In an analysis of the phase III POLLUX and CASTOR trials reported in the Journal of Clinical Oncology, Avet-Loiseau et al found that the addition of daratumumab to standard therapy was associated with higher rates of—and more prolonged—measurable residual disease (MRD) negativity in patients with relapsed or refractory multiple myeloma. Moreover, this effect was associated with prolonged progression-free survival.
In the previously reported primary analyses, the addition of daratumumab to lenalidomide/dexamethasone (D-Rd) in the POLLUX trial and to bortezomib/dexamethasone (D-Vd) in the CASTOR trial significantly improved progression-free survival.
“Daratumumab-based combinations induce higher rates of sustained MRD negativity vs standard of care, which are associated with durable remissions and prolonged clinical outcomes.”— Avet-Loiseau et al
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Study Details
In the trials, MRD was assessed by next-generation sequencing (10−5) at suspected complete response; 3 and 6 months following confirmed complete response (POLLUX); 6 and 12 months following the first dose (CASTOR); and every 12 months post–complete response in both studies. Sustained MRD negativity (≥ 6 or ≥ 12 months) was evaluated in the intention-to-treat (ITT) and complete response or better populations.
Key Findings
Median follow-up was 54.8 months in POLLUX and 50.2 months in CASTOR. In the ITT population, MRD negativity rates were 32.5% vs 6.7% for D-Rd vs Rd and 15.1% vs 1.6% for D-Vd vs Vd (P < .0001 for both). Among patients with complete response or better, MRD negativity rates were 57.4% with D-Rd vs 29.2% with Rd (P = .0001) and 52.8% with D-Vd vs 17.4% with Vd (P = .0035).
In the ITT population, more patients had MRD negativity sustained for ≥ 6 months with D-Rd vs Rd (20.3% vs 2.1%, P < .0001) and D-Vd vs Vd (10.4% vs 1.2%, P < .0001). For ≥ 12 months, rates with D-Rd vs Rd were 16.1% vs 1.4% (P < .0001), and for D-Vd vs Vd, rates were 6.8% vs 0% (P < .0001).
Among patients with complete response or better, more patients had MRD negativity sustained for ≥ 6 months with D-Rd vs Rd (35.8% vs 9.2%, P <.0001) and D-Vd vs Vd (36.1% vs 13.0%, P = .0404) and for ≥ 12 months with D-Rd vs Rd (28.4% vs 6.2%, P = .0001) and D-Vd vs Vd (23.6% vs 0%, P = .0098).
In both studies, progression-free survival was significantly prolonged in patients who had MRD negativity sustained for ≥ 6 months vs MRD-positive patients, irrespective of treatment group. Progression-free survival was significantly prolonged among patients receiving daratumumab-containing regimens who sustained MRD negativity for ≥ 12 months vs all MRD-positive patients.
Among all patients, those who achieved MRD negativity and had complete response or better had significantly prolonged progression-free survival vs those with MRD positivity and less than complete response (hazard ratio = 0.20, P < .0001). In pooled analysis, progression-free survival was significantly prolonged among patients receiving daratumumab-containing regimens who achieved MRD negativity and had complete response or better vs patients who received comparator regimens with MRD negativity and complete response or better (HR = 0.51, P = .0358).
The investigators concluded, “Daratumumab-based combinations induce higher rates of sustained MRD negativity vs standard of care, which are associated with durable remissions and prolonged clinical outcomes.”
Hervé Avet-Loiseau, MD, of the Unite de Genomique du Myelome, IUC-Oncopole, Toulouse, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by Janssen Research and Development, LLC. For full disclosures of the study authors, visit ascopubs.org.
