Combining the anti-CD38 antibody daratumumab with lenalidomide and dexamethasone led to a lower risk of disease progression and death, compared with lenalidomide and dexamethasone alone, according to results from the phase III POLLUX trial of patients with relapsed/refractory multiple myeloma (RRMM).
"Daratumumab induced deep responses when combined with standard of care, more than doubling rates of complete response in these previously treated patients," POLLUX investigator Meletios A. Dimopoulos, MD, from the National and Kapodistrian University of Athens School of Medicine in Greece, said during his presentation of the results at the European Hematology Association's 21st Congress. "These striking results underscore the potential clinical benefit of daratumumab as a backbone treatment option for patients who had received one or more prior lines of therapy."
The open-label, randomized POLLUX trial compared safety and efficacy of lenalidomide and dexamethasone with or without daratumumab in 569 patients with RRMM (median age = 65 years) who had received one or more prior therapies, were not refractory to previous lenalidomide, and had a creatinine clearance â‰¥30 mL/min. Patients were randomized 1:1 to receive either:
- daratumumab 16 mg/kg (administered once weekly for 8 weeks, once every 2 weeks for 16 weeks, then once every 4 weeks until disease progression) plus lenalidomide 25 mg (administered orally on days 1-21 of each 28-day cycle) and dexamethasone 40 mg administered weekly (DRd; n=286)
- lenalidomide and dexamethasone alone in the same dosing and schedule (Rd; n=283)
Patients in the Rd arm could receive daratumumab if their disease had progressed.
Patients were treated with a median of one prior line of therapy (range = 1-11 therapies); 19 percent were treated with three or more prior therapies. Most patients (86%) were treated with a proteasome inhibitor (PI), while 55 percent received a prior immunomodulatory drug (IMiD). Eighteen percent were treated previously with lenalidomide, while 44 percent received both a PI and IMiD. Overall, 27 percent of patients were refractory to the most recent line of therapy, with 18 percent refractory to a PI.
After a median follow-up of 13.5 months, DRd significantly improved patients' median progression-free survival (PFS; primary endpoint): the median PFS in the DRd group was not reached, compared with 18.4 months in the Rd arm (p<0.0001), translating to a 63 percent reduced risk of disease progression or death compared with Rd (hazard ratio = 0.37; 95% CI 0.27-0.52; p<0.0001). Pre-specified subgroup analyses demonstrated that the PFS benefit with daratumumab was consistent among patient subgroups.
Similarly, overall survival at 18 months (a secondary endpoint) was higher for daratumumab-treated patients: 86 percent for DRd and 76 percent for Rd.
In addition to meeting the primary endpoint of improved PFS, daratumumab led to a higher overall response rate (ORR; secondary endpoint), more than doubling the rate of complete responses or better:
- ORR: 93% vs. 76% (p<0.0001)
- very good partial response or better: 76% vs. 44% (p<0.0001)
- complete response or better: 43% vs. 19% (p<0.0001)
The median duration of response was longer in the DRd group (not reached vs. 17.4 months) and the median time to response was shorter (1 month vs. 1.3 months), though p values were not provided.
The most common treatment-related adverse events (AEs; occurring in <25% of patients) in the DRd and Rd groups included neutropenia (59% vs. 43%), diarrhea (43% vs. 25%), fatigue (35% vs. 28%), upper respiratory tract infection (32% vs. 21%), anemia (31% vs. 35%), constipation (29% vs. 25%), cough (29% vs. 13%), thrombocytopenia (27% for each), and muscle spasms (26% vs. 19%). Grade 3/4 infections occurred in 28 percent of DRd-treated patients and 23 percent of Rd-treated patients – the most common of which was pneumonia (8% for each treatment arm).
Infusion-related reactions occurred in 48 percent of DRd-treated patients during the first infusion and were mostly grade 1/2.Treatment discontinuation due to AEs (n=198) was similar between the DRd and Rd groups (7% vs. 8%), the investigators noted.
Daratumumab is also being studied as a treatment option for RRMM in the randomized, controlled, phase III CASTOR trial, where it is combined with bortezomib and dexamethasone in an all-oral triplet regimen. Results from CASTOR presented at the 2016 ASCO Annual Meeting showed that daratumumab again extended PFS and time to progression, providing "unprecedented" results in this setting.
Dimopoulos MA, Oriol A, Nahi H, et al. An open-label, randomised phase 3 study of daratumumab, lenalidomide, and dexamethasone (DRF) versus lenalidomide and dexamethasone (RD) in relapsed or refractory multiple myeloma (RRMM): POLLUX. Abstract LB2238. Presented at the EHA 21st Congress, June 10, 2016; Copenhagen, Denmark.