Adverse reactions : תופעות לוואי

4.8      Undesirable effects
Summary of the safety profile
In ICARIA-MM, the most frequent adverse reactions (>20%) are neutropenia (46.7%), infusion reactions (38.2%), pneumonia (30.9%), upper respiratory tract infection (28.3%), diarrhoea (25.7%) 8 and bronchitis (23.7%). Serious adverse reactions occurred in 61.8% of patients receiving Isa-Pd. The most frequent serious adverse reactions are pneumonia (25.7%) and febrile neutropenia (6.6%). Permanent discontinuation of treatment because of adverse reactions was reported in 7.2% of patients treated with Isa-Pd. Adverse reactions with a fatal outcome during treatment were reported in 7.9% of patients treated with Isa-Pd (those occurring in more than 1% of patients were pneumonia occurring in 1.3% of patients and other infections occurring in 2.0% of patients).

In IKEMA, the most frequent adverse reactions (≥20%) are infusion reactions (45.8%), hypertension (36.7%), diarrhoea (36.2%), upper respiratory tract infection (36.2%), pneumonia (28.8%), fatigue (28.2%), dyspnoea (27.7%), insomnia (23.7%), bronchitis (22.6%), and back pain (22.0%). Serious adverse reactions occurred in 59.3% of patients receiving Isa-Kd. The most frequent serious adverse reaction is pneumonia (21.5%). Permanent discontinuation of treatment because of adverse reactions was reported in 8.5% of patients treated with Isa-Kd. Adverse reactions with a fatal outcome during treatment were reported in 3.4% of patients treated with Isa-Kd (those occurring in more than 1% of patients were pneumonia and cardiac failure both occurring in 1.1% of patients).

Tabulated list of adverse reactions
Adverse reactions are described using the NCI Common Toxicity Criteria, the COSTART and the MedDRA terms. Frequencies are defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from available data). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

The adverse reactions were reported from the 152 patients who received Isa-Pd with a median duration of exposure of 41 weeks in ICARIA-MM study (see section 5.1).

Table 3a: Adverse reactions reported in patients with multiple myeloma treated with isatuximab in combination with pomalidomide and low-dose dexamethasone (ICARIA-MM)b 
System Organ Class Adverse reaction                    Frequency             Incidence (%) Preferred Term                                                                (N=152) Any Grade     Grade ≥3
Infections and                   Pneumonia     cd      Very common
47 (30.9)     40 (26.3) infestations
Upper respiratory tract Very common infection*                              43 (28.3)      5 (3.3)
Bronchitis*             Very common     36 (23.7)      5 (3.3)
Herpes zoster         Common             7 (4.6)       1 (0.7)



Neoplasms benign,                Skin cancer           Common              6 (3.9)       4 (2.6) malignant and       Solid tumour (non-skin Common                          3 (2.0)       2 (1.3) unspecified (incl   cancer) cystsand polyps)e   Haematology            Uncommon                        1 (0.7)       1 (0.7) malignancy
Blood and lymphatic Neutropenia f          Very common                   71 (46.7)     70 (46.1) 
 system disorders              Febrile neutropenia       Very common      18 (11.8)       18 (11.8) Immune system                 Anaphylactic reactiong    Uncommon         5 (0.3%)          5 (0.3%) disorders
Metabolism and                Decreased appetite*       Common           15 (9.9)         2 (1.3) nutrition disorders
Cardiac disorders             Atrial fibrillation        Common           7 (4.6)         3 (2.0) Respiratory, thoracic Dyspnoea*                         Very common and mediastinal                                                          23 (15.1)        6 (3.9) disorders
Gastrointestinal              Diarrhoea*                Very common
39 (25.7)        3 (2.0) disorders
Nausea*                   Very common
23 (15.1)           0
Vomiting*                 Very common
18 (11.8)        2 (1.3)
Investigations                   Weight decreased*          Common          10 (6.6)            0 
Injury, poisoning                Infusion reaction         Very common      58 (38.2)        4 (2.6) and procedural complications
 a
Only TEAEs are reported in Table 3. The haematology laboratory values are reported in Table 5.
b
Cut-off date of 11-Oct-2018. Median follow-up time=11.60 months.
c
The term pneumonia is a grouping of the following terms: atypical pneumonia, bronchopulmonary aspergillosis, pneumonia, pneumonia haemophilus, pneumonia influenzal, pneumonia pneumococcal, pneumonia streptococcal, pneumonia viral, , pneumonia bacterial, haemophilus infection, lung infection, pneumonia fungal and pneumocystis jirovecii pneumonia.
d
See “Description of selected adverse reactions”.
e
Cut-off date of 14-Mar-2022. Median follow-up time=52.44 months. Based on second primary malignancies reported during study treatment period and during post-treatment period.
f
Haematology laboratory values were recorded as TEAEs only if they led to treatment discontinuation and/or dose modification and/or fulfilled a serious criterion and/or were defined as an AESI.
g
Based on multiple myeloma clinical trials.
* No grade 4

The adverse reactions were reported from the 177 patients who received Isa-Kd with a median duration of exposure of 80.0 weeks in IKEMA study (see section 5.1).

