Recombinant Human Hyaluronidase Research Articles

Long-term safety and tolerability of hyaluronidase-facilitated subcutaneous immunoglobulin 10% as maintenance therapy for chronic inflammatory demyelinating polyradiculoneuropathy: Results from the ADVANCE-CIDP 3 trial.

Hyaluronidase-facilitated subcutaneous immunoglobulin (fSCIG) consists of subcutaneous human immunoglobulin G (IgG) 10% with recombinant human hyaluronidase (rHuPH20) and can be administered at the same dose and interval as intravenous IgG (IVIG). fSCIG recently received US approval as maintenance therapy for adults with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and European approval for adults and children with CIDP after stabilization with IVIG. ADVANCE-CIDP 3 (NCT02955355) was an open-label long-term extension of the Phase 3 double-blind randomized placebo-controlled ADVANCE-CIDP 1 study (NCT02549170) that examined fSCIG safety and efficacy as maintenance CIDP therapy. Primary outcomes were safety, tolerability, and immunogenicity. Efficacy was an exploratory outcome. The study provided 220 patient-years of follow-up data from 85 patients. Median (range) exposure was 33 (0-77) months. Patients received fSCIG every 4 weeks (88.2%) or every 3 weeks (11.8%). Median (range) 4-weekly IgG dose equivalent was 64.0 (28.0-200.0) g. Mean (standard deviation) infusion duration was 135.5 (62.8) minutes. Most adverse events (AEs) were mild or moderate and self-limiting. Of the 1406 AEs, only 48 were severe and 30 were serious. fSCIG-related AEs (n = 798) included infusion site reactions such as pain, redness, and pruritus. Three infusions (0.1%) were reduced in rate, interrupted, or stopped due to intolerability. Relapse occurred in 10 of 77 patients (13.0%); annual relapse rate was 4.5%. An anti-rHuPH20 antibody titer ≥1:160 was detected in 14 of 84 patients (16.7%); patients who tested positive (≥1:160) had similar relapse rates versus those who tested negative (16.7% vs. 12.3%, respectively). ADVANCE-CIDP 3 demonstrated favorable fSCIG long-term safety and tolerability consistent with its established safety profile, and a low relapse rate, supporting use as maintenance CIDP treatment.

FSCIG 10% in pediatric primary immunodeficiency diseases: a European post-authorization safety study

BackgroundThe safety, tolerability, and immunogenicity of hyaluronidase-facilitated subcutaneous immunoglobulin (fSCIG) 10% (dual-vial unit of human immunoglobulin 10% and recombinant human hyaluronidase [rHuPH20]) were assessed in children with primary immunodeficiency diseases (PIDs).MethodsThis phase 4, post-authorization, prospective, interventional, multicenter study (NCT03116347) conducted in the European Economic Area, enrolled patients aged 2 to < 18 years with a documented PID diagnosis who had received immunoglobulin therapy for ≥ 3 months before enrollment. New fSCIG 10% starters underwent fSCIG 10% dose ramp-up for ≤ 6 weeks (epoch 1) before receiving fSCIG 10% for ≤ 3 years (epoch 2); patients pretreated with fSCIG 10% entered epoch 2 directly. The primary outcome was the number and rate (per infusion) of all noninfectious treatment-related serious and severe adverse events (AEs).ResultsIn total, 42 patients were enrolled and dosed (median [range] age: 11.5 [3–17] years; 81% male; 23 new starters; 19 pretreated). Overall, 49 related noninfectious, treatment-emergent AEs (TEAEs) were reported in 15 patients; most were mild in severity (87.8%). No treatment-related serious TEAEs were reported. Two TEAEs (infusion site pain and emotional distress) were reported as severe and treatment-related in a single new fSCIG 10% starter. The rate of local TEAEs was lower in pretreated patients (0.1 event/patient-year) versus new starters (1.3 events/patient-year). No patients tested positive for binding anti-rHuPH20 antibodies (titer of ≥ 1:160).ConclusionsNo safety signals were identified, and the incidence of local AEs declined over the duration of fSCIG 10% treatment. This study supports fSCIG 10% long-term safety in children with PIDs.Trial registration number (ClinicalTrials.gov)NCT03116347.

Subcutaneous versus intravenous nivolumab for renal cell carcinoma

The evolving oncology treatment paradigm has created an unmet need for administration options that improve patient experiences and health care efficiencies. CheckMate 67T (NCT04810078) was a phase III, open-label, multicenter, noninferiority trial in which patients with advanced/metastatic clear cell renal cell carcinoma were randomized to subcutaneous nivolumab (1200 mg every 4 weeks; coformulated with recombinant human hyaluronidase PH20 20 000 units) or intravenous nivolumab (3 mg/kg every 2 weeks). The primary objective was to assess the noninferiority of subcutaneous versus intravenous nivolumab by coprimary endpoints determined from a population pharmacokinetics analysis [time-averaged serum concentration over the first 28 days (Cavgd28), and minimum steady-state serum concentration (Cminss); noninferiority threshold: lower boundary of 90% confidence interval (CI) of the geometric mean ratios (GMR) ≥0.8]. Objective response rate (ORR) was a key secondary endpoint powered for noninferiority [noninferiority threshold: lower boundary of 95% CI of relative risk of ORR (subcutaneous versus intravenous nivolumab) ≥0.60]. Overall, 495 patients were randomized. Relative exposure in the subcutaneous versus intravenous arm reported by the GMR of Cavgd28 and Cminss was 2.098 (90% CI 2.001-2.200) and 1.774 (90% CI 1.633-1.927), respectively. After 8 months of minimum follow-up, ORR was 24.2% with subcutaneous nivolumab (95% CI 19.0%-30.0%) versus 18.2% with intravenous nivolumab [95% CI 13.6%-23.6%; relative risk: 1.33 (95% CI 0.94-1.87)]. Coprimary endpoints and ORR met noninferiority thresholds. Additional efficacy and safety measures were similar. Subcutaneous nivolumab was noninferior to intravenous nivolumab based on pharmacokinetics and ORR. No new safety signals were observed.

