Daratumumab Regimen Maintains Favorable Performance in Relapsed/Refractory Myeloma

Meletios Dimopoulos, MD

Progression-free survival (PFS) remained superior over time in patients with relapsed/refractory multiple myeloma treated (RRMM) treated with combination therapy that included the anti-CD38 antibody daratumumab (Darzalex), according to an updated analysis of the POLLUX trial.

After a median follow-up approaching 3 years, the median PFS had yet to be reached among patients treated with daratumumab, lenalidomide, and dexamethasone (DRd). In contrast, patients who received just lenalidomide and dexamethasone (Rd) had a median PFS of 17.5 months.

The magnitude of the risk reduction for death or progression remained steady as compared with findings from an initial analysis performed after 14 months of follow-up. The proportion of patients who achieved minimum residual disease (MRD) negativity was more than three times greater in the DRd group, as reported at the 2017 ASH Annual Meeting

“DRd continues to significantly improve progression-free survival with longer follow-up,” said Meletios Dimopoulos, MD, chair of clinical therapeutics at the University of Athens in Greece. “DRd induces deep and durable responses, and more patients receiving DRd achieved MRD negativity versus Rd. MRD negativity occurs more rapidly with DRd and increases over time. DRd does not negatively impact outcomes of subsequent therapy.”

The safety profile remained unchanged with longer follow-up, he added.

The report extended favorable preliminary data from the multicenter, randomized phase III POLLUX trial that evaluated lenalidomide and dexamethasone with or without daratumumab. In initial results, treatment with DRd reduced the hazard for disease progression or death by 63% compared with Rd.

The updated analysis showed a 30-month PFS of 58% with DRd and 35% with Rd. The difference in median PFS values translated into a 56% reduction in the hazard for progression or death (P <.0001). The large difference emerged even though the 17.5-month median PFS for the comparator was “one of the best PFS ever reported for lenalidomide and dexamethasone,” said Dimopoulos.

DRd induced an overall response rate (ORR) of 93%. More than half of patients (56%) had complete response (CR), compared with 43% in the initial data analysis. Patients randomly assinged to Rd had an ORR of 76% (P <.0001) and 23% had CR, compared with 19% the first analysis.

Analysis of MRD status showed a significant (P <.0001) advantage for DRd, regardless of the definition applied to MRD: 1 cell in 10^-4 (36% vs 9%), 1 in 10^-5 (27% vs 5%), or 1 in 10^-6 (6% vs 0.4%).

PFS improved with depth of response, as patients who achieved MRD negativity had the best PFS, said Dimopoulos. The time to MRD negativity (10^-5) was substantially shorter with DRd than Rd, and the magnitude of difference in MRD negativity increased over time.

Patients also initiated next therapy sooner with Rd than DRd. The median time to next therapy had yet to be reached in the daratumumab arm as compared with a median of 22.3 months with Rd (HR, 0.37; 95% CI, 0.29-0.48; P <.0001).

The PFS advantage with DRd persisted into the subsequent line of therapy (PFS2), Dimopoulos continued. The 30-month PFS2 with DRd was 73% versus 58% for Rd (HR, 0.51; 95% CI, 0.38-0.67; P <.0001). The median PFS2 had yet to be reached among patients randomized to daratumumab, as compared with 32.3 months for patients in the Rd arm.

The safety profile varied minimally between the initial and follow-up analyses. Patients randomized to DRd remained on therapy for a median duration of 30.4 months as compared with 16.0 months for Rd. Discontinuation because of treatment-emergent adverse events (TEAEs) was 13% in both groups.

DRd was associated with more all-grade neutropenia (62% vs 47%), diarrhea (56% vs 34%), upper respiratory tract infection (41% vs 27%), cough (34% vs 15%), nausea (27% vs 18%), and pneumonia (24% vs 16%). Grade 3/4 infections occurred in 39% of the DRd arm and 26% of the Rd group.

“These updated findings continue to support the use of DRd in patients with relapsed and refractory multiple myeloma,” Dimopoulos concluded.

Dimopoulos MA, White DJ, Benboubker L, et al. Daratumumab, lenalidomide, and dexamethasone (drd) versus lenalidomide and dexamethasone (rd) in relapsed or refractory multiple myeloma (RRMM): updated efficacy and safety analysis of POLLUX. Presented at: American Society of Hematology 59th Annual meeting; December 9-12, 2017; Atlanta, GA. Abstract 739.