Daratumumab (10) – Darzalex®

• Clinical trials
  • In the randomised, open-label, controlled Phase III CASTOR trial, treatment with daratumumab in combination with bortezomib and dexamethasone (DVd) was compared with the combination therapy of bortezomib and dexamethasone (Vd).
  • In the randomised, open-label, controlled Phase III POLLUX trial, daratumumab in combination with lenalidomide and dexamethasone (DRd) was compared with lenalidomide in combination with dexamethasone (Rd).

a) Adults with multiple myeloma who have already received at least one course of treatment

• Consequently, based on the meta-analytical evaluation of the CASTOR and POLLUX studies, the G-BA has determined that there is proof of considerable additional benefit for daratumumab in combination with Rd or Vd, respectively, compared with Vd or Rd.
• mortality
  • For the endpoint of overall survival, the meta-analysis of the CASTOR and POLLUX studies revealed a statistically significant difference in favour of the daratumumab combination therapy compared with lenalidomide in combination with dexamethasone or bortezomib in combination with dexamethasone.
  • This prolongation of survival time achieved through treatment with the daratumumab combination therapy is regarded as a significant improvement.
• Morbidity – Progression-free survival (PFS)
  • PFS was the primary endpoint of the CASTOR and POLLUX studies and was defined as the time from randomisation to the first documented evidence of disease progression according to International Myeloma Working Group (IMWG) criteria or death from any cause.
  • In both studies, PFS was statistically significantly prolonged in the intervention arm compared with the control arm.
  • The PFS endpoint is a composite endpoint comprising endpoints from the ‘mortality’ and ‘morbidity’ categories.
  • This does not affect the overall conclusion regarding additional benefit.
• Morbidity – Symptoms
  • Symptoms of the disease were assessed in the CASTOR and POLLUX studies using the symptom scales of the cancer-specific EORTC QLQ-C30 questionnaire.
  • The meta-analysis of the CASTOR and POLLUX studies showed no difference between daratumumab combination therapy and treatment with lenalidomide in combination with dexamethasone or bortezomib in combination with dexamethasone.
  • With regard to symptoms, therefore, there are neither positive nor negative effects of daratumumab combination therapy.
• Morbidity – Health status (EQ-5D Visual Analogue Scale)
  • Health status was assessed in the CASTOR and POLLUX studies using the visual analogue scale (VAS) of the EQ-5D questionnaire.
  • The meta-analysis of the CASTOR and POLLUX studies showed no difference between daratumumab combination therapy and treatment with lenalidomide in combination with dexamethasone or bortezomib in combination with dexamethasone.
  • Consequently, there are therefore neither positive nor negative effects of daratumumab combination therapy with regard to health status.
• Health-related quality of life
  • Health-related quality of life was assessed in the CASTOR and POLLUX studies using the functional scales of the cancer-specific EORTC QLQ-C30 questionnaire.
  • The meta-analysis of the CASTOR and POLLUX studies showed no difference between daratumumab combination therapy and treatment with lenalidomide in combination with dexamethasone or bortezomib in combination with dexamethasone.
  • With regard to health-related quality of life, therefore, there are neither positive nor negative effects of daratumumab combination therapy.
• Side effects – Serious adverse events (SAEs)
  • The meta-analysis of the CASTOR and POLLUX studies revealed no statistically significant difference between the treatment groups in terms of serious adverse events.
• Side effects – Severe AEs (CTCAE grade ≥ 3)
  • For severe adverse events with a CTCAE grade of ≥ 3, the meta-analysis of the CASTOR and POLLUX studies revealed a statistically significant disadvantage for daratumumab combination therapy.
  • There was an effect modification by the ‘International Staging System (ISS) stage’ for severe AEs.
  • In light of the uncertainties described, the existing data on the observed effect modification by the ‘ISS stage’ variable for the endpoint of severe AEs (CTCAE grade ≥ 3) is not considered sufficient to draw separate conclusions regarding additional benefit in the overall assessment with the requisite certainty.
• Side effects – discontinuation due to AEs
  • For the endpoint ‘discontinuation due to AEs’, the meta-analysis of the CASTOR and POLLUX studies revealed no statistically significant difference between the treatment groups.
• Side effects – Specific AEs
  • For the specific AEs vomiting (PT, AE), disorders of the blood and lymphatic system (SOC, severe AE), disorders of the respiratory tract, thoracic cavity and mediastinum (SOC, severe AE), diarrhoea (PT, severe AE) and hypertension (PT, severe AE), the meta-analysis of the CASTOR and POLLUX studies revealed a statistically significant disadvantage in each case for daratumumab combination therapy.
  • In summary, with regard to side effects, a disadvantage of daratumumab combination therapy can be identified due to the negative effects observed in severe AEs (CTCAE grade ≥ 3) and, in detail, in the specific AEs.
• Overall assessment
  • For the endpoint of overall survival, the available results show a statistically significant prolongation of survival with daratumumab combination therapy compared with treatment with lenalidomide in combination with dexamethasone or bortezomib in combination with dexamethasone, which is regarded as a marked improvement.
  • No statistically significant difference was observed between the treatment groups in terms of symptoms (assessed using the EORTC QLQ-C30) and health status (assessed using the EQ-5D VAS).
  • There is also no statistically significant difference between the treatment groups in terms of health-related quality of life (assessed using the EORTC QLQ-C30).
  • With regard to adverse events, the daratumumab combination therapy is associated with disadvantages in terms of the incidence of severe adverse events (CTCAE grade ≥ 3) and, in detail, specific adverse events.
  • In summary, a marked improvement in terms of prolonged survival is offset by a disadvantage regarding severe adverse events (CTCAE grade ≥ 3) and, more specifically, certain specific adverse events.
  • On balance, the G-BA concludes that for daratumumab in combination with lenalidomide and dexamethasone or with bortezomib and dexamethasone for the treatment of adult patients with multiple myeloma who have already received at least one prior therapy, offers a considerable additional benefit compared with lenalidomide in combination with dexamethasone or bortezomib in combination with dexamethasone.

Courtesy translation only, please refer to the German original.