Daratumumab (14) – Darzalex®

• Clinical trials
  • The pharmaceutical manufacturer submitted the results of the open-label, randomised Phase III CEPHEUS trial for the benefit assessment.
  • The CEPHEUS trial investigated the safety and efficacy of daratumumab in combination with bortezomib, lenalidomide and dexamethasone (D-VRd) compared with bortezomib, lenalidomide and dexamethasone (VRd).

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

• As a result, the G-BA has concluded that daratumumab in combination with bortezomib, lenalidomide and dexamethasone for the treatment of adult patients with newly diagnosed multiple myeloma who are not suitable for autologous stem cell transplantation and who therefore have a minor additional benefit compared to Bortezomib, lenalidomide and dexamethasone.
• Taking the aforementioned uncertainties into account, there is, on the whole, a hint that supports the established additional benefit.
• mortality
  • In the CEPHEUS study, overall survival is defined as the time from randomisation to death, loss to follow-up, withdrawal of informed consent, or the end of the study, whichever occurs first.
  • For the endpoint of overall survival, there is no statistically significant difference between the treatment arms.
• Morbidity – Progression-free survival (PFS)
  • In the CEPHEUS study, PFS is defined as the time from randomisation to the first sign of disease progression, assessed according to the criteria of the International Myeloma Working Group (IMWG), or to the time of death from any cause, whichever occurs first.
  • For the PFS endpoint, there is a statistically significant advantage for daratumumab + bortezomib + lenalidomide + dexamethasone compared with bortezomib + lenalidomide + dexamethasone.
  • The PFS endpoint in question is a composite endpoint comprising endpoints from the ‘mortality’ and ‘morbidity’ categories.
  • 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 the extent of the additional benefit.
• Morbidity – Minimal Residual Disease (MRD)
  • The MRD negativity rate was the primary endpoint of the CEPHEUS study and was defined as the proportion of study participants who, after randomisation and at any time during the study, but prior to disease progression or subsequent myeloma therapy, or both, achieved MRD negativity and a complete response as determined by bone marrow aspiration.
  • The MRD negativity rate endpoint is not used to derive additional benefit. As it may be a relevant prognostic factor, the endpoint is presented here for supplementary information.
  • The results for the MRD negativity rate endpoint at 3 years after randomisation and at a threshold of 10–5 cells show a statistically significant advantage in favour of daratumumab + bortezomib + lenalidomide + dexamethasone compared with bortezomib + lenalidomide + dexamethasone.
• Morbidity – Symptoms (EORTC QLQ-C30; EORTC QLQ-MY20)
  • In the CEPHEUS study, disease symptoms were assessed using the cancer-specific questionnaire EORTC QLQ-C30 and the supplementary module EORTC QLQ-MY20.
  • The pharmaceutical manufacturer provided analyses of the time to first deterioration, using a response threshold of ≥ 10 points.
  • A statistically significant advantage in favour of daratumumab + bortezomib + lenalidomide + dexamethasone compared with bortezomib + lenalidomide + dexamethasone was observed only for the symptom of constipation.
  • With regard to the other symptom scales of the EORTC QLQ-C30 and the EORTC QLQ-MY20, there were no statistically significant differences between the treatment arms.
• quality of life
  • Health-related quality of life is assessed in the CEPHEUS study using the functional scales of the EORTC-QLQ C30 and the supplementary module EORTC QLQ-MY20.
  • No statistically significant differences were observed between the treatment arms in the analyses of the time to first deterioration of ≥ 10 points.
• Side effects – Serious adverse events (SAEs) and severe adverse events (SEs)
  • For the endpoints SUEs and severe AEs, there are no statistically significant differences between the treatment arms in the presented study.
• Overall assessment
  • Data are available from the CEPHEUS study for the assessment of the additional benefit of daratumumab in combination with bortezomib, lenalidomide and dexamethasone for the treatment of adult patients with newly diagnosed multiple myeloma who are not eligible for autologous stem cell transplantation, the CEPHEUS study provides results on mortality, morbidity, quality of life and side effects compared with the combination therapy of bortezomib + lenalidomide + dexamethasone.
  • With regard to overall survival, there is no statistically significant difference between the study arms.
  • With regard to symptoms, assessed using the EORTC QLQ-C30 and EORTC QLQ-MY20, the only statistically significant advantage for daratumumab + bortezomib + lenalidomide + dexamethasone was observed for the symptom of constipation, which, given the extent and clinical relevance of the observed effect, is not taken into account when deriving the additional benefit.
  • With regard to health status, based on the results from the EQ-5D VAS, an advantage for daratumumab + bortezomib + lenalidomide + dexamethasone can be identified for the time to confirmed permanent deterioration.
  • With regard to health-related quality of life, assessed using the EORTC QLQ-C30 and EORTC QLQ-MY20, and with respect to the endpoint category of side effects, no statistically significant differences were observed between the treatment arms.
  • An overall review of the results for patient-relevant endpoints reveals an advantage in the morbidity end point category with regard to health status. For the other endpoints relating to morbidity, health-related quality of life and side effects, neither an advantage nor a disadvantage can be identified for daratumumab in combination with bortezomib, lenalidomide and dexamethasone.

Courtesy translation only, please refer to the German original.