Administration-related Reactions Research Articles

Evaluation of administration-related reactions with subcutaneous daratumumab with and without premedication.

Daratumumab-hyaluronidase-fihj (Dara-SQ) is frequently used in the treatment of plasma cell disorders and is associated with improved outcomes. Dara-SQ was shown to be non-inferior to intravenous daratumumab (Dara-IV) in efficacy, safety, and associated with fewer administration-related reactions (ARRs). Despite the lower ARR risk with Dara-SQ, package labeling still recommends indefinite premedication. In this study, we investigated the safety of premedication discontinuation after one cycle of Dara-SQ. This pre-post interventional quality improvement study included all patients aged 18 years and older diagnosed with multiple myeloma or light chain (AL) amyloidosis who received at least one dose of Dara-SQ. Patients in Arm 1 received Dara-SQ per package labeling, while patients in Arm 2 had premedication omitted (excluding dexamethasone) after cycle 1. The primary endpoint was the incidence of ARR after cycle 1. Overall ARR rate and therapy time saved were also evaluated. A total of 102 patients (63 in Arm 1 and 39 in Arm 2) were included. There were zero reactions in either arm after cycle 1 across 1479 Dara-SQ doses administered over a 30-month period with or without premedication omission. The overall ARR rate was 2.9% (3/102), which all occurred prior to premedication omission. Therapy timed saved from premedication omission was 194 hours in a 6-month period, equating to approximately $140 000 USD. ARRs to Dara-SQ were rare, mild, and occurred during cycle 1 prior to premedication omission. Omission of noncorticosteroid premedication is safe, feasible, and carries substantial time and cost savings for patients and infusion centers.

Subcutaneous amivantamab and lazertinib as first-line treatment in patients with EGFR-mutated, advanced non-small cell lung cancer (NSCLC): Results from the phase 2 PALOMA-2 study.

LBA8612 Background: Amivantamab (ami), an EGFR-MET bispecific antibody with immune cell-directing activity, is approved as an intravenous (IV) formulation. IV ami + lazertinib (laz), a 3rd-generation EGFR TKI, demonstrated superior progression-free survival (PFS) in patients (pts) with treatment-naïve, advanced EGFR-mutated NSCLC vs osimertinib (Cho Ann Oncol 2023). Subcutaneous (SC) ami substantially reduced infusion-related reactions (16% vs 67%) and administration time (≤7 mins vs 2–4 hours) vs historical IV experience (Minchom JCO 2023). PALOMA-2 (NCT05498428) evaluated the efficacy, safety, and pharmacokinetics (PK) of first-line SC ami+laz. Methods: Cohorts 1 and 6 enrolled pts with treatment-naïve, EGFR Ex19del or L858R-mutated advanced NSCLC. Prophylactic anticoagulation for the first 4 months (mo) of treatment was recommended in cohort 1 and mandatory in cohort 6. SC ami was administered by manual injection in the abdomen at 1600 mg (≥80 kg: 2240 mg) weekly for the first 4 weeks and every 2 weeks thereafter. Laz was dosed orally at 240 mg daily. The primary endpoint was objective response rate (ORR) as assessed by the investigator per RECIST v1.1. Results: As of 6 Jan 2024, 68 and 58 pts were enrolled in cohorts 1 and 6, respectively. Overall, median age was 59 years, 60% were female, and 68% Asian. The median follow-up was 10 mo for cohort 1 and 6 mo for cohort 6. ORR (confirmed responses) in cohort 1 was 68% (95% CI, 55–79) by investigator and 72% (95% CI, 60–82) by independent central review. ORR in cohort 6 was 64% (95% CI, 49–78) and 73% (95% CI, 58–85), respectively. At data cutoff, 40/46 responders in cohort 1 and 29/29 responders in cohort 6 were receiving ongoing treatment. Best overall response rates (includes unconfirmed responses) were 81% (95% CI, 70–89) for cohort 1 and 76% (95% CI, 61–87) for cohort 6. Median time to response was 2 mo (range, 1.4–5.3). Median duration of response, PFS, and overall survival were not estimable. Administration-related reactions (ARRs) were reported in 13 (19%) pts in cohort 1 and 6 (11%) pts in cohort 6, all grade 1–2. EGFR- and MET-related AEs were primarily grade 1–2. Total of 71% of pts in cohort 1 and 100% in cohort 6 received prophylactic anticoagulation. Venous thromboembolic events (VTE) were reported in 18% and 7% of pts in cohorts 1 and 6, respectively. There were no dose reductions or discontinuations due to VTE. Rate of bleeding was 2% among pts receiving anticoagulation. Mean ami concentrations on cycle 2 day 1 were 328 µg/mL (n=49) in cohort 1 and 371 µg/mL (n=41) in cohort 6, consistent with historic IV levels. Conclusions: SC ami+laz showed a response rate similar to historic IV ami+laz in first-line EGFR-mutated NSCLC, with an improved safety profile that included significantly lower ARR rates. Further, prophylactic anticoagulation can be safely implemented and reduced incidence of VTE. Clinical trial information: NCT05498428 .