Table 4a: Adverse reactions reported in patients with multiple myeloma treated with isatuximab in combination with carfilzomib and dexamethasone (IKEMA)

Incidence (%)
System Organ Class                                                                 (N=177) Adverse reaction         Frequency
Preferred Term
Any Grade      Grade ≥3
Infections and                   Pneumoniab c                 Very common      28.8%          20.9% infestations
Upper respiratory tract
Very common      36.2%           3.4% infection*
Bronchitis*                  Very common      22.6%           2.3%
Herpes zoster                 Common          2.3%            0.6%
Vascular disorders               Hypertension*                Very common      36.7%          20.3% Neoplasms benign,                Skin cancers*                 Common          5.1%            0.6% 
 malignant and
Solid tumours other than unspecified (incl cysts                                      Common         3.4%             1.7% skin cancers and polyps)
Blood and lymphatic
Neutropeniad                Common         4.5%             4.0% system disorders
Immune system
Anaphylactic reactione     Uncommon      5 (0.3%)          5 (0.3%) disorders
Respiratory, thoracic            Dyspnoea*                  Very common    27.7%             5.1% and mediastinal disorders                        Cough*                     Very common    19.8%              0% Gastrointestinal
Diarrhoea*                 Very common    36.2%             2.8% disorders
Vomiting*                  Very common    15.3%             1.1%
General disorders and administration               Fatigue*                   Very common    28.2%             3.4% site conditions
Injury, poisoning
Infusion reactionc* and procedural                                              Very common    45.8%             0.6% complications a
Only TEAEs are reported in Table 4. The haematology laboratory values are reported in Table 6.
b
The term pneumonia is a grouping of the following terms: atypical pneumonia, pneumocystis jirovecii pneumonia, pneumonia, pneumonia influenzal, pneumonia legionella, pneumonia streptococcal, pneumonia viral, and pulmonary sepsis.
c
See “Description of selected adverse reactions”.
d
Haematology laboratory values were recorded as TEAEs only if they led to treatment discontinuation and/or dose modification or fulfilled a serious criterion.
e
Based on multiple myeloma clinical trials
* No grade 4 or 5.

Description of selected adverse reactions

Infusion reactions
In ICARIA-MM, infusion reactions were reported in 58 patients (38.2%) treated with SARCLISA. All patients who experienced infusion reactions, experienced them during the 1st infusion of SARCLISA, with 3 patients (2.0%) also having infusion reactions at their 2nd infusion, and 2 patients (1.3%) at their 4th infusion. Grade 1 infusion reactions were reported in 3.9%, Grade 2 in 31.6%, Grade 3 in 1.3%, and Grade 4 in 1.3% of the patients. All infusion reactions were reversible and resolved the same day in 98% of the infusions. Signs and symptoms of Grade 3 or 4 infusion reactionsincluded dyspnoea, hypertension and bronchospasm.

The incidence of infusion interruptions because of infusion reactions was 28.9%. The median time to infusion interruption was 55 minutes.

Discontinuations from treatment due to infusion reaction were reported in 2.6% of patients in Isa-Pd group.

In IKEMA, infusion reactions were reported in 81 patients (45.8%) treated with Isa-Kd. Grade 1 infusion reactions were reported in 13.6%, Grade 2 in 31.6%, and Grade 3 in 0.6% of the patients treated with Isa- Kd. All infusion reactions were reversible and resolved the same day in 73.8% of episodes in Isa-Kd patients and in more than 2 days in 2.5% of episodes in Isa-Kd patients. Signs and symptoms of Grade 3 infusion reactions included dyspnoea and hypertension. The incidence of patients with isatuximab infusion interruptions because of infusion reactions was 29.9%. The median time to isatuximab infusion interruption was 63 minutes. Isatuximab was discontinued in 0.6% of patients due to infusion reactions (see sections 4.2 and 4.4).


   Infections
In ICARIA-MM, the incidence of Grade 3 or higher infections was 42.8%. Pneumonia was the most commonly reported severe infection with Grade 3 reported in 21.7% of patients in the Isa-Pd group compared to 16.1% in the Pd group,and Grade 4 in 3.3% of patients in the Isa-Pd group compared to 2.7% in the Pd group. Discontinuations from treatment due to infection were reported in 2.6% of patients in the Isa-Pd group compared to 5.4% in the Pd group. Fatal infections were reported in 3.3%of patients in the Isa-Pd group and 4.0% in the Pd group. In IKEMA, the incidence of Grade 3 or higher infections was 38.4%. Pneumonia was the most commonly reported severe infection with Grade 3 reported in 15.8% of patients in the Isa-Kd group compared to 10.7% in the Kd group, and Grade 4 in 3.4% of patients in the Isa-Kd group compared to 2.5% in the Kd group. Treatment was discontinued due to infection in 2.8% of patients in the Isa-Kd group compared to 4.9% in the Kd group. Fatal infections were reported in 2.3% of patients in the Isa-Kd group and 0.8% in the Kd group. (see section 4.4).

In relapsed and refractory multiple myeloma clinical trials, herpes zoster was reported in 2.0% of patients. In ICARIA-MM, the incidence of herpes zoster was 4.6% in the Isa-Pd group compared to 0.7% in the Pd group, and in IKEMA, incidence was 2.3% in the Isa-Kd group compared to 1.6% in the Kd group.

Cardiac failure
In IKEMA, cardiac failure (including cardiac failure, cardiac failure congestive, cardiac failure acute, cardiac failure chronic, left ventricular failure, and pulmonary oedema) was reported in 7.3% of patients with the Isa-Kd group (4.0% of Grade ≥3) and in 6.6% of patients with the Kd group (4.1% of Grade ≥3).
Serious cardiac failure was observed in 4.0% of patients in the Isa-Kd group and in 3.3% of patients in the Kd group. Cardiac failure with a fatal outcome during treatment was reported in 1.1% of patients in the Isa-Kd group and not reported in the Kd group (see the current prescribing information for carfilzomib).

Haematology laboratory values

Table 5: Haematology laboratory abnormalities in patients receiving isatuximab combined with pomalidomide and dexamethasone–versus pomalidomide and dexamethasone(ICARIA-MM) 
Laboratory              SARCLISA + Pomalidomide                   Pomalidomide + parameter                    + Dexamethasone                    Dexamethasone n(%)                                   n(%)
(N=152)                                 (N=147)
All grades Grade 3 Grade 4            All grades Grade 3       Grade 4 Anemia               151 (99.3) 48 (31.6) 0                145 (98.6) 41 (27.9) 0 Neutropenia          146 (96.1) 37 (24.3) 92 (60.5)        137 (93.2) 57 (38.8) 46 (31.3) Lymphopenia          140 (92.1) 64 (42.1) 19 (12.5)        137 (93.2) 52 (35.4) 12 (8.2) Thrombocytopenia 127 (83.6) 22 (14.5) 25 (16.4)            118 (80.3) 14 (9.5)      22 (15.0) The denominator used for the percentage calculation is the number of patients with at least 1 evaluation of the laboratory test during the considered observation period.

Table 6: Haematology laboratory abnormalities in patients receiving isatuximab combined with carfilzomib and dexamethasone versus carfilzomib and dexamethasone (IKEMA) 
Laboratory             SARCLISA + Carfilzomib +               Carfilzomib + Dexamethasone parameter                      Dexamethasone
(N=177)                               (N=122)
All grades Grade 3 Grade 4 All grades Grade 3                   Grade 4 Anaemia                 99.4%       22.0%         0%         99.2%      19.7%            0% Neutropenia             54.8%       17.5%        1.7%        43.4%       6.6%           0.8% Lymphopenia             94.4%       52.0%       16.9%        95.1%      43.4%          13.9% Thrombocytopenia 94.4%              18.6%       11.3%        87.7%      15.6%           8.2% The denominator used for the percentage calculation is the number of patients with at least 1 evaluation of the laboratory test during the considered observation period.


Immunogenicity
Across 9 clinical studies in multiple myeloma (MM) with isatuximab single agent and combination therapies including ICARIA-MM and IKEMA (N=1018), the incidence of treatment emergent ADAs was 1.9%. No effect of ADAs was observed on pharmacokinetics, safety or efficacy of isatuximab.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il/