Daratumumab (4) – Darzalex®

• Clinical trials
  • The pharmaceutical manufacturer has submitted data from the open-label, randomised, controlled Phase III ALCYONE trial for the benefit assessment.
  • In this ongoing trial, daratumumab in combination with bortezomib + melphalan + prednisone (D-VMP regimen) is being compared with bortezomib + melphalan + prednisone (VMP regimen).

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

• mortality
  • With regard to overall survival, there is a statistically significant advantage of daratumumab plus bortezomib plus melphalan plus prednisone compared with bortezomib plus melphalan plus prednisone.
  • The median time to event had not yet been reached at the third data cut-off. There were 59 events in the study arm compared with 83 events in the control arm (hazard ratio (HR): 0.68; [95% confidence interval (CI): 0.49; 0.95]; p-value = 0.023).
  • With regard to overall survival, this therefore indicates an additional benefit of the daratumumab combination, the extent of which is classified as considerable.
• Morbidity – Progression-free survival (PFS)
  • Progression-free survival is the primary endpoint of the ALCYONE study. It is defined as the time from randomisation to the occurrence of disease progression or death.
  • In the daratumumab arm, 134 patients (38.3%) experienced the event, compared with 223 patients (62.6%) in the control arm. This difference was statistically significant (HR: 0.43 [0.35; 0.54]; p < 0.0001).
  • The PFS endpoint is a composite endpoint comprising endpoints from the ‘mortality’ and ‘morbidity’ categories. The ‘mortality’ component of the 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 – EORTC-QLQ C30 – functional scales
  • Health-related quality of life is assessed in the ALCYONE study using the functional scales of the EORTC-QLQ C30.
  • There was no statistically significant difference between the treatment and control arms on any of the scales (general health status, role functioning, emotional functioning, physical functioning, cognitive functioning or social functioning).
  • An additional benefit of daratumumab in the quality of life category is not proven.
• Side effects
  • Almost every patient in both the treatment and control arms experienced an adverse event. The results for the endpoint ‘Total adverse events’ are presented here for supplementary information only.
  • Serious adverse events occurred in 43.6% of patients receiving daratumumab combination therapy, compared with 32.5% in the control arm. The difference between the two treatment arms was not statistically significant.
  • With regard to severe adverse events (CTCAE grade ≥ 3), there was also no statistically significant difference between the daratumumab arm (79.2%) and the control arm (78.0%).
  • With regard to the endpoint ‘therapy discontinuation of all treatment components due to adverse events’, there was a statistically significant difference in favour of the daratumumab combination therapy (HR: 0.48 [0.26; 0.86], p = 0.013). In the daratumumab arm, 22 patients (6.4%) discontinued treatment with all active components, compared with 33 patients (9.3%) in the control arm.
  • Statistically significant disadvantages to the detriment of the daratumumab quadruple combination were observed for the endpoint ‘infections and parasitic diseases (SUEs)’ (D-VMP: n = 83 (24.0 %), VMP: n = 42 (11.9 %); HR: 1.85 [1.27; 2.71], p = 0.001), ‘vascular disorders (severe adverse events [CTCAE grade ≥ 3]’ (D-VMP: n = 20 (5.8 %), VMP: n = 8 (2.3 %); HR: 2.38 [1.04; 5.44], p = 0.040) and “Respiratory, thoracic and mediastinal disorders (AEs)” (D-VMP: n = 140 (40.5 %), VMP: n = 74 (20.9%); HR: 1.91 [1.43; 2.55], p < 0.001).
  • There is a statistically significant, albeit modest, advantage in favour of daratumumab for the endpoint ‘peripheral neuropathies (UEs)’ (D-VMP: n = 110 (31.8 %), VMP: n = 133 (37.6%); HR: 0.75 [0.58; 0.96], p = 0.025).
  • Overall, in the category of side effects, the daratumumab combination thus offers advantages in terms of therapy discontinuations, as well as both advantages and disadvantages with regard to specific side effects. As the disadvantages associated with some specific AEs are not reflected in the overall rates of AEs, SAEs and AEs (CTCAE Grade 3–4), they are not taken into account when downgrading the additional benefit.
• Overall assessment / Conclusion
  • For the assessment of the additional benefit of daratumumab in combination with bortezomib, melphalan and prednisone for the treatment of adult patients with newly diagnosed multiple myeloma who are not suitable for autologous stem cell transplantation, the ALCYONE study provides results on mortality, morbidity, quality of life and side effects compared with the combination therapy of bortezomib, melphalan and prednisone.
  • With regard to mortality, there is a statistically significant advantage in favour of the daratumumab combination therapy, which is interpreted as a moderate prolongation of survival.
  • In terms of morbidity, there is a statistically significant but only slight extent of difference in the symptom of fatigue in favour of the daratumumab combination therapy.
  • The results on health-related quality of life show no statistically significant difference between the daratumumab quadruple combination and the triple combination.
  • With regard to side effects, there is an advantage in terms of the endpoint ‘therapy discontinuations’. As the advantages and disadvantages of some specific AEs are not reflected in the overall rates of AEs, serious AEs and AEs (CTCAE Grade 3–4), they are not used to downgrade the additional benefit in the ‘side effects’ category.
  • In summary, daratumumab in combination with bortezomib, melphalan and prednisone for the treatment of patients with newly diagnosed multiple myeloma who are unsuitable for ASZT, a considerable advantage compared with the standard of care is identified, based on an advantage in terms of overall survival, which is classified as a moderate prolongation of life, a considerable additional benefit has been identified compared with the appropriate comparator therapy.

Courtesy translation only, please refer to the German original.