Subcutaneous Daratumumab with Rapid Corticosteroid Tapering in Relapsed or Refractory Multiple Myeloma Patients: Part 3 Update of the Open-Label, Multicenter, Phase 1b Pavo Study
Authors: Nahi Hareth , Usmani Saad Z. , Mateos Maria-Victoria , van de Donk Niels W.C.J. , Moreau Philippe , Oriol Albert , Plesner Torben , Bandyopadhyay Nibedita , Hellemans Peter , Tromp Brenda , Nnane Ivo , Zemlickis Donna , Farnsworth Andrew , Chari Ajai 
Published: November 2021

Abstract
Introduction: Daratumumab (DARA) is a human monoclonal IgGκ monoclonal antibody targeting CD38 with a direct on-tumor and immunomodulatory mechanism of action. DARA is approved as monotherapy or in combination with standard-of-care regimens for the treatment of relapsed or refractory multiple myeloma (RRMM). The phase 1b 3-part PAVO study investigated subcutaneous delivery of DARA (DARA SC) in patients (pts) with RRMM. Part 1 demonstrated that a mix-and-deliver formula of DARA with recombinant human hyaluronidase PH20 (rHuPH20; ENHANZE ® drug delivery technology Halozyme, Inc.) was safe and effective (Usmani SZ, et al. Blood. 2019). In Part 2, a co-formulated DARA SC (DARA 1,800 mg + rHuPH20 30,000 U, in 15 mL) produced similar trough concentrations (C trough) to intravenous DARA (DARA IV) with no new safety concerns (San-Miguel J, et al. Haematologica. 2021). Here, we present the results from Part 3 of the PAVO study, which investigated the safety of pre- and post-dose corticosteroid tapering during DARA SC administration.
Methods: Pts were aged ≥18 years and had RRMM with ≥2 prior treatment lines of anti-myeloma therapy including a proteosome inhibitor and immunomodulatory drug (IMiD). All pts received DARA SC (DARA 1,800 mg + rHuPH20 30,000 U, in 15 mL) QW in Cycles (28-day) 1 and 2, Q2W in Cycles 3-6 and Q4W thereafter. In conjunction, pts received either a 3-week (wk) tapering schedule (corticosteroid-free by Cycle 1 Day 22), with methylprednisolone (MP) given PO/IV pre-dose (100 mg, Cycle 1 Day 1; 60 mg, Cycle 1 Day 8; 30 mg, Cycle 1 Day 15) and PO post-dose (20 mg, Cycle 1 Day 1 for 2 days; 20 mg, Cycle 1 Day 8 for 1 day; 20 mg, Cycle 1 Day 15 for 1 day), a 2-wk tapering schedule (corticosteroid-free by Cycle 1 Day 15), with MP given PO/IV pre-dose (100 mg, Cycle 1 Day 1; 60 mg, Cycle 1 Day 8) and PO post-dose (20 mg, Cycle 1 Day 1 for 2 days; 20 mg, Cycle 1 Day 8 for 1 day), or a 1-wk tapering schedule (corticosteroid-free by Cycle 1 Day 8), with dexamethasone (d) given IV pre-dose (20 mg, Cycle 1 Day 1).