Long-Term Safety of Facilitated Subcutaneous Immunoglobulin 10% Treatment in US Clinical Practice in Patients with Primary Immunodeficiency Diseases: Results from a Post-Authorization Safety Study

Facilitated subcutaneous immunoglobulin (fSCIG) 10% is an immunoglobulin replacement therapy that utilizes recombinant human hyaluronidase (rHuPH20) to enhance immunoglobulin dispersion and absorption, allowing for longer treatment intervals similar to intravenous immunoglobulin (up to once monthly). fSCIG 10% is indicated in the USA for treating adults and children aged ≥ 2 years with primary immunodeficiency diseases (PIDs). This prospective, non-interventional, open-label, multicenter, post-authorization safety study (NCT02593188) was conducted in the USA from November 2015 to October 2021 to assess the long-term safety of fSCIG 10% in routine clinical practice. Patients with PIDs aged ≥ 16 years who were prescribed and/or had started fSCIG 10% treatment were enrolled. In total, 253 patients were enrolled and included (full analysis set). Participants received fSCIG 10% treatment for a median (interquartile range) of 10.0 (3.5–11.8) months, with the majority of infusions administered every 4 weeks (54.4% [1197/2201 infusions]) and at home (62.6% [1395/2230 infusions]). Overall, 98.5% of infusions were administered without rate reduction, interruption, or discontinuation due to adverse events (AEs). Treatment-related, non-serious AEs were experienced by 52 patients (20.6%, 284 events). Two patients (0.8%) each experienced one treatment-related serious AE (aseptic meningitis and deep vein thrombosis). Development of antibodies against rHuPH20 was uncommon; 14/196 patients (7.1%) tested positive for binding antibodies (titer ≥ 1:160) with no neutralizing antibodies detected. There was no relationship between anti-rHuPH20 antibody positivity and the occurrence of treatment-related serious or non-serious AEs. Long-term, repeated self-administration of fSCIG 10% was well tolerated in US clinical practice by patients with PIDs.

Tolerability and Safety of Large-Volume Hyaluronidase-Facilitated Subcutaneous Immunoglobulin 10% Administered with or without Dose Ramp-Up: A Phase 1 Study in Healthy Participants

PurposeFacilitated subcutaneous immunoglobulin (fSCIG; immune globulin infusion 10% [human] with recombinant human hyaluronidase [rHuPH20]) permits high-volume subcutaneous immunoglobulin (SCIG) infusion, shorter infusion times and reduced dosing frequency relative to conventional SCIG. It is initiated by gradually increasing infusion volumes over time (dose ramp-up) to achieve target dose level (TDL). Whether ramp-up strategies have tolerability or safety advantages over direct initiation at full TDL has not been evaluated clinically.MethodsThis phase 1 open-label study assessed tolerability and safety of fSCIG 10% with accelerated or no ramp-up compared with conventional ramp-up in healthy adults (NCT04578535). Participants were assigned to one of the three ramp-up arms to achieve TDLs of 0.4 or 1.0 g/kg/infusion. The primary endpoint was the proportion of infusions completed without interruption or infusion rate reduction owing to treatment-emergent adverse events (TEAEs). Safety was assessed as a secondary endpoint.ResultsOf 51 participants enrolled, 50 (98.0%) tolerated all fSCIG 10% infusions initiated (n = 174). Infusion rate was reduced in one participant owing to headache in the 0.4 g/kg/infusion conventional ramp-up arm. Study discontinuations were higher in the no ramp-up arm (70%) versus the conventional (0%) and accelerated (22%) arms at the 1.0 g/kg/infusion TDL. Safety outcomes did not substantially differ between treatment arms.ConclusionThe favorable tolerability and safety profiles of fSCIG 10% in healthy participants support initiating treatment with fSCIG 10% with accelerated ramp-up at TDLs up to 1.0 g/kg. Data support no ramp-up at TDLs close to 0.4 g/kg but additional data are needed for higher doses.

Subcutaneous (SC) nivolumab (NIVO) vs intravenous (IV) NIVO in patients with previously treated advanced or metastatic clear cell renal cell carcinoma (ccRCC): Safety and patient-reported outcomes (PROs) of the randomized phase 3 CheckMate 67T trial.

4532 Background: CheckMate 67T (NCT04810078), a multicenter, randomized, open-label, phase 3 study, evaluated pharmacokinetics and objective response rate (ORR) noninferiority of NIVO SC vs IV in previously treated patients with advanced/metastatic ccRCC. Noninferiority endpoints of exposure (time-averaged serum concentration over the first 28 days and trough serum concentration at steady state) and efficacy (ORR by BICR) were met. Safety was comparable in the SC vs IV arms. NIVO-related immunogenicity was as expected for SC administration and further assessments did not identify apparent clinically meaningful impact. This report focuses on additional safety analyses and PROs. Methods: Patients were randomized 1:1 to NIVO SC 1200 mg + recombinant human hyaluronidase PH20 Q4W (n = 248) or NIVO IV 3 mg/kg Q2W (n = 247). Eligibility criteria were previously reported. Safety analyses were performed for all-causality adverse events (AEs) across weight categories (&lt; 50 kg, ≥ 50 kg–&lt; 70 kg, ≥ 70–&lt; 90 kg, ≥ 90 kg–&lt; 110 kg, and ≥ 110 kg). The onset, management, and resolution of treatment-related select AEs were studied; duration and grade of local site reactions and the effect of immunogenicity on local site reactions were reported. PROs were assessed using the Functional Assessment of Chronic Illness Therapy (FACIT) GP5 item. Results: The overall AE incidence rates in the SC arm were generally comparable to or lower than in the IV arm across weight categories, but limited by small sample sizes in the &lt; 50 kg and ≥110 kg subgroups. Across the treatment-related select AE categories, most events were manageable with established algorithms and resolved with immune-modulating medications. Local site reactions were mild to moderate with a median duration of 2.0 and 0.01 days in the SC and the IV arms, respectively; most resolved without treatment. The proportion of patients with a local site reaction of any grade was 8.1% in the SC arm and 2.0% in the IV arm. In patients testing NIVO-specific anti-drug antibody (ADA)-positive, 15.2% of patients in the SC arm reported a local site reaction, but all were grade 1–2 and most resolved without treatment. No hypersensitivity/infusion reaction select AEs were reported in ADA-positive patients in either arm. A majority of patients in SC and IV arms reported minimal bother by treatment side effects in their FACIT GP5 scores. Conclusions: The safety profile of SC was consistent with IV, supporting the use of NIVO SC as an option improving patient experience. This aligns with patient preference for SC administration over IV. Analyses based on weight and ADA subgroups were consistent with the known NIVO safety profile. Toxicity was manageable with immune-modulating medications. FACIT GP5 scores indicated no bother by treatment side effects. Clinical trial information: NCT04810078 .

