Daratumumab (11) – Darzalex®

• Clinical trials
  • In the ongoing ALCYONE and OCTANS trials, daratumumab is being compared in combination with bortezomib + melphalan + prednisone (D-VMP regimen) against bortezomib + melphalan + prednisone (VMP regimen).

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

• In summary, daratumumab in combination with bortezomib, melphalan and prednisone has been found to offer considerable additional benefit over bortezomib, melphalan and prednisone.
• There are significant uncertainties regarding the certainty of the evidence, as the studies also included patients who, according to current eligibility criteria, might be suitable for autologous stem cell transplantation (ASCT). The certainty of the evidence is overall classified as an indication.
• mortality
  • Overall survival was defined in the ALCYONE and OCTANS studies as the time from randomisation to the date of death from any cause.
  • The meta-analytic synthesis of the ALCYONE and OCTANS studies reveals a statistically significant difference in favour of daratumumab + bortezomib + melphalan + prednisone compared with bortezomib + melphalan + prednisone.
  • Taking these considerations into account, the statistically significant advantage of the daratumumab combination in terms of the overall survival endpoint is interpreted as a marked prolongation of survival.
• Morbidity – Progression-free survival (PFS)
  • Progression-free survival (PFS) is the primary endpoint of the ALCYONE study and a secondary endpoint of the OCTANS study. It is defined in each case as the time from randomisation to the occurrence of disease progression or death.
  • In both the ALCYONE and OCTANS studies, there is a statistically significant difference in PFS in favour of daratumumab + bortezomib + melphalan + prednisone compared with bortezomib + melphalan + prednisone.
  • The PFS endpoint is a composite endpoint comprising endpoints from the ‘mortality’ and ‘morbidity’ categories.
• Morbidity – EORTC QLQ-C30 – symptom scales (fatigue)
  • In the meta-analytic summary of the ALCYONE and OCTANS trials, there is a statistically significant difference in favour of daratumumab + bortezomib + melphalan + prednisone compared with bortezomib + melphalan + prednisone for the symptom of fatigue.
  • For the remaining symptoms, the meta-analytic summary of the ALCYONE and OCTANS studies shows no significant differences between the study arms.
  • Overall, therefore, there is a detailed advantage of the daratumumab combination for the symptom of fatigue.
• Morbidity – Health status (EQ-5D VAS)
  • Health status is assessed in the present studies using the visual analogue scale (VAS) of the European Quality of Life Questionnaire 5 Dimensions (EQ-5D).
  • In the meta-analytic summary of ALCYONE and OCTANS, no statistically significant difference in health status was found between the study arms.
• Quality of life – EORTC QLQ-C30 – functional scales (overall health status)
  • Health-related quality of life is assessed in the ALCYONE and OCTANS studies using the functional scales of the EORTC QLQ-C30.
  • In the meta-analytic summary of ALCYONE and OCTANS, there is a statistically significant difference in global health status in favour of daratumumab + bortezomib + melphalan + prednisone compared with bortezomib + melphalan + prednisone.
  • In the meta-analytic summary of ALCYONE and OCTANS, no statistically significant differences between the study arms were observed for the remaining functional scales (physical functioning, role functioning, emotional functioning, cognitive functioning, social functioning).
  • Overall, therefore, a detailed analysis reveals an advantage of the daratumumab combination in terms of overall health status.
• Side effects – serious adverse events (SAEs), severe adverse events and discontinuation due to adverse events (at least one treatment component)
  • In the meta-analytic summary of ALCYONE and OCTANS, no statistically significant differences were found between the study arms for the endpoints SAE, severe AEs and discontinuation due to AEs (at least one treatment component).
• Conclusion on side effects
  • Overall, there are no statistically significant differences between the treatment arms in the endpoint category of side effects for SAE, severe AEs and discontinuations due to AEs.
  • For individual specific AEs, the ALCYONE study revealed disadvantages associated with daratumumab combination therapy. As these disadvantages are not reflected in the overall rates of AEs, SAEs and severe AEs in the meta-analytical summary of ALCYONE and OCTANS, these differences do not lead to a change in the assessment of the additional benefit.
• Overall assessment
  • With regard to overall survival, the meta-analysis reveals a statistically significant advantage in favour of the daratumumab combination, the extent of which is generally interpreted as a marked prolongation of survival.
  • With regard to morbidity, the meta-analysis shows an advantage of daratumumab combination therapy in the ‘fatigue’ subscale of the EORTC QLQ-C30. In the other symptom scales and in the EQ-5D VAS, no significant differences between the study arms were identified in the meta-analysis.
  • With regard to health-related quality of life, the meta-analysis shows, in detail, an advantage of daratumumab combination therapy for the ‘global health status’ function scale of the EORTC QLQ-C30. For the other functional scales, no significant differences between the study arms were observed in the meta-analysis.
  • With regard to the endpoint category of side effects, no statistically significant differences were observed between the treatment arms for the overall rate of severe AEs, severe SAEs or discontinuations due to AEs. For individual specific AEs, the daratumumab combination therapy was found to have disadvantages. As these disadvantages are not reflected in the overall rates of AEs, SAEs and severe AEs, these differences do not lead to a change in the assessment of the additional benefit.
  • In summary, daratumumab in combination with bortezomib, melphalan and prednisone is found to offer considerable additional benefit compared with bortezomib, melphalan and prednisone.

Courtesy translation only, please refer to the German original.