Daratumumab, Bortezomib, Melphalan, and Prednisone (D-VMP) Versus Bortezomib, Melphalan, and Prednisone (VMP) Alone in Transplant-Ineligible Asian Patients with Newly Diagnosed Multiple Myeloma: Final Analysis of the Phase 3 Octans Study

Introduction: Daratumumab is a human IgGκ monoclonal antibody targeting CD38 with a direct on-tumor and immunomodulatory mechanism of action and has shown clinical efficacy for the treatment of multiple myeloma (MM). In an updated analysis of the global phase 3 ALCYONE study, D-VMP demonstrated a significant progression-free survival (PFS) benefit compared to VMP in transplant-ineligible patients with newly diagnosed MM (NDMM). A prior analysis of the phase 3 OCTANS study (median follow-up, 12.3 months) also showed a favorable clinical benefit/risk profile for D-VMP versus VMP in transplant-ineligible Asian patients with NDMM. Here, we report results from the final analysis of OCTANS, with a median follow-up of >3 years. Methods: The randomized, phase 3 OCTANS study (NCT03217812) enrolled Asian patients with NDMM who were ineligible for autologous stem-cell transplant due to age or presence of comorbidities. Patients were randomized 1:2 (VMP:D-VMP) to receive up to nine 42-day cycles of VMP (bortezomib 1.3 mg/m 2 SC twice weekly in Cycle 1 and weekly in Cycles 2-9, and melphalan 9 mg/m 2 and prednisone 60 mg/m 2 orally on Days 1-4 of each cycle) or D-VMP (VMP + daratumumab 16 mg/kg IV weekly in Cycle 1, every 3 weeks in Cycles 2-9, and every 4 weeks thereafter until disease progression). Per a protocol amendment, patients receiving daratumumab IV were permitted to switch to daratumumab SC 1,800 mg (same schedule as IV) on Day 1 of any cycle. The primary endpoint was achievement of a very good partial response (VGPR) or better. Results: A total of 220 patients were randomized to D-VMP (n = 146) or VMP (n = 74). At the time of the final analysis, with a median follow-up of 41.2 months, the rate of VGPR or better was significantly higher with D-VMP versus VMP (80.1% vs 47.3%; P <0.0001; Table). The rate of measurable residual disease negativity (10 -5) was also higher with D-VMP versus VMP (40.4% vs 10.8%; P <0.0001). D-VMP continued to show a significant improvement in PFS versus VMP (median, 38.7 vs 19.2 months; HR, 0.35; 95% CI, 0.23-0.52; P <0.0001; Table, Figure), as well as a longer time to subsequent antimyeloma therapy (median, 46.8 vs 20.6 months; HR, 0.31; 95% CI, 0.20-0.47; P <0.0001). However, median overall survival was not yet reached for either group. The overall safety profile of D-VMP was consistent with that observed for the primary analysis. Grade 3/4 treatment-emergent adverse events (TEAEs) were reported for 133 (92.4%) patients who received D-VMP and 60 (84.5%) patients who received VMP and were primarily hematologic events; nonhematologic grade 3/4 TEAEs in ≥10% of patients included pneumonia (D-VMP, 31.3% vs VMP, 18.3%), hypokalemia (15.3% vs 4.2%), and hypertension (13.2% vs 8.5%). Grade 3/4 infection TEAEs were reported for 67 (46.5%) and 22 (31.0%) patients who received D-VMP or VMP, respectively. Serious TEAEs were reported for 75 (52.1%) and 28 (39.4%) patients in the D-VMP and VMP groups, respectively, and TEAEs led to treatment discontinuation in 6 (4.2%) and 4 (5.6%) patients, respectively. The incidence of infusion-related reaction TEAEs in the D-VMP group was 33.3%, which is consistent with that previously reported for daratumumab; most events were of grade 1 or 2 severity. The risk of immunogenicity to daratumumab was low, with 1 of 130 evaluable patients testing positive for daratumumab antibodies. Within the D-VMP group, 76 patients switched from daratumumab IV to SC administration. Among these patients, 64 (84.2%) patients preferred SC administration, 7 (9.2%) preferred IV administration, and 15 (19.7%) had no preference on ≥1 of 2 surveys. Of the 64 patients who preferred SC administration, primary reasons included treatment administration time (84.4%), more comfortable administration process (57.8%), less caregiver burden (31.2%), and fewer administration-related reactions (26.6%). Conclusions: With a median follow-up of >3 years, this final analysis of OCTANS demonstrated a continued clinical benefit with D-VMP versus VMP in Asian patients, with PFS improvement comparable to that observed in the global ALCYONE study (HR, 0.35 vs 0.42, respectively). No new safety concerns were identified for D-VMP with extended follow-up. In addition, daratumumab SC administration was preferred by the majority of patients who switched from daratumumab IV. These results further support the use of daratumumab IV or SC in combination with VMP in transplant-ineligible Asian patients with NDMM.

