https://orcid.org/0000-0003-2390-1218
Daratumumab is approved as monotherapy and in combination regimens for the treatment of relapsed or refractory multiple myeloma (RRMM) or newly diagnosed multiple myeloma [Citation1,Citation2]. The PAVO study (ClinicalTrials.gov Identifier: NCT02519452) of daratumumab plus recombinant human hyaluronidase PH20 (rHuPH20; ENHANZE® drug delivery technology, Halozyme, Inc., San Diego, CA) in a mix-and-deliver formulation (part 1) or a pre-mixed subcutaneous formulation (DARA SC; part 2) demonstrated consistent safety, pharmacokinetics, and efficacy as the daratumumab intravenous (IV) formulation in patients with RRMM [Citation3–5].
Corticosteroids are administered pre- and post-daratumumab (IV or SC) to mitigate the risk of infusion-related reactions (IRRs) [Citation1,Citation2]. Immunosuppressive effects of corticosteroids may reduce immunotherapy efficacy, and patients have indicated a preference for treatments with limited steroid use [Citation6–10]. Here, we present findings from PAVO part 3, which evaluated 3 pre- and post-dose corticosteroid-tapering schedules during DARA SC administration.
PAVO is an open-label, nonrandomized, multicenter, phase 1 b study that included patients with measurable RRMM, ≥2 prior lines of treatment (including a proteasome inhibitor and immunomodulatory drug), and an Eastern Cooperative Oncology Group performance status score ≤2 [Citation3,Citation4]. In part 3, patients received DARA SC (DARA 1,800 mg + rHuPH20 30,000 U in 15 mL) as previously described [Citation3]. Patients received 3-week, 2-week, or 1-week corticosteroid-tapering schedules (Supplemental Figure 1). Patients provided written informed consent; the study received institutional review board and independent ethics committee approvals.
The primary endpoint was safety; key secondary endpoints included overall response rate (ORR) and complete response (CR) rate per International Myeloma Working Group consensus recommendations [Citation11,Citation12]. Safety assessments included treatment-emergent adverse events (TEAEs), serious TEAEs, IRRs, and dose-limiting toxicities (DLTs). DARA SC serum concentrations, serum anti-daratumumab, and plasma anti-rHuPH20 antibodies were evaluated at prespecified time points.
No formal statistical hypothesis testing was performed; data were summarized descriptively. Safety and efficacy populations included all patients who received ≥1 dose of study drug. The pharmacokinetic-evaluable and immunogenicity populations included all patients who received ≥1 dose of study drug and provided ≥1 post-infusion pharmacokinetic or immunogenicity sample, respectively. Additional details regarding the methods are included in the Supplemental Methods.
From 21 November 2018 to 10 May 2021, 42 patients were enrolled in PAVO part 3 (3-week and 2-week tapering cohorts, n = 15 each; 1-week tapering cohort, n = 12), with a median (range) age of 69.5 (52–86) years (). Median (range) duration of follow-up was 9.2 (1.9–25.5), 11.1 (1.7–24.0), and 8.3 (0.4–13.1) months for the 3-week, 2-week, and 1-week tapering cohorts, respectively. Median treatment duration was 6.5 months in all cohorts. Patients received a median (range) of 18 (2–38) DARA SC doses. Thirteen (86.7%) patients each in the 3-week and 2-week cohorts and 7 (58.3%) patients in the 1-week tapering cohort discontinued treatment, mostly due to progressive disease (PD; 10 [66.7%], 12 [80.0%], and 5 [41.7%], respectively). Two (13.3%), 2 (13.3%), and 5 (41.7%) patients in the 3-week, 2-week, and 1-week tapering cohorts, respectively, were still receiving treatment.
Table 1. Baseline demographic and disease characteristics.
Five (11.9%) patients experienced an IRR during the first administration; no IRRs occurred with subsequent administrations during corticosteroid tapering. In the 3-week, 2-week, and 1-week tapering cohorts, IRRs occurred in 0, 3 (20.0%), and 2 (16.7%) patients, respectively. The most common IRRs (≥5%) were chills and pyrexia (3 [7.1%] each). IRRs of tachycardia, increased blood pressure, and oropharyngeal pain occurred in 1 (2.4%) patient each. Median (range) time to onset among all IRRs was 79.0 (31–555) minutes; all IRRs resolved the same day. IRRs were generally mild, with one grade 3 IRR (increased blood pressure; 2-week tapering cohort, resolved on day of onset). No grade 4 IRRs, IRRs meeting DLT definition, or IRRs leading to treatment interruption/discontinuation occurred.
