Adverse reactions : תופעות לוואי

4.8    Undesirable effects

Summary of the safety profile
The most frequent adverse reactions were CRS (77%), dysgeusia (72%), hypogammaglobulinaemia (67%), nail disorder (56%), musculoskeletal pain (48%), anaemia (47%), skin disorder (43%), fatigue (43%), weight decreased (40%), rash (39%), dry mouth (36%), neutropenia (35%), pyrexia (33%), xerosis (32%), thrombocytopenia (30%), upper respiratory tract infection (29%), lymphopenia (27%), dysphagia (24%), diarrhoea (25%), pruritus (23%), cough (23%), pain (22%), decreased appetite (22%) and headache (20%).

Serious adverse reactions reported in patients included CRS (13%), pyrexia (5%), ICANS (3.8%), sepsis (3.8%), COVID-19 (3.2%), bacterial infection (2.4%), pneumonia (2.4%), viral infection (2.4%), neutropenia (2.1%) and pain (2.1%).

The most frequent adverse reactions leading to treatment discontinuation were ICANS (1.1%) and weight decreased (0.9%).

Tabulated list of adverse reactions

The safety of TALVEY was evaluated in 339 adult patients with relapsed or refractory multiple myeloma, including patients treated with TALVEY at the recommended dosing regimen with or without prior T cell redirection therapy in MonumenTAL-1. The median duration of treatment was 7.4 (range: 0.0 to 32.9) months.

Table 7 summarises adverse reactions reported in patients who received TALVEY. The safety data of TALVEY was also evaluated in the All Treated population (N=501) with no additional adverse reactions identified.

