As reported in the Journal of Clinical Oncology by Sonneveld et al, the final overall survival analysis of the phase III CASTOR trial has shown a significant overall survival benefit with daratumumab plus bortezomib/dexamethasone (D-Vd) vs bortezomib/dexamethasone alone (Vd) in patients with relapsed or refractory multiple myeloma.

The primary analysis from the trial (median follow-up = 7.4 months) showed that D-Vd significantly prolonged progression-free survival and supported the November 2016 approval of daratumumab in combination with bortezomib and dexamethasone in this setting.

Study Details

In the international open-label trial, 498 patients who had received at least one line of prior therapy were randomly assigned between September 2014 and September 2015 to receive D-Vd (n = 251) or Vd (n = 247). All patients received up to eight 21-day cycles of Vd as bortezomib at 1.3 mg/m² subcutaneously on days 1, 4, 8, and 11 and dexamethasone at 20 mg orally or intravenously on days 1, 2, 4, 5, 8, 9, 11, and 12. Daratumumab at 16 mg/kg was given on days 1, 8, and 15 in cycles 1 to 3, once every 3 weeks on day 1 in cycles 4 to 8, and once every 4 weeks thereafter until disease progression or unacceptable toxicity. After a protocol amendment, patients in the Vd group were offered daratumumab monotherapy after disease progression.  

Overall Survival Analysis

At clinical cutoff for the final analysis (in June 2021), with a median follow-up of 72.6 months (range = 0.0–79.8) months, 148 (59.0%) of 251 patients in the D-Vd group and 171 (69.2%) of 247 patients in the Vd group had died. Median overall survival was 49.6 months (95% confidence interval [CI] = 42.2–62.3 months) in the D-Vd group vs 38.5 months (95% CI = 31.2–46.2 months) in the Vd group (hazard ratio [HR] = 0.74, 95% CI = 0.59–0.92, P = .0075).

Prespecified subgroup analyses showed that hazard ratios s favored D-Vd for most subgroups, including: 

• Patients aged ≥ 65 years (HR = 0.64, 95% CI = 0.46–0.89)
• Those with one (HR = 0.56, 95% CI = 0.39–0.80) and with two prior lines of therapy (HR = 0.87, 95% CI = 0.57–1.32)
• Those with International Staging System stage III disease (HR = 0.77, 95% CI = 0.48–1.24)
• Those with high-risk cytogenetics (HR = 0.77, 95% CI = 0.41–1.46)
• Those who had previously received bortezomib (HR = 0.81, 95% CI = 0.62–1.07).

Overall, 161 (66.3%) of 243 patients in the D-Vd group and 200 (84.4%) of 237 in the Vd group received subsequent anticancer therapies (median = two vs three); a total of 52.7% of patients in the Vd group received subsequent daratumumab. Median progression-free survival-2 was 37.7 vs 19.9 months (HR= 0.43, P < .0001). Among 87 patients in the Vd group who crossed over to daratumumab monotherapy after disease progression according to protocol, 35 (40.2%) were alive at time of analysis, with a median overall survival of 63.4 months (95% CI = 51.2–72.4 months).

Adverse Events

No new safety concerns were identified with the longer follow-up. The most common grade 3 or 4 adverse events in the D-Vd group were thrombocytopenia (46.1% vs 32.9% in Vd group), anemia (16.0% vs 16.0%), neutropenia (13.6% vs 4.6%), pneumonia (10.7% vs 10.1%), and lymphopenia (10.3% vs 2.5%). Grade 3 or 4 infections occurred in 29.6% vs 19.0% of patients. With extended follow-up, second primary malignancies occurred in 20 patients (8.2%) vs 5 patients (2.1%); after adjustment for exposure to study treatment, the rate of second primary malignancies was 0.35 vs 0.46 events per 100 patient-months at risk. Adverse events led to death in 17 patients (7.0%) in the D-Vd group and 14 patients (5.9%) in the Vd group, with the most common causes being pneumonia (0.8% in each group) and general physical health deterioration (0.4% vs 1.3%).

The investigators concluded, “D-Vd significantly prolonged overall survival in patients with relapsed or refractory multiple myeloma, with the greatest overall survival benefit observed in patients with one prior line of therapy. To our knowledge, our results, together with the overall survival benefit observed with daratumumab plus lenalidomide and dexamethasone in the phase III POLLUX study, demonstrate for the first time an overall survival benefit with daratumumab-containing regimens in relapsed or refractory multiple myeloma.”

Pieter Sonneveld, MD, PhD, of Erasmus MC Cancer Institute, Rotterdam, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by Janssen Research & Development, LLC. For full disclosures of the study authors, visit ascopubs.org.