Subcutaneous Daratumumab (DARA SC) Plus Standard-of-Care (SoC) Regimens in Multiple Myeloma (MM) across Lines of Therapy in the Phase 2 Pleiades Study: Initial Results of the Dara SC Plus Carfilzomib/Dexamethasone (D-Kd) Cohort, and Updated Results for the Dara SC Plus Bortezomib/Melphalan/Prednisone (D-VMP) and Dara SC Plus Lenalidomide/Dexamethasone (D-Rd) Cohorts
Authors: Moreau Philippe , Chari Ajai , Haenel Mathias , Oriol Albert , Rodriguez-Otero Paula , McCarthy Helen , Suzuki Kenshi , Hungria Vania T. M. , Sureda Balari Anna , Clement-Filliatre Lauriane , Hulin Cyrille , Magen Hila , Iida Shinsuke , Maisnar Vladimir , Karlin Lionel , Pour Luděk , Touzeau Cyrille , Yang Shiyi , Kosh Michele , Delioukina Maria , Heuck Christoph , Goldschmidt Hartmut 
Published: November 2020

Introduction: DARA is a human IgGκ monoclonal antibody targeting CD38 and is approved for intravenous (IV) infusion across lines of therapy for MM. In phase 3 clinical studies, DARA IV plus Rd for RRMM (POLLUX) and DARA IV plus VMP for transplant-ineligible (TIE) NDMM (ALCYONE) led to deep and durable responses and reduced the risk of disease progression or death by ≥56% (Kaufman J, Blood 2019. 134[Suppl 1]:1866; Mateos M, Lancet 2020). In the phase 1b MMY1001 study of DARA IV plus carfilzomib/dexamethasone (Kd) in RRMM, DARA IV plus Kd was well tolerated and demonstrated deep responses, regardless of prior lenalidomide treatment (Chari A, Blood 2019.134[Suppl 1]:1876). In the phase 3 CANDOR study, DARA IV plus Kd reduced the risk of disease progression or death by 37% in pts with RRMM (Dimopoulos M, Lancet 2020). A formulation of DARA for subcutaneous administration (DARA SC) was developed (1,800 mg DARA co-formulated with recombinant human hyaluronidase PH20 [rHuPH20]; ENHANZE® drug delivery technology, Halozyme, Inc.). Advantages of DARA SC include reduced administration time (3-5 minutes) and lower rates of infusion-related reactions (IRRs). The phase 2 PLEIADES study is evaluating the safety and efficacy of DARA SC combined with SoC for MM, including D-Kd for RRMM, D-Rd for RRMM, and D-VMP for TIE NDMM. In the primary analysis of the D-Rd and D-VMP cohorts in PLEIADES, D-Rd and D-VMP demonstrated clinical activity and safety comparable to corresponding DARA IV regimens, with low rates of IRRs, leading to approval in the United States (Chari A, Clin Lymphoma Myeloma Leuk 2019.19[10]:e16-e17). Here, we present the primary analysis of the D-Kd cohort and updated data for the D-Rd and D-VMP cohorts of PLEIADES.
Methods: RRMM pts with 1 prior line of therapy (including 2 consecutive cycles of lenalidomide therapy) received 28-day cycles of Kd (K: 20 mg/m2 IV Cycle 1 Day 1, escalated to 70 mg/m2 on Cycle 1 Days 8 and 15, then 70 mg/m2 on Days 1, 8 and 15 of each cycle thereafter; d: 40 mg IV or PO QW) with DARA SC (QW for Cycles 1-2, Q2W for Cycles 3-6, and Q4W for Cycles 7+). RRMM pts with ≥1 prior line received 28-day cycles of Rd (R: 25 mg PO Days 1-21; d: 40 mg IV or PO QW for each cycle) with DARA SC (QW for Cycles 1-2, Q2W for Cycles 3-6, and Q4W for Cycles 7+). TIE NDMM pts received 9, 6-week cycles of VMP (V: 1.3 mg/m2 SC twice weekly in Cycle 1 and QW in Cycles 2-9; M [9 mg/m2] and P [60 mg/m2] PO on Days 1-4 of Cycles 1-9) with DARA SC (QW for Cycle 1, Q3W for Cycles 2-9, and Q4W for Cycles 10+ in 28-day cycles). All pts were treated until disease progression/unacceptable toxicity. Overall response rate (ORR) was the primary endpoint for each cohort. Additional outcomes were VGPR or better rate, CR or better rate, duration of response, minimal residual disease (MRD)-negativity rate, DARA serum concentrations, and safety.
Results: At the time of the clinical cutoff for the D-Kd cohort, 66 pts were treated and the median duration of follow-up was 8.7 months. The ORR for D-Kd was 84.8% (90% CI, 75.7-91.5; Table) and response rates were consistent with DARA IV plus Kd in CANDOR (Dimopoulos M, Lancet 2020). For the updated analysis of the D-Rd cohort (n=65), median follow-up was 23.1 months, and the ORR was 93.8% (90% CI, 86.5-97.9; Table). Response rates for D-Rd were consistent with DARA IV plus Rd in POLLUX (Kaufman J, Blood 2019. 134[Suppl 1]:1866). For the updated analysis of the D-VMP cohort (n=67), median follow-up was 22.6 months. The ORR for D-VMP was 89.6% (90% CI, 81.3-95.0; Table), and response rates were consistent with DARA IV plus VMP in ALCYONE (Mateos M, Lancet 2020). The median duration of DARA SC administration was 5 minutes for all D-Kd injections. The safety profile of D-Kd was consistent with DARA IV as combination therapy with SoC regimens. The rates of IRRs and injection-site reactions were comparable to those observed with DARA SC monotherapy in the COLUMBA study (Mateos M, Lancet Haematol 2020).
Additional data will be presented including MRD-negativity rates for all cohorts and updated safety data for the D-Rd and D-VMP cohorts.
Conclusions: The primary analysis of the D-Kd cohort demonstrated comparable clinical activity and safety to DARA IV plus Kd. With extended follow-up in the D-Rd and D-VMP cohorts, clinical activity was comparable to corresponding DARA IV-containing regimens (DARA IV plus Rd [POLLUX]; DARA IV plus VMP [ALCYONE]). A low incidence of IRRs and a short duration of administration were reported in the D-Kd cohort in PLEIADES.
Table 1

