Subcutaneous daratumumab plus standard treatment regimens in patients with multiple myeloma across lines of therapy (PLEIADES): an open‐label Phase II study

Abstract

Summary Daratumumab is a CD38‐targeting monoclonal antibody approved for intravenous (IV) infusion for multiple myeloma (MM). We describe the Phase II PLEIADES study of a subcutaneous formulation of daratumumab (DARA SC) in combination with standard‐of‐care regimens: DARA SC plus bortezomib/lenalidomide/dexamethasone (D‐VRd) for transplant‐eligible newly diagnosed MM (NDMM); DARA SC plus bortezomib/melphalan/prednisone (D‐VMP) for transplant‐ineligible NDMM; and DARA SC plus lenalidomide/dexamethasone (D‐Rd) for relapsed/refractory MM. In total, 199 patients were treated (D‐VRd, n = 67; D‐VMP, n = 67; D‐Rd, n = 65). The primary endpoints were met for all cohorts: the ≥very good partial response (VGPR) rate after four 21‐day induction cycles for D‐VRd was 71·6% [90% confidence interval (CI) 61·2–80·6%], and the overall response rates (ORRs) for D‐VMP and D‐Rd were 88·1% (90% CI 79·5–93·9%) and 90·8% (90% CI 82·6–95·9%). With longer median follow‐up for D‐VMP and D‐Rd (14·3 and 14·7 months respectively), responses deepened (ORR: 89·6%, 93·8%; ≥VGPR: 77·6%, 78·5%), and minimal residual disease–negativity (10‒5) rates were 16·4% and 15·4%. Infusion‐related reactions across all cohorts were infrequent (≤9·0%) and mild. The median DARA SC administration time was 5 min. DARA SC with standard‐of‐care regimens demonstrated comparable clinical activity to DARA IV–containing regimens, with low infusion‐related reaction rates and reduced administration time.

Monoclonal Antibodies to Treat Multiple Myeloma: A Dream Come True

“…The sc route of administration was not inferior to the iv route in terms of efficacy (ORR 41% vs. 37%, respectively), while safety was better with the sc route in terms of IRRs (13% vs. 34%). In the PLEIADES study, Dara sc added to SOC regimens showed a clinical activity similar to that of Dara iv-containing regimens, thus further confirming the superiority of the sc route also in combination regimens [68].…”

Monoclonal Antibodies and Antibody Drug Conjugates in Multiple Myeloma

“…The COLUMBA trial showed noninferiority of subcutaneous administration compared to intravenous administration of daratumumab as monotherapy for RRMM patients [65]. Following, PLEIADES study investigated various combination regimens with subcutaneous daratumumab (Dara-VMP, Dara-RD) [66]. In addition, a phase Ib clinical trial is evaluating the safety and tolerability of subcutaneous isatuximab (NCT04045795).…”

Exposure‐Response and Population Pharmacokinetic Analyses of a Novel Subcutaneous Formulation of Daratumumab Administered to Multiple Myeloma Patients

“…One patient (<1%) was positive for anti‐DARA antibodies with intravenous DARA, and no patients were positive with subcutaneous DARA; other clinical trials of intravenous DARA also reported low frequency of anti‐DARA antibodies (monotherapy, 0%; combination therapy, <1%) 17 . In the phase 2 PLEIADES study, subcutaneous DARA in combination with bortezomib, lenalidomide, and dexamethasone (D‐VRd) and bortezomib, melphalan, and prednisone (D‐VMP) in patients with newly diagnosed multiple myeloma and subcutaneous DARA in combination with lenalidomide and dexamethasone (D‐Rd) in patients with relapsed or refractory multiple myeloma demonstrated similar activity and safety to the corresponding historical data for intravenous DARA combination therapies, with lower rates of IRRs and a shorter duration of administration 23 . Based on the results from the COLUMBA and PLEIADES studies, a Biologics License Application was submitted for subcutaneous DARA in the United States; subcutaneous DARA was approved by the United States Food and Drug Administration in May 2020 followed by approvals in the European Union, Canada, South Korea, and Brazil 25…”