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

Abstract

Purpose: With the initial analysis of POLLUX at a median follow-up of 13.5 months, daratumumab in combination with lenalidomide and dexamethasone (D-Rd) significantly prolonged progression-free survival versus lenalidomide and dexamethasone (Rd) alone in patients with relapsed or refractory multiple myeloma (RRMM). We report updated efficacy and safety results at the time of final analysis for overall survival (OS).

Methods: POLLUX was a multicenter, randomized, open-label, phase III study during which eligible patients with ≥ 1 line of prior therapy were randomly assigned 1:1 to D-Rd or Rd until disease progression or unacceptable toxicity. After positive primary analysis and protocol amendment, patients receiving Rd were offered daratumumab monotherapy after disease progression.

Results: Significant OS benefit was observed with D-Rd (hazard ratio, 0.73; 95% CI, 0.58 to 0.91; P = .0044) at a median (range) follow-up of 79.7 months (0.0-86.5). The median OS was 67.6 months for D-Rd compared with 51.8 months for Rd. Prespecified analyses demonstrated an improved OS with D-Rd versus Rd in most subgroups, including patients age ≥ 65 years and patients with one, two, or three prior lines of therapy, International Staging System stage III disease, high-risk cytogenetic abnormalities, and refractoriness to their last prior line of therapy or a proteasome inhibitor. The most common (≥ 10%) grade 3/4 treatment-emergent adverse events with D-Rd versus Rd were neutropenia (57.6% v 41.6%), anemia (19.8% v 22.4%), pneumonia (17.3% v 11.0%), thrombocytopenia (15.5% v 15.7%), and diarrhea (10.2% v 3.9%).

Conclusion: D-Rd significantly extended OS versus Rd alone in patients with RRMM. To our knowledge, for the first time, our findings, together with the OS benefit observed with daratumumab plus bortezomib and dexamethasone in the phase III CASTOR trial, demonstrate OS improvement with daratumumab-containing regimens in RRMM (ClinicalTrials.gov identifier: NCT02076009 [POLLUX]).

FIG 1.

CONSORT diagram for POLLUX.

FIG 2.

Kaplan-Meier estimates of (A) OS and (B) PFS2 in the ITT population, which included all patients who underwent random assignment. D-Rd, daratumumab, lenalidomide, and dexamethasone; HR, hazard ratio; ITT, intention-to-treat; OS, overall survival; PFS2, progression-free survival on the subsequent line of therapy; Rd, lenalidomide 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. CA, Canada; CrCl, creatinine clearance; D-Rd, daratumumab, lenalidomide, and dexamethasone; ECOG PS, Eastern Cooperative Oncology Group performance status; EU, European Union; HR, hazard ratio; IgG, immunoglobulin G; ISS, International Staging System; ITT, intention-to-treat; MM, multiple myeloma; NE, not estimable; OS, overall survival; PI, proteasome inhibitor; Rd, lenalidomide and dexamethasone.

FIG 4.

Kaplan–Meier estimates of OS by MRD status (10^–5) among patients in the ITT population. D-Rd, daratumumab, lenalidomide, and dexamethasone; ITT, intention-to-treat; MRD, minimal residual disease; OS, overall survival; Rd, lenalidomide and dexamethasone.