Disclosures
Moreau: Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Honoraria; Abbvie: Consultancy, Honoraria; Novartis: Honoraria. Chari:Janssen, Celgene, Novartis, Amgen, Pharmacyclics, Seattle Genetics, Millennium/Takeda: Research Funding; Janssen, Celgene, Novartis, Amgen, Bristol-Myers Squibb, Karyopharm, Sanofi, Genzyme, Seattle Genetics, Oncopeptides, Millennium/Takeda, Antengene, Glaxo Smith Kline, Secura Bio: Consultancy. Haenel:Amgen, Novartis, Roche, Celgene, Takeda, Bayer: Honoraria. Oriol:Janssen: Consultancy; Amgen: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees. Rodriguez-Otero:Abbvie: Consultancy, Honoraria; Oncopeptides: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); GlaxoSmithKline: Consultancy, Current Employment, Current equity holder in publicly-traded company, Honoraria; Medscape: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Sanofi: Consultancy, Honoraria; Kite: Consultancy, Honoraria. McCarthy:Janssen: Honoraria; Abbvie: Membership on an entity's Board of Directors or advisory committees. Suzuki:Bristol-Myers Squibb, Celgene and Amgen: Research Funding; Takeda, Amgen, Janssen and Celgene: Consultancy; Takeda, Celgene, ONO, Amgen, Novartis, Sanofi, Bristol-Myers Squibb, AbbVie and Janssen: Honoraria. Sureda Balari:BMS: Speakers Bureau; Janssen: Consultancy, Honoraria; Incyte: Consultancy; Celgene: Consultancy, Honoraria; Gilead/Kite: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Merck Sharpe and Dohme: Consultancy, Honoraria, Speakers Bureau; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; Roche: Honoraria. Hulin:Celgene/Bristol-Myers Squibb, Janssen, GlaxoSmithKline, and Takeda: Honoraria. Magen:AbbVie: Research Funding; Merck Sharpe and Dohme: Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Ono: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Sano: Honoraria, Research Funding; Chugai: Research Funding; Kyowa Kirin: Research Funding. Iida:Bristol-Myers Squibb: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Ono: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Merck Sharpe Dohme: Research Funding; AbbVie: Research Funding; Kyowa Kirin: Research Funding; Chugai: Research Funding; Sanofi: Honoraria, Research Funding. Maisnar:Janssen, Amgen, Takeda, Celgene/Bristol-Myers Squibb, Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Karlin:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, personal fees; Sanofi: Honoraria; Celgene: Other: Personal fees. Touzeau:Takeda: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; GlaxoSmithKline: Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Abbvie: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding. Yang:Janssen: Current Employment. Kosh:Janssen: Current Employment. Delioukina:Maria Delioukina: Current Employment. Heuck:Christoph Heuck: Current Employment, Current equity holder in publicly-traded company. Goldschmidt:GlaxoSmithKline (GSK): Honoraria; Merck Sharp and Dohme (MSD): Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; University Hospital Heidelberg, Internal Medicine V and National Center for Tumor Diseases (NCT), Heidelberg, Germany: Current Employment; Mundipharma GmbH: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; Novartis: Honoraria, Research Funding; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Incyte: Research Funding; Adaptive Biotechnology: 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: Grants and/or provision of Investigational Medicinal Product, Research Funding; Johns Hopkins University: Other: Grants and/or provision of Investigational Medicinal Product; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; Chugai: Honoraria, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; Dietmar-Hopp-Foundation: Other: Grants and/or provision of Investigational Medicinal Product:; Molecular Partners: Research Funding.

OffLabel Disclosure:
This abstract includes discussion of a combination therapy with subcutaneous daratumumab plus carfilzomib and dexamethasone, which is currently under investigation in clinical trials, but has not yet been approved. Subcutaneous daratumumab is approved as monotherapy and in combination with other standard-of-care regimens for the treatment of multiple myeloma.