Adverse reactions observed during clinical studies are listed below by frequency category. Frequency categories are defined as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10 000 to < 1/1 000); very rare (< 1/10 000) and not known (frequency cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 7:       Adverse reactions in patients with multiple myeloma treated with TALVEY in MonumenTAL-1 (N=339)
System Organ Class                                         Frequency         Any Grade Grade 3 or 4 Adverse Reaction                                            category             (%)         (%) Infections and infestations
Bacterial infection*                                   Very common          40 (12%)    11 (3.2%) 
Fungal infection*                                           Very common   39 (12%)    1 (0.3%) COVID-19*#                                                  Very common   63 (19%)    10 (2.9%) Upper respiratory tract infection*                          Very common   98 (29%)    7 (2.1%) Sepsis*#                                                      Common      15 (4.4%)   14 (4.1%) Pneumonia*                                                    Common       23 (7%)    11 (3.2%) Viral infection*                                              Common       23 (7%)    6 (1.8%) Blood and lymphatic system disorders
Neutropenia*                                                Very common   119 (35%)   103 (30%) Anaemia*                                                    Very common   158 (47%)   99 (29%) Thrombocytopenia                                            Very common   101 (30%)   71 (21%) Lymphopenia                                                 Very common    91 (27%)   83 (25%) Leukopenia                                                  Very common    62 (18%)   38 (11%) Haemorrhage1                                                  Common       27 (8%)     5 (1.5%) Febrile neutropenia                                           Common       7 (2.1%)    7 (2.1%) Immune system disorders
Cytokine release syndrome                                   Very common   260 (77%)   5 (1.5%) Hypogammaglobulinaemia2                                     Very common   227 (67%)       0 Metabolism and nutrition disorders
Decreased appetite                                          Very common   76 (22%)    4 (1.2%) Hypokalaemia                                                Very common   55 (16%)    12 (3.5%) Hypophosphataemia*                                          Very common   49 (15%)     21 (6%) Hypomagnesaemia                                             Very common   35 (11%)        0 Nervous system disorders
Immune effector cell-associated neurotoxicity syndrome*                                                   Very common   26 (10%)    6 (2.3%) Encephalopathy3                                             Very common   36 (11%)        0 Headache*                                                   Very common   69 (20%)    2 (0.6%) Motor dysfunction4                                          Very common   38 (11%)    2 (0.6%) Dizziness*                                                  Very common   42 (12%)    8 (2.4%) Sensory neuropathy5                                         Very common   34 (10%)        0 Respiratory, thoracic and mediastinal disorders
Cough*                                                      Very common   78 (23%)        0 Dyspnoea6#                                                  Very common   39 (12%)    5 (1.5%) Oral pain*                                                  Very common   42 (12%)        0 Gastrointestinal disorders
Dysgeusia‡7                                                 Very common   245 (72%)       0 Dry mouth‡                                                  Very common   122 (36%)       0 Dysphagia                                                   Very common    82 (24%)   3 (0.9%) Diarrhoea                                                   Very common    84 (25%)   4 (1.2%) Stomatitis8                                                 Very common    67 (20%)   4 (1.2%) Nausea                                                      Very common    64 (19%)       0 Constipation                                                Very common    61 (18%)       0 Abdominal pain*                                             Very common    35 (10%)   1 (0.3%) Vomiting                                                    Very common    34 (10%)   2 (0.6%) Skin and subcutaneous tissue disorders
Rash*                                                       Very common   132 (39%)   12 (3.5%) Skin disorder*                                              Very common   145 (43%)       0 Xerosis9                                                    Very common   109 (32%)       0 Pruritus                                                    Very common    79 (23%)   1 (0.3%) Nail disorder*                                              Very common   191 (56%)       0 Alopecia                                                      Common       30 (9%)        0 Musculoskeletal and connective tissue disorders
Musculoskeletal pain*                                       Very common   164 (48%)   12 (3.5%) General disorders and administrate site conditions
Fatigue*                                                    Very common   147 (43%)   12 (3.5%) Weight decreased                                            Very common   134 (40%)   11 (3.2%) Pyrexia*                                                    Very common   113 (33%)   6 (1.8%) Pain*                                                       Very common    76 (22%)   7 (2.1%) Oedema10                                                                 Very common                   59 (17%)                 0 Injection site reaction11                                                Very common                   45 (13%)                 0 Chills                                                                   Very common                   39 (12%)             1 (0.3%) Investigations
Fibrinogen decreased                                                     Very common                   52 (15%)            12 (3.5%) aPTT prolonged                                                           Very common                   49 (15%)                0 Transaminase elevation12                                                 Very common                   48 (14%)            12 (3.5%) INR increased                                                            Very common                   47 (14%)            1 (0.3%) Gamma-glutamyltransferase increased                                      Very common                   36 (11%)            16 (4.7%) Adverse reactions are coded using MedDRA Version 24.0.
‡
Per CTCAE v4.03, maximum toxicity grade for dysgeusia is 2 and maximum toxicity grade for dry mouth is 3.
*
Grouped term
#
Contains fatal outcome(s)
1
Haemorrhage includes: Conjunctival haemorrhage, Epistaxis, Haematoma, Haematuria, Lower gastrointestinal haemorrhage, Periorbital haemorrhage, Petechiae, Rectal haemorrhage, Subdural haematoma and Vaginal haemorrhage.
2
Hypogammaglobulinaemia includes: hypogammaglobulinaemia and/or subjects with laboratory IgG levels below 500 mg/dL following treatment with talquetamab.
3
Encephalopathy includes: agitation, amnesia, aphasia, bradyphrenia, confusional state, delirium, disorientation, encephalopathy, hallucination, lethargy, memory impairment, restlessness, sleep disorder and somnolence.
4
Motor dysfunction includes: dysgraphia, dysphonia, gait disturbance, muscle spasms, muscular weakness and tremor.
5
Sensory neuropathy includes: dysaesthesia, hypoaesthesia, hypoaesthesia oral, neuralgia, peripheral sensory neuropathy, sciatica and vestibular neuronitis.
6
Dyspnoea includes: acute respiratory failure, dyspnoea, dyspnoea exertional, respiratory failure and tachypnoea.
7
Dysgeusia includes: ageusia, dysgeusia, hypogeusia and taste disorder.
8
Stomatitis includes: cheilitis, glossitis, glossodynia, mouth ulceration, oral discomfort, oral mucosal erythema, oral pain, stomatitis, swollen tongue, tongue discomfort, tongue erythema, tongue oedema and tongue ulceration.
9
Xerosis includes: dry eye, dry skin and xerosis.
10
Oedema includes: fluid retention, gingival swelling, hypervolaemia, joint swelling, lip swelling, oedema, oedema peripheral, periorbital oedema, peripheral swelling and swelling.
11
Injection site reaction includes: injection site discomfort, injection site erythema, injection site haemorrhage, injection site inflammation, injection site irritation, injection site plaque, injection site pruritus, injection site rash and injection site reaction.
12
Transaminase elevation includes: alanine aminotransferase increased, aspartate aminotransferase increased, and transaminases increased.


