As reported in the Journal of Clinical Oncology by Pieter Sonneveld, MD, PhD, of Erasmus MC Cancer Institute, Rotterdam, the Netherlands, and colleagues, the final overall survival analysis of the phase III CASTOR trial has shown a significant benefit of the addition of daratumumab to bortezomib/dexamethasone (D-Vd) vs bortezomib/dexamethasone alone (Vd) in patients with relapsed or refractory multiple myeloma.1
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/dexamethasone in this setting.
Pieter Sonneveld, MD, PhD
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 the positive findings in the primary analysis and subsequent protocol amendment, patients receiving Vd were offered daratumumab monotherapy after disease progression or after a washout period if they were receiving subsequent therapy after disease progression. Patients had received a median of two prior lines of therapy (range = 1–10); prior therapies included bortezomib (65.5%), thalidomide (49.4%), lenalidomide (42.0%), and both a proteasome inhibitor and an immunomodulatory drug (48.4%).
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 of 251 patients (59.0%) in the D-Vd group and 171 of 247 patients (69.2%) 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 favored D-Vd for most subgroups, including 119 vs 122 patients aged 65 and older (median = 49.6 vs 36.1 months, HR = 0.64, 95% CI = 0.46–0.89); 122 vs 113 patients with one (median = not estimable vs 47.0 months, HR = 0.56, 95% CI = 0.39–0.80 ) and 70 vs 74 with two prior lines of therapy (median = 38.8 vs 33.5 months, HR = 0.87, 95% CI = 0.57–1.32); 59 vs 51 patients with International Staging System stage III disease (median = 21.6 vs 12.9 months, HR = 0.77, 95% CI = 0.48–1.24); 40 vs 35 patients with high-risk cytogenetic abnormalities (median = 38.4 vs 28.8 months, HR = 0.77, 95% CI = 0.41–1.46); and 162 vs 164 patients with prior bortezomib treatment (median = 42.2 vs 33.5 months, HR = 0.81, 95% CI = 0.62–1.07). Measurable residual disease (MRD)-negative status (10-5 threshold) was achieved in 15.1% vs 1.6% of patients (P < .0001). MRD negativity was associated with improved overall survival among all patients.
Overall, 161 of 243 patients (66.3%) in the D-Vd group and 200 of 237 patients (84.4%) in the Vd group received subsequent anticancer therapies (median = 2 vs 3, range = 1–9 vs 1–10). Median time to subsequent therapy was 25.4 vs 9.7 months (HR = 0.27, 95% CI = 0.21–0.34, P < .0001). The most common subsequent therapies included dexamethasone (59.3%), lenalidomide (39.9%), cyclophosphamide (28.0%), pomalidomide (23.0%), carfilzomib (21.0%), and bortezomib (19.8%) in the D-Vd group and dexamethasone (66.2%), daratumumab (52.7%), lenalidomide (46.0%), cyclophosphamide (33.8%), pomalidomide (32.1%), carfilzomib (24.9%), and bortezomib (23.2%) in the Vd group. Median progression-free survival-2 (time from random assignment to disease progression on the next line of therapy) was 37.7 vs 19.9 months (HR = 0.43, 95% CI = 0.34–0.54, 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 the time of analysis, with median overall survival of 63.4 months (95% CI = 51.2–72.4 months).
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. Serious adverse events occurred in 55.1% vs 34.2%, most commonly pneumonia (10.7% vs 10.1%). Adverse events led to discontinuation of treatment in 10.7% vs 9.3%. With extended follow-up, second primary malignancies (cutaneous, invasive, and hematologic) 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%). One patient in the D-Vd group and two in the Vd group died of COVID-19 infection.
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].”
DISCLOSURE: The study was supported by Janssen Research & Development, LLC. Dr. Sonneveld has served as a consultant or advisor to Celgene, Janssen, Amgen, Karyopharm Therapeutics, and CARsgen Therapeutics; and has received institutional research funding from Janssen, Amgen, Skyline Dx, and Bristol Myers Squibb/Celgene.
1. Sonneveld P, Chanan-Khan A, Weisel K, et al: Overall survival with daratumumab, bortezomib, and dexamethasone in previously treated multiple myeloma (CASTOR): A randomized, open-label, phase III trial. J Clin Oncol. November 22, 2022 (early release online).