Daratumumab (DARA) + bortezomib/lenalidomide/dexamethasone (VRd) in transplant-eligible (TE) patients (pts) with newly diagnosed multiple myeloma (NDMM): Analysis of minimal residual disease (MRD) in the PERSEUS trial.

7502 Background: In the primary analysis of the phase 3 PERSEUS study, subcutaneous DARA (DARA SC) + VRd (D-VRd) induction/consolidation (ind/consol) and D-R maintenance improved progression-free survival (PFS) and increased depth of response (complete response or better [≥CR] and MRD negativity [neg]) compared to VRd ind/consol and R maintenance for TE NDMM. Here, we report further results on deepening of response and MRD neg during maintenance. Methods: TE pts with NDMM were randomized 1:1 to D-VRd or VRd. Pts in both arms received up to six 28-day cycles (4 pre-ASCT ind, 2 post-ASCT consol) of VRd (V 1.3 mg/m2 SC on Days [D] 1, 4, 8, 11; R 25 mg PO on D 1-21; d 40 mg PO/IV on D 1-4, 9-12) followed by R maintenance (10 mg PO on D 1-28 until progressive disease [PD]). Pts in the D-VRd arm also received DARA SC (DARA 1,800 mg + recombinant human hyaluronidase PH20 [rHuPH20; 2,000 U/mL; Halozyme]) QW in Cycles 1-2, Q2W in Cycles 3-6, and Q4W during maintenance until PD. MRD-neg rate (clonoSEQ) was defined as the proportion of ITT pts who achieved both ≥CR and MRD neg. Results: In the 709 pts randomized (D-VRd, n=355; VRd, n=354), responses deepened over time with D-VRd vs VRd, including rates of ≥CR (end of consol: 44.5% vs 34.7%; P= 0.0078 and overall: 87.9% vs 70.1%; P&lt;0.0001). MRD-neg rates increased over time and were higher with D-VRd vs VRd at 12, 24, and 36 mo after Cycle 1 Day 1 (all P&lt;0.0001; Table). Rates of sustained MRD neg for ≥12 mo were higher for D-VRd vs VRd (10–5: 64.8% vs 29.7%; P&lt;0.0001; 10–6: 47.3% vs 18.6%; P&lt;0.0001); results were consistent across prespecified clinically relevant subgroups. Among pts who were MRD positive (pos) at end of consol, significantly higher proportions of pts in the D-VRd group vs the VRd group achieved MRDneg during maintenance at 10−5 (60.2% vs 40.5%; P= 0.0049) and 10−6 (56.7% vs 25.2%; P&lt;0.0001) and sustained MRD neg for ≥12 mo at 10−5 (38.6% vs 17.4%; P= 0.0006) and 10−6 (31.3% vs 10.3%; P&lt;0.0001). End of consol and overall MRD neg at both 10–5 and 10–6 were associated with improved PFS. Additional data on response rates in different study phases and sustained MRD neg will be presented. Conclusions: During maintenance, a greater proportion of pts with MRD-pos status achieved MRD neg with D-R vs R. The higher rates of deep (10–6) and sustained MRD neg achieved with D-VRd ind/consol and D-R maintenance vs VRd ind/consol and R maintenance translated to a clinically meaningful benefit of improved PFS. These data further support D-VRd and D-R maintenance as a new standard of care for TE pts with NDMM and highlight the benefit of DARA SC in maintenance. Clinical trial information: NCT03710603 . [Table: see text]

A phase 2, open-label, 2-cohort study to evaluate patient preference for nivolumab (NIVO) + relatlimab (RELA) fixed-dose combination (FDC) subcutaneous (SC) vs NIVO + RELA FDC intravenous (IV) and NIVO SC vs NIVO IV in participants with melanoma.

TPS9619 Background: The oncology burden on healthcare resources and patients increases as the number of individuals with cancer grows, necessitating treatment options offering improved convenience to patients. SC delivery of monoclonal antibodies in various cancer indications has previously been shown to be effective, well tolerated, and preferred by patients over IV infusion. In CheckMate 67T (NCT04810078), noninferiority of exposure (time-averaged serum concentration at Day 28 and trough serum concentration at steady state) and efficacy (objective response rate by BICR) were previously reported for NIVO SC 1200 mg + recombinant human hyaluronidase PH20 (rHuPH20) vs IV in patients with locally advanced/metastatic clear cell renal cell carcinoma. RELATIVITY-127 (NCT05625399) is ongoing to establish exposure noninferiority of NIVO + RELA + rHuPH20 FDC SC to IV in patients with previously untreated metastatic/unresectable melanoma. This phase 2, open-label study CA224-1044 (NCT06101134) assesses patient preference for NIVO SC or NIVO + RELA FDC SC vs IV formulations after transitioning from IV to SC in patients with melanoma and aims to further characterize the safety profile of immuno-oncology therapy during IV-to-SC switch. Methods: Cohort 1 includes adult patients with previously untreated stage III (unresectable) or stage IV (metastatic) melanoma who will receive NIVO + RELA FDC IV every 4 weeks (Q4W) for 2 cycles (28-day cycle) followed by NIVO + RELA + rHuPH20 FDC SC Q4W until disease progression, unacceptable toxicity, or a maximum total treatment duration of 2 years, whichever comes first. Cohort 2 includes adult patients with completely resected stage IIB/C, stage III or stage IV melanoma who will receive NIVO IV Q4W for 2 cycles (28-day cycle) followed by NIVO SC + rHuPH20 Q4W until disease recurrence, unacceptable toxicity, or a maximum total treatment duration of 1 year, whichever comes first. The primary endpoint is the proportion of participants preferring the SC route of administration based on question 7 of the Patient Experience and Preference Questionnaire after the Cycle 4 Day 1 dose. This question evaluates patient preference for IV or SC or no preference in treatment administration and was previously used in CheckMate 8KX. Secondary endpoints include safety outcomes such as adverse events (AEs), serious AEs, treatment-related AEs, AEs leading to discontinuation, immune-mediated AEs, other events of special interest, injection/infusion-related AEs, deaths, and laboratory abnormalities. Safety is assessed for IV period, SC period (8 weeks each) and overall study period. Exploratory endpoints include additional measures of patient experience and preference for IV vs SC. The study is recruiting to enroll 50 patients per cohort. Clinical trial information: NCT06101134 .

Long-term safety of hyaluronidase-facilitated subcutaneous immunoglobulin 10%: a European post-authorization study.

