6 ADVERSE REACTIONS

The following clinically significant adverse reactions from SARCLISA are also described in other sections of the labeling:

Infusion-Related Reactions [see Warnings and Precautions (5.1)]
Infections [see Warnings and Precautions (5.2)]
Neutropenia [see Warnings and Precautions (5.3)]
Second Primary Malignancies [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.

Relapsed and/or Refractory Multiple Myeloma

Combination treatment with pomalidomide and dexamethasone (Isa-Pd)

The safety of SARCLISA was evaluated in ICARIA-MM, a randomized, open-label clinical trial in patients with previously treated multiple myeloma. Patients received SARCLISA 10 mg/kg intravenously, weekly in the first cycle and every two weeks thereafter, in combination with pomalidomide and dexamethasone (Isa-Pd) (n=152) or pomalidomide and dexamethasone (Pd) (n=149) [see Clinical Studies (14)]. Among patients receiving Isa-Pd, 66% were exposed to SARCLISA for 6 months or longer and 24% were exposed for greater than 12 months or longer.

Serious adverse reactions occurred in 62% of patients receiving Isa-Pd. Serious adverse reactions in >5% of patients who received Isa-Pd included pneumonia (26%), upper respiratory tract infections (7%), and febrile neutropenia (7%). Fatal adverse reactions occurred in 11% of patients (those that occurred in more than 1% of patients were pneumonia and other infections [3%]).

Permanent treatment discontinuation due to an adverse reaction (grades 1–4) occurred in 7% of patients who received Isa-Pd. The most frequent adverse reactions requiring permanent discontinuation in patients who received Isa-Pd were infections (2.6%). SARCLISA alone was discontinued in 3% of patients due to infusion-related reactions.

Dosage interruptions due to an adverse reaction occurred in 31% of patients who received SARCLISA. The most frequent adverse reaction requiring dosage interruption was infusion-related reaction (28%).

The most common adverse reactions (≥20%) were upper respiratory tract infection, infusion-related reactions, pneumonia, and diarrhea.

Table 4 summarizes the adverse reactions in ICARIA-MM.

Table 4: Adverse Reactions (≥10%) in Patients Receiving SARCLISA, Pomalidomide, and Dexamethasone with a Difference Between Arms of ≥5% Compared to Control Arm in ICARIA-MM Trial
Adverse Reactions	SARCLISA + Pomalidomide + Dexamethasone (Isa-Pd)			Pomalidomide + Dexamethasone (Pd)
	(N=152)			(N=149)
	All Grades (%)	Grade 3 (%)	Grade 4 (%)	All Grades (%)	Grade 3 (%)	Grade 4 (%)
CTCAE version 4.03
* Infusion-related reaction includes infusion-related reaction, cytokine release syndrome, and drug hypersensitivity. † Upper respiratory tract infection includes bronchiolitis, bronchitis, bronchitis viral, chronic sinusitis, fungal pharyngitis, influenza-like illness, laryngitis, nasopharyngitis, parainfluenzae virus infection, pharyngitis, respiratory tract infection, respiratory tract infection viral, rhinitis, sinusitis, tracheitis, upper respiratory tract infection, and upper respiratory tract infection bacterial. ‡ Pneumonia includes atypical pneumonia, bronchopulmonary aspergillosis, pneumonia, pneumonia haemophilus, pneumonia influenzal, pneumonia pneumococcal, pneumonia streptococcal, pneumonia viral, candida pneumonia, pneumonia bacterial, haemophilus infection, lung infection, pneumonia fungal, and pneumocystis jirovecii pneumonia. § Dyspnea includes dyspnea, dyspnea exertional, and dyspnea at rest.
General disorders and administration site conditions
Infusion-related reaction*	38	1.3	1.3	0	0	0
Infections
Upper respiratory tract infection†	57	9	0	42	3.4	0
Pneumonia‡	31	22	3.3	23	16	2.7
Blood and lymphatic system disorders
Febrile neutropenia	12	11	1.3	2	1.3	0.7
Respiratory, thoracic and mediastinal disorders
Dyspnea§	17	5	0	12	1.3	0
Gastrointestinal disorders
Diarrhea	26	2	0	19	0.7	0
Nausea	15	0	0	9	0	0
Vomiting	12	1.3	0	3.4	0	0

Table 5 summarizes the hematology laboratory abnormalities in ICARIA-MM.

