A Study of Teclistamab in Combination with Daratumumab and Lenalidomide (Tec-DR) and Talquetamab in Combination with Daratumumab and Lenalidomide (Tal-DR) in Participants with Newly Diagnosed Multiple Myeloma

Current primary outcome measure as of 30/10/2024:
1. Progression-free survival (PFS), defined as the time interval between the date of randomisation to the date of either progressive disease or death, whichever comes first, measured up to 9 years. Disease progression will be determined according to the International Myeloma Working Group (IMWG) response criteria.
2. 12-Month Minimal Residual Disease (MRD)-Negative Complete Response (CR), 12-month MRD-negative CR is defined as participants who achieve MRD-negative status at 12 months, as determined by next-generation sequencing (NGS) with sensitivity of 10^-5, prior to progressive disease or subsequent anti-myeloma therapy and who also achieve CR or better, according to IMWG criteria.

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Previous primary outcome measure as of 03/01/2024 to 30/10/2024:
1. Progression-free survival (PFS), defined as the time interval between the date of randomisation to the date of either progressive disease or death, whichever comes first, measured up to 9 years. Disease progression will be determined according to the International Myeloma Working Group (IMWG) response criteria.
2. Complete response (CR) or better, defined as the percentage of participants achieving CR or stringent complete response (sCR) prior to subsequent antimyeloma therapy in accordance with the IMWG criteria during or after the study treatment, determined from randomisation up to 9 years.

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Previous primary outcome measure from 14/09/2023 to 03/01/2024:
1. Progression-free survival (PFS), defined as the time interval between the date of randomisation to the date of either progressive disease or death, whichever comes first, measured up to 9 years.
2. Sustained minimal residual disease (MRD)-negative complete response (CR), defined as participants who sustain MRD-negative status (determined by next-generation sequencing (NGS) with a sensitivity of 10^-5) for at least 12 months without any examination showing MRD positive status or progressive disease in between, assessed up to 9 years.

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Original primary outcome measure:
1. Progression-free survival (PFS), defined as the time interval between the date of randomisation to the date of either progressive disease or death, whichever comes first, measured up to 7 years.
2. Sustained minimal residual disease (MRD)-negative complete response (CR), defined as participants who sustain MRD-negative status (determined by next-generation sequencing (NGS) with a sensitivity of 10^-5) for at least 12 months without any examination showing MRD positive status or progressive disease in between, assessed up to 7 years.