Aim: To assess the long-term safety of hyaluronidase-facilitated subcutaneous immunoglobulin (fSCIG) 10% in European routine clinical practice.Materials & methods: This prospective, noninterventional, open-label, post-authorization safety study (EUPAS5812) sourced data on adverse events, immunogenicity, treatment regimens and product administration for 106 adult patients prescribed fSCIG 10% across 17 sites in six European countries from July2014 to February2020.Results: In total, 1171 treatment-emergent adverse events were reported in 94 patients (88.7%); 25.5% of these events were considered related to fSCIG 10%. Positive binding antibody titers developed in three patients; no neutralizing antibodies to recombinant human hyaluronidase were detected.Conclusion: This real-world study of fSCIG 10% is the longest to date and confirms its long-term safety and tolerability in adults with antibody deficiency diseases.

D.1 Efficacy, safety, and tolerability of subcutaneous efgartigimod in chronic inflammatory demyelinating polyneuropathy: results from the ADHERE trial

Background: Efgartigimod, a human immunoglobulin G (IgG)1 antibody Fc fragment, blocks the neonatal Fc receptor, decreasing IgG recycling and reducing pathogenic IgG autoantibody levels. ADHERE assessed the efficacy and safety of efgartigimod PH20 subcutaneous (SC; co-formulated with recombinant human hyaluronidase PH20) in chronic inflammatory demyelinating polyneuropathy (CIDP). Methods: ADHERE enrolled participants with CIDP (treatment naive or on standard treatments withdrawn during run-in period) and consisted of open-label Stage A (efgartigimod PH20 SC once weekly [QW]), and randomized (1:1) Stage B (efgartigimod or placebo QW). Primary outcomes were clinical improvement (assessed with aINCAT, I-RODS, or mean grip strength; Stage A) and time to first aINCAT score deterioration (relapse; Stage B). Secondary outcomes included treatment-emergent adverse events (TEAEs) incidence. Results: 322 participants entered Stage A. 214 (66.5%) were considered responders, randomized, and treated in Stage B. Efgartigimod significantly reduced the risk of relapse (HR: 0.394; 95% CI: 0.25–0.61) versus placebo (p=0.000039). Reduced risk of relapse occurred in participants receiving corticosteroids, intravenous or SC immunoglobulin, or no treatment before study entry. Most TEAEs were mild to moderate; 3 deaths occurred, none related to efgartigimod. Conclusions: Participants treated with efgartigimod PH20 SC maintained a clinical response and remained relapse-free longer than those treated with placebo.

Modeling the subcutaneous pharmacokinetics of antibodies co-administered with rHuPH20.

Predicting the subcutaneous (SC) pharmacokinetics (PK) of antibodies in humans is challenging, with clinical data currently being the only reliable data source for modeling SC absorption and bioavailability. Recombinant human hyaluronidase PH20 (rHuPH20) is an enzyme that facilitates SC delivery of high-dose, high-volume therapeutics. Numerous monoclonal antibodies have been co-administered SC with rHuPH20 in a clinical setting, establishing an extensive PK database. The goal of this work is to demonstrate how aggregated clinical data can be leveraged in a universal modeling framework for characterizing SC antibody PK, resulting in parameterization that can be used in predictive simulations of new antibodies. Data for 10 individual antibodies co-administered SC with rHuPH20 were obtained from publicly available sources. PK modeling of each antibody was conducted using the same model structure, but uniquely parameterized. The model structure consisted of a two-compartment model to capture linear kinetics, plus a target-binding mechanism to accommodate nonlinear kinetics driven by antibody-target complex formation and elimination. The clinical PK profiles for all antibodies were accurately described using the universal modeling framework. The SC PK parameters of absorption and bioavailability were consistent across the range of antibody and target properties evaluated. SC administration with rHuPH20 yielded a 30% increase in absorption rate on average and similar or better bioavailability. These parameter values can serve as initial conditions for model-based PK predictions for new antibodies co-administered SC with rHuPH20 to enable evaluation of optimal SC dose and schedule regimens prior to and during clinical development.

Subcutaneous nivolumab (NIVO SC) vs intravenous nivolumab (NIVO IV) in patients with previously treated advanced or metastatic clear cell renal cell carcinoma (ccRCC): Pharmacokinetics (PK), efficacy, and safety results from CheckMate 67T.

LBA360 Background: NIVO IV has improved outcomes in multiple tumor types. Evolving treatment paradigms have created a need for administration options that address treatment burden and improve efficiencies of healthcare systems. SC delivery of antibodies for various cancer indications has proved safe and effective. CheckMate 67T (NCT04810078) is a multicenter, randomized, open-label, phase 3 study that evaluated PK and objective response rate (ORR) noninferiority of NIVO SC vs IV in patients (pts) with locally advanced or metastatic ccRCC. Methods: Enrolled pts had measurable disease that progressed during or after 1–2 prior systemic regimens, no prior immuno-oncology treatment, and a Karnofsky performance score ≥ 70. Pts were randomized 1:1 to receive NIVO SC 1200 mg + recombinant human hyaluronidase PH20 Q4W or NIVO IV 3 mg/kg Q2W until disease progression, unacceptable toxicity, withdrawal of consent, completion of 2 years’ treatment, or death. The co-primary PK endpoints for noninferiority testing were time-averaged serum concentration over the first 28 days (Cavgd28) and minimum serum concentration at steady state (Cminss) determined by a population PK analysis. ORR by blinded independent central review (BICR) was a key powered secondary endpoint for noninferiority testing. Other secondary objectives included additional PK exposure measures, safety, efficacy, and immunogenicity. Results: A total of 495 pts were randomized to NIVO SC (n = 248) or NIVO IV (n = 247). The median age was 64/66 years in the SC/IV arms. Most pts were male. Average injection time with NIVO SC was &lt; 5 minutes. Noninferiority for the co-primary PK and key powered secondary ORR endpoints was met (see table). Incidence of NIVO SC local injection-site reactions was 8.1%; reactions were low grade and transient. Most deaths were due to disease progression; study drug toxicity led to 3/1 deaths with NIVO SC/IV. Conclusions: The co-primary PK and key powered secondary ORR endpoints were met, supporting the use of NIVO SC as a new option to improve healthcare efficiency. The safety profile for NIVO SC was consistent with NIVO IV. Clinical trial information: NCT04810078 .[Table: see text]

Model-Based Dose Selection of Subcutaneous Nivolumab in Patients with Advanced Solid Tumors.