Daratumumab, Bortezomib, and Dexamethasone (D-Vd) Versus Bortezomib and Dexamethasone (Vd) Alone in Chinese Patients with Relapsed/Refractory Multiple Myeloma: Final Analysis of the Phase 3 Lepus Study

Introduction: Daratumumab is a human IgGκ monoclonal antibody targeting CD38 with a direct on-tumor and immunomodulatory mechanism of action. D-Vd prolonged progression-free survival (PFS) and induced deeper and more durable responses versus Vd alone in patients with relapsed/refractory multiple myeloma (RRMM) in the global phase 3 CASTOR study. A prior updated analysis of the phase 3 LEPUS study (median follow-up, 25.1 months) showed significant clinical benefit for D-Vd versus Vd in Chinese patients who have RRMM, and a safety profile generally consistent with that observed in CASTOR. Here, we report results from the final analysis of LEPUS with an extended median follow-up of >3 years. Methods: In the randomized, multicenter, phase 3 LEPUS study (ClinicalTrials.gov Identifier: NCT03234972), Chinese patients with RRMM who had received ≥1 prior line of therapy were randomized 2:1 to 8 cycles (21 days/cycle) of Vd (bortezomib 1.3 mg/m 2 SC on Days 1, 4, 8, and 11; dexamethasone 20 mg PO/IV on Days 1, 2, 4, 5, 8, 9, 11, and 12) ± daratumumab (16 mg/kg IV weekly in Cycles 1-3, every 3 weeks in Cycles 4-8, and every 4 weeks thereafter until disease progression). Per a protocol amendment, on Day 1 of any cycle patients receiving daratumumab IV were permitted to switch to daratumumab SC 1800 mg (same schedule as IV). The primary endpoint was PFS. Results: A total of 211 patients were randomized to D-Vd (n = 141) or Vd (n = 70). At a median follow-up of 37.1 months, D-Vd continued to prolong PFS versus Vd alone (median, 14.9 vs 6.3 months; hazard ratio [HR], 0.36; 95% confidence interval [CI], 0.25-0.52; P <0.00001; Figure 1). Time to progression (median, 15.7 vs 6.8 months; HR, 0.34; 95% CI, 0.23-0.51; P <0.00001) and overall survival (median, not reached vs 40.7 months; HR, 0.76; 95% CI, 0.50-1.17; P = 0.21; Figure 2) were longer with D-Vd versus Vd. The duration of response among patients who achieved a partial response or better was also longer with D-Vd versus Vd (median, 16.8 vs 9.0 months). The measurable residual disease-negativity rate (10 -5) was higher with D-Vd versus Vd (32.6% vs 4.3%; odds ratio, 10.81; 95% CI, 3.23-36.23; P <0.0001). The safety profile of D-Vd observed at the final analysis was generally consistent with that observed for the prior updated analysis. Grade 3/4 treatment-emergent adverse events (TEAEs) were primarily hematologic events. Grade 3/4 infections were reported for 77 (55.0%) patients who received D-Vd and 28 (41.2%) patients who received Vd; lung infection (30.7% vs 22.1%, respectively) was the only nonhematologic grade 3/4 TEAE reported in ≥20% of patients. For patients who received D-Vd and Vd, respectively, TEAEs were classified as serious for 76 (54.3%) and 27 (39.7%) patients, led to treatment discontinuation in 7 (5.0%) and 2 (2.9%) patients, and led to death in 6 (4.3%) and 7 (10.3%) patients. None of the 123 patients in the D-Vd group who had appropriate immunogenicity samples were positive for antibodies to daratumumab. A total of 31 patients in the D-Vd group switched from daratumumab IV to daratumumab SC during the study (after completion of bortezomib and dexamethasone); among these patients, 24 (77.4%) preferred SC administration, 2 (6.5%) preferred IV administration, and 5 (16.1%) had no preference. For the 24 patients who indicated they preferred daratumumab SC administration, key reasons for their preference included treatment administration time (83.3%), more comfortable administration process (70.8%), fewer administration-related reactions (45.8%), and less caregiver burden (25.0%). Among the 31 patients who switched to daratumumab SC, 6 (19.4%) patients experienced grade 3 TEAEs (most commonly hyperglycemia and hypokalemia, n = 2 each) and 2 (6.5%) patients experienced serious AEs (pyrexia and hyperglycemia, n = 1 each). Conclusions: In this final analysis of LEPUS with a median follow-up of >3 years, D-Vd continued to demonstrate substantial efficacy benefits versus Vd and the safety profile of D-Vd remained stable, with no new safety concerns identified. In addition, several patients switched their daratumumab administration from IV to SC, which was preferred by most patients who switched. These results further support the feasibility of daratumumab SC administration and the use of D-Vd as a standard of care in Chinese patients with RRMM who have received ≥1 prior line of therapy.