Current secondary outcome measures as of 30/10/2024:
1. Very good partial response (VGPR) or better, defined as the percentage of participants achieving VGPR and CR (including stringent complete response [sCR]) prior to subsequent antimyeloma therapy in accordance with the International Myeloma Working Group (IMWG) criteria during or after the study treatment, determined from randomisation up to 9 years.
2. Complete response (CR) or better, defined as the percentage of participants achieving CR or stringent complete response (sCR) prior to subsequent antimyeloma therapy in accordance with the IMWG criteria during or after the study treatment, determined from randomisation up to 9 years.
3. Sustained minimal residual disease (MRD)-negative complete response (CR), defined as participants with CR or better who sustain MRD-negative status, as determined by next-generation sequencing (NGS) with a sensitivity of 10^-5, for at least 12 months without any examination showing MRD positive status or progressive disease in between, determined from randomisation up to 9 years.
4. MRD-negative CR, defined as the percentage of participants who achieve MRD-negative status, (determined by NGS with a sensitivity of 10^-5) at any time after randomisation and prior to progressive disease or subsequent antimyeloma therapy and who achieve CR or better, determined from randomisation up to 9 years.
5. Progression-free survival on next-line therapy (PFS2), defined as the time interval between the date of randomisation and the date of the event, which is defined as progressive disease as assessed by the investigator that starts after the next line of subsequent therapy, or death from any cause, whichever occurs first, measured from randomisation up to 9 years.
6. Overall survival (OS), defined as the time interval from the date of randomisation to the date of death due to any cause, measured from randomisation up to the date of death (up to 9 years).
7. Number of participants with adverse events (AEs) by severity determined from randomisation up to 9 years. An adverse event is any untoward medical occurrence in a clinical study participant administered a pharmaceutical (investigational or non-investigational) product and does not necessarily have a causal relationship with the treatment. Severity will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. The severity scale ranges from Grade 1 mild, Grade 2: moderate, Grade 3: severe, Grade 4: life-threatening, and Grade 5 death related to adverse event.
8.. Number of participants with abnormalities in laboratory parameters (serum chemistry and haematology) determined from randomisation up to 9 years.
9. Number of participants with abnormalities in vital signs (temperature, pulse/heart rate, respiratory rate, blood pressure) determined from randomisation up to 9 years.
10. Number of participants with abnormalities in physical examination determined from randomisation up to 9 years.
11. Number of participants with abnormalities in electrocardiogram (ECG) determined from randomisation up to 9 years.
12. Serum concentrations of Teclistamab and Talquetamab measured by validated, specific and sensitive methods from randomisation up to 9 years.
13. Number of participants with anti-drug antibodies (ADAs) to Teclistamab and Talquetamab determined from randomisation up to 9 years.
14. Change from baseline in symptoms, functioning, and health-related quality of life (HRQoL) as assessed by a European organisation for research and treatment of cancer quality-of-life questionnaire core 30 (EORTC-QLQ-C30) determined from baseline up to 9 years. The EORTC-QLQ-C30 Version 3 includes 30 items that make up 5 functional scales (physical, role, emotional, cognitive, and social), 1 global health status scale, 3 symptom scales (pain, fatigue, and nausea /vomiting), and 5 single symptom items (dyspnoea, insomnia, appetite loss, constipation, and diarrhoea) and a single impact item (financial difficulties). The recall period is 7 days (“past week”), and responses are reported using verbal and numeric rating scales. The item and scale scores are transformed to a 0 to 100 scale. A high scale score represents a higher response level.
Thus, a high score for a functional scale represents a high/healthy level of functioning and a high score for the global health status represents high HRQoL, but a high score for a symptom scale /item represents a high level of symptomatology/problems.
15. Change from baseline in treatment-related symptoms as assessed by patient-reported outcomes version of the common terminology criteria for adverse events (PRO-CTCAE), determined from baseline up through to cycle 6 (each cycle of 28 days) (up to 196 days). The National Cancer Institute's (NCI's) PRO-CTCAE is an item library of common AEs experienced by people with cancer that are appropriate for self-reporting of treatment tolerability. Each symptom selected for inclusion can be rated by up to 3 attributes characterising the presence/frequency, severity, and/or interference of the AEs. It ranges from 0 to 4 with higher scores indicating higher frequency or greater severity /impact.
16. Change from baseline in symptoms, functioning, and overall HRQoL as assessed by EuroQol five dimension questionnaire 5-level (EQ-5D-5L), determined from baseline up to 9 years. The EQ-5D-5L is a 5-item questionnaire that assesses 5 domains including mobility, self-care, usual activities, pain/discomfort, and anxiety/depression plus a visual analogue scale rating “health
today” with anchors ranging from 0 (worst imaginable) to 100 (best imaginable health state).
17. Time to sustained worsening in symptoms, functioning and HRQoL, defined as the time interval from the date of randomisation to the start date of meaningful change, measured from randomisation up to 9 years.

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Previous secondary outcome measures as of 03/01/2024 to 30/10/2024:

1. Very good partial response (VGPR) or better, defined as the percentage of participants achieving VGPR and CR (including stringent complete response [sCR]) prior to subsequent antimyeloma therapy in accordance with the International Myeloma Working Group (IMWG) criteria during or after the study treatment, determined from randomisation up to 9 years.
2. Sustained minimal residual disease (MRD)-negative complete response (CR), defined as participants with CR or better who sustain MRD-negative status, as determined by next-generation sequencing (NGS) with a sensitivity of 10^-5, for at least 12 months without any examination showing MRD positive status or progressive disease in between, determined from randomisation up to 9 years.
3. MRD-negative CR, defined as the percentage of participants who achieve MRD-negative status, (determined by NGS with a sensitivity of 10^-5) at any time after randomisation and prior to progressive disease or subsequent antimyeloma therapy and who achieve CR or better, determined from randomisation up to 9 years.
4. Progression-free survival on next-line therapy (PFS2), defined as the time interval between the date of randomisation and the date of the event, which is defined as progressive disease as assessed by the investigator that starts after the next line of subsequent therapy, or death from any cause, whichever occurs first, measured from randomisation up to 9 years.
5. Overall survival (OS), defined as the time interval from the date of randomisation to the date of death due to any cause, measured from randomisation up to the date of death (up to 9 years).
6. Number of participants with adverse events (AEs) by severity determined from randomisation up to 9 years. An adverse event is any untoward medical occurrence in a clinical study participant administered a pharmaceutical (investigational or non-investigational) product and does not necessarily have a causal relationship with the treatment. Severity will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. The severity scale ranges from Grade 1 mild, Grade 2: moderate, Grade 3: severe, Grade 4: life-threatening, and Grade 5 death related to adverse event.
7. Number of participants with abnormalities in laboratory parameters (serum chemistry and haematology) determined from randomisation up to 9 years.
8. Number of participants with abnormalities in vital signs (temperature, pulse/heart rate, respiratory rate, blood pressure) determined from randomisation up to 9 years.
9. Number of participants with abnormalities in physical examination determined from randomisation up to 9 years.
10. Number of participants with abnormalities in electrocardiogram (ECG) determined from randomisation up to 9 years.
11. Serum concentrations of Teclistamab and Talquetamab measured by validated, specific and sensitive methods from randomisation up to 9 years.
12. Number of participants with anti-drug antibodies (ADAs) to Teclistamab and Talquetamab determined from randomisation up to 9 years.
13. Change from baseline in symptoms, functioning, and health-related quality of life (HRQoL) as assessed by a European organisation for research and treatment of cancer quality-of-life questionnaire core 30 (EORTC-QLQ-C30) determined from baseline up to 9 years. The EORTC-QLQ-C30 Version 3 includes 30 items that make up 5 functional scales (physical, role, emotional, cognitive, and social), 1 global health status scale, 3 symptom scales (pain, fatigue, and nausea /vomiting), and 5 single symptom items (dyspnoea, insomnia, appetite loss, constipation, and diarrhoea) and a single impact item (financial difficulties). The recall period is 7 days (“past week”), and responses are reported using verbal and numeric rating scales. The item and scale scores are transformed to a 0 to 100 scale. A high scale score represents a higher response level.
Thus, a high score for a functional scale represents a high/healthy level of functioning and a high score for the global health status represents high HRQoL, but a high score for a symptom scale /item represents a high level of symptomatology/problems.
14. Change from baseline in treatment-related symptoms as assessed by patient-reported outcomes version of the common terminology criteria for adverse events (PRO-CTCAE), determined from baseline up through to cycle 6 (each cycle of 28 days) (up to 196 days). The National Cancer Institute's (NCI's) PRO-CTCAE is an item library of common AEs experienced by people with cancer that are appropriate for self-reporting of treatment tolerability. Each symptom selected for inclusion can be rated by up to 3 attributes characterising the presence/frequency, severity, and/or interference of the AEs. It ranges from 0 to 4 with higher scores indicating higher frequency or greater severity /impact.
15. Change from baseline in symptoms, functioning, and overall HRQoL as assessed by EuroQol five dimension questionnaire 5-level (EQ-5D-5L), determined from baseline up to 9 years. The EQ-5D-5L is a 5-item questionnaire that assesses 5 domains including mobility, self-care, usual activities, pain/discomfort, and anxiety/depression plus a visual analogue scale rating “health
today” with anchors ranging from 0 (worst imaginable) to 100 (best imaginable health state).
16. Time to sustained worsening in symptoms, functioning and HRQoL, defined as the time interval from the date of randomisation to the start date of meaningful change, measured from randomisation up to 9 years.

