Belantamab-Mafodotin (3) – Blenrep®

• Clinical trials
  • To demonstrate the additional benefit of belantamab-mafodotin in combination with bortezomib and dexamethasone for the treatment of adults with relapsed or refractory multiple myeloma who have already received at least one prior therapy, the pharmaceutical manufacturer has presented the results of the global cohort from the ongoing, open-label, multicentre Phase III DREAMM-7 trial, in which belantamab-mafodotin in combination with bortezomib and dexamethasone (BVd) is being compared with daratumumab in combination with bortezomib and dexamethasone (DVd).

a1) Adults with relapsed or refractory multiple myeloma who have received one to three prior lines of treatment and for whom daratumumab in combination with bortezomib and dexamethasone represents a suitable individualised treatment

• mortality
  • In the DREAMM-7 trial, overall survival is defined as the time from randomisation to death from any cause.
  • For the endpoint of overall survival, there is a statistically significant advantage in favour of BVd compared with DVd.
• morbidity
  • Progression-free survival (PFS)
  • In the DREAMM-7 study, progression-free survival is defined as the time from randomisation to the date of documented disease progression according to IMWG criteria or the time of death from any cause, whichever occurs first.
  • For the PFS endpoint, there is a statistically significant advantage for BVd.
  • The PFS endpoint in question is a composite endpoint comprising endpoints from the ‘mortality’ and ‘morbidity’ categories.
  • The morbidity component ‘disease progression’ is assessed according to IMWG criteria and is therefore not symptom-based, but rather determined using laboratory parameters, imaging and haematological procedures.
  • Taking the above aspects into account, there are differing views within the GBA regarding the patient relevance of the PFS endpoint. This does not affect the overall conclusion regarding the extent of the additional benefit.
  • Symptoms were assessed using the EORTC QLQ-C30 symptom scales and the Item Library-52
  • Symptoms were assessed in the DREAMM-7 study using the EORTC QLQ-C30 and, in addition, the EORTC Item Library (IL)-52.
  • In the dossier, the pharmaceutical manufacturer presents analyses for the time to first deterioration and the time to first improvement.
  • Given the expected course of the disease in this therapeutic indication, the time to first deterioration (an increase of ≥ 10 points) is used for the benefit assessment.
  • The IL-52 corresponds to the ‘Disease Symptoms’ scale of the EORTC Quality of Life Questionnaire – Multiple Myeloma 20 (EORTC QLQ-MY20), which consists of a total of four scales.
  • The selective use of a single scale from the EORTC QLQ-MY20 in the DREAMM-7 study is not appropriate. The results of the EORTC IL-52 are therefore not used for the benefit assessment.
  • In the EORTC QLQ-C30, there is no statistically significant difference between the study arms.
  • Symptoms assessed using the Patient Global Impression of Symptom Severity (PGIS) and the Patient Global Impression of Change (PGIC)
  • The PGIS consists of a single question that assesses the symptoms of the cancer on the day of assessment.
  • The pharmaceutical manufacturer provides analyses in the dossier for the time to first deterioration and the time to first improvement.
  • Given the expected course of the disease in this therapeutic indication, the time to first deterioration (increase of ≥ 1 point) is used for the benefit assessment.
  • The PGIC consists of a single question that assesses changes in cancer symptoms compared with the start of treatment.
  • Given the expected course of the disease in this therapeutic indication, the time to first deterioration is used for the benefit assessment (reaching a scale value of ‘much worse’ or ‘slightly worse’ compared with the start of the study).
  • No statistically significant differences were observed between the study arms for either the PGIS or the PGIC.
  • Health status (assessed using the EQ-5D VAS)
  • Health status was assessed using the visual analogue scale (VAS) of the EQ-5D questionnaire.
  • For the benefit assessment, the pharmaceutical manufacturer provides analyses in the dossier covering the time to first deterioration and the time to first improvement.
  • In line with the comments in the ‘Symptoms’ section, the analyses for the time to first deterioration (decrease of ≥ 15 points) are used.
  • There is no statistically significant difference between the study arms.
• quality of life
  • Health-related quality of life is assessed in the DREAMM-7 study using the EORTC QLQ-C30.
  • For the benefit assessment, the pharmaceutical manufacturer provides analyses in the dossier for the time to first deterioration and the time to first improvement.
  • In line with the comments in the ‘Symptoms’ section, the analyses for time to first deterioration are used.
  • In the EORTC QLQ-C30, a statistically significant disadvantage in terms of cognitive functioning compared to BVd is observed for the endpoint.
  • No statistically significant difference is observed for the endpoints of global health status, physical functioning, role functioning, emotional functioning and social functioning.
  • With regard to health-related quality of life, no overall advantage or disadvantage is identified for BVd.
• Side effects
  • Cross-endpoint note
  • The definition of adverse events (AEs) in the DREAMM-7 study stipulates, in accordance with the study protocol, that progression, signs or symptoms of the disease under investigation should not be recorded as AEs unless these were more severe than would have been expected given the participant’s condition.
  • The definition of adverse events not to be recorded in the study covers not only those reflecting progression of the underlying disease, but is majorly broader in scope, as it also includes non-specific signs and symptoms of the diseases.
  • The decision as to which events are to be documented as AEs rests with the investigator.
  • Particularly in an open-label study, this may lead to the recording of AEs being potentially unsystematic and/or incomplete, and may also potentially result in a bias in the results.
  • Despite the existing uncertainty, the effects outlined below are not called into question in the present data set due to their magnitude.
  • Total adverse events (AEs) (presented as supplementary data)
  • In the DREAMM-7 study, adverse events occurred in all patients. The results are presented here only as supplementary information.
  • Serious AEs (SAEs), severe AEs (CTCAE grade ≥ 3), therapy discontinuations due to AEs
  • For the endpoints SAEs, severe AEs and therapy discontinuations due to AEs, a statistically significant difference was observed in each case to the disadvantage of BVd.
  • Specific AEs
  • No suitable data are available for the endpoint of peripheral neuropathies.