The pharmacokinetics (PK) of intravenous (i.v.) nivolumab is well characterized. A subcutaneous (s.c.) nivolumab formulation with and without recombinant human hyaluronidase PH20 enzyme is being evaluated in CheckMate 8KX (NCT03656718). A model-based analysis was conducted to characterize the PKof nivolumab s.c. and predict systemic exposures after i.v. and s.c. administration to guide dosing regimen selection for nivolumab s.c. A prior i.v. model was modified to incorporate an s.c. extravascular compartment and estimate the absorption rate constant and bioavailability of nivolumab s.c. Serum concentration-time data from 82 patients treated with nivolumab s.c. 720, 960, or 1,200 mg were pooled with existing i.v. data from multiple studies for model development. Prediction-corrected visual predictive check (pcVPC) plots assessed the model's performance. Stochastic simulations were conducted to predict exposures for i.v. and s.c. administration. The data were described by a two-compartment model with time-varying clearance, zero-order infusion into the central compartment after i.v. dosing, and first-order absorption from the extravascular compartment after s.c. dosing. The pcVPC suggested that the model adequately described the observed nivolumab s.c. data. Predicted nivolumab exposures at 1,200 mg s.c. every 4 weeks (q4w) were higher than those at the approved dose of 3 mg/kg i.v. q2w and lower than those at the highest tested safe dose of 10 mg/kg i.v. q2w. Nivolumab PK is well-characterized using the combined s.c./i.v. population PK model. The model-based analysis facilitated a comprehensive benefit-risk assessment of nivolumab s.c. and informed selection of 1,200 mg s.c. q4w for phase III evaluation.

A Phase 1 Open-Label Study to Assess the Tolerability, Safety, and Immunogenicity of Hyaluronidase-Facilitated Subcutaneous Immunoglobulin 20% in Healthy Adults

PurposeHyaluronidase-facilitated subcutaneous immunoglobulin (fSCIG) 20% will allow reduced infusion volumes and frequency versus existing subcutaneous therapies such as fSCIG 10% and conventional subcutaneous immunoglobulin 20%, respectively. We assessed the tolerability, safety, and immunogenicity of warmed and unwarmed fSCIG 20%.MethodsThis phase 1, single-dose, open-label, three-arm study enrolled healthy adults aged 19–50 years (inclusive) at a single US center (NCT05059977). Post-screening, participants received a single fSCIG 20% dose comprising recombinant human hyaluronidase and varying doses of in-line warmed or unwarmed immunoglobulin G (IgG) during a 4-day treatment period in a sentinel and sequential dosing design (treatment arm 1, warmed IgG 20% 0.4 g/kg; treatment arm 2, warmed IgG 20% 1.0 g/kg; treatment arm 3, unwarmed IgG 20% 1.0 g/kg). Participants were followed for 12 (± 1) weeks post-infusion. The primary endpoint was tolerability (“tolerable” infusions were not interrupted, stopped, or reduced in rate owing to fSCIG 20%-related treatment-emergent adverse events (TEAEs)). Secondary endpoints included occurrence of TEAEs.ResultsOverall, 24 participants were included, 8 per treatment arm (mean age 39.0 years, 54.2% men). All participants tolerated the infusions. All TEAEs were mild (107 events, in all participants), and all participants experienced fSCIG 20%-related (105 events) and local (102 events) TEAEs. Infusion site erythema and infusion site swelling were most frequently reported. No serious TEAEs occurred, and no participants discontinued the study owing to TEAEs.ConclusionfSCIG 20% was well-tolerated with a favorable safety profile in healthy adults. Future studies will evaluate fSCIG 20% in primary immunodeficiency diseases.Trial registration number (ClinicalTrials.gov): NCT05059977 (registered 28 September 2021).

Subcutaneous Administration of a Zwitterionic Chitosan-Based Hydrogel for Controlled Spatiotemporal Release of Monoclonal Antibodies.

Subcutaneous (SC) administration of monoclonal antibodies (mAbs) is a proven strategy for improving therapeutic outcomes and patient compliance. The current FDA-/EMA-approved enzymatic approach, utilizing recombinant human hyaluronidase (rHuPH20) to enhance mAbs SC delivery, involves degrading the extracellular matrix's hyaluronate to increase tissue permeability. However, this method lacks tunable release properties, requiring individual optimization for each mAb. Seeking alternatives, physical polysaccharide hydrogels emerge as promising candidates due to their tunable physicochemical and biodegradability features. Unfortunately, none have demonstrated simultaneous biocompatibility, biodegradability, and controlled release properties for large proteins (≥150kDa) after SC delivery in clinical settings. Here, a novel two-component hydrogel comprising chitosan and chitosan@DOTAGA is introduced that can be seamlessly mixed with sterile mAbs formulations initially designed for intravenous (IV) administration, repurposing them as novel tunable SC formulations. Validated in mice and nonhuman primates (NHPs) with various mAbs, including trastuzumab and rituximab, the hydrogel exhibited biodegradability and biocompatibility features. Pharmacokinetic studies in both species demonstrated tunable controlled release, surpassing the capabilities of rHuPH20, with comparable parameters to the rHuPH20+mAbs formulation. These findings signify the potential for rapid translation to human applications, opening avenues for the clinical development of this novel SC biosimilar formulation.

In Vitro Analysis of Dissolution of 18 HA-based Dermal Fillers with Tailored Hyaluronidase Dosing to Achieve Urgent Reversal of Vascular Complications

Introduction: Hyaluronidase (HYAL), a hyaluronic acid-degrading enzyme, is commonly used “off-label” as part of the gold standard management of hyaluronic acid (HA) dermal filler complications. It is paramount that injectors be cognizant to diagnose and treat filler complications, particularly vascular emboli, where there may be a narrow window for timely treatment. There is a paucity of studies, however, that provide HYAL dosage guidelines in the setting of acute vascular obstruction that are specific to each of the 18 reversible HA-based dermal fillers commercially available on the current US market. Differences in resistance to HYAL degradation is based on variation in cross-linking technique, concentration of HA, and cohesive properties that each filler may possess. This in vitro study investigates optimal dosage parameters of HYAL to achieve gross dissolution of every reversible HA-based filler commercially available to better improve outcomes after filler-induced vascular complications. Methods: Standardized in vitro analysis using 0.5-mL aliquots of all 18 commercially available HA-based fillers included all Restylane products (Lyft, Restylane-L, Silk, Refyne, Defyne, Kysse, Contour), Juvederm products (Volbella, Vollure, Voluma, Ultra XC, Ultra Plus XC), Revanesse products (Versa+, Lips+), Teoxane products (RHA 2, RHA 3, RHA 4), and Belotero. Hylenex, recombinant human HYAL, was used in 150 IU increments for total quantities of either 300, 450, 600, or 750 IU to achieve timed assessment of the gross dissolution of filler using photographic and videographic documentation. Inert dye was used to improve filler visibility against the HYAL. Mechanical integration of HYAL into the filler mimicked massage technique commonly implemented to incorporate HYAL into the perivascular soft tissue to help relieve a filler-induced vascular obstruction. Results: The cross-linking technology utilized by each HA-filler manufacturer played a significant role in the readiness of filler dissolution with HYAL. Fastest dissolution times ranged from 11 seconds to approximately 32 minutes, with a strong correlation with Restylane products dissolving the fastest, followed by Juvederm &amp; Revanesse products. The slowest to achieve gross dissolution were Belotero and the RHA series. Discussion: All 18 HA-based fillers achieved complete gross dissolution within the first 32 minutes, however, due to differences in cross-linking technology and molecular properties, there was large variation in in vitro HYAL-induced degradation that can be extrapolated clinically to help reverse urgent vascular obstruction. This may also help beginner injectors strategically choose the HA-based dermal fillers that have the fastest degradation response to HYAL. Further in vivo studies are necessary to integrate these into clinical practice.