Table 5: Hematology Laboratory Abnormalities During the Treatment Period in Patients Receiving Isa-Pd versus Pd in ICARIA-MM
Laboratory Parameter	SARCLISA + Pomalidomide + Dexamethasone (Isa-Pd)			Pomalidomide + Dexamethasone (Pd)
	(N=152)			(N=149)
	All Grades (%)	Grade 3 (%)	Grade 4 (%)	All Grades (%)	Grade 3 (%)	Grade 4 (%)
The denominator used to calculate the percentages was based on the safety population.
Hemoglobin decreased	99	32	0	97	28	0
Neutrophils decreased	96	24	61	92	38	31
Lymphocytes decreased	92	42	13	92	35	8
Platelets decreased	84	14	16	79	9	15

Combination treatment with carfilzomib and dexamethasone (Isa-Kd)

The safety of SARCLISA was evaluated in IKEMA, a randomized, open-label clinical trial in patients with previously treated multiple myeloma. Patients received SARCLISA 10 mg/kg intravenously weekly in the first cycle, and every two weeks thereafter, in combination with carfilzomib and dexamethasone (Isa-Kd) (n=177) or carfilzomib and dexamethasone (Kd) (n=122) [see Clinical Studies (14)]. Among patients receiving Isa-Kd, 68% were exposed to SARCLISA for 12 months or longer and 51% were exposed for greater than 18 months.

Serious adverse reactions occurred in 59% of patients receiving Isa-Kd. The most frequent serious adverse reactions in >5% of patients who received Isa-Kd were pneumonia (25%) and upper respiratory tract infections (9%). Adverse reactions with a fatal outcome during treatment were reported in 3.4% of patients in the Isa-Kd group (those occurring in more than 1% of patients were pneumonia occurring in 1.7% and cardiac failure in 1.1% of patients).

Permanent treatment discontinuation due to an adverse reaction (grades 1–4) occurred in 8% of patients who received Isa-Kd. The most frequent adverse reactions requiring permanent discontinuation in patients who received Isa-Kd were infections (2.8%). SARCLISA alone was discontinued in 0.6% of patients due to infusion-related reactions.

Dosage interruptions due to an adverse reaction occurred in 33% of patients who received SARCLISA. The most frequent adverse reaction requiring dosage interruption was infusion-related reaction (30%).

The most common adverse reactions (≥20%) were upper respiratory tract infection, infusion-related reactions, fatigue, hypertension, diarrhea, pneumonia, dyspnea, insomnia, bronchitis, cough, and back pain.

Table 6 summarizes the adverse reactions in IKEMA.

Table 6: Adverse Reactions (≥10%) in Patients Receiving SARCLISA, Carfilzomib, and Dexamethasone with a Difference Between Arms of ≥5% Compared to Control Arm in IKEMA
Adverse Reactions	SARCLISA + Carfilzomib + Dexamethasone (Isa-Kd)			Carfilzomib + Dexamethasone (Kd)
	(N=177)			(N=122)
	All Grades (%)	Grade 3 (%)	Grade 4 (%)	All Grades (%)	Grade 3 (%)	Grade 4 (%)
* Infusion-related reaction includes infusion-related reaction, cytokine release syndrome, and hypersensitivity. † Fatigue includes fatigue and asthenia. ‡ Upper respiratory tract infection includes acute sinusitis, chronic sinusitis, H1N1 influenza, H3N2 influenza, influenza, laryngitis, laryngitis viral, nasal herpes, nasopharyngitis, pharyngitis, pharyngotonsillitis, respiratory syncytial virus infection, rhinitis, sinusitis, sinusitis bacterial, tonsillitis, tracheitis, upper respiratory tract infection, viral rhinitis, respiratory tract infection, respiratory tract infection viral, influenza like illness, parainfluenzae virus infection, respiratory tract infection bacterial, and viral upper respiratory tract infection. § Pneumonia includes atypical pneumonia, lower respiratory tract infection, lower respiratory tract infection viral, pneumocystis jirovecii pneumonia, pneumonia, pneumonia influenzal, pneumonia legionella, pneumonia pneumococcal, pneumonia respiratory syncytial viral, pneumonia streptococcal, pneumonia viral, pulmonary sepsis, and pulmonary tuberculosis. ¶ Bronchitis includes bronchitis, bronchitis viral, respiratory syncytial virus bronchitis, bronchitis chronic, and tracheobronchitis. # Hypertension includes hypertension, blood pressure increased, and hypertensive crisis. Þ Dyspnea includes dyspnea and dyspnea exertional. ß Cough includes cough, productive cough, and allergic cough.
General disorders and administration site conditions
Infusion-related reaction*	46	0.6	0	3.3	0	0
Fatigue†	42	5	0	32	3.3	0
Infections
Upper respiratory tract infection‡	67	9	0	57	7	0
Pneumonia§	36	19	3.4	30	15	2.5
Bronchitis¶	24	2.3	0	13	0.8	0
Vascular disorders
Hypertension#	37	20	0.6	32	18	1.6
Respiratory, thoracic and mediastinal disorders
DyspneaÞ	29	5	0	24	0.8	0
Coughß	23	0	0	15	0	0
Gastrointestinal disorders
Diarrhea	36	2.8	0	29	2.5	0
Vomiting	15	1.1	0	9	0.8	0

