Daratumumab (8) – Darzalex®

a) Adults with multiple myeloma who have received prior treatment, including a proteasome inhibitor and lenalidomide, and who were refractory to lenalidomide

• An additional benefit is not proven.
• As the pharmaceutical manufacturer has not provided suitable data to assess the additional benefit for patient population a) compared with the appropriate comparator therapy, the additional benefit is not proven for D-Pd.

b1) Adults with multiple myeloma who have received at least two prior treatments, including lenalidomide and a proteasome inhibitor, and who have shown disease progression during the last treatment

• Hint of a minor additional benefit
• Overall, the G-BA finds a hint of a minor additional benefit for D-Pd compared with Pd.
• mortality
  • In the APOLLO study, the endpoint of overall survival is defined as the time from randomisation to death from any cause.
  • No statistically significant difference was observed between the treatment arms. The median survival time had not been reached in the D-Pd arm.
• Morbidity – Progression-free survival (PFS)
  • PFS was the primary endpoint of the APOLLO study and was defined as the time from randomisation to the date of disease progression or death from any cause.
  • For the PFS endpoint, there is a statistically significant advantage in favour of D-Pd.
  • The PFS endpoint is a composite endpoint comprising endpoints from the categories of mortality and morbidity. The ‘mortality’ component of the endpoint is already assessed as a standalone endpoint via the secondary endpoint of overall survival. The ‘disease progression’ component of morbidity was assessed according to IMWG criteria and was 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.
• Morbidity – Symptoms (fatigue)
  • A statistically significant difference in favour of D-Pd was observed for the fatigue symptom scale.
• Morbidity – Health status (EQ-5D VAS)
  • When considering the time to confirmed permanent deterioration, no statistically significant difference was observed between the treatment arms for any of the response criteria.
• Health-related quality of life – future prospects
  • Statistically significant differences in favour of D-Pd were observed for the ‘future prospects’ scale of the EORTC QLQ-MY20.
• Side effects – adverse events (AE), total
  • Adverse events (AEs) occurred in almost all study participants. The results are presented here for supplementary information only.
• Side effects – serious adverse events (SAEs), severe AEs (CTCAE grade ≥ 3), discontinuation due to AEs (≥ 1 active ingredient)
  • For the endpoints serious adverse events (SAEs), severe AEs (CTCAE grade ≥ 3) and discontinuation due to AEs (≥ 1 active ingredient), there was no statistically significant difference between the treatment arms in any case.
• Side effects – Specific AEs (CTCAE grade ≥ 3)
  • For the specific Preferred Terms (PT) lymphopenia and febrile neutropenia, there is a statistically significant difference to the detriment of D-Pd in each case.
• Conclusion on side effects
  • An overall review of the results on side effects reveals no differences between the treatment arms that are relevant to the benefit assessment. In detail, the specific side effects of lymphopenia and febrile neutropenia show disadvantages for D-Pd.
• Overall assessment
  • There is no statistically significant difference in overall survival between the study arms.
  • For patient-reported endpoints, the analysis considers the time to deterioration, taking into account baseline values at the start of the study, the available responder analyses and the expected progressive course of the disease. As a deterioration that persists over a period of time is considered more relevant for patients than an initial deterioration due to its persistence, the present assessment is based on the analyses of the time to confirmed persistent deterioration.
  • In the morbidity endpoint category, the Fatigue symptom scale of the EORTC-QLQ-C30 shows an advantage for D-Pd over Pd. With regard to health status as assessed using the EQ-5D VAS, no statistically significant differences are observed.
  • With regard to health-related quality of life, D-Pd shows an advantage over Pd on the emotional functioning and future prospects scales.
  • For the endpoint category ‘side effects’, there are no differences between the treatment arms that are relevant for the benefit assessment. In detail, D-Pd shows disadvantages for the specific AEs of lymphopenia and febrile neutropenia.
  • Overall, therefore, D-Pd shows advantages on individual scales of the questionnaires on patient-reported morbidity and health-related quality of life. On balance, the G-BA concludes that daratumumab in combination with pomalidomide and dexamethasone for the treatment of adults with multiple myeloma who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor, and who have shown disease progression during their most recent treatment, there is a minor additional benefit compared with pomalidomide in combination with dexamethasone.

b2) Adults with multiple myeloma who have received at least two prior treatments, including lenalidomide and a proteasome inhibitor, and who have shown disease progression following the last treatment

• An additional benefit is not proven.
• As the pharmaceutical manufacturer has not provided suitable data to assess the additional benefit for patient population b2) compared with the appropriate comparator therapy, the additional benefit for D-Pd is not proven.

Courtesy translation only, please refer to the German original.