Daratumumab (6) – Darzalex®

• Clinical trials
  • To demonstrate the additional benefit, the pharmaceutical manufacturer has submitted data from the randomised controlled trial CASSIOPEIA.
  • The CASSIOPEIA trial consists of two parts.
  • In Part 1, induction therapy is administered, followed by high-dose therapy with subsequent autologous stem cell transplantation (ASCT) and followed by consolidation therapy.

Adult patients with newly diagnosed multiple myeloma who are suitable for autologous stem cell transplantation

• mortality
  • In the CASSIOPEIA study, overall survival is defined as the time from randomisation to death from any cause.
  • Data from the first and second data cut-offs are available for the overall survival endpoint.
  • At the time of the first data cut-off, the median follow-up duration was 8.8 months in the treatment arm and 18.9 months in the control arm. At the second data cut-off, the median observation time was 29.3 months in the treatment arm and 29.2 months in the control arm.
  • At both data cut-off points, a statistically significant difference was observed in favour of daratumumab in combination with bortezomib + thalidomide + dexamethasone (D-VTd) compared with bortezomib + thalidomide + dexamethasone (VTd) (1st data cut-off: hazard ratio (HR): 0.43; [95% confidence interval (CI): 0.23; 0.80]; p-value = 0.007; 2nd data cut-off HR: 0.52; [95% CI: 0.33; 0.85]).
  • In both arms, only a minor number of events had occurred at these time points (1st data cut-off: n = 14 (2.6%) vs. n = 32 (5.9%); 2nd data cut-off: n = 26 (4.8%) vs. n = 48 (8.9%)).
  • The study thus demonstrates a clearly positive effect with the daratumumab-based quadruple combination D-VTd. There are reported uncertainties regarding the results for this endpoint, due to the transition of patients into the maintenance phase.
• Morbidity – Progression-free survival
  • The endpoint of progression-free survival from the first randomisation is defined in the CASSIOPEIA study as the time from randomisation to the onset of disease progression according to IMWG criteria or death.
  • There is a statistically significant difference between the two study arms at both the first and second data cut-offs.
  • At the time of the second data cut-off, 83 patients on daratumumab + bortezomib + thalidomide + dexamethasone (15.3 per cent) had experienced an event, compared with 151 patients (27.9 per cent) in the bortezomib + thalidomide + dexamethasone arm (HR: 0.49; [95% CI: 0.38; 0.65; p < 0.0001]).
  • The PFS endpoint is a composite endpoint comprising endpoints from the ‘mortality’ and ‘morbidity’ categories. The ‘mortality’ 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 G-BA regarding the clinical relevance of the PFS endpoint to patients. This does not affect the overall conclusion regarding additional benefit.
• 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.
  • A statistically significant advantage was observed for the ‘global health status’ functional scale in favour of daratumumab in combination with bortezomib, thalidomide and dexamethasone compared with the triple combination of bortezomib, thalidomide and dexamethasone.
  • In the other functional scales (‘physical functioning’, ‘role functioning’, ‘emotional functioning’, ‘cognitive functioning’ and ‘social functioning’), no statistically significant difference was observed between the two treatment arms.
  • In the quality of life category, therefore, an advantage is evident with regard to the ‘overall health status’ scale.
• Side effects – Total adverse events (AEs)
  • The results for the endpoint ‘total adverse events’ are presented for supplementary information only.
  • In both treatment arms, almost every patient experienced an adverse event (D-VTd: 535 patients (99.8%); VTd: 536 patients (99.6%)).
• Overall assessment / Conclusion
  • Results for the additional benefit of Daratumumab in combination with Bortezomib + Thalidomid + Dexamethason compared randomised, controlled CASSIOPEIA trial are available for the endpoint categories of mortality, morbidity, health-related quality of life and side effects.
  • Even at the time of the first data cut-off, a significant proportion of patients had progressed to maintenance therapy (Part 2), which does not correspond to the standard of care in either arm. Although it is assumed that this does not bias the results between the two study arms and, furthermore, that results on overall survival will only be influenced by maintenance therapy at a later stage, there are nevertheless significant uncertainties regarding the endpoint of overall survival.
  • With regard to overall survival, a statistically significant, clearly positive effect in favour of the daratumumab quadruple combination is evident at both the first and second data cut-off points. However, it must be borne in mind that only minor numbers of events had occurred at the time of the data cut-offs. Furthermore, the uncertainties described regarding the transition to the maintenance phase remain.
  • With regard to morbidity, the daratumumab combination therapy showed a statistically significant advantage in terms of disease symptoms on the ‘pain’ subscale of the EORTC QLQ-C30. No statistically significant difference was observed in health status as assessed using the EQ-5D VAS.
  • With regard to health-related quality of life, the daratumumab quadruple combination shows an advantage on the ‘global health status’ subscale of the EORTC QLQ-C30 functional scales.
  • In the category of side effects, no statistically significant differences were observed in the endpoints of serious side effects, severe side effects (CTCAE grade ≥ 3) or discontinuation due to side effects.
  • Overall, therefore, there is a clearly positive effect of the daratumumab quadruple combination on overall survival. However, due to the uncertainties outlined, the extent of this effect cannot be quantified. Furthermore, the daratumumab combination therapy shows advantages in terms of morbidity and quality of life.

Courtesy translation only, please refer to the German original.