Daratumumab (15) – Darzalex®

• Clinical trials
  • For the benefit assessment, the pharmaceutical manufacturer has submitted the results of the pre-specified data cut-off of 1 May 2024 from the ongoing open-label, randomised, controlled Phase III AQUILA trial, in which daratumumab monotherapy is compared with no intervention.

Adults with smouldering multiple myeloma and a high risk of developing multiple myeloma

• Hint for a minor additional benefit.
• Consequently, daratumumab is found to provide a minor additional benefit compared with a watch-and-wait approach, particularly due to the moderate advantages observed in the endpoint categories of morbidity and health-related quality of life.
• Overall, there is a hint of the certainty of the findings regarding the identified additional benefit.
• mortality
  • In the AQUILA study, overall survival is defined as the time from randomisation to death from any cause.
  • For the endpoint of overall survival, a statistically significant advantage in favour of daratumumab compared with a ‘watch-and-wait’ approach is observed.
  • However, there are significant uncertainties regarding the generalisability of this result from the AQUILA study to real-world clinical practice.
  • In this regard, the patient population analyses reveal an effect modification by the characteristic ‘region’. Specifically, for the patient population in the ‘Western Europe and USA’ region, there is no statistically significant difference between daratumumab and watchful waiting.
  • Furthermore, with regard to the data on follow-up treatments, it must be assumed that the follow-up treatments in the AQUILA study do not adequately reflect the current standard of care.
  • In addition to these uncertainties, the statistically significant result for the overall survival endpoint is based on a minor number of events in both study arms at the time of the current data cut-off.
• Morbidity – Progression-free survival (PFS)
  • In the AQUILA study, progression-free survival is defined as the time from randomisation to the date of disease progression to multiple myeloma according to the IMWG criteria or the date of death from any cause, whichever occurs first.
  • For the PFS endpoint, there is a statistically significant advantage for daratumumab.
  • The PFS endpoint in question is a composite endpoint comprising endpoints from the ‘mortality’ and ‘morbidity’ categories.
  • Taking the above aspects into account, there are differing views within the G-BA regarding the clinical relevance of the PFS endpoint. The overall conclusion regarding the extent of the additional benefit remains unaffected.
• quality of life
  • Health-related quality of life is assessed in the AQUILA study using the EORTC QLQ-C30 and the ‘Future Prospects’ functional scale of the EORTC QLQ-MY20.
  • The ‘Future Prospects’ functional scale of the EORTC QLQ-MY20 is also not used for the reasons stated in the ‘Symptoms’ section.
  • In the EORTC QLQ-C30, a statistically significant advantage for daratumumab is observed for the endpoints of global health status and emotional functioning.
  • No statistically significant difference was observed for the endpoints of physical functioning, role functioning, cognitive functioning and social functioning.
• Side effects – Total adverse events (AEs)
  • In the AQUILA trial, adverse events occurred in 96.9% of patients in the intervention arm and in 82.7% of patients in the control arm. The results are presented here for supplementary information only.
• Overall assessment
  • For the assessment of the additional benefit of daratumumab as monotherapy for the treatment of adults with smouldering multiple myeloma who are at high risk of developing multiple myeloma, the pharmaceutical manufacturer presents the results of the AQUILA study, which compares daratumumab with a watch-and-wait approach.
  • For the endpoint of overall survival, there is a statistically significant advantage in favour of daratumumab compared with a watch-and-wait approach. However, there are significant uncertainties regarding the generalisability of this result from the AQUILA study to real-world clinical practice. In this regard, the patient population analyses reveal an effect modification by the characteristic ‘region’. Specifically, for the patient population in the ‘Western Europe and USA’ region, there is no statistically significant difference between daratumumab and watchful waiting. Furthermore, with regard to the information on follow-up treatments, it must be assumed that the follow-up treatments in the AQUILA study do not adequately reflect the current standard of care. In addition to these uncertainties, the statistically significant result for the overall survival endpoint is based on a small number of events in both study arms at the time of the current data cut-off.
  • Overall, for the morbidity endpoint category, taking into account the significant benefits on the ‘pain’ and ‘dyspnoea’ symptom scales of the EORTC QLQ-C30, there is a moderate advantage in favour of daratumumab.
  • Overall, for the health-related quality of life endpoint category, taking into account the significant benefits in the ‘global health status’ and ‘emotional functioning’ domains of the EORTC QLQ-C30, there is a moderate advantage in favour of daratumumab.
  • With regard to side effects, the overall rates of serious AEs (SAEs) and severe AEs (CTCAE grade ≥ 3) show no differences between the study arms that are relevant to the benefit assessment. No suitable data are available for the endpoint of discontinuation due to AEs. In detail, disadvantages are evident with regard to specific AEs.
  • Consequently, daratumumab is found to offer a minor additional benefit over a ‘wait-and-see’ approach, particularly due to the moderate advantages in the endpoint categories of morbidity and health-related quality of life.

Courtesy translation only, please refer to the German original.