Pomalidomid (2) – Imnovid®

• Clinical trials
  • In this randomised, actively controlled, open-label Phase IIItrial, 455 patients with relapsed or refractory multiple myeloma were allocated to either an intervention group, in which pomalidomide was administered in combination with low-dose dexamethasone, or a control group, in which high-dose dexamethasone was administered, in a 2:1 ratio.

a) Patients for whom dexamethasone (high-dose) constitutes the individualised treatment as determined by the doctor

• Mortality – overall survival
  • In the CC-4047-MM-003 study, overall survival was assessed as a secondary endpoint.
  • At the time of the first data cut-off (7 September 2012), there was a statistically significant difference in overall survival in favour of the combination of pomalidomide and dexamethasone (HR = 0.53; 95% CI [0.37; 0.74]; p < 0.001). A median overall survival could only be determined in the control group receiving high-dose dexamethasone (34 weeks); the crossover rate was 29%.
  • At the time of the final analysis of overall survival as planned in the study protocol (data cut-off 1 March 2013) the median survival time with the combination of pomalidomide and dexamethasone was 54 weeks versus 34.9 weeks with high-dose dexamethasone (HR = 0.70; 95% CI [0.54–0.92]; p = 0.009). Treatment with pomalidomide and dexamethasone thus resulted in a statistically significant prolongation of median overall survival by 19.1 weeks; the crossover rate was 53%.
  • A further data cut-off, not specified in the study protocol, was carried out on 1 September 2013. The median overall survival in the intervention group was 56.9 weeks versus 35.3 weeks in the control group (HR = 0.72; 95% CI [0.56–0.92]; p = 0.009). This represents a statistically significant prolongation of median overall survival by 21.6 weeks; the crossover rate was 56%.
  • When assessing the extent of the observed effects on overall survival, whilst taking into account the uncertainties regarding bias, the additional benefit with regard to the endpoint of overall survival is classified as considerable.
• Morbidity – Progression-Free Survival (PFS)
  • Progression-free survival, defined as the time from randomisation to death or disease progression according to IMWG criteria, was the primary endpoint of the study.
  • Assessment of disease progression was carried out in a blinded manner by an independent review committee.
  • At the time of the final PFS analysis (data cut-off 7 September 2012), the median progression-free survival was 15.7 weeks in the intervention group versus 8.0 weeks in the control group (HR = 0.45; 95% CI [0.35–0.59]; p < 0.001), corresponding to a statistically significant difference of 7.7 weeks.
  • The PFS endpoint is a composite endpoint comprising endpoints from the categories of mortality and morbidity.
  • Taking the above aspects into account, there are differing views within the G-BA regarding the clinical relevance of the PFS endpoint. The overall conclusion regarding additional benefit remains unaffected.
• Health-related quality of life – time to deterioration in health-related quality of life
  • Data on quality of life were collected in an open-label manner using the EORTC QLQ-C30 and EORTC QLQ-MY20 patient questionnaires on Day 1 of each treatment cycle and at the time of treatment discontinuation or disease progression.
  • For the ‘physical functioning’, ‘emotional functioning’ and ‘role functioning’ subscales, the MM-003 study showed a statistically significant effect in favour of pomalidomide in each case.
  • For the subscales ‘general health status/quality of life’, ‘social functioning’ and ‘cognitive functioning’, no statistically significant differences were observed between the intervention and control groups.
  • For the ‘future prospects’ and ‘body image’ subscales, study CC-4047-MM-003 showed a statistically significant effect in favour of pomalidomide in each case.
  • Overall, an advantage for pomalidomide can be observed in terms of stabilising existing health-related quality of life, as the vast majority of the parameters used to measure quality of life indicate positive effects of pomalidomide.
• Side effects
  • Due to the varying lengths of the observation periods between the study arms, a quantitative interpretation of the results for the endpoints SAE and CTCAE grades 3 and 4 based on relative risks is not meaningful.
  • Despite the longer follow-up period in the intervention arm receiving pomalidomide and dexamethasone, there was no statistically significant difference between the intervention and control groups for the endpoints SAE, severe AEs (CTCAE Grade 3 to 4) and therapy discontinuations due to AEs.
  • When considering side effects as a whole, the frequencies of AEs are generally comparable between the two treatment groups, although the side effect profiles differ in terms of treatment-specific patterns.
  • Overall, the side effects observed in the intervention arm are classified as significant for patients, but predominantly as manageable and treatable.
  • In particular, taking into account the severity of the condition and the lack of alternative treatment options, these side effects do not, in the G-BA’s assessment, lead to a downgrading of the extent of the additional benefit.
• Overall assessment
  • A comprehensive review of the results on mortality, morbidity, quality of life and side effects reveals that pomalidomide offers a significant improvement in treatment-related benefit not previously achieved, in particular a moderate prolongation of survival, whilst also having positive effects on health-related quality of life.
  • Classifying the additional benefit as ‘major’ is not justified, not least because the treatment does not achieve a cure of the disease, long-term freedom from serious symptoms or the widespread avoidance of serious side effects.
  • Based on these considerations, the information in the dossier, the results of the benefit assessment and the statements submitted, the G-BA concludes that pomalidomide offers considerable additional benefit.

b) Patients for whom dexamethasone (high-dose) does not constitute the individualised treatment prescribed by the doctor

• The additional benefit is not proven.
• For patients for whom high-dose dexamethasone does not constitute the individualised treatment prescribed by the doctor, the additional benefit compared with the appropriate comparator therapy is not proven, as the pharmaceutical manufacturer has not submitted any study that would have been suitable for assessing the additional benefit compared with the appropriate comparator therapy.

Courtesy translation only, please refer to the German original.