_____

Previous secondary outcome measures from 14/09/2023 to 03/01/2024:

1. Very good partial response (VGPR) or better, defined as the percentage of participants achieving VGPR and CR (including stringent complete response [sCR]) prior to subsequent antimyeloma therapy in accordance with the International Myeloma Working Group (IMWG) criteria during or after the study treatment, determined up to 11 years.
2. Complete response (CR) or better, defined as the percentage of participants achieving CR or sCR prior to subsequent antimyeloma therapy in accordance with the IMWG criteria during or after the study treatment, determined for up to 11 years.
3. MRD-negative CR, defined as the percentage of participants who achieve MRD-negative status, (determined by NGS with a sensitivity of 10^-5) at any time after randomisation and prior to progressive disease or subsequent antimyeloma therapy and who achieve CR or better, determined up to 11 years.
4. Progression-free survival on next-line therapy (PFS2), defined as the time interval between the date of randomisation and the date of the event, which is defined as progressive disease as assessed by the investigator that starts after the next line of subsequent therapy, or death from any cause, whichever occurs first, measured up to 11 years.
5. Overall survival (OS), defined as the time interval from the date of randomisation to the date of death due to any cause, measured up to 11 years.
6. Number of participants with adverse events (AEs) by severity determined up to 11 years. An adverse event is any untoward medical occurrence in a clinical study participant administered a pharmaceutical (investigational or non-investigational) product and does not necessarily have a causal relationship with the treatment. Severity will be graded according to the National Cancer
Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. Severity scale ranges from Grade 1 mild, Grade 2: moderate, Grade 3: severe, Grade 4: life-threatening, and Grade 5 death related to adverse event.
7. Number of participants with abnormalities in laboratory parameters (serum chemistry and haematology) determined up to 11 years.
8. Number of participants with abnormalities in vital signs (temperature, pulse/heart rate, respiratory rate, blood pressure) determined up to 11 years.
9. Number of participants with abnormalities in physical examination determined up to 11 years.
10. Number of participants with abnormalities in electrocardiogram (ECG) determined up to 11 years.
11. Serum concentrations of Teclistamab and Talquetamab measured by validated, specific and sensitive methods up to 11 years.
12. Number of participants with anti-drug antibodies (ADAs) to Teclistamab and Talquetamab determined up to 11 years.
13. Change from baseline in symptoms, functioning, and health-related quality of life (HRQoL) as assessed by a European organisation for research and treatment of cancer quality-of-life questionnaire core 30 (EORTC-QLQ-C30) determined from baseline up to 11 years. The EORTC-QLQ-C30 Version 3 includes 30 items that makeup 5 functional scales (physical, role, emotional, cognitive, and social), 1 global health status scale, 3 symptom scales (pain, fatigue, and nausea /vomiting), and 5 single symptom items (dyspnoea, insomnia, appetite loss, constipation, and diarrhoea) and a single impact item (financial difficulties). The recall period is 7 days (“past week”), and responses are reported using verbal and numeric rating scales. The item and scale scores are transformed to a 0 to 100 scale. A high scale score represents a higher response level.
Thus, a high score for a functional scale represents a high/healthy level of functioning and a high score for the global health status represents high HRQoL, but a high score for a symptom scale /item represents a high level of symptomatology/problems.
14. Change from baseline in treatment-related symptoms as assessed by patient-reported outcomes version of the common terminology criteria for adverse events (PRO-CTCAE), determined from baseline up through to cycle 6. The National Cancer Institute's (NCI's) PRO-CTCAE is an item library of common AEs experienced by people with cancer that are appropriate for self-reporting of treatment tolerability. Each symptom selected for inclusion can be rated by up to 3 attributes characterising the presence/frequency, severity, and/or interference of the AEs. It ranges from 0 to 4 with higher scores indicating higher frequency or greater severity /impact.
15. Change from baseline in symptoms, functioning, and overall HRQoL as assessed by EuroQol five dimension questionnaire 5-level (EQ-5D-5L), determined from baseline up to 11 years. The EQ-5D-5L is a 5-item questionnaire that assesses 5 domains including mobility, self-care, usual activities, pain/discomfort, and anxiety/depression plus a visual analogue scale rating “health
today” with anchors ranging from 0 (worst imaginable) to 100 (best imaginable health state).
16. Time to sustained worsening in symptoms, functioning and HRQoL, defined as the time interval from the date of randomisation to the start date of meaningful change, measured up to 11 years.

