Final analysis of carfilzomib, dexamethasone, and daratumumab vs carfilzomib and dexamethasone in the CANDOR study

Abstract

CANDOR (NCT03158688) is a phase 3, randomized, open-label trial comparing carfilzomib, daratumumab, and dexamethasone (KdD) versus carfilzomib and dexamethasone (Kd) in adults with relapsed/refectory multiple myeloma (RRMM) with 1-3 prior therapies. The CANDOR study met its primary endpoint of progression-free survival (PFS) in the primary analysis. Here we report the final analysis of the study, including secondary endpoints and subgroup analyses thereof. Median follow-up was 50 months. Patients treated with KdD had higher minimal residual disease-negative (MRD-) achievement rates (28% vs 9%; odds ratio [OR], 4.22 [95% CI, 2.28-7.83]) and MRD- complete response rates (22% vs 8%; OR, 3.55 [1.83-6.88]) than those treated with Kd. Median PFS was 28.4 months for KdD versus 15.2 months for Kd (hazard ratio [HR], 0.64 [95% CI, 0.49-0.83]). Median overall survival (OS) was 50.8 months versus 43.6 months, respectively (HR, 0.78 [0.60-1.03]; P=0.042). Trends toward improved OS occurred in predefined subgroups, including patients refractory to lenalidomide (KdD, not reached; Kd, 38.2 months; HR, 0.69 [0.43-1.11]) and refractory to proteasome inhibitor (KdD, 43.2 months; Kd, 30.0 months; HR, 0.70 [0.45-1.09]), and there was significant improvement in patients with high-risk cytogenetics (KdD, 34.3 months; Kd: 17.1 months; HR, 0.52 [0.29-0.94]). No new safety signals were identified. In summary, the final analysis of CANDOR confirmed the PFS benefit and showed a trend in OS benefit with KdD versus Kd. These findings reinforce KdD as a standard of care for RRMM, especially in clinically relevant patient subgroups.

Subsequent therapy and outcomes in patients with newly diagnosed multiple myeloma experiencing disease progression after quadruplet combinations

“…For instance, the median PFS for daratumumab, pomalidomide and dexamethasone were 12.4 months, and for isatuximab, pomalidomide and dexamethasone were 11.5 months in the APOLLO 10 and ICARIA‐MM 12 studies respectively. Combination of anti‐CD38 moAbs with carfilzomib, an agent used in 14.3% of patients progressing after ≥18 months in our cohort, yields median PFS of 28.4 and 35.7 months when combined with daratumumab 14 and isatuximab, 11 respectively, in patients not previously exposed to anti‐CD38 moAb. The relatively high OS for this group, 81.2%, 12 months after QUAD failure, despite short PFS, likely indicates a reasonable likelihood of clinical benefit from subsequent therapies, with the majority receiving T‐cell redirecting therapy.…”

“…The addition of anti‐CD38 monoclonal antibodies like daratumumab and isatuximab to PI and IMIDs has significantly improved overall response rates, depth of response and MRD negativity in patients with multiple myeloma both in NDMM 4,5,7 as well as in relapsed/refractory settings 9–14 . Patients with disease refractory to anti‐CD38 moAb have a very poor response to subsequent lines of therapy as well as short survival, 18–21 yet such information is based on patients with RRMM.…”

“…Because patients initially treated with QUADs are exposed to all three main classes of anti‐MM agents and treatment failure are uncommon, little is known about outcomes once there is disease progression. Additionally, all regimens developed in the context of large phase 3 trials for the treatment of patients with RRMM were tested in populations without prior exposure to anti‐CD38 MoAbs 9–14 . Therefore, there is no high‐level evidence to guide the management of transplant‐eligible patients with NDMM who experience disease relapse after up‐front quadruplet induction.…”

Isatuximab in combination with carfilzomib and dexamethasone in 1q21+ patients with relapsed/refractory multiple myeloma: Long‐term outcomes in the Phase 3 IKEMA study

“…[19][20][21] To date, comparable analyses in 1q21þ patient subgroups have not been reported from the randomized Phase 3 CANDOR study of daratumumab in combination with Kd versus Kd. 19,22 In the recent, prespecified, long-term PFS analysis of the IKEMA trial in patients with RRMM (44.2 month median follow-up), the improvement in PFS with Isa-Kd versus Kd reported at the interim analysis (hazard ratio [HR] 0.53; 99% confidence interval [CI]: 0.32-0.89, one sided p = 0.0007) was confirmed (HR 0.58; 95.4% CI: 0.42-0.79) with a median PFS (mPFS) of 35.7 months reached with Isa-Kd versus 19.2 months with Kd, clinically meaningful increases in the rates of complete response or better (≥CR, 44.1% vs. 28.5%) and minimal residual disease negativity (MRD-, 33.5% vs. 15.4%; MRD-≥ CR 26.3% vs. 12.2%), along with a manageable safety profile. 17 In this updated subgroup analysis of IKEMA, we evaluated PFS and depth of response with Isa-Kd vs. Kd in RRMM patients with 1q21þ status and in related patient subgroups, at the long-term follow-up of 44.2 months.…”

“…Isa is approved in various countries in combination with pomalidomide‐dexamethasone for patients with RRMM who have received ≥2 prior therapies and in combination with carfilzomib‐dexamethasone for patients with RRMM who have received ≥1 prior therapy 19–21 . To date, comparable analyses in 1q21+ patient subgroups have not been reported from the randomized Phase 3 CANDOR study of daratumumab in combination with Kd versus Kd 19,22 …”