Ocrelizumab and ofatumumab, but not rituximab, trigger complement induction in vitro

The clinical and adverse effects of the therapeutic monoclonal antibodies (mAb) ocrelizumab, ofatumumab and rituximab in multiple sclerosis (MS) are presently subject to extensive study. While the two former are approved for MS, the older and less costly rituximab is used off label, and adverse effect profiles are important in their evaluation. The three mAbs all induce B cell depletion, with complement-dependent cytotoxicity (CDC) as one of several mechanisms of action. Complement activation is also postulated to underlie adverse reactions related to infusion/injection. Such administration-related reactions are associated with all three mAbs, but comparisons have so far been indirect, resting on incidence reports from separate clinical trials. The objective of this study was to perform head-to-head comparison of complement activation by ofatumumab, ocrelizumab and rituximab. In vitro experiments were performed in whole blood from healthy donors. The complement-activating potential of the three mAbs was analyzed after 30 min of exposure to 0.3 mg/mL or 0.9 mg/mL of each drug, and compared with those of the well-known TNF inhibitory mAbs adalimumab and infliximab, the latter with recognized potential for infusion reactions. Ofatumumab, ocrelizumab, and infliximab, but not rituximab and adalimumab, triggered statistically significant complement activation measured as increased levels of terminal C5b-9 complement complex (TCC), a sensitive marker of such activation. While results demand careful interpretation, they provide an indication of distinct complement-inducing potential among anti-CD20 mAbs currently used to treat MS.

Clinical Administration Characteristics of Subcutaneous and Intravenous Administration of Daratumumab in Patients With Multiple Myeloma at Mayo Clinic Infusion Centers.

Median duration of daratumumab (DARA) administration for treatment of multiple myeloma is 3-7 hours for the intravenous formulation (DARA IV) and 3-5 minutes for the subcutaneous formulation (DARA SC). Here, we describe clinical administration characteristics of DARA using a novel method for data extraction from electronic health records. Time-based measurements were extracted using a scheduling/pharmacy software program that tracked patient movement through appointments for patients initiating DARA in Mayo Clinic infusion centers from April 5, 2017, to October 14, 2021. Cohorts included patients who received DARA IV or DARA SC, or converted from DARA IV to DARA SC. The DARA SC cohort was further analyzed before (DARA SC initial) and after (DARA SC shortened) a reduction in the postadministration observation time mandated by the treatment plan. Events associated with administration-related reactions (ARRs) were also identified. Median total clinic times were 2.7-3.0 hours shorter for DARA SC versus DARA IV. Median clinic times were highest at dose 1 and decreased with subsequent doses. Median total chair times were 2.7-2.8 hours shorter for DARA SC versus DARA IV. Incidences of ARR-related events with DARA SC were low across doses. Reduced clinic times were observed with DARA SC, indicating that use of DARA SC as a treatment option results in time savings that may free clinic resources. Furthermore, novel methods of electronic health record data extraction can provide insights that may help inform clinic resource optimization.

English version of Japanese guidance for use of biologics for psoriasis (the 2022 version).

This is the English version of Japanese guidance for use of biologics for psoriasis (the 2022 version). As the first biologics for psoriasis in Japan, infliximab and adalimumab, anti-tumor necrosis factor-α antibodies, became available in the field of dermatology in 2010, followed by ustekinumab, an anti-interleukin (IL)-12/IL-23p40 antibody, which was launched in Japan in 2011. Moreover, after 2015, three IL-17 inhibitors, the IL-17A antibody preparations secukinumab and ixekizumab, and an anti-IL-17 receptor antibody preparation brodalumab were marketed. Furthermore, after 2018, the anti-IL23p19 antibody preparations guselkumab and risankizumab, the TNF inhibitor certolizumab pegol, the IL-23 inhibitor tildrakizumab, and the anti-IL-17A/F antibody bimekizumab were marketed. It is important for physicians to select appropriate biologic therapy for each psoriatic patient after due consideration of disease factors, treatment factors, and patient background factors, sharing such information with patients. The followings can be listed as points to be considered for the selection of biologics: drug effects (e.g., strength of effectiveness, time to onset of effectiveness, effectiveness against arthritis, primary failure, secondary failure), safety (e.g., infections, administration-related reactions, and relationships with other comorbidities), convenience for patients (e.g., hospital visit intervals, self-injection, maintenance therapy at clinics, feasibility of drug discontinuation/re-administration), and payment (medical costs) borne by patients. This guidance has been prepared with the aim of allowing dermatologists experienced in the treatment of psoriasis to use biologics appropriately according to the circumstances of individual patients after consideration of the above-mentioned factors.