a2) Adults with relapsed or refractory multiple myeloma who have received one to three prior lines of treatment and for whom daratumumab in combination with bortezomib and dexamethasone does not constitute a suitable individualised treatment

• The DREAMM-7 study is not suitable for deriving additional benefit, as only the combination of DVd was used in the comparator arm of this study.
• Consequently, additional benefit is not proven for adults with relapsed or refractory multiple myeloma who have received one to three prior treatments and for whom daratumumab in combination with bortezomib and dexamethasone does not constitute a suitable individualised treatment.

b1) Adults with relapsed or refractory multiple myeloma who have received at least four prior treatments and for whom daratumumab in combination with bortezomib and dexamethasone constitutes a suitable individualised treatment

• mortality
  • In the DREAMM-7 trial, overall survival is defined as the time from randomisation to death from any cause.
  • For the endpoint of overall survival, a statistically significant advantage was observed in favour of BVd compared with DVd.
• morbidity
  • Progression-free survival (PFS)
  • In the DREAMM-7 study, progression-free survival is defined as the time from randomisation to the date of documented disease progression according to IMWG criteria or the time of death from any cause, whichever occurs first.
  • For the PFS endpoint, there is a statistically significant advantage for BVd.
  • The PFS endpoint in question is a composite endpoint comprising endpoints from the ‘mortality’ and ‘morbidity’ categories.
  • The ‘mortality’ endpoint component is already assessed as a standalone endpoint via the ‘overall survival’ endpoint.
  • The ‘disease progression’ component of morbidity is assessed according to IMWG criteria and is therefore not symptom-based, but rather determined using laboratory parameters, imaging and haematological procedures.
  • Taking the above aspects into account, there are differing views within the GBA regarding the clinical relevance of the PFS endpoint to patients. This does not affect the overall conclusion regarding the extent of the additional benefit.
  • Symptoms were assessed using the EORTC QLQ-C30 symptom scales and the Item Library-52
  • Symptoms were assessed in the DREAMM-7 study using the EORTC QLQ-C30 and, in addition, the EORTC Item Library (IL)-52.
  • In the dossier, the pharmaceutical manufacturer presents analyses for the time to first deterioration and the time to first improvement.
  • Given the expected course of the disease in this therapeutic indication, the time to first deterioration (an increase of ≥ 10 points) is used for the benefit assessment.
  • The IL-52 corresponds to the ‘Disease Symptoms’ scale of the EORTC Quality of Life Questionnaire – Multiple Myeloma 20 (EORTC QLQ-MY20), which consists of a total of four scales.
  • The selective collection of data from a single scale of the EORTC QLQ-MY20 in the DREAMM-7 study is not appropriate. The results of the EORTC IL-52 are therefore not used for the benefit assessment.
  • In the EORTC QLQ-C30, there is no statistically significant difference between the study arms.
  • Symptoms assessed using the Patient Global Impression of Symptom Severity (PGIS) and the Patient Global Impression of Change (PGIC)
  • The PGIS consists of a single question that assesses the symptoms of the cancer on the day of assessment.
  • The pharmaceutical manufacturer provides analyses in the dossier for the time to first deterioration and the time to first improvement.
  • Given the expected course of the disease in this therapeutic indication, the time to first deterioration (increase of ≥ 1 point) is used for the benefit assessment.
  • The PGIC consists of a question that assesses changes in cancer symptoms compared with the start of treatment.
