Subcutaneous Daratumumab Plus Standard Treatment Regimens in Patients with Multiple Myeloma across Lines of Therapy: Pleiades Study Update

Abstract

Introduction : Daratumumab (DARA) 16 mg/kg intravenous (IV) is approved as monotherapy for relapsed or refractory multiple myeloma (RRMM) and in combination with standard-of-care regimens for transplant-ineligible newly diagnosed multiple myeloma (NDMM). A subcutaneous (SC) co-formulation of DARA (DARA SC; 1,800 mg) with recombinant human hyaluronidase PH20 (rHuPH20; ENHANZE® drug delivery technology, Halozyme, Inc.) is under investigation in a number of ongoing studies. In the phase 3 COLUMBA study, DARA SC was shown to be noninferior to DARA IV, demonstrating similar efficacy and pharmacokinetics (PK), with a significantly decreased rate of infusion-related reactions (IRRs) and reduced administration time (median, 5 minutes; Mateos MV, et al. J Clin Oncol. 2019). This phase 2, open-label, multicenter study (PLEIADES) assessed the efficacy and safety of DARA SC combined with bortezomib, lenalidomide, and dexamethasone (D-VRd) and bortezomib, melphalan, and prednisone (D-VMP) in patients with NDMM, and combined with lenalidomide and dexamethasone (D-Rd) in patients with RRMM. The primary analysis of PLEIADES is to be presented at an upcoming meeting; here, we report updated results with longer follow-up. Methods: Transplant-ineligible NDMM patients received DARA SC (QW for Cycle 1 and Q3W for Cycles 2-9 in 42-day cycles, and Q4W for Cycles 10+ in 28-day cycles until disease progression) in combination with VMP for 9 cycles (V 1.3 mg/m2 SC on Days 1, 4, 8, 11, 22, 25, 29, and 32 for Cycle 1 and Days 1, 8, 22, and 29 for Cycles 2-9; M 9 mg/m2 orally [PO] Days 1-4 for Cycles 1-9; P 60 mg/m2 PO Days 2-4 for Cycles 1-9) and dexamethasone (20 mg PO QW for Cycle 1, Days 1 and 22 for Cycles 2-9, and Day 1 for Cycles 10+). RRMM patients with ≥1 prior line of therapy received DARA SC (QW for Cycles 1-2, Q2W for Cycles 3-6, Q4W for Cycles 7+ until disease progression in 28-day cycles) in combination with Rd (R 25 mg PO Days 1-21 and d 40 mg IV or PO QW for each cycle until disease progression). Transplant-eligible NDMM patients received 4 cycles of DARA SC (QW for Cycles 1-3, Day 1 for Cycle 4 in 21-day cycles) in combination with VRd induction therapy for 4 cycles (V 1.3 mg/m2 SC Days 1, 4, 8, and 11 for each cycle; R 25 mg PO Days 1-14 for each cycle; d 20 mg IV or PO Days 1, 2, 8, 9, 15, and 16 for each cycle); subsequent therapy/autologous stem cell transplant were performed off study. Primary efficacy endpoints were overall response rate (ORR) for D-VMP and D-Rd and rate of very good partial response (VGPR) or better for D-VRd. Secondary endpoints included rate of VGPR or better for the D-VMP and D-Rd treatment cohorts and ORR for the D-VRd cohort. Secondary endpoints included rate of complete response or better, duration of response, minimal residual disease (MRD)-negativity rate, and DARA serum concentrations. Safety data included rates of treatment-emergent adverse events and IRRs. Results: 199 patients were enrolled (D-VMP, n = 67; D-Rd, n = 65; D-VRd, n = 67). At the clinical cutoff date (8 July 2019), median duration of follow up was 11.0 months for D-VMP, 11.2 months for D-Rd, and 7.1 months for D-VRd. ORR for D-VMP was 89.6% (90% confidence interval [CI], 81.3 - 95.0) and for D-Rd was 93.8% (90% CI, 86.5 - 97.9). Rate of VGPR or better for D-VRd was 70.1% (90% CI, 59.6 - 79.3). Response rates were comparable to published ORRs from the ALCYONE (Mateos MV, et al. N Engl J Med. 2018) and POLLUX (Dimopoulos MA, et al. N Engl J Med. 2016) studies of DARA IV plus VMP and Rd, respectively. The median duration of DARA SC administration was 5 minutes in all cohorts for the first, second, and all subsequent injections. The safety profiles in all cohorts were consistent with DARA IV in combination with various backbone standard-of-care regimens. Rates of IRRs and injection site reactions were consistent with those observed with DARA SC monotherapy in the COLUMBA study. The PK of DARA SC and each regimen was consistent with historical data and immunogenicity of DARA and rHuPH20 were comparable to previous reports. Updated efficacy data based on longer follow-up, including MRD-negativity rate, and updated safety data will be presented at the meeting. Conclusions: With longer follow-up, DARA SC in combination with standard-of-care regimens demonstrated comparable clinical activity and safety to corresponding DARA IV regimens, with considerably lower IRR rates and substantially shorter durations of administration. Disclosures Chari: Janssen, Celgene, Novartis Pharmaceuticals, Amgen, Bristol Myers Squibb, Pharmacyclics, Karyopharm, Sanofi, Seattle Genetics, OncoPeptides, Millenium/Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. San-Miguel:Amgen, Bristol-Myers Squibb, Celgene, Janssen, MSD, Novartis, Roche, Sanofi, and Takeda: Consultancy, Honoraria. McCarthy:Janssen: Honoraria, Other: Educational grant to attend meetings . Suzuki:Celgene: Honoraria; Janssen: Honoraria; Ono: Research Funding; BMS: Honoraria, Research Funding; Takeda: Honoraria. Hungria:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Sureda:Sanofi: Honoraria; BMS: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Roche: Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; Gilead: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support; Amgen: Membership on an entity's Board of Directors or advisory committees. Perrot:jannsen: Honoraria, Membership on an entity's Board of Directors or advisory committees; takeda: Honoraria; Amgen: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria. Hulin:Janssen, AbbVie, Celgene, Amgen: Honoraria; celgene: Consultancy, Honoraria. Iida:Daichi Sankyo: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Chugai: Research Funding; Kyowa Kirin: Research Funding; Abbvie: Research Funding; MSD: Research Funding; Sanofi: Research Funding; Teijin Pharma: Research Funding; Astellas: Research Funding; Gilead: Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Maisnar:Janssen, Amgen, Celgene, Takeda, BMS: Consultancy, Honoraria. Karlin:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; AMGEN: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support. Parasrampuria:Janssen: Employment, Equity Ownership. Masterson:Janssen: Employment, Equity Ownership. Kosh:Janssen: Employment, Equity Ownership. Yang:Janssen: Employment, Equity Ownership. Delioukina:Janssen: Employment, Equity Ownership. Qi:Janssen: Employment. Carson:Janssen: Employment, Equity Ownership. OffLabel Disclosure: This abstract includes data from a phase 2 clinical trial of a subcutaneous formulation of daratumumab in combination with standard-or-care regimens. Subcutaneous daratumumab is currently under investigation in several clinical trials, but has not yet been approved. However, the intravenous formulation of daratumumab is approved as monotherapy and in combination with standard-of-care regimens for the treatment of multiple myeloma.