882TiP Subcutaneous vs intravenous nivolumab in patients with melanoma following complete resection

Nivolumab (NIVO), a programmed death-1 immune checkpoint inhibitor, is approved globally as an effective treatment across multiple cancer types. Several studies are investigating subcutaneous (SC) NIVO, co-formulated with recombinant human hyaluronidase PH20 (rHuPH20), as it may benefit patients, clinicians, and the healthcare system. Patients with cancer often prefer SC over IV administration. SC dosing may alleviate the need for IV vein ports, lower the risk of dosing errors, allow more patient flexibility, and reduce dose preparation and administration times, thereby optimizing occupancy in infusion centres. In CheckMate 8KX, SC NIVO + rHuPH20 was well tolerated in patients with different solid tumours and exposures were comparable to IV NIVO 3 mg/kg Q2W (from historical data). Investigations of SC NIVO vs IV NIVO in patients with clear cell renal cell carcinoma (phase 3 CheckMate 67T study) or melanoma following complete resection are ongoing. CheckMate 6GE is a multicentre, randomized, open-label, phase 3 study evaluating the pharmacokinetic (PK) noninferiority of SC NIVO + rHuPH20 vs IV NIVO in patients with melanoma following complete resection. Inclusion criteria are stage IIIA/B/C/D or stage IV melanoma, complete resection ≤ 12 weeks before randomization or treatment assignment, and ECOG performance status ≤ 1. Key exclusion criteria include a history of uveal/mucosal melanoma, untreated/unresected CNS metastases, concurrent malignancy or history of prior malignancy active ≤ 2 years before randomization or treatment assignment, known or suspected autoimmune disease, serious/uncontrolled medical disorder 4 weeks before screening, and prior immunotherapy. Patients (N ≈ 286) are randomized (1:1) to receive SC NIVO or IV NIVO in part 1 (stratified by stage [IIIA/B vs IIIC/D/IV] and weight [< 80 kg vs ≥ 80 kg]) or enrolled in the part 2 PK cohort. PK, safety, efficacy, immunogenicity, and cancer treatment satisfaction will be evaluated (Table).Table: 882TiPPrimary endpointsTime-averaged NIVO serum concentration over the first 28 daysCmin at steady stateSecondary endpointsSafety and tolerability, eg, AEs, serious AEs, immune-mediated AEs, death, administration-related reactions, laboratory abnormalitiesRecurrence-free survivalOverall survivalAdditional PK parameters: Cmin on Day 28, Cmax after the first dose, time to Cmax after the first dose, Cmax at steady state, time-averaged NIVO serum concentration at steady stateImmunogenicity (anti-NIVO and neutralizing antibodies)Cancer Treatment Satisfaction QuestionnaireAE, adverse event; Cmax, maximum NIVO serum concentration; Cmin, minimum NIVO serum concentration. Open table in a new tab AE, adverse event; Cmax, maximum NIVO serum concentration; Cmin, minimum NIVO serum concentration. NCT05297565. Professional medical writing and editorial assistance was provided by George Hsu, PhD, and Matthew Weddig, BA, of Spark Medica Inc., funded by Bristol Myers Squibb. Bristol Myers Squibb.

Safety and Efficacy of Subcutaneous Rituximab in Previously Untreated Patients with CD20+ Diffuse Large B-Cell Lymphoma or Follicular Lymphoma: Results from an Italian Phase IIIb Study.

