In an updated analysis of the pivotal phase III CANDOR trial reported in The Lancet Oncology, Saad Z. Usmani, MD, of Levine Cancer Institute/Atrium Health, and colleagues found that the addition of daratumumab to carfilzomib and dexamethasone (KdD) continued to show a large progression-free survival benefit in patients with relapsed or refractory multiple myeloma.¹

The primary analysis of the trial supported the August 2020 approval of carfilzomib and daratumumab for use in combination with dexamethasone for treatment of adults with relapsed or refractory multiple myeloma who have received one to three lines of therapy.

Study Details

In the open-label trial, 466 patients with at least a partial response to one to three prior lines of therapy from sites in 19 countries across North America, Europe, Australia, and Asia were randomly assigned between June 2017 and June 2018 to receive KdD (n = 312) or carfilzomib/dexamethasone (Kd; n = 154). Stratification factors included International Staging System (ISS) stage, previous proteasome inhibitor exposure, and number of previous lines of therapy.

Saad Z. Usmani, MD

All patients received carfilzomib twice per week at 56 mg/m² (20 mg/m² on days 1 and 2 during cycle 1) on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle. Daratumumab at 8 mg/kg was given on days 1 and 2 of cycle 1 and at 16 mg/kg weekly for the remaining doses of the first two cycles and then every 2 weeks in cycles 3 through 6 and every 4 weeks thereafter. All patients received dexamethasone at 40 mg weekly (20 mg for patients older than age 75). Treatment was continued until patients exhibited disease progression or unacceptable toxicity.

For the KdD vs Kd groups, ISS stage was I in 47% vs 51%, II in 33% vs 31%, and III in 20% vs 18%. The number of previous therapies was one in 46% vs 45% and two to three in 54% vs 55%. Of these patients, 92% vs 87% had prior bortezomib exposure, and 28% vs 31% were refractory to prior bortezomib; 39% vs 48% had prior lenalidomide exposure, and 32% vs 36% were refractory to prior lenalidomide; and 66% vs 71% had prior immunomodulatory drug exposure, and 42% vs 42% were refractory to the immunomodulatory drug.

The primary analysis of the trial showed median progression-free survival of not reached in the KdD group vs 15.8 months in the Kd group (hazard ratio [HR] = 0.63, 95% confidence interval [CI] = 0.46–0.85, P = .0027) after a median follow-up of 16.9 months. The current analysis presents findings after approximately 27 months of follow-up. The analysis was a preplanned interim analysis for overall survival; however, overall survival rates were not mature at the time of data cutoff (June 2020).

Progression-Free Survival

Median follow-up was 27.8 months (interquartile range [IQR] = 25.6–29.5 months) in the KdD group and 27.0 months (IQR = 13.2–28.6 months) in the Kd group. At data cutoff, 71% of the KdD group and 81% of the Kd group had discontinued carfilzomib and 63% of the KdD group had discontinued daratumumab. Median study treatment duration was 18.3 months (IQR = 6.5–28.0 months) in the KdD group and 9.3 months (IQR = 3.5–21.5 months) in the Kd group.

Median progression-free survival was 28.6 months (95% CI = 22.7 months to not estimable) in the KdD group vs 15.2 months (95% CI = 11.1–19.9 months) in the Kd group (HR = 0.59, 95% CI = 0.45–0.78, P < .0001).

In stratification subgroup analyses, median progression-free survival was not reached vs 15.8 months (HR = 0.60, 95% CI = 0.44–0.81) for ISS stage I to II and 13.0 vs 7.4 months (HR = 0.57, 95% CI = 0.32–1.03) for stage III; not reached vs 21.3 months (HR = 0.66, 95% CI = 0.42–1.04) for one prior treatment and 24.2 vs 12.5 months (HR = 0.55, 95% CI = 0.39–0.78) for two to three prior treatments; and 27.4 vs 14.6 months (HR = 0.57, 95% CI = 0.43–0.76) for prior bortezomib or ixazomib exposure and not reached vs not reached (HR = 0.79, 95% CI = 0.27–2.34) for no prior exposure.

In other subgroup analyses, median progression-free survival was not reached vs 16.6 months (HR = 0.58, 95% CI = 0.40–0.82) and 13.1 vs 8.7 months (HR = 0.65, 95% CI = 0.42–1.00) for not refractory vs refractory to bortezomib or ixazomib; 25.9 vs 11.1 months (HR = 0.49, 95% CI = 0.33–0.74) for prior lenalidomide exposure and not reached vs 21.3 months (HR = 0.64, 95% CI = 0.43–0.95) for no prior exposure; 28.6 vs 19.9 months (HR = 0.63, 95% CI = 0.44–0.90) and 28.1 vs 11.1 months (HR = 0.46, 95% CI = 0.28–0.73) for not refractory vs refractory to lenalidomide; 25.9 vs 12.5 months (HR = 0.60, 95% CI = 0.44–0.83) and not reached vs 22.2 months (HR = 0.52, 95% CI = 0.30–0.91) for prior vs no prior immunomodulatory drug exposure; and not reached vs 21.3 months (HR = 0.68, 95% CI = 0.47–1.00) and 25.9 vs 9.3 months (HR =0.48, 95% CI = 0.32–0.73) for not refractory vs refractory to the immunomodulatory drug.

At data cutoff, 89 patients (29%) in the KdD group and 51 patients (33%) in the Kd group had died.

Adverse Events

Adverse events were consistent with those reported in the primary analysis. Grade ≥ 3 adverse events occurred in 87% of patients in the KdD group vs 76% of those in the Kd group; the most common adverse events in the KdD group were thrombocytopenia (25% vs 16% in the Kd group), hypertension (21% vs 15%), pneumonia (18% vs 9%), and anemia (17% vs 15%). Serious adverse events occurred in 63% vs 50% of patients. Adverse events led to study treatment discontinuation in 28% vs 25% of patients, including discontinuation of carfilzomib in 26% vs 22%. Adverse events led to death in 9% vs 5% of patients, the most common causes being septic shock (2% vs 1%) and pneumonia (1% vs 0%). No treatment-related deaths were observed since the primary analysis.

The investigators concluded: “A clear, maintained progression-free survival benefit of KdD over Kd with longer follow-up was confirmed, making KdD an emerging standard-of-care for patients with relapsed or refractory multiple myeloma.” 

DISCLOSURE: The study was funded by Amgen and Janssen. Dr. Usmani has received research funding from Amgen, Array Biopharma, BMS, Celgene, GSK, Janssen, Merck, Pharmacyclics, Sanofi, Seattle Genetics, SkylineDX, and Takeda; has served as a consultant for Abbvie, Amgen, BMS, Celgene, EdoPharma, Genentech, Gilead, GSK, Janssen, Oncopeptides, Sanofi, Seattle Genetics, SecuraBio, SkylineDX, Takeda, and TeneoBio; and served as a speaker for Amgen, BMS, Janssen, and Sanofi.

REFERENCE

1. Usmani SZ, Quach H, Mateos M-V, et al: Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma (CANDOR): Updated outcomes from a randomised, multicentre, open-label, phase 3 study. Lancet Oncol 23:65-76, 2022.