All patients experienced ≥1 TEAE; 21 (50.0%) patients reported a grade ≥3 TEAE, and 16 (38.1%) patients experienced a serious TEAE. For the combined cohorts, the most common grade ≥3 TEAEs (≥5%) were anemia, lymphopenia, neutropenia, and bone pain (). The most common any grade TEAEs (n [%]) by tapering cohort were nausea (3-week; 8 [53.3%]); nasopharyngitis (2-week; 5 [33.3%]); and anemia, diarrhea, asthenia, and peripheral edema (1-week; 4 [33.3%] each). The most common grade ≥3 TEAEs (n [%]) by respective tapering cohorts were lymphopenia (2 [13.3%]), neutropenia (3 [20.0%]), and anemia (2 [16.7%]). Grade ≥3 infections were reported in 3 (20.0%), 2 (13.3%), and 1 (8.3%) patients in the 3-week, 2-week, and 1-week tapering cohorts, respectively. Six patients died during the study, including 2 patients in the 3-week tapering cohort (complications from diffuse large B-cell lymphoma and PD), 1 patient in the 2-week tapering cohort (PD), and 3 patients in the 1-week tapering cohort (staphylococcal pneumonia and pulmonary embolism [both grade 5 TEAEs] and PD).
Table 2. Most common TEAEs by preferred term.
In the pharmacokinetic-evaluable population (n = 37), the mean (standard deviation [SD]) daratumumab serum concentration was 676 (314) µg/mL at Cycle 3 Day 1 (C3D1). The mean (SD) daratumumab serum concentrations were similar in the 3-week, 2-week, and 1-week tapering cohorts (604 [280], 731 [382], and 706 [270] µg/mL, respectively; Supplemental Figure 2). For the immunogenicity-evaluable population (n = 41), no patient tested positive for anti-daratumumab antibodies. Among rHuPH20 immunogenicity-evaluable patients in the 3-week, 2-week, and 1-week tapering cohorts, 6 (40.0%), 3 (20.0%), and 1 (9.1%) patients had anti-rHuPH20 antibodies (none were neutralizing).
Across cohorts, the ORR was 40.5% (median follow-up, 8.3 months), with 10 (23.8%) patients achieving very good partial response or better (≥VGPR) and 2 (4.8%) patients achieving ≥ CR (Supplemental Figure 3). In the 3-week tapering cohort, the ORR was 40.0%, with 3 (20.0%) patients achieving ≥ VGPR and 1 (6.7%) patient achieving ≥ CR. In the 2-week tapering cohort, the ORR was 40.0%, with 5 (33.3%) patients achieving ≥ VGPR and no patient achieving ≥ CR. In the 1-week tapering cohort, the ORR was 41.7%, with 2 (16.7%) patients achieving ≥ VGPR and 1 (8.3%) patient achieving ≥ CR.
Among responders (n = 17), the median time to first and best responses were 1.0 and 1.1 months, respectively. In the 3-week, 2-week, and 1-week tapering cohorts, median time to best response was 1.5, 1.9, and 1.0 months, respectively. Median duration of response (DoR) was 16.7 months in the 2-week tapering cohort and not reached in the 3-week and 1-week tapering cohorts; 9-month DoR rates were 83.3%, 83.3%, and 100% in the 3-week, 2-week, and 1-week tapering cohorts, respectively.
Median progression-free survival (PFS) was 5.9 months, with an estimated 9-month PFS rate of 40.7% across cohorts. At a median follow-up of 9.2, 11.1, and 8.3 months for the 3-week, 2-week, and 1-week tapering cohorts, the median PFS was 5.9, 4.7, and 7.4 months, respectively. Estimated 9-month PFS rates were 40.0%, 36.1%, and 46.7% for the 3-week, 2-week, and 1-week tapering cohorts, respectively.
Despite the potent activity of corticosteroids in multiple myeloma, cumulative toxicities associated with long-term use are well-established [Citation13]. Clinical benefits of corticosteroid use in multiple myeloma should be evaluated against potential risk of toxicity and effects on quality of life. Patients with RRMM in a Canadian study prioritized treatments that increased life expectancy and limited corticosteroid use due to negative effects (insomnia, cognitive impairment, mood disturbances) [Citation10]. A phase 3 study of elderly, intermediate/fit, NDMM patients showed that switching to reduced-dose lenalidomide without dexamethasone after 9 cycles of lenalidomide + dexamethasone was feasible with similar outcomes to continuous lenalidomide + dexamethasone [Citation14].
