyspnea	20	3.9	22	2.6
Psychiatric disorders
Insomnia	18	3.9	11	2
Musculoskeletal and connective tissue disorders
Back pain	16	1.9	10	1.3

Adverse Reactions Occurring at a Frequency of < 15%

Blood and lymphatic system disorders: neutropenia, lymphopenia, leukopenia, febrile neutropenia
Cardiac disorders: atrial fibrillation
Gastrointestinal disorders: vomiting, constipation
General disorders and administration site conditions: peripheral edema, asthenia, chills
Infections: influenza, urinary tract infection, sepsis, septic shock
Metabolism and nutrition disorders: decreased appetite, hyperglycemia, hypocalcemia, dehydration
Musculoskeletal and connective tissue disorders: muscle spasms, arthralgia, musculoskeletal chest pain
Nervous system disorders: headache, dizziness, peripheral sensory neuropathy, paresthesia, posterior reversible encephalopathy syndrome
Respiratory, thoracic and mediastinal disorders: pulmonary edema
Skin and subcutaneous tissue disorders: rash, pruritus

Combination Treatment with Once-Weekly (20/70 mg/m 2) Carfilzomib and Dexamethasone

The safety of DARZALEX in combination with once-weekly carfilzomib and dexamethasone was evaluated in EQUULEUS [see Clinical Studies (14.2)] . Adverse reactions described in Table 18 reflect exposure to DARZALEX for a median treatment duration of 19.8 months (range: 0.3 to 34.5 months).

Serious adverse reactions were reported in 48% of patients. The most frequent serious adverse reactions reported were pneumonia (4.7%), upper respiratory tract infection (4.7%), basal cell carcinoma (4.7%), influenza (3.5%), general physical health deterioration (3.5%), and hypercalcemia (3.5%). Fatal adverse reactions within 30 days of the last dose of any study treatment occurred in 3.5% of patients who died of general physical health deterioration, multi-organ failure secondary to pulmonary aspergillosis, and disease progression.

Permanent discontinuation of DARZALEX due to an adverse reaction occurred in 8% of patients. No adverse reactions which resulted in permanent discontinuation of DARZALEX occurred in more than one patient.

Infusion-related reactions that occurred on the day of administration of any DARZALEX dose or on the next day occurred in 44% of patients. For patients who received the split first dose of DARZALEX, infusion-related reactions that occurred in 36% and 4% on the first and second day of administration of DARZALEX, respectively.

Table 18: Adverse Reactions (≥15%) of Patients Who Received DARZALEX in Combination with Carfilzomib and Dexamethasone in EQUULEUS
Adverse Reaction	DKd (N=85)
Adverse Reaction	All Grades (%)	Grades 3 or 4 (%)
Key: D=daratumumab; Kd=carfilzomib-dexamethasone.
* Thrombocytopenia includes platelet count decreased and thrombocytopenia. † Anemia includes anemia, hematocrit decreased and hemoglobin decreased. ‡ Neutropenia includes neutrophil count decreased and neutropenia. § Lymphopenia includes lymphocyte count decreased and lymphopenia ¶ Fatigue includes fatigue and asthenia. # The incidence of infusion related reactions is based on a group of symptoms (including hypertension, pyrexia, rash, myalgia, hypotension, blood pressure increased, urticaria, acute kidney injury, bronchospasm, face edema, hypersensitivity, rash, syncope, wheezing, eye pruritus, eyelid edema, renal failure, swelling face) related to infusion reactions which occurred within 1 day after DKd administration. Þ Respiratory tract infection includes respiratory tract infection, lower respiratory tract infection, upper respiratory tract infection and viral upper respiratory tract infection. ß Cough includes productive cough and cough.
Blood and lymphatic system disorders
Thrombocytopenia *	68	32
Anemia †	52	21
Neutropenia ‡	31	21
Lymphopenia §	29	25
General disorder and administration site conditions
Fatigue ¶	54	18
Infusion-related reactions #	53	12
Pyrexia	37	1.2
Infections
Respiratory tract infection Þ	53	3.5
Bronchitis	19	0
Nasopharyngitis	18	0
Influenza	17	3.5
Gastrointestinal disorders
Nausea	42	1.2
Vomiting	40	1.2
Diarrhea	38	2.4
Constipation	17	0
Respiratory, thoracic and mediastinal disorders
Dyspnea	35	3.5
Cough ß	33	0
Vascular disorders
Hypertension	33	20
Psychiatric disorders
Insomnia	33	4.7
Nervous system disorders
Headache	27	1.2
Musculoskeletal and connective tissue disorders
Back pain	25	0
Pain in extremity	15	0