Table 7 summarizes the hematology laboratory abnormalities in IKEMA.

Table 7: Hematology Laboratory Abnormalities During the Treatment Period in Patients Receiving Isa-Kd versus Kd in IKEMA
Laboratory Parameter	SARCLISA + Carfilzomib + Dexamethasone (Isa-Kd)			Carfilzomib + Dexamethasone (Kd)
	(N=177)			(N=122)
	All Grades (%)	Grade 3 (%)	Grade 4 (%)	All Grades (%)	Grade 3 (%)	Grade 4 (%)
The denominator used to calculate the percentage was based on the safety population.
Hemoglobin decreased	99	22	0	99	20	0
Lymphocytes decreased	94	52	17	95	43	14
Platelets decreased	94	19	11	88	16	8
Neutrophils decreased	55	18	1.7	43	7	0.8

Newly Diagnosed Multiple Myeloma not Eligible for Autologous Stem Cell Transplant

Combination treatment with bortezomib, lenalidomide, and dexamethasone (Isa-VRd)

The safety of SARCLISA was evaluated in IMROZ, a randomized, open-label clinical trial in patients with newly diagnosed multiple myeloma. Patients received SARCLISA 10 mg/kg intravenously on day 1, 8, 15, 22, and 29 in the first 42-day cycle, followed by every two weeks from cycle 2 to 4 (42-day cycles), followed by every two weeks from cycle 5 to 17 (28-day cycles), and then on day 1 from cycle 18 and onwards (28-day cycles), in combination with bortezomib, lenalidomide, and dexamethasone (Isa-VRd) (n=263) or bortezomib, lenalidomide, and dexamethasone (VRd) (n= 181) [see Clinical Studies (14)]. In IMROZ, median duration of exposure to treatment was 53 (range: 0.5–69) months in patients treated with Isa-VRd and 31 (range 0.6–67) months in patients treated with VRd.

Serious adverse reactions occurred in 71% of patients receiving Isa-VRd. The serious adverse reaction in > 5% of patients who received Isa-VRd was pneumonia (30%). Fatal adverse reactions occurred in 11% of patients with Isa-VRd (those occurring in more than 1% of patients were pneumonia (5%).

Permanent discontinuation of treatment due to an adverse reaction occurred in 22.8% of patients treated with Isa-VRd. The most frequent adverse reactions requiring permanent discontinuation in patients who received Isa-VRd were infections (8%). SARCLISA alone was discontinued in 2.3% of patients.

Dosage interruptions due to an adverse reaction occurred in 21% of patients who received SARCLISA. The most frequent adverse reaction requiring dosage interruption was infusion related reaction (21%).

The most common adverse reactions (≥20%) were upper respiratory tract infections, diarrhea, fatigue, peripheral sensory neuropathy, pneumonia, musculoskeletal pain, cataract, constipation, peripheral edema, rash, infusion-related reaction, insomnia, and COVID-19. The most common hematologic laboratory abnormalities (≥80%) were decreased hemoglobin, decreased leukocytes, decreased lymphocytes, decreased platelets, and decreased neutrophils.