Subcutaneous (SC) rituximab may be beneficial in terms of convenience and tolerability, with potentially fewer and less severe administration-related reactions (ARRs) compared to the intravenous (IV) form. This report presents the results of a phase IIIb study conducted in Italy. The study included adult patients with CD20+ DLBCL or FL having received at least one full dose of IV RTX 375 mg/m2 during induction or maintenance. Patients on induction received ≥4 cycles of RTX SC 1400 mg plus standard chemotherapy and FL patients on maintenance received ≥6 cycles of RTX SC. Overall, 159 patients (73 DLBCL, 86 FL) were enrolled: 103 (54 DLBCL, 49 FL) completed induction and 42 patients with FL completed 12 maintenance cycles. ARRs were reported in 10 patients (6.3%), 3 (4.2%) with DLBCL and 7 (8.1%) with FL, all of mild severity, and resolved without dose delay/discontinuation. Treatment-emergent adverse events (TEAEs) and serious adverse events occurred in 41 (25.9%) and 14 patients (8.9%), respectively. Two patients with DLBCL had fatal events: Klebsiella infection (related to rituximab) and septic shock (related to chemotherapy). Neutropenia (14 patients, 8.9%) was the most common treatment-related TEAE. Two patients with DLBCL (2.8%) and 6 with FL (7.0%) discontinued rituximab due to TEAEs. 65.2% and 69.7% of patients with DLBCL and 67.9% and 73.6% of patients with FL had complete response (CR) and CR unconfirmed, respectively. The median time to events (EFS, PFS, and OS) was not estimable due to the low rate of events. At a median follow-up of 29.5 and 47.8 months in patients with DLBCL and FL, respectively, EFS, PFS, and OS were 70.8%, 70.8%, and 80.6% in patients with DLBCL and 77.9%, 77.9%, and 95.3% in patients with FL, respectively. The switch from IV to SC rituximab in patients with DLBCL and FL was associated with low risk of ARRs and satisfactory response in both groups. This trial was registered with NCT01987505.

Successful Conversion and Implementation to Subcutaneous Daratumumab in Patients with Multiple Myeloma (MM) and Light Chain (AL) Amyloidosis

IntroductionIntravenous (IV) daratumumab has become a standard in the treatment of MM and AL amyloidosis largely due to its significant clinical benefit. Due to the high risk of infusion-related reactions (IRRs) prolonged infusion times are required at time of treatment initiation. These lengthy administrations can limit clinic capacity, require split dose infusions, increase chair time, and decrease patient satisfaction. Fixed-dose subcutaneous (SC) formulation of daratumumab (daratumumab and hyaluronidase-fihj) was approved in 2020 for the treatment of MM and subsequently, AL amyloidosis in 2021. While landmark trials have demonstrated its efficacy, there is lack of consensus around the standardized pre-medications and post-injection monitoring times for SC daratumumab. We present real world evidence from a large academic center with adoption and standardization of SC formulation of daratumumab into clinical practice.MethodsWe evaluated all patients that received SC daratumumab for MM and/or AL amyloidosis at Boston Medical Center from June 1, 2020 to February 28, 2021. Baseline demographics were collected, including patient diagnosis, chemotherapy regimen, prior daratumumab administration details, and total doses of daratumumab received. Patients that were naïve to daratumumab, started their first dose as a SC injection. Patients were monitored for 30 minutes following the first SC dose and were pre-medicated with all oral agents: acetaminophen, dexamethasone, and diphenhydramine. Infusion chair time, improvement in clinic efficiency (using our standard infusion time of 90 minutes for IV daratumumab infusions after the 2nd dose), and safety were evaluated.ResultsA total of 41 patients were treated with SC daratumumab. Eighteen patients (44%) were switched from IV daratumumab to SC daratumumab. All other patients were naïve to SC daratumumab (n=23). All patients were monitored for 30 minutes after their first SC daratumumab dose only. In the absence of an ARR (administration-related reactions), patients were not monitored after subsequent injections. One patient had facial and neck swelling 2 days after administration of SC daratumumab (with no other symptoms) but resolved within 24 hours of an additional dose of dexamethasone and did not recur upon re-challenge of SC daratumumab. One patient experienced nausea following her first dose of SC daratumumab but it resolved without intervention. All patients received dexamethasone 20-40 mg (as anti-myeloma dose), acetaminophen 650 mg, and diphenhydramine 25-50 mg prior to the dose of SC daratumumab. Fourteen patients (24%) received montelukast 10 mg and 19 patients (46%) received famotidine 20-40 mg prior to the dose of SC daratumumab at provider discretion. Dexamethasone 4 mg daily for two days post-injection was not administered with SC formulation as was previously routine with the IV formulation. When analyzing the chair time saved by this standard monitoring protocol, a total of 478.8 hours of chair time were saved that were used for other patients in our practice (average of 11.7 hours saved per patient).ConclusionWe report a successful conversion and adoption of SC daratumumab at our ambulatory hematology/oncology clinic. A standard 30-minute monitoring parameter can safely be implemented following the first SC daratumumab dose. Furthermore, less aggressive supportive medications can also be used. Integration of the SC formulation yielded significant chair time savings and may have the ability to create a more efficient clinic workflow. [Display omitted] DisclosuresHughes: Rigel: Other: Advisory Board, Research Funding; Amgen: Speakers Bureau; Karyopharm: Other: Advisory Board, Speakers Bureau; Abbvie: Speakers Bureau. Sloan: Pharmacosmos: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria; Stemline: Honoraria. Sanchorawala: Abbvie: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Caelum: Membership on an entity's Board of Directors or advisory committees, Research Funding; Regeneron: Membership on an entity's Board of Directors or advisory committees; Proclara: Membership on an entity's Board of Directors or advisory committees; Oncopeptide: Research Funding; Karyopharm: Research Funding; Sorrento: Research Funding; Pfizer: Honoraria.