Adverse Reactions Occurring at a Frequency of < 15%

Blood and lymphatic system disorders: leukopenia, febrile neutropenia
Cardiac disorders: atrial fibrillation
Gastrointestinal disorders: pancreatitis
General disorders and administration site conditions: peripheral edema, chills
Infections: pneumonia, urinary tract infection, sepsis, septic shock
Metabolism and nutrition disorders: decreased appetite, hyperglycemia, dehydration, hypocalcemia
Musculoskeletal and connective tissue disorders: muscle spasms, musculoskeletal chest pain, arthralgia
Nervous system disorders: dizziness, paresthesia, peripheral sensory neuropathy
Skin and subcutaneous tissue disorders: pruritus, rash

Combination Treatment with Pomalidomide and Dexamethasone

The safety of DARZALEX in combination with pomalidomide and dexamethasone was evaluated in EQUULEUS [see Clinical Studies (14.2)] . Adverse reactions described in Table 19 reflect exposure to DARZALEX, pomalidomide and dexamethasone (DPd) for a median treatment duration of 6 months (range: 0.03 to 16.9 months).

The overall incidence of serious adverse reactions was 49%. Serious adverse reactions reported in ≥5% patients included pneumonia (7%). Adverse reactions resulted in discontinuations for 13% of patients.

Table 19: Adverse Reactions With Incidence ≥10% Reported in EQUULEUS
Adverse Reaction	DPd (N=103)
Adverse Reaction	All Grades (%)	Grade 3 (%)	Grade 4 (%)
Key: D=daratumumab, Pd=pomalidomide-dexamethasone.
* Infusion-related reaction includes terms determined by investigators to be related to infusion † edema, edema peripheral, peripheral swelling ‡ acute tonsillitis, bronchitis, laryngitis, nasopharyngitis, pharyngitis, respiratory syncytial virus infection, rhinitis, sinusitis, tonsillitis, upper respiratory tract infection § lung infection, pneumonia, pneumonia aspiration ¶ cough, productive cough, allergic cough # dyspnea, dyspnea exertional
General disorders and administration site conditions
Fatigue	50	10	0
Infusion-related reactions *	50	4	0
Pyrexia	25	1	0
Chills	20	0	0
Edema peripheral †	17	4	0
Asthenia	15	0	0
Non-cardiac chest pain	15	0	0
Pain	11	0	0
Infections
Upper respiratory tract infection ‡	50	4	1
Pneumonia §	15	8	2
Respiratory, thoracic and mediastinal disorders
Cough ¶	43	1	0
Dyspnea #	33	6	1
Nasal congestion	16	0	0
Gastrointestinal disorders
Diarrhea	38	3	0
Constipation	33	0	0
Nausea	30	0	0
Vomiting	21	2	0
Musculoskeletal and connective tissue disorders
Muscle spasms	26	1	0
Back pain	25	6	0
Arthralgia	22	2	0
Pain in extremity	15	0	0
Bone pain	13	4	0
Musculoskeletal chest pain	13	2	0
Psychiatric disorders
Insomnia	23	2	0
Anxiety	13	0	0
Nervous system disorders
Dizziness	21	2	0
Tremor	19	3	0
Headache	17	0	0
Metabolism and nutrition disorders
Hypokalemia	16	3	0
Hyperglycemia	13	5	1
Decreased appetite	11	0	0

Laboratory abnormalities worsening during treatment are listed in Table 20.

Table 20: Treatment-Emergent Hematology Laboratory Abnormalities in EQUULEUS
	DPd (N=103)
	All Grades (%)	Grade 3 (%)	Grade 4 (%)
Key: D=daratumumab, Pd=pomalidomide-dexamethasone.
Neutropenia	95	36	46
Lymphopenia	94	45	26
Thrombocytopenia	75	10	10
Anemia	57	30	0

Monotherapy

The safety of DARZALEX was evaluated in 156 adult patients with relapsed and refractory multiple myeloma in three open-label, clinical trials. Patients received DARZALEX 16 mg/kg. The median duration of exposure was 3.3 months (range: 0.03 to 20.04 months).