Subcutaneous daratumumab and hyaluronidase-fihj in newly diagnosed or relapsed/refractory multiple myeloma

“…As in the COLUMBA study, the bodyweight subgroup analysis in the PLEAIDES study found the lowest bodyweight subgroups (⩽65 kg) had higher C trough , and the heaviest bodyweight subgroups had lower C trough , with Dara-SC across the D-VRd, D-VMP, and D-Rd cohorts. 16 However, the mean C trough at the end of weekly dosing was above the previously determined recommended target saturation for Dara-IV 19 across all cohorts, and as discussed previously, the ORRs of the Dara-SC combination therapies in the PLEAIDES study were comparable with those with Dara-IV reported previously. Based on the results of the bodyweight subgroup analyses in COLUMBA and PLEAIDES, bodyweight does not appear to have a clinically significant effect on the safety or efficacy of fixed-dose Dara-SC.…”

“…Moreover, Dara-SC in clinical trials has been shown to have comparable efficacy and a similar safety profile to the intravenous formulation, with significantly lower rates of IRRs, making Dara-SC a favorable treatment option. [14][15][16] Here, we review the first in-human study of Dara-SC (PAVO) that assessed the safety and pharmacokinetics (PK) of subcutaneous daratumumab, and the phase III COLUMBA and phase II PLEAIDES trials that led to the approval of Dara-SC. We also highlight important clinical considerations for the use of Dara-SC and provide practical guidelines for the administration of Dara-SC in the clinic.…”

“…In summary, the COLUMBA study found that Dara-SC was noninferior in terms of efficacy and PK profile, with a similar safety profile but significantly lower rates of IRRs when compared with the intravenous formulation.Dara-SC is also being studied in the ongoing phase II trial PLEIADES, which is a non-randomized, open-label study of Dara-SC combined with standard MM backbone regimens in both NDMM and RRMM. The primary endpoint analysis and updated efficacy and safety data were recently published 16. In the two NDMM arms of the study, Dara-SC 1800 mg was administered in combination with either bortezomib, lenalidomide, and dexamethasone (D-VRd; n = 67) in transplant-eligible patients, or bortezomib, melphalan, and prednisone (D-VMP; n = 67) in transplant-ineligible patients.…”

<p>Evaluating Daratumumab in the Treatment of Multiple Myeloma: Safety, Efficacy and Place in Therapy</p>

“…Besides establishing the efficacy of monotherapy SC daratumumab monotherapy, there are other ongoing trials examining the efficacy of SC daratumumab in combination with other novel agents PLEIADES (NCT03412565) is a phase II trial that is currently adding SC daratumumab to various standard regimens (VRd, VMP, Rd, and Kd). 79 So far results reveal that SC daratumumab leads to similar efficacy as the IV formulation. Outcomes here will compare the treatment arms to phase III data on the established agents without daratumumab to again see how these novel regimens will help patients achieve a PR or better.…”