Phase 2 Study of Daratumumab (DARA) Plus Bortezomib, Cyclophosphamide, and Dexamethasone (D-VCd) in a Diverse Patient Population with Newly Diagnosed Amyloid Light Chain (AL) Amyloidosis: Aquarius

Background: AL amyloidosis is a rare disorder in which deposition of insoluble amyloid fibrils composed of misfolded light chains in vital organs, such as the heart or kidney, leads to serious and life-threatening organ dysfunction. Cardiac involvement is the primary determinant of clinical outcomes for patients with AL amyloidosis, and survival expectations decrease with increasing cardiac stage. Subcutaneous DARA (DARA SC) in combination with VCd recently became the first and only approved treatment for newly diagnosed AL amyloidosis based on results of the phase 3 ANDROMEDA study. In the ANDROMEDA study, a higher hematologic complete response rate was consistently achieved with D-VCd versus VCd in patients with newly diagnosed AL amyloidosis, regardless of baseline cardiac stage (Kastritis E, et al. N Engl J Med. 2021;385[1]:46-58). However, cardiac involvement leads to challenges in the attribution of cardiac events to underlying disease and/or treatments. Additionally, among patients randomized to receive D-VCd in the ANDROMEDA study, 15.4% were Asian, 4.6% were Hispanic or Latino, and 3.1% were Black or African American, limiting the interpretation of safety, efficacy, and pharmacokinetic results among patients of different racial and ethnic backgrounds. Therefore, the ongoing phase 2 AQUARIUS (AMY2009) study will characterize the cardiac safety of different D-VCd treatment regimens in patients with newly diagnosed AL amyloidosis with cardiac involvement to identify potential mitigation strategies for cardiac toxicity, as well as better characterize the safety, efficacy, and pharmacokinetics of D-VCd among racial and ethnic minorities. Study Design and Methods: This ongoing multicenter, multicohort, open-label phase 2 study will enroll ~150 patients aged ≥18 years with newly diagnosed systemic AL amyloidosis and measurable disease from ~45 sites across 10 countries. Patients in Cohort 1 (n = ~120) will have cardiac involvement (AL amyloidosis Mayo Cardiac Stage II and Stage IIIa) with or without other organ involvement. Patients in Cohort 2 (n = ~30) will be of racial or ethnic minority (including ≥15 Black or African American patients) and have ≥1 organ affected by systemic AL amyloidosis. Patients in Cohort 1 will be stratified by baseline cardiac stage (Stages II and IIIa) and randomly assigned (2:1) to receive DARA SC plus immediate VCd (Arm A) or DARA SC plus deferred VCd (Arm B; Figure 1). In both arms, DARA SC (DARA 1,800 mg co-formulated with recombinant human hyaluronidase PH20 [rHuPH20; 2,000 U/mL; ENHANZE ® drug delivery technology, Halozyme, Inc., San Diego, CA, USA]) will be administered QW during Cycles 1-2, Q2W during Cycles 3-6, and Q4W thereafter until a maximum of 24 cycles or the start of subsequent therapy. In Arm A, starting at Cycle 1 Day 1, VCd will be administered weekly in every 28-day cycle for a maximum of 6 cycles. In Arm B, starting at Cycle 4 Day 1, VCd will be administered weekly in every 28-day cycle for a maximum of 6 cycles. Patients in Cohort 2 will receive DARA SC plus immediate VCd. Several unique initiatives were incorporated into the study to enhance enrollment of patients of racial or ethnic minority in Cohort 2, including selecting sites from the ANDROMEDA study that enrolled racially/ethnically diverse patients, targeting new sites in diverse communities, raising awareness of AL amyloidosis and the AQUARIUS study among minority patients at the local and national levels, and educating sites on engagement of patients from diverse backgrounds. The first primary endpoint is incidence of any toxicity grade cardiac events for the different D-VCd treatment regimens (DARA SC + immediate VCd and DARA SC + deferred VCd). The second primary endpoint is trough serum concentration (C trough) of DARA at the end of QW dosing (Cycle 3 Day 1 predose). Efficacy evaluations include assessment of hematologic response and organ response. Data will be summarized using descriptive statistics. The first patient was enrolled on March 17, 2022. As of July 10, 2023, the study has enrolled 75 patients; 71 in Cohort 1 and 4 in Cohort 2. In the US, 2 of the 8 patients enrolled were of racial minority ( Figure 2). Efforts to increase enrollment of minorities continue to be optimized and new collaborative initiatives explored to ensure representative and diverse enrollment in clinical trials. The ClinicalTrials.gov Identifier is NCT05250973.