Table 8 summarizes the adverse reactions in IMROZ.

Table 8: Adverse Reactions (≥ 20%) in Patients Receiving SARCLISA, Bortezomib, Lenalidomide, and Dexamethasone in IMROZ
	IMROZ study
Adverse Reactions	SARCLISA + Bortezomib + Lenalidomide + Dexamethasone (N=263)		Bortezomib + Lenalidomide + Dexamethasone (N=181)
Adverse Reactions	All Grades (%)	Grade 3 or 4 (%)	All Grades (%)	Grade 3 or 4 (%)
* Includes other related terms † Includes 1 patient (0.6%) with fatal URTI. ‡ Pneumonia includes Atypical pneumonia, Bronchopulmonary aspergillosis, COVID-19 pneumonia, Lower respiratory tract infection, Pneumocystis jirovecii pneumonia, Pneumonia, Pneumonia aspiration, Pneumonia bacterial, Pneumonia influenzal, Pneumonia klebsiella, Pneumonia legionella, Pneumonia parainfluenzae viral, Pneumonia pneumococcal, Pneumonia pseudomonal, Pneumonia respiratory syncytial viral, Pneumonia viral, Pulmonary sepsis. § Includes 14 patients (5%) with fatal pneumonia. ¶ Includes 4 patients (2.2%) with fatal pneumonia. # COVID-19 includes COVID-19 infections other than COVID-19 pneumonia. Þ Includes 2 patients (1.1%) with fatal COVID-19. ß Fatigue includes Fatigue, Asthenia, or Malaise. à Rash includes Dermatitis, Dermatitis acneiform, Dermatitis allergic, Dermatitis atopic, Dermatitis exfoliative generalized, Drug eruption, Rash, Rash erythematous, Rash macular, Rash maculo-papular, Rash pruritic, Rash pustular, Skin exfoliation, Skin hyperpigmentation, Skin lesion, Skin reaction, and Toxic skin eruption.
Infections and infestations
Upper respiratory tract infection*	65	4.6	57†	6
Pneumonia‡	45§	26	31¶	19
COVID-19#	22	0.8	17 Þ	1.7
General disorders and administration site conditions
Fatigueß	55	11	50	9
Edema peripheral	33	0	33	1.1
Infusion-related reaction	24	0.4	1.1	0
Gastrointestinal disorders
Diarrhea	55	8	49	8
Constipation	36	2.3	41	1.7
Nervous system disorders
Peripheral sensory neuropathy	54	7	61	6
Eye disorders
Cataract	38	16	25	11
Musculoskeletal and connective tissue disorders
Musculoskeletal pain*	38	4.2	33	3.3
Skin and subcutaneous tissue disorders
Rashà	32	5	34	5
Psychiatric disorders
Insomnia	22	3.8	24	2.2

Table 9 summarizes the hematology laboratory abnormalities in IMROZ.

Table 9: Hematology Laboratory Abnormalities During the Treatment Period in Patients Receiving Isa-VRd Versus VRd in IMROZ
Laboratory parameter	SARCLISA + Bortezomib + Lenalidomide + Dexamethasone*		Bortezomib + Lenalidomide + Dexamethasone*
Laboratory parameter	All Grades (%)	Grade 3–4 (%)	All Grades (%)	Grade 3–4 (%)
* The denominator used to calculate the rate is based on the number of patients with a baseline value and at least one post-baseline value.
Decreased hemoglobin	99	17	98	16
Decreased leukocytes	97	32	88	17
Decreased lymphocytes	95	60	92	53
Decreased platelets	95	30	85	28
Decreased neutrophils	87	54	80	37

Description of Selected Adverse Reactions

Cardiac failure

In IKEMA, cardiac failure (including cardiac failure, cardiac failure congestive, cardiac failure acute, cardiac failure chronic, left ventricular failure, and pulmonary edema) was reported in 7% of patients with the Isa-Kd group (grade ≥3 in 4%) and in 7% of patients with the Kd group (grade ≥3 in 4.1%). Serious cardiac failure was observed in 4% of patients in the Isa-Kd group and in 3.3% of patients in the Kd group. See the current prescribing information for carfilzomib for more information.