Results from PAVO part 3 showed that tolerability profiles across cohorts with different corticosteroid-tapering schedules were comparable to previous reports of daratumumab, with no increase in IRR rates [Citation3,Citation4,Citation15]. The number of patients with grade ≥3 infections was generally similar across corticosteroid-tapering cohorts. The pharmacokinetic and immunogenicity results reported here were consistent with those previously reported in PAVO parts 1 and 2 [Citation3,Citation4]. Similar mean serum daratumumab concentrations were observed across tapering schedules. No patients evaluable for daratumumab immunogenicity were positive for anti-daratumumab antibodies, indicating a low risk for immunogenicity for DARA SC with corticosteroid tapering.
These results indicate that corticosteroid tapering does not diminish DARA SC monotherapy efficacy, as patients who received DARA SC with/without tapering achieved similar efficacy [Citation3,Citation15]. The ORR in the combined cohorts of PAVO part 3 was 40.5%, which was similar to the ORRs reported in PAVO parts 1 and 2 (42.2% and 52%, respectively) [Citation3,Citation4]. While additional studies are warranted, these findings will inform the future use of DARA SC combination regimens, where no/limited concurrent corticosteroids may be preferred including chimeric antigen receptor (CAR)-T cell therapy, T-cell redirecting bispecific antibodies, and checkpoint inhibitors.
In conclusion, these findings demonstrate that corticosteroid tapering over 1 to 3 weeks is safe, not associated with increased IRRs, and does not compromise efficacy in patients with RRMM receiving DARA SC.
Author contributions
All authors developed the manuscript, provided a full review and approval of the final version of the article, and are fully responsible for all content and accuracy of the data.
Data-sharing statement
The data-sharing policy of Janssen Pharmaceutical Companies of Johnson & Johnson is available at https://www.janssen.com/clinical-trials/transparency. As noted on this site, requests for access to the study data can be submitted through the Yale Open Data Access (YODA) Project site at http://yoda.yale.edu.
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The authors would like to acknowledge the patients participating in this study and their families, the staff members at the study sites, the data and safety monitoring committees, and the staff members who were involved in data collection and analyses.
Disclosure statement
HN has nothing to disclose.
SZU received research funding from Amgen, Array BioPharma, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Merck, Pharmacyclics, Sanofi, Seattle Genetics, SkylineDX, and Takeda; consulted for Amgen, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Merck, Sanofi, SkylineDx, and Takeda; and served on speakers bureaus for Amgen, Celgene, Janssen, and Takeda.
M-VM served on speakers bureaus and advisory boards for AbbVie, Adaptive, Amgen, Celgene, GlaxoSmithKline, Janssen, Mundipharma, Oncopeptides, PharmaMar, Roche, Seattle Genetics, and Takeda.
NWCJvdD received research funding from Amgen, Bristol Myers Squibb, Cellectis, Celgene, Janssen, and Novartis; and consulted for Adaptive, Amgen, Bayer, Bristol Myers Squibb, Celgene, Janssen, Novartis, Servier, and Takeda.
AO consulted for Sanofi, GlaxoSmithKline, Amgen, Bristol Myers Squibb/Celgene, and Janssen.
TP served as an advisor for Janssen, Celgene, Takeda, Oncopeptides, Genentech, and AbbVie; and received research support from AbbVie, Janssen, Genmab, Celgene, Takeda, Oncopeptides, Genentech, and Roche.
NB, PH, and IN are employees of Janssen and hold equity in Johnson & Johnson.
BT holds equity in Johnson & Johnson and was an employee of Janssen at the time of the study.
DZ is an employee of Janssen.
AC consulted for Amgen, Antengene, Bristol Myers Squibb, Celgene, Janssen, Karyopharm, Novartis, Oncopeptides, Sanofi, Seattle Genetics, and Takeda; and received research funding from Amgen, Celgene, Janssen, Novartis, Pharmacyclics, Seattle Genetics, and Takeda.
PM received honoraria from and served as a consultant for AbbVie, Amgen, Bristol Myers Squibb, Celgene, Janssen, and Sanofi.
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References
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