Daratumumab, Bortezomib and Dexamethasone for Previously Treated Myeloma – Comparing Real-World Outcomes in England to the Castor Phase III Clinical Trial

Introduction: Daratumumab/bortezomib/dexamethasone (DVd) was commissioned by the Cancer Drugs Fund (CDF) in England for routine use in relapsed myeloma based on outcomes from the CASTOR trial. The CDF allows interim access to therapies whilst collecting real world outcomes to inform long term funding decisions. The commissioning criteria followed the eligibility criteria for CASTOR, and approval permitted patients treated with 1 prior line only.

Real world analyses of DVd have previously been limited by small numbers and heterogeneous patient populations. Here we present, to our knowledge, the largest study of the efficacy of DVd used as second line therapy in relapsed myeloma and compare outcomes with those seen in CASTOR.

Methods: Patients treated with DVd via CDF funding between March 2019 and June 2021 were identified from the NHS England Blueteq system, and the Systemic Anti-Cancer Therapy dataset (SACT) collected by the National Disease Registration Service (NDRS). Using Kaplan-Meier, Time to Next Treatment (TTNT) was calculated from the date DVd commenced until initiation of a subsequent therapy or death and considered a surrogate for PFS. Overall survival (OS) was calculated from DVd initiation until death. All patients were traced for their vital status on 25 March 2024, with SACT follow-up until 31 August 2023. Results were compared with CASTOR intention to treat (ITT) population and 1 prior line subgroup.

Results: 2,545 patients were identified, 59% male and 41% female. Median age was 70 years (range 21, 94) compared to 64 in CASTOR. ECOG performance status was 0/1 in 67% (23% unknown). Prior therapies included bortezomib (70%, vs 51% in CASTOR 1 prior line), lenalidomide (12%, vs 12% in CASTOR 1 prior line). 42% of patients had received prior autologous stem cell transplant (ASCT). The median TTNT was 16.9 months [95% CI: 15.8, 18.3]. The median OS was 51.8 months [95% CI: 48.5, 56.2]. These results were consistent with CASTOR ITT (n=251), where PFS and OS were 16.7 months (Spencer, 2018) and 49.6 months (Sonneveld, 2023) respectively. PFS and OS were longer in CASTOR 1 prior line subgroup (n=122), (27.0 months [Mateos, 2020] and not reached (Sonneveld, 2023) respectively).

TTNT for patients treated with prior ASCT vs no ASCT did not significantly differ (17.1 months [95% CI: 15.3, 18.6] vs 16.8 months [95% CI: 15.6, 19.1], p=0.66) however OS was significantly longer for those who received prior ASCT (not reached (NR) vs 45.1 months [95% CI: 41.1, 49.8], p<0.0001). Bortezomib naïve patients had improved TTNT (22.7 months [95% CI: 20.0, 25.8]) vs bortezomib exposed (15.6 months [95% CI: 14.5, 16.6], p<0.0001) and prolonged OS (NR vs 49.8 months [95% CI: 46.3, 53.7], p<0.028). TTNT did not significantly differ in patients with prior lenalidomide treatment vs no prior lenalidomide (14.7 months [95% CI: 12.6, 18.9] vs 17.3 months [95% CI: 16.0, 18.6], p=0.21) whereas prior lenalidomide was associated with shorter OS (43.4 vs 53.6 months [95% CI: 49.8, 56.8], p<0.0058). In comparison, PFS was 7.8 months for lenalidomide refractory patients in CASTOR ITT, whilst lenalidomide exposed patients in CASTOR 1 prior line (n=15) exhibited PFS 21.2 months (Mateos, 2020).

Discussion: These results show DVd treatment in the real-world setting produced TTNT and OS outcomes comparable to PFS and OS in CASTOR ITT population. These results highlight the efficacy of this regimen in the real-world setting. Results from CASTOR 1 prior line subgroup suggested prior lenalidomide exposure did not preclude favourable outcomes with DVd. Our study found similar results and has therefore validated these findings in a larger cohort. Prior ASCT did not significantly alter TTNT suggesting the efficacy of DVd in a transplant ineligible population in the real-world setting which is consistent with CASTOR (Mateos 2020).