Daratumumab With Standard Regimen Improves PFS in Multiple Myeloma, Independent of Cytogenetic Risk

In August 2016, daratumumab (Darzalex), was granted breakthrough designation as second-line treatment for use in combination with either lenalidomide (Revlimid) and dexamethasone (DRd regimen, POLLUX trial) or bortezomib (Velcade) and dexamethasone (DVd regimen, CASTOR trial) for patients with relapsed, refractory multiple myeloma (RRMM) who have received at least 1 prior therapy. Now, updated trial results, presented at the 2017 American Society of Clinical Oncology Annual Meeting, have found that the combination regimens in both trials prolonged progression-free survival (PFS) and improved the depth of response, independent of the patients’ cytogenetic risk.

Daratumumab is a human monoclonal antibody that targets CD38, a cell-surface receptor overexpressed in multiple myeloma, resulting in complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, and antibody-dependent cellular phagocytosis. Knowing the efficacy of the DRd and DVd regimens, the authors examined their efficacy among RRMM patients with standard or high cytogenetic risk status.

Bone marrow aspirates for patients who participated in the open-label, multicenter, active-controlled, randomized POLLUX and CASTOR studies were collected at screening and assessed centrally via next generation sequencing (NGS). Patients with high-risk cytogenetics included those who had at least 1 of the following translocations or deletions: t(4;14), t(14;16), or del17p. Patients at standard risk were defined as those confirmed negative for these abnormalities. The trial evaluated progression-free survival (PFS) and overall response rate (ORR).

Three-hundred and eleven patient samples were analyzed via NGS from the POLLUX trial and 353 from the CASTOR trial. At a median follow-up of 25.4 months, 65% of patients receiving DRd in the intention-to-treat (ITT) population in the POLLUX trial had a median PFS of 24 months compared with 41% of the control Rd population who had a median PFS of 17.5 months (Hazard ratio [HR], 0.41; 95% CI, 0.31 to 0.53; P<.0001). Among patients who had received 1 prior line of therapy, the median PFS was not reached in 79% of the cohort receiving DRd, compared with 19.6 months PFS in 40% of those treated with Rd (HR, 0.39; 95% CI, 0.26 to 0.58; P<.0001).

At the end of a 19.4-month follow-up period for the CASTOR trial, 49% of patients receiving DVd had a median PFS of 18.7 months, compared with 8% patients treated with Vd who had a median PFS of 7.1 months (HR, 0.31; 95% CI, 0.24 to 0.39; P<.0001). For patients who had received 1 prior line of therapy, median PFS was not reached in 60% of patients in the DVd arm, compared with a median PFS of 7.9 months in 12% of patients in the Vd arm (HR, 0.19; 95% CI, 0.12 to 0.29; P<.0001).

Cytogenetic risk analysis in patients enrolled in the POLLUX study showed that DRd improved median PFS to 22.6 months in the high-risk patient population, compared with 18.2 months in the Rd arm (HR, 0.53; 95% CI, 0.25 to 1.13; P =.0021). Median PFS was not reached in the standard risk patients treated with DRd, compared with PFS of 18.5 months in those receiving Rd (HR, 0.30; 95% CI, 0.20 to 0.47; P<.0001).

Similarly, the median PFS for high-risk patients in the CASTOR study was 11.2 months in the DVd arm, compared with 7.2 months in the Vd arm (HR, 0.45; 95% CI, 0.25 to 0.80; P =.0053). In the standard risk patients, including daratumumab improved median PFS to 19.6 months, compared with 7.9 months with Vd (HR, 0.26; 95% CI, 0.18 to 0.37; P<.0001).

Based on their results, the authors concluded that daratumumab included in standard-of-care regimens in RRMM prolongs PFS and improves the depth of response regardless of cytogenetic risk. Longer-term survival results are awaited for both trials.