Daratumumab (5) – Darzalex®

• Clinical trials
  • The benefit assessment is based on the results of the open-label, randomised, controlled MAIA trial. The trial compares daratumumab in combination with lenalidomide and dexamethasone against the dual combination of lenalidomide and dexamethasone.

Adult patients with newly diagnosed multiple myeloma who are not suitable for autologous stem cell transplantation

• mortality
  • There is no statistically significant difference between the two treatment arms in terms of overall survival. This event occurred in 85 patients (23.1%) receiving daratumumab + lenalidomide + dexamethasone and in 103 patients (27.9%) receiving lenalidomide + dexamethasone.
  • The additional benefit of daratumumab in combination with lenalidomide + dexamethasone for the endpoint of overall survival is not proven.
• Morbidity – Progression-free survival
  • Progression-free survival (PFS) is the primary endpoint of the MAIA study. It is defined as the time from randomisation to the occurrence of disease progression according to IMWG criteria or death. There is a statistically significant difference between the two study arms. In the daratumumab + lenalidomide + dexamethasone arm, 120 patients (32.6 per cent) had experienced an event at the time of the second data cut-off, compared with 171 patients (46.3 per cent) in the lenalidomide + dexamethasone arm.
  • The PFS endpoint is a composite endpoint comprising endpoints from the ‘mortality’ and ‘morbidity’ categories. The ‘mortality’ component of this endpoint 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 G-BA regarding the clinical relevance of the PFS endpoint to patients. The overall conclusion regarding additional benefit remains unaffected by this.
• Quality of life – Health-related quality of life
  • Health-related quality of life was operationalised using the functional scales of the cancer-specific EORTC QLQ-C30 questionnaire and assessed as the time to a deterioration of ≥ 10 points. The assessment was carried out up to 16 weeks after the onset of disease progression.
  • Statistically significant advantages were observed with daratumumab + lenalidomide + dexamethasone in relation to the two functional scales ‘physical functioning’ and ‘social functioning’.
  • No statistically significant difference was observed in the functional scales ‘global health status’, ‘role functioning’, ‘emotional functioning’ and ‘cognitive functioning’.
  • In the category of health-related quality of life, there is therefore an overall advantage for the daratumumab combination therapy in the ‘physical functioning’ and ‘social functioning’ scales.
• Side effects – Total adverse events (AEs)
  • The results for the endpoint ‘total adverse events’ are presented for supplementary information only.
  • In both study arms, almost every patient experienced an adverse event (daratumumab + lenalidomide + dexamethasone: 100 per cent; lenalidomide + dexamethasone: 99.2 per cent).
• Overall assessment / Conclusion
  • Data from the MAIA study are available for the assessment of the additional benefit of daratumumab in combination with lenalidomide + dexamethasone for the treatment of adult patients with newly diagnosed multiple myeloma who are not suitable for autologous stem cell transplantation, in the categories of mortality, morbidity, health-related quality of life and side effects.
  • With regard to mortality, there is neither an advantage nor a disadvantage for the daratumumab triple combination.
  • In terms of morbidity, an advantage was observed with treatment using daratumumab + lenalidomide + dexamethasone with regard to the endpoints of pain and dyspnoea. In particular, the advantage relating to the endpoint of pain is considered a clinically relevant benefit.
  • With regard to health status as assessed using the EQ-5D VAS, no clinically relevant difference between the two treatment arms can be concluded with sufficient certainty.
  • In the quality of life category, advantages were observed in terms of physical functioning and social functioning.
  • With regard to adverse events, there is a disadvantage to the daratumumab triple combination in terms of the incidence of severe adverse events (CTCAE grade ≥ 3). There are no statistically significant differences with regard to serious adverse events (AEs) and discontinuations due to AEs (discontinuation of ≥ 1 component).
  • Overall, advantages in terms of symptoms and quality of life are offset by disadvantages in terms of severe adverse events (CTCAE grade ≥ 3). The disadvantages relating to severe adverse events (CTCAE grade ≥ 3) are assessed as moderate. The adverse effects do not, in this context, call into question the positive, relevant effects, particularly with regard to pain.
• Overall assessment / Conclusion
  • Data from the MAIA study are available for assessing the additional benefit of daratumumab in combination with lenalidomide + dexamethasone for the treatment of adult patients with newly diagnosed multiple myeloma who are not suitable for autologous stem cell transplantation, in the categories of mortality, morbidity, health-related quality of life and side effects.
  • With regard to mortality, there is neither an advantage nor a disadvantage for the daratumumab triple combination.
  • In terms of morbidity, an advantage was observed with treatment using daratumumab + lenalidomide + dexamethasone with regard to the endpoints of pain and dyspnoea. In particular, the advantage relating to the endpoint of pain is considered a clinically relevant benefit.
  • With regard to health status as assessed using the EQ-5D VAS, no clinically relevant difference between the two treatment arms can be concluded with sufficient certainty.
  • In the quality of life category, advantages were observed in terms of physical functioning and social functioning.
  • With regard to adverse events, there is a disadvantage to the daratumumab triple combination in terms of the incidence of severe adverse events (CTCAE grade ≥ 3). There are no statistically significant differences with regard to serious adverse events and discontinuations due to adverse events (discontinuation of ≥ 1 component).
  • Overall, advantages in terms of symptoms and quality of life are offset by disadvantages in terms of severe adverse events (CTCAE grade ≥ 3). The disadvantages relating to severe adverse events (CTCAE grade ≥ 3) are assessed as moderate. The adverse effects do not, in this context, call into question the positive, relevant effects, particularly with regard to pain.

Courtesy translation only, please refer to the German original.