Phase 3 Randomized Study of Daratumumab (DARA) + Bortezomib, Lenalidomide, and Dexamethasone (VRd) Versus Vrd Alone in Patients (Pts) with Newly Diagnosed Multiple Myeloma (NDMM) Who Are Eligible for Autologous Stem Cell Transplantation (ASCT): Primary Results of the Perseus Trial

Introduction: DARA plus bortezomib, thalidomide, and dexamethasone (D-VTd) quadruplet therapy has shown clinical benefit versus VTd alone and is approved for transplant-eligible pts with NDMM. VRd induction followed by autologous stem cell transplant (ASCT), VRd consolidation, and lenalidomide (R) maintenance is also considered a standard of care for transplant-eligible NDMM. In the phase 2 GRIFFIN study, intravenous DARA combined with VRd (D-VRd) induction/consolidation followed by D-R maintenance improved depth of response and progression-free survival (PFS) versus VRd induction/consolidation and R maintenance in transplant-eligible pts with NDMM after &amp;gt;4 years of follow-up. The phase 3 PERSEUS study is evaluating subcutaneous DARA (DARA SC) in combination with VRd induction/consolidation followed by D-R maintenance versus VRd induction/consolidation and R maintenance in transplant-eligible NDMM. Here we report the primary analysis of PERSEUS. Methods: Pts with NDMM who were aged 18-70 years and eligible for high-dose therapy and ASCT were randomized 1:1 to D-VRd or VRd, stratified by International Staging System (ISS) stage and cytogenetic risk. All pts received up to six 28-day cycles (4 pre-ASCT induction, 2 post-ASCT consolidation) of VRd (V: 1.3 mg/m2 SC on Days [D] 1, 4, 8, 11; R: 25 mg PO on D 1-21; d 40 mg PO/IV on D 1-4, 9-12) followed by R maintenance therapy (10 mg PO on D 1-28 until progressive disease [PD]). Pts in the D-VRd arm also received DARA SC (DARA 1,800 mg co-formulated with recombinant human hyaluronidase PH20 [rHuPH20; 2,000 U/mL; ENHANZE® drug delivery technology, Halozyme, Inc.]) weekly in Cycles 1-2, every 2 weeks in Cycles 3-6, and every 4 weeks during maintenance until PD. The primary endpoint is PFS; key secondary endpoints include overall complete response or better (≥CR) rate, overall minimal residual disease (MRD)-negativity rate (10-5 threshold; clonoSEQ®), and overall survival. Response and disease progression were assessed using a computerized algorithm based on IMWG response criteria. Overall MRD-negativity rate was defined as the proportion of pts who achieved MRD negativity and ≥CR at any time. Results: 709 pts were randomized (D-VRd, n=355; VRd, n=354). Median (range) age was 60 (31-70) years; 14.8% had ISS stage III disease, and 21.7% had high cytogenetic risk (t[4;14], t[14;16], or del[17p]). At clinical cutoff, 314 pts in the D-VRd arm and 299 pts in the VRd arm had completed all 4 induction and 2 consolidation cycles, 309 and 294 pts had undergone ASCT, and 322 and 300 pts entered maintenance. At a median follow-up of 47.5 months, PFS was significantly improved with D-VRd versus VRd (HR, 0.42; 95% CI, 0.30-0.59; P &amp;lt;0.0001 [crossing the prespecified stopping boundary of 0.0126]; Figure). Median PFS was not reached in either arm; estimated 48-month PFS rates were 84.3% for D-VRd versus 67.7% for VRd. Prespecified subgroup analyses showed a consistent PFS improvement with D-VRd versus VRd across clinically relevant subgroups, including pts with ISS stage III disease and pts with high cytogenetic risk. Overall rates of ≥CR (87.9% vs 70.1%; P &amp;lt;0.0001) and MRD negativity (75.2% vs 47.5%; P &amp;lt;0.0001) were significantly higher with D-VRd versus VRd. Overall survival was immature, with 78 deaths on study (D-VRd, 34 [9.6%]; VRd, 44 [12.4%]). Overall, 7 deaths due to COVID-19 occurred (D-VRd, 4; VRd, 3). The most frequent (≥10%) grade 3/4 treatment-emergent adverse events (TEAEs) for the D-VRd/VRd arms were neutropenia (62.1%/51.0%), thrombocytopenia (29.1%/17.3%), diarrhea (10.5%/7.8%), pneumonia (10.5%/6.1%), and febrile neutropenia (9.4%/10.1%). For D-VRd and VRd, serious TEAEs occurred in 57.0% versus 49.3% of pts, and TEAEs leading to treatment discontinuation occurred in 8.8% versus 21.3% of pts. Conclusions: DARA SC combined with VRd in transplant-eligible pts with NDMM significantly improved PFS and increased depth of response (≥CR and MRD negativity), with consistent PFS benefit across clinically relevant subgroups. The safety profile was consistent with the known safety profiles for DARA SC and VRd. These data, together with results from the phase 2 GRIFFIN study, demonstrate the consistent and clinically meaningful benefit of quadruplet DARA plus VRd followed by D-R maintenance versus triplet VRd followed by R maintenance and support the combination of DARA plus VRd followed by D-R maintenance as a new standard of care for transplant-eligible NDMM.

Real-World Usage of Hyaluronidase-Facilitated Subcutaneous Immunoglobulin 10% in Patients with Multiple Myeloma Diagnosed with Secondary Immunodeficiency Disease

Introduction: In patients with mature B-cell malignancies such as multiple myeloma (MM), both the underlying disease and immunosuppressive therapy can result in patients developing secondary immunodeficiency disease (SID). SID often manifests in severe, recurrent, or persistent infections that can impair a patient's quality of life and are a major cause of morbidity and mortality in patients with MM, thereby resulting in significant clinical and socioeconomic burden. The use of immunoglobulin (Ig) replacement therapy is well established for the treatment of hypogammaglobulinemia in patients with primary immunodeficiency disease (PIDD). Hyaluronidase-facilitated subcutaneous immunoglobulin (fSCIG) 10% is a dual-vial unit of IgG 10% and recombinant human hyaluronidase (rHuPH20). fSCIG 10% is approved in the USA for the treatment of adults and children aged 2 years or older with PIDD, and in the EU for adults and children of any age with PIDD or SID. fSCIG 10% is not fully integrated into standard of care for patients with SID in many countries, in part owing to comparatively less familiarity of hematologists and oncologists with the evidence supporting the use of fSCIG 10% than for intravenous IgG therapy in patients with SID. Therefore, the HyMMy study (NCT05879757) aims to generate real-world evidence to gain a better understanding of patterns of fSCIG 10% use and outcomes in patients with MM and SID. Methods: HyMMy is a prospective, noninterventional, observational study that will be conducted at 30 centers in Europe and South America. It is planned for 100 patients to be enrolled and observed over a 12-month follow-up period. The overall duration of the study will be 38 months. Patients will be eligible for inclusion if they are aged 18 years or older, have a diagnosis of MM, and fulfill the diagnosis criteria for SID: patient suffers from severe, recurrent, or persistent infection despite appropriate anti-infective treatment, and has proven specific antibody failure or a serum IgG trough level of less than 4 g/L (excluding paraprotein). Patients may enter the study after being diagnosed with SID and no more than 30 days after fSCIG 10% treatment initiation, or with no more than 2 doses of fSCIG 10% already infused ( Figure). Patients newly starting fSCIG 10% have a 30-day window from enrollment to inclusion. Patients will be excluded if they have PIDD, have received Ig treatment or prophylaxis within 3 months of enrollment, have an ongoing serious infection requiring intravenous antimicrobial therapy, have a history of malignancy other than MM within 3 years of enrollment, or have had major surgery within 2 weeks of enrollment. The primary endpoint is to characterize the real-world infusion parameters of fSCIG 10% administration (dosing and administration characteristics; treatment interval; infusion volume, sites, rate, and duration; training visits; and fSCIG 10% discontinuation, interruption, or switch to other treatment). Secondary endpoints will examine the disease course and clinical management of MM (including overall survival and healthcare resource utilization) in patients treated with fSCIG 10%. The exploratory endpoints include: burden of infection; infection rate, type, duration, and severity; patient-reported outcomes pertaining to health-related quality of life, collected via questionnaire at the patients' visit; and overall physician assessment of fSCIG 10% utilization, tolerability, and effectiveness, as measured by a 5-point Likert scale questionnaire. Results: Patient recruitment started in June 2023. Interim analysis is planned after enrollment of the first 50 patients, and the estimated end of the study is 2026. Conclusions: HyMMy is the first prospective, observational study that focuses on the assessment of fSCIG 10% utilization patterns in adults with MM diagnosed with SID. The study will help to improve understanding of the treatment patterns and options available for patients with SID and hematologic malignancies, in particular MM. Takeda Development Center Americas, Inc. funded this study. Takeda Pharmaceuticals International AG funded writing support.

