Ciltacabtagen autoleucel (2) – Carvykti®

a1) Adults with relapsed and refractory multiple myeloma who have received one to three prior lines of treatment, have shown disease progression during the last line of treatment, and are refractory to lenalidomide; prior treatment includes an immunomodulator and a proteasome inhibitor

• Hint for a considerable additional benefit
• In summary, for Ciltacabtagen autoleucel in adults with relapsed and refractory multiple myeloma who have received one to three prior therapies (prior treatment includes an immunomodulator and a proteasome inhibitor), who have shown disease progression during their most recent treatment and are refractory to lenalidomide, a considerable additional benefit has been established compared with individualised therapy comprising DPd or PVd.
• In summary, with regard to the certainty of the evidence (probability of additional benefit), the G-BA derives a hint about the established additional benefit.
• mortality
  • Overall survival was defined in the CARTITUDE-4 study as the period between randomisation and the date of death from any cause.
  • Overall, there is a statistically significant difference in favour of Ciltacabtagen autoleucel compared with DPd or PVd. The statistically significant advantage is interpreted overall as a marked prolongation of survival.
• morbidity
  • Progression-free survival (PFS)
  • Progression-free survival is the primary endpoint of the CARTITUDE-4 study and is defined as the time between randomisation and the date of the first documented disease progression according to the International Myeloma Working Group (IMWG) criteria or death from any cause, whichever occurs first.
  • There is a statistically significant difference in favour of Ciltacabtagen autoleucel compared with DPd and PVd, respectively.
  • 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 in this assessment remains unaffected by this.
  • With regard to morbidity [...], no suitable data are available based on patient-reported endpoints (EORTC QLQ-C30, PGIS, EQ-5D VAS, MySIm-Q and PRO-CTCAE), as no PROs were collected during relevant phases of the CAR-T cell therapy regimen.
• Side effects
  • Comment applicable across all endpoints
  • In the CARTITUDE-4 study, adverse events (AEs), the associated severe AEs (Common Terminology Criteria for Adverse Events [CTCAE] grade ≥ 3), serious adverse events (SAEs) and adverse events of particular interest to patients were recorded in full to varying extents between the two treatment arms.
  • The results of sensitivity analysis 1 are used for the benefit assessment.
  • For SUEs, severe AEs and therapy discontinuations due to AEs, no statistically significant differences between the treatment arms were observed in the CARTITUDE-4 study.
  • Significant differences to the detriment of Ciltacabtagen autoleucel were observed in the following specific SAEs: severe neurological toxicity (SAE, SOC: nervous system disorders), headache (PT, adverse events), thrombocytopenia (PT, severe AEs, CTCAE grade 3 or 4), anaemia (PT, severe AEs, CTCAE grade 3 or 4), lymphopenia (PT, severe AEs, CTCAE Grade 3 or 4), leucopenia (PT, severe AEs, CTCAE Grade 3 or 4), metabolic and nutritional disorders (SOC, severe AEs, CTCAE Grade 3 or 4), hypogammaglobulinaemia (PT, severe AEs, CTCAE Grade 3 or 4).
  • For the specific AE of insomnia (PT, AEs), there is a significant difference in favour of Ciltacabtagen autoleucel.
  • Conclusion on side effects
  • Overall, there are no statistically significant differences between the treatment arms in the endpoint category of side effects for SAE, severe AEs and discontinuations due to AEs. In detail, the specific AEs predominantly show disadvantages for Ciltacabtagen autoleucel.
  • As these disadvantages are not reflected in the overall rates of AEs, SAE and severe AEs, these differences do not lead to a change in the assessment of the additional benefit. Overall, therefore, neither an advantage nor a disadvantage is identified for the ‘side effects’ endpoint category.
• Overall assessment
  • For the assessment of the additional benefit of Ciltacabtagen autoleucel for the treatment of adults with relapsed and refractory multiple myeloma who have previously received one to three lines of therapy, including an immunomodulator and a proteasome inhibitor, and who experienced disease progression during their most recent treatment and are refractory to lenalidomide, results are available for the endpoint categories of mortality, morbidity, quality of life and side effects from the CARTITUDE-4 study, which compared Ciltacabtagen autoleucel with DPd and PVd respectively.
  • With regard to overall survival, a statistically significant advantage was observed in favour of Ciltacabtagen autoleucel, whose extent is generally interpreted as a marked prolongation of survival.
  • With regard to morbidity, health-related quality of life and side effects, no suitable data are available based on patient-reported endpoints (EORTC QLQ-C30, PGIS, EQ-5D VAS, MySIm-Q and PRO-CTCAE), as no PROs were collected during relevant phases of the CAR-T cell therapy regimen.
  • With regard to side effects, no significant differences were observed between the treatment arms in terms of severe SAEs, severe adverse reactions (SARs) or treatment discontinuation due to AEs. In detail, the specific AEs predominantly showed disadvantages for Ciltacabtagen autoleucel.
  • Overall, neither an advantage nor a disadvantage is inferred for the endpoint category of side effects.

a2) Adults with relapsed and refractory multiple myeloma who have received at least four prior treatments, have shown disease progression during the last treatment and are refractory to lenalidomide; prior treatment includes an immunomodulator and a proteasome inhibitor

• An additional benefit is not proven.
• The CARTITUDE-4 study is not suitable for determining additional benefit, as this study exclusively included patients who had received between one and three prior treatments. Consequently, additional benefit for adults who have received at least four prior treatments is not proven.

Courtesy translation only, please refer to the German original.