  • The pharmaceutical manufacturer must provide analyses in the dossier for the time to first worsening and the time to first improvement.
  • Given the expected course of the disease in this therapeutic indication, the time to first deterioration is used for the benefit assessment (reaching a scale value of ‘much worse’ or ‘slightly worse’ compared with the start of the study).
  • No statistically significant differences were observed between the study arms for either the PGIS or the PGIC.
  • Health status (assessed using the EQ-5D VAS)
  • Health status was assessed using the visual analogue scale (VAS) of the EQ-5D questionnaire.
  • For the benefit assessment, the pharmaceutical manufacturer provides analyses in the dossier covering the time to first deterioration and the time to first improvement.
  • In line with the comments in the ‘Symptoms’ section, the analyses for the time to first deterioration (decrease of ≥ 15 points) are used.
  • There is no statistically significant difference between the study arms.
• quality of life
  • Health-related quality of life is assessed in the DREAMM-7 study using the EORTC QLQ-C30.
  • For the benefit assessment, the pharmaceutical manufacturer presents analyses in the dossier for the time to first deterioration and the time to first improvement.
  • In line with the comments in the ‘Symptoms’ section, the analyses for the time to first deterioration are used.
  • In the EORTC QLQ-C30, a statistically significant difference in favor of BVd is observed for the endpoint ‘cognitive functioning’.
  • No statistically significant difference is observed for the endpoints of global health status, physical functioning, role functioning, emotional functioning and social functioning.
  • With regard to health-related quality of life, no overall advantage or disadvantage is inferred for BVd.
• Side effects
  • Cross-endpoint note
  • The definition of adverse events (AEs) in the DREAMM-7 study stipulates, in accordance with the study protocol, that progression, signs or symptoms of the disease under investigation should not be recorded as AEs unless these were more severe than would have been expected given the participant’s condition.
  • The definition of adverse events not to be recorded in the study covers not only those reflecting progression of the underlying disease, but is majorly broader in scope, as it also includes non-specific signs and symptoms of the diseases.
  • The decision as to which events are to be documented as AEs rests with the investigator.
  • Particularly in an open-label study, this may result in the recording of AEs being potentially unsystematic and/or incomplete, and may also potentially lead to a bias in the results.
  • Total adverse events (AEs) (presented as supplementary data)
  • In the DREAMM-7 trial, adverse events occurred in all patients. The results are presented here for supplementary information only.
  • Serious AEs (SAEs), severe AEs (CTCAE grade ≥ 3), therapy discontinuations due to AEs
  • For the endpoints of SAEs and therapy discontinuations due to AEs, there was no statistically significant difference between the study arms in either case.

b2) Adults with relapsed or refractory multiple myeloma who have received at least four prior treatments and for whom daratumumab in combination with bortezomib and dexamethasone does not represent a suitable individualised treatment

• The DREAMM-7 study is not suitable for deriving additional benefit, as only the combination of DVd was used in the comparator arm of this study.
• Consequently, additional benefit is not proven for adults with relapsed or refractory multiple myeloma who have received at least four prior treatments and for whom daratumumab in combination with bortezomib and dexamethasone does not constitute a suitable individualised treatment.

Courtesy translation only, please refer to the German original.