Clinical Administration Characteristics of Subcutaneous and Intravenous Administration of Daratumumab in Multiple Myeloma Patients at Mayo Clinic

Clinical Administration Characteristics of Subcutaneous and Intravenous Administration of Daratumumab in Multiple Myeloma Patients at Mayo Clinic

SUBCUTANEOUS DARATUMUMAB + BORTEZOMIB, CYCLOPHOSPHAMIDE, AND DEXAMETHASONE (VCD) IN PATIENTS WITH NEWLY DIAGNOSED LIGHT CHAIN (AL) AMYLOIDOSIS: UPDATED RESULTS FROM THE PHASE 3 ANDROMEDA STUDY

Systemic AL amyloidosis is a plasma cell disease characterized by the deposition of insoluble amyloid fibrils causing organ dysfunction and death. Primary results from the ANDROMEDA study showed that addition of subcutaneous (SC) daratumumab (DARA) to the standard of care combination of bortezomib, cyclophosphamide, and dexamethasone (VCd) was superior to VCd alone, with higher rates of hematologic complete response (CR) and an acceptable safety profile. DARA-VCd was approved for newly diagnosed AL amyloidosis in January 2021. Here we present an update of the primary ANDROMEDA study results with longer follow-up. ANDROMEDA is a randomized, open-label, active-controlled phase 3 study. Adult patients with newly diagnosed AL amyloidosis were randomized 1:1 to DARA-VCd or VCd and were treated for 6 cycles 28 days each. Bortezomib (1.3 mg/m 2 ), cyclophosphamide (300 mg/m 2 ; maximum weekly dose 500 mg), and dexamethasone (40 mg) were given weekly. DARA SC was given weekly (cycle 1–2) and every 2 weeks (cycle 3–6). After cycle 6, patients in the DARA-VCd group received DARA SC alone every 4 weeks for up to 24 cycles from first dose. Disease status was evaluated every 4 weeks in cycle 1–6 and every 8 weeks after cycle 7. The primary endpoint was overall hematologic CR rate in the intent-to-treat population. Secondary endpoints were major organ deterioration progression-free survival (PFS), organ response rate, time to hematologic response, survival, and safety. Of 388 randomized patients, 195 were randomized to DARA-VCd and 193 to VCd. As of November 2020, the median follow-up was 20.3 months (mo), with a median treatment duration of 18.5 mo for DARA-VCd and 5.3 mo for VCd; 78 patients (40%) in the DARA-VCd group were still on treatment. The overall hematologic CR rate continued to be higher with DARA-VCd than VCd (59% vs 19%; odds ratio [OR] 5.9; 95% CI 3.7–9.4; p < 0.0001). More patients achieved a very good partial response or better (≥VGPR) with DARA-VCd than VCd (79% vs 50%; OR 3.7; 95% CI 2.4–5.9; p < 0.0001). Among responders, median time from randomization to ≥VGPR was shorter for DARA-VCd than VCd (0.56 vs 0.82 months). Cardiac response rates were higher with DARA-VCd than VCd at 6 months (42% vs 22%) and at 12 months (57% vs 28%); renal response rates were 54% vs 27% at 6 months and 57% vs 27% at 12 months. A total of 71 deaths occurred (DARA-VCd, n = 31; VCd, n = 40). From cycle 7 onward in the DARA-VCd group, no grade 3/4 treatment-emergent adverse events occurred in ≥5% of patients. There were no systemic administration-related reactions with DARA-VCd after cycle 6. Analysis of major organ deterioration PFS will be updated after ̃200 events have occurred. DARA-VCd (versus VCd alone) demonstrated robust hematologic and organ responses with no new safety concerns with longer follow-up. Updated results from the ANDROMEDA study reinforce the clinical superiority of DARA-VCd over VCd in pts with newly diagnosed AL amyloidosis. Based on its recent approval, DARA-VCd represents a new standard of care in AL amyloidosis. This trial was registered at www.clinicaltrials.gov as NCT03201965.

Clinical Perspectives on the Molecular and Pharmacological Attributes of Anti-CD20 Therapies for Multiple Sclerosis.