Efficacy and Safety of Daratumumab (DARA) Monotherapy in Patients with Intermediate-Risk or High-Risk Smoldering Multiple Myeloma (SMM): Final Analysis of the Phase 2 Centaurus Study

Introduction: SMM is a precursor disorder to multiple myeloma (MM) (Rajkumar SV, et al. Blood. 2015;125[20]:3069-3075). Current guidelines for SMM recommend active monitoring, with treatment initiation only upon progression to MM. However, therapeutic intervention at the SMM stage may help delay the progression to MM (Lonial S, et al. J Clin Oncol. 2020;38[11]:1126-1137; Mateos MV, et al. ASH 2022. Abstract 118). DARA is a human IgGκ monoclonal antibody targeting CD38 with a direct on-tumor and immunomodulatory mechanism of action. Given the deep and durable responses and favorable safety profile of DARA monotherapy in patients (pts) with relapsed/refractory MM (Usmani SZ, et al. Blood. 2016;128[1]:37-44), we hypothesized that DARA could delay the progression of SMM to MM. In the primary analysis of the phase 2 CENTAURUS study (NCT02316106), after a 15.8-month median follow-up, DARA monotherapy showed activity and was well tolerated in pts with intermediate- or high-risk SMM (Landgren CO, et al. Leukemia. 2020;34[7]:1840-1852). Activity and tolerability of DARA monotherapy were also observed in CENTAURUS after an additional 10 months of median follow-up (Landgren CO, et al. ASH 2018. Abstract 1994). Here, we present the final analysis of the CENTAURUS study, with a median follow-up of 85.2 months (~7 years). Methods: Eligible pts had a diagnosis of intermediate-risk or high-risk SMM for &amp;lt;5 years. Pts were randomized (1:1:1) to receive 8-week cycles of DARA 16 mg/kg intravenously (IV) on 1 of 3 dosing schedules. In the Intense dosing arm, pts received DARA QW (Cycle 1), Q2W (Cycles 2-3), Q4W (Cycles 4-7), and Q8W (Cycles 8-20). In the Intermediate dosing arm, pts received DARA QW (Cycle 1) and Q8W (Cycles 2-20). In the Short dosing arm, pts received 1 cycle of DARA QW. For pts in the Intense and Intermediate arms, there was an option to extend treatment (Extension phase) with DARA IV or with subcutaneous DARA (DARA SC; DARA 1,800 mg co-formulated with recombinant human hyaluronidase PH20 [2,000 U/mL; Halozyme, Inc.]) Q8W after the end of Cycle 20 per investigator discretion if there was a positive benefit/risk ratio, no grade ≥3 treatment-related toxicity, and at least stable disease had been achieved. Rate of complete response or better (≥CR) was a primary endpoint. Secondary endpoints included overall response rate (ORR) and overall survival (OS). Results: A total of 123 pts (41 pts per arm) were randomized. Median (range) age was 61 (31-81) years. Median duration of study treatment overall during the study was 44.0 months in the Intense arm, 35.2 months in the Intermediate arm, and 1.6 months in the Short arm. A total of 36 pts (21 pts in the Intense arm and 15 pts in the Intermediate arm) continued to receive DARA Q8W in the Extension phase (Cycles 21+). During the Extension phase, median duration of study treatment was 45.2 months in the Intense arm and 46.1 months in the Intermediate arm ( Table 1). 16 pts in the Intense arm and 10 pts in the Intermediate arm switched from DARA IV to DARA SC during the Extension phase. Efficacy results are summarized in Table 2. At a median (range) follow-up of 85.2 (0-94.3) months, ORR and ≥CR rate were higher in the Intense and Intermediate arms than in the Short arm. In the Intense and Intermediate arms combined, the ≥CR rate was 8.5%. Median OS was not reached in any dosing arm; the 84-month OS rate was 81.3%, 89.5%, and 88.1% in the Intense, Intermediate, and Short arms, respectively. Safety results are summarized in Table 1. Grade 3/4 treatment-emergent adverse events (TEAEs) occurred in 65.9%, 41.5%, and 15.0% of pts in the Intense, Intermediate, and Short arms, respectively; grade 3/4 TEAEs were reasonably related to DARA in 12.2%, 2.4%, and 5.0% of pts, respectively. TEAEs that led to discontinuation of DARA occurred in 7.3%, 2.4%, and 5.0% of pts in the Intense, Intermediate, and Short arms, respectively. Conclusions: Findings from this final analysis of CENTAURUS continue to demonstrate the clinical activity of DARA monotherapy in pts with intermediate- or high-risk SMM after a median follow-up of ~7 years. A high proportion (44%) of pts in the Intense and Intermediate arms completed 20 cycles and remained on DARA monotherapy per investigator discretion, with a median duration of additional treatment of 46.0 months (~4 years) in the Extension phase. No new safety concerns were observed with extended follow-up.