Overall Survival With Daratumumab, Bortezomib, and Dexamethasone in Previously Treated Multiple Myeloma (CASTOR): A Randomized, Open-Label, Phase III Trial

Abstract

Purpose: At the primary analysis of CASTOR (median follow-up, 7.4 months), daratumumab plus bortezomib and dexamethasone (D-Vd) significantly prolonged progression-free survival versus bortezomib and dexamethasone (Vd) alone in relapsed or refractory multiple myeloma (RRMM). We report updated efficacy and safety results at the final analysis for overall survival (OS).

Methods: CASTOR was a multicenter, randomized, open-label, phase III study during which eligible patients with ≥ 1 line of prior therapy were randomly assigned to Vd (up to eight cycles) with or without daratumumab (until disease progression). After positive primary analysis and protocol amendment, patients receiving Vd were offered daratumumab monotherapy after disease progression.

Results: At a median (range) follow-up of 72.6 months (0.0-79.8), significant OS benefit was observed with D-Vd (hazard ratio, 0.74; 95% CI, 0.59 to 0.92; P = .0075). Median OS was 49.6 months with D-Vd versus 38.5 months with Vd. Prespecified subgroup analyses demonstrated an OS advantage with D-Vd versus Vd for most subgroups, including patients age ≥ 65 years and patients with one or two prior lines of therapy, International Staging System stage III disease, high-risk cytogenetic abnormalities, and prior bortezomib treatment. The most common (≥ 10%) grade 3/4 treatment-emergent adverse events with D-Vd versus Vd were thrombocytopenia (46.1% v 32.9%), anemia (16.0% v 16.0%), neutropenia (13.6% v 4.6%), lymphopenia (10.3% v 2.5%), and pneumonia (10.7% v 10.1%).

Conclusion: D-Vd significantly prolonged OS in patients with RRMM, with the greatest OS benefit observed in patients with one prior line of therapy. To our knowledge, our results, together with the OS benefit observed with daratumumab plus lenalidomide and dexamethasone in the phase III POLLUX study, demonstrate for the first time an OS benefit with daratumumab-containing regimens in RRMM (ClinicalTrials.gov identifier: NCT02136134 [CASTOR]).

FIG 1.

CONSORT diagram for CASTOR.

FIG 2.

Kaplan–Meier estimates of (A) OS and (B) PFS2 in the ITT population, which included all patients who underwent random assignment. D-Vd, daratumumab, bortezomib, and dexamethasone; HR, hazard ratio; ITT, intention-to-treat; OS, overall survival; PFS2, progression-free survival on the subsequent line of therapy; Vd, bortezomib and dexamethasone.

FIG 3.

The results of OS in prespecified subgroups of the ITT population defined by baseline characteristics. The ISS disease stage is derived on the basis of the combination of serum β₂-microglobulin and albumin levels. Higher stages indicate more severe disease. Cytogenetic risk was assessed locally by fluorescence in situ hybridization or karyotype testing; high risk was defined as the presence of t(4;14), t(14;16), or del17p. The subgroup analysis of the type of MM was performed on data from patients who had measurable disease in serum. CrCl, creatinine clearance; D-Vd, daratumumab, bortezomib, and dexamethasone; ECOG PS, Eastern Cooperative Oncology Group performance status; EU, European Union; HR, hazard ratio; IgG, immunoglobulin G; IMiD, immunomodulatory drug; ISS, International Staging System; ITT, intention-to-treat; MM, multiple myeloma; NE, not estimable; OS, overall survival; Vd, bortezomib and dexamethasone.

FIG 4.

Kaplan–Meier estimates of OS by MRD status among patients in the ITT population. D-Vd, daratumumab, bortezomib, and dexamethasone; ITT, intention-to-treat; MRD, minimal residual disease; OS, overall survival; Vd, bortezomib and dexamethasone.