Anti-CD20 therapies have demonstrated considerable efficacy in the treatment of relapsing multiple sclerosis, constituting a high-efficacy treatment approach for reducing relapse risk and mitigating disability progression. These therapies have been shown to strongly deplete circulating B cells and small subsets of CD3+ CD4 and CD8 T cells that express low levels of CD20. While the clinical profiles of the various anti-CD20 monoclonal antibodies used in treating multiple sclerosis are well-described in the literature, greater understanding of the implications of their distinct molecular and pharmacological attributes is needed. In this review, we focus on four anti-CD20 monoclonal antibodies—rituximab, ocrelizumab, ofatumumab, and ublituximab—that are currently used, approved, or in late-stage clinical development for the treatment of multiple sclerosis. We provide clinical perspectives on the potential implications of differences in molecular structures, target epitopes, dosing regimens, mechanisms and impact on B-cell depletion and reconstitution, immunogenicity, administration-related reactions, and infection risks.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40263-021-00843-8.

Daratumumab-Based Treatment for Immunoglobulin Light-Chain Amyloidosis

BackgroundSystemic immunoglobulin light-chain (AL) amyloidosis is characterized by deposition of amyloid fibrils of light chains produced by clonal CD38+ plasma cells. Daratumumab, a human CD38-targeting antibody, may improve outcomes for this disease.MethodsWe randomly assigned patients with newly diagnosed AL amyloidosis to receive six cycles of bortezomib, cyclophosphamide, and dexamethasone either alone (control group) or with subcutaneous daratumumab followed by single-agent daratumumab every 4 weeks for up to 24 cycles (daratumumab group). The primary end point was a hematologic complete response.ResultsA total of 388 patients underwent randomization. The median follow-up was 11.4 months. The percentage of patients who had a hematologic complete response was significantly higher in the daratumumab group than in the control group (53.3% vs. 18.1%) (relative risk ratio, 2.9; 95% confidence interval [CI], 2.1 to 4.1; P<0.001). Survival free from major organ deterioration or hematologic progression favored the daratumumab group (hazard ratio for major organ deterioration, hematologic progression, or death, 0.58; 95% CI, 0.36 to 0.93; P=0.02). At 6 months, more cardiac and renal responses occurred in the daratumumab group than in the control group (41.5% vs. 22.2% and 53.0% vs. 23.9%, respectively). The four most common grade 3 or 4 adverse events were lymphopenia (13.0% in the daratumumab group and 10.1% in the control group), pneumonia (7.8% and 4.3%, respectively), cardiac failure (6.2% and 4.8%), and diarrhea (5.7% and 3.7%). Systemic administration-related reactions to daratumumab occurred in 7.3% of the patients. A total of 56 patients died (27 in the daratumumab group and 29 in the control group), most due to amyloidosis-related cardiomyopathy.ConclusionsAmong patients with newly diagnosed AL amyloidosis, the addition of daratumumab to bortezomib, cyclophosphamide, and dexamethasone was associated with higher frequencies of hematologic complete response and survival free from major organ deterioration or hematologic progression. (Funded by Janssen Research and Development; ANDROMEDA ClinicalTrials.gov number, NCT03201965.)

Real-life burden of adverse reactions to biological therapy in inflammatory bowel disease: a single-centre prospective case series.

Biologics represent a key therapeutic option in inflammatory bowel disease (IBD), but are associated with several side effects. Post-marketing surveillance, through a spontaneous adverse drug reactions (ADRs) monitoring system, is essential to assess the safety profile of biologics. The aim of the study was to prospectively evaluate the occurrence of ADRs in IBD patients treated with biologics from a single centre in Southern Italy. Data from patients with Crohn's Disease (CD) and Ulcerative Colitis (UC) who underwent biological therapy were prospectively collected. ADRs were classified according to the Medical Dictionary for Regulatory Activities (MedDRA®). Overall, 68 (54% male, 68% with UC and 32% with CD) biologic-naïve IBD patients underwent biological therapy. Mean follow-up was 11.7 ± 6.2 months. As a results of switches, for 68 patients we obtained 96 biologic prescriptions. Overall, 45 ADRs occurred in 36 (53%) patients, distributed as follows (ADRs/prescriptions): 19/37 with IFX-Remicade, 5/12 with IFX-Remsima, 8/9 with GOL, 11/26 with ADA, and 2/12 with VDZ. Mild ADRs were 29 (64%), moderate 15 (34%) and 1 (2%) severe. General disorders and administration related reactions were the most frequent ADRs (35%), followed by skin and subcutaneous tissue disorders (20%), infections (15%), musculoskeletal (11%), respiratory (6%) blood (4%), gastrointestinal (4%), and vascular disorders (2%). In 9 cases (20%) the ADRs resulted in definitive discontinuation of biologic therapy. In a prospective cohort of IBD patients, more than half experienced ADRs during biologic therapy. General disorders and administration related reactions were the most common ADRs, while infections were less common and rarely led to discontinuation of therapy. Findings underline the importance of surveillance in management of IBD patients during biologic therapy and implementing safety protocols with data from real-life settings.

Efficacy and Safety of Subcutaneous or Intravenous Administration of Rituximab in Patients with CD20+ Diffuse Large B-Cell Lymphoma or