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Original secondary outcome measures:

1. Very good partial response (VGPR) or better, defined as the percentage of participants achieving VGPR and CR (including stringent complete response [sCR]) prior to subsequent antimyeloma therapy in accordance with the International Myeloma Working Group (IMWG) criteria during or after the study treatment, determined up to 9 years.
2. Complete response (CR) or better, defined as the percentage of participants achieving CR or sCR prior to subsequent antimyeloma therapy in accordance with the IMWG criteria during or after the study treatment, determined for up to 9 years.
3. MRD-negative CR, defined as the percentage of participants who achieve MRD-negative status, (determined by NGS with a sensitivity of 10^-5) at any time after randomisation and prior to progressive disease or subsequent antimyeloma therapy and who achieve CR or better, determined up to 9 years.
4. Progression-free survival on next-line therapy (PFS2), defined as the time interval between the date of randomisation and the date of the event, which is defined as progressive disease as assessed by the investigator that starts after the next line of subsequent therapy, or death from any cause, whichever occurs first, measured up to 9 years.
5. Overall survival (OS), defined as the time interval from the date of randomisation to the date of death due to any cause, measured up to 9 years.
6. Number of participants with adverse events (AEs) by severity determined up to 9 years. An adverse event is any untoward medical occurrence in a clinical study participant administered a pharmaceutical (investigational or non-investigational) product and does not necessarily have a causal relationship with the treatment. Severity will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5. Severity scale ranges from Grade 1 mild, Grade 2: moderate, Grade 3: severe, Grade 4: life-threatening, and Grade 5 death related to adverse event.
7. Number of participants with abnormalities in laboratory parameters (serum chemistry and haematology) determined up to 9 years.
8. Number of participants with abnormalities in vital signs (temperature, pulse/heart rate, respiratory rate, blood pressure) determined up to 9 years.
9. Number of participants with abnormalities in physical examination determined up to 9 years.
10. Number of participants with abnormalities in electrocardiogram (ECG) determined up to 9 years.
11. Serum concentrations of Teclistamab measured by validated, specific and sensitive methods up to 9 years.
12. Number of participants with anti-drug antibodies (ADAs) to Teclistamab determined up to 9 years.
13. Change from baseline in symptoms, functioning, and health-related quality of life (HRQoL) as assessed by a European organisation for research and treatment of cancer quality-of-life questionnaire core 30 (EORTC-QLQ-C30) determined from baseline up to 9 years. The EORTC-QLQ-C30 Version 3 includes 30 items that makeup 5 functional scales (physical, role, emotional, cognitive, and social), 1 global health status scale, 3 symptom scales (pain, fatigue, and nausea/vomiting), and 5 single symptom items (dyspnoea, insomnia, appetite loss, constipation, and diarrhoea) and a single impact item (financial difficulties). The recall period is 7 days (“past week”), and responses are reported using verbal and numeric rating scales. The item and scale scores are transformed to a 0 to 100 scale. A high scale score represents a higher response level. Thus, a high score for a functional scale represents a high/healthy level of functioning and a high score for the global health status represents high HRQoL, but a high score for a symptom scale/item represents a high level of symptomatology/problems.
14. Change from baseline in treatment-related symptoms as assessed by patient-reported outcomes version of the common terminology criteria for adverse events (PRO-CTCAE), determined from baseline up to day 15 of cycle 6. The National Cancer Institute's (NCI's) PRO-CTCAE is an item library of common AEs experienced by people with cancer that are appropriate for self-reporting of treatment tolerability. Each symptom selected for inclusion can be rated by up to 3 attributes characterizing the presence/frequency, severity, and/or interference of the AEs. It ranges from 0 to 4 with higher scores indicating higher frequency or greater severity/impact.
15. Change from baseline in symptoms, functioning, and overall HRQoL as assessed by EuroQol five dimension questionnaire 5-level (EQ-5D-5L), determined from baseline up to 9 years. The EQ-5D-5L is a 5-item questionnaire that assesses 5 domains including mobility, self-care, usual activities, pain/discomfort, and anxiety/depression plus a visual analogue scale rating “health today” with anchors ranging from 0 (worst imaginable) to 100 (best imaginable health state).
16. Time to sustained worsening in symptoms, functioning and HRQoL, defined as the time interval from the date of randomisation to the start date of meaningful change, measured up to 9 years.