Serious adverse reactions were reported in 51 (33%) patients. The most frequent serious adverse reactions were pneumonia (6%), general physical health deterioration (3%), and pyrexia (3%).

Adverse reactions resulted in treatment delay for 24 (15%) patients, most frequently for infections. Adverse reactions resulted in discontinuations for 6 (4%) patients.

Adverse reactions occurring in at least 10% of patients are presented in Table 21. Table 22 describes Grade 3–4 laboratory abnormalities reported at a rate of ≥10%.

Table 21: Adverse Reactions With Incidence ≥10% in Patients With Multiple Myeloma Treated With DARZALEX 16 mg/kg
Adverse Reaction	DARZALEX (N=156)
Adverse Reaction	All Grades (%)	Grade 3 (%)	Grade 4 (%)
* Infusion-related reaction includes terms determined by investigators to be related to infusion † Pneumonia also includes the terms streptococcal pneumonia and lobar pneumonia.
General disorders and administration site conditions
Infusion-related reaction *	48	3	0
Fatigue	39	2	0
Pyrexia	21	1	0
Chills	10	0	0
Gastrointestinal disorders
Nausea	27	0	0
Diarrhea	16	1	0
Constipation	15	0	0
Vomiting	14	0	0
Musculoskeletal and connective tissue disorders
Back pain	23	2	0
Arthralgia	17	0	0
Pain in extremity	15	1	0
Musculoskeletal chest pain	12	1	0
Respiratory, thoracic and mediastinal disorders
Cough	21	0	0
Nasal congestion	17	0	0
Dyspnea	15	1	0
Infections
Upper respiratory tract infection	20	1	0
Nasopharyngitis	15	0	0
Pneumonia †	11	6	0
Metabolism and nutrition disorders
Decreased appetite	15	1	0
Nervous system disorders
Headache	12	1	0
Vascular disorders
Hypertension	10	5	0

Table 22: Treatment-Emergent Grade 3–4 Laboratory Abnormalities (≥10%)
	Daratumumab 16 mg/kg (N=156)
	All Grades (%)	Grade 3 (%)	Grade 4 (%)
Lymphopenia	72	30	10
Neutropenia	60	17	3
Thrombocytopenia	48	10	8
Anemia	45	19	0

Herpes Zoster Virus Reactivation

Prophylaxis for Herpes Zoster Virus reactivation was recommended for patients in some clinical trials of DARZALEX. In monotherapy studies, herpes zoster was reported in 3% of patients. In the combination therapy studies, herpes zoster was reported in 2–5% of patients receiving DARZALEX.

Infections

Grade 3 or 4 infections were reported as follows:

Relapsed/refractory patient studies: DVd: 21% vs. Vd: 19%; DRd: 28% vs. Rd: 23%; DPd: 28%; DKd 1: 37%, Kd 1: 29%; DKd 2: 21%
Newly diagnosed patient studies: D-VMP: 23%, VMP: 15%; DRd: 32%, Rd: 23%; DVTd: 22%; VTd: 20%.

Pneumonia was the most commonly reported severe (Grade 3 or 4) infection across studies. In active controlled studies, discontinuations from treatment due to infections occurred in 1–4% of patients.

Fatal infections (Grade 5) were reported as follows:

Relapsed/refractory patient studies: DVd: 1%, Vd: 2%; DRd: 2%, Rd: 1%; DPd: 2%; DKd 1: 5%, Kd 1: 3%; DKd 2: 0%
Newly diagnosed patient studies: D-VMP: 1%, VMP: 1%; DRd: 2%, Rd: 2%; DVTd: 0%, VTd: 0%.

Fatal infections were generally infrequent and balanced between the DARZALEX containing regimens and active control arms. Fatal infections were primarily due to pneumonia and sepsis.

1: where carfilzomib 20/56 mg/m2 was administered twice-weekly
2: where carfilzomib 20/70 mg/m2 was administered once-weekly

Hepatitis B Virus (HBV) Reactivation

Hepatitis B virus reactivation has been reported in less than 1% of patients (including fatal cases) treated with DARZALEX in clinical trials.

Other Clinical Trials Experience

The following adverse reactions have been reported following administration of daratumumab and hyaluronidase for subcutaneous injection:

Nervous System disorders: Syncope

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of daratumumab. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Immune System disorders: Anaphylactic reaction, IRR (including deaths)

Gastrointestinal disorders: Pancreatitis

Infections: Cytomegalovirus, Listeriosis