Results: Pts (3-wk group, n=15; 2-wk group, n=15; 1-wk group, n=12) received a median of 3 (range, 2-7) prior lines of therapy, with 45.2% refractory to both a PI and an IMiD. In total, infusion-related reactions (IRRs) were reported in 5 (11.9%) pts (2-wk group, n=3; 1-wk group, n=2), of which 1 was grade 3 (2-wk group); all IRRs occurred on the first DARA SC administration and resolved, with none occurring after steroid tapering; median onset time was 79 minutes (range, 31-555). Overall, grade ≥3 treatment-emergent adverse events (TEAEs) were reported in 21 (50.0%) pts (3-wk group, n=9; 2-wk group, n=8; 1-wk group, n=4); the most common (≥5%) grade ≥3 TEAEs were anemia (9.5%), lymphopenia, neutropenia, and bone pain (7.1% each). One (2.4%) pt discontinued treatment due to a TEAE (1-wk group; pulmonary embolism). In total, TEAEs led to death in 3 (7.1%) pts (2-wk group, n=1; 1-wk group, n=2) due to general health deterioration (2-wk group), pneumonia staphylococcal (1-wk group), and pulmonary embolism (1-wk group). Pharmacokinetic (PK) results were consistent with previous reports of DARA SC. The mean (SD) serum DARA concentrations at Cycle 3, Day 1 (pre-dose) were 604 (280) μg/mL for the 3-wk group, 731 (382) μg/mL for the 2-wk group, and 706 (270) for the 1-wk group following weekly dosing of DARA SC. None of the 41 evaluable pts tested positive for anti-DARA antibodies. Ten (24.4%) of the 41 evaluable pts tested positive for treatment-emergent anti-rHuPH20 antibodies; 6 pts in the 3-wk group, 3 pts in the 2-wk group, and 1 pt in the 1-wk group. None of the anti-rHuPH20 antibody positive samples were neutralizing or correlated with injection-site reactions. With a median follow-up of 9.2 months for the 3-wk group, 11.1 months for the 2-wk group, and 8.3 months for the 1-wk group, the overall response rate was 40.0% (95% CI, 16.3%-67.7%) for both the 3-wk and 2-wk groups, and 41.7% (95% CI, 15.2%-72.3%) for the 1-wk group; the rate of very good partial response or better was 20.0% (95% CI, 4.3%-48.1%), 33.3% (95% CI, 11.8%-61.6%), and 16.7% (95% CI, 2.1%-48.4%), respectively.
Conclusion: Rapid corticosteroid tapering over 1 to 3 weeks is safe and tolerable in RRMM pts receiving DARA SC, with PK, immunogenicity, and safety results consistent with previous reports of DARA SC. These data will help guide treatment with future DARA SC combinations where limiting concurrent corticosteroids may be preferred (ie, T-cell redirectors, CAR-T, or checkpoint inhibitors).

Disclosures
Nahi: XNK Therapeutics AB: Consultancy. Usmani: Takeda: Consultancy, Research Funding, Speakers Bureau; SkylineDX: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; EdoPharma: Consultancy; Sanofi: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Merck: Consultancy, Research Funding; Janssen Oncology: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding; GSK: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding, Speakers Bureau; Array BioPharma: Consultancy, Research Funding; Abbvie: Consultancy; Amgen: Consultancy, Research Funding, Speakers Bureau. Mateos: Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene - Bristol Myers Squibb: 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; Regeneron: 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; Sea-Gen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bluebird bio: Honoraria; GSK: Honoraria; Oncopeptides: Honoraria. van de Donk: Cellectis: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Moreau: Sanofi: Honoraria; Celgene BMS: Honoraria; Abbvie: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Oncopeptides: Honoraria. Oriol: GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Plesner: Janssen: Other: Advisor, Research Funding; Celgene: Other: Advisor, Research Funding; Takeda: Research Funding; Oncopeptides: Other: Advisor, Research Funding; Genentech: Other: Advisor, Research Funding; CSL Behring: Other: Advisor; AbbVie: Other: Advisor, Research Funding; Genmab: Research Funding. Bandyopadhyay: Janssen: Current Employment, Current equity holder in publicly-traded company. Hellemans: Janssen: Current Employment, Current equity holder in publicly-traded company. Tromp: Janssen: Current Employment, Current equity holder in publicly-traded company. Nnane: Janssen: Current Employment. Zemlickis: Janssen: Current Employment. Farnsworth: Janssen: Current Employment, Current equity holder in publicly-traded company. Chari: Secura Bio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Research Funding; Millenium/Takeda: Consultancy, Research Funding; Sanofi Genzyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Research Funding; Antengene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.