Description of selected adverse reactions
Cytokine release syndrome
In MonumenTAL-1 (N=339), CRS occurred in 77% of patients. Most events were Grade 1 or 2, with Grade 3 events occurring in 1.5% of patients. Thirty one percent (31%) of patients experienced more than one CRS event. Most events occurred during the step-up phase following the 0.01 mg/kg dose (29%), the 0.06 mg/kg dose (44%), the 0.3 mg/kg dose (for patients who received biweekly [every 2 weeks] dosing; 33%), or the initial treatment dose (0.4 mg/kg [30%] or 0.8 mg/kg [12%]). Less than
4% of CRS events occurred from week 5 onward; all events were Grade 1. The median time to onset of CRS was 27 hours from the last dose, 91% of events occurred within 48 hours from the last dose, and the median duration was 17 hours. Tocilizumab, corticosteroids and tocilizumab in combination with corticosteroids were used to treat CRS in 39%, 5% and 3.5% of CRS events, respectively.
Clinical signs and symptoms of CRS may include but are not limited to pyrexia (76%), hypotension (15%), chills (12%), hypoxia (7%), headache (4.7%), tachycardia (5%) and elevated transaminases (aspartate aminotransferase [1.5%] and alanine aminotransferase [0.9%]).

Neurologic toxicities

In MonumenTAL-1 (N=339), neurologic toxicity events were reported in 29% of patients receiving TALVEY. Neurologic toxicity events were Grade 1 (17%), Grade 2 (11%), Grade 3 (2.3%) or Grade 4 (0.3%). The most frequently reported neurologic toxicity event was headache (9%).

ICANS were only collected for Phase 2 in MonumenTAL-1. Of the 265 patients in Phase 2, ICANS occurred in 9.8% (n=26) of patients. Most events were Grade 1 or 2, with Grade 3 and 4 events occurring in 2.3% of patients. The most frequent clinical manifestation of ICANS reported were confusional state (3.8%), disorientation (1.9%), somnolence (1.9%) and depressed level of consciousness (1.9%). Sixty-eight percent (68%) were concurrent with CRS (during or within 7 days of CRS resolution). Three percent (3%) of patients experienced more than one ICANS event. In addition, one fatal ICANS event was reported in MonumenTAL-1. Most patients experienced ICANS during the step-up phase following the 0.01 mg/kg dose, the 0.06 mg/kg dose, or the initial treatment dose (0.4 mg/kg and 0.8 mg/kg) (3% each). The median time to onset of ICANS was 28 hours from the last dose, 68% of events started within 48 hours from the last dose, 32% of events occurred after 48 hours, and the median duration of ICANS was 9 hours.

Oral toxicity
In MonumenTAL-1 (N=339), 78% of patients had Grade 1 or 2 events, with Grade 3 events occurring in 2% of patients. Oral toxicity events included dysgeusia, dry mouth, dysphagia, and stomatitis were reported.

Serious infections
In MonumenTAL-1 (N=339), Grade 3 or Grade 4 infections occurred in 19% of patients; fatal infections occurred in 1.5% of patients - COVID-19 pneumonia, fungal sepsis, infection and septic shock. The most frequently reported (≥ 2%) Grade 3 or 4 infection was pneumonia. Febrile neutropenia was observed in 1% of patients with 1.2% experiencing serious febrile neutropenia. See section 4.4 for monitoring and management guidance.

Hypogammaglobulinaemia
Post baseline IgG values of less than 500 mg/dl consistent with hypogammaglobulinaemia have been reported in 64% of patients treated with talquetamab at the 0.4 mg/kg weekly dose schedule, 66% of patients at the 0.8 mg/kg biweekly dose schedule and in 71% of patients with prior T cell redirection therapy (see section 4.4).

Skin reactions
In MonumenTAL-1 (N=339), the majority of rash cases were Grade 1 or 2, with Grade 3 events occurring in 3.5% of patients. The median time to onset from the first treatment dose for rash was 22 days. The majority of non-rash skin toxicities were Grade 1 or 2, with Grade 3 pruritus occurring in
0.3% of patients. Nail disorders occurred in 56% of patients and were Grade 1 or 2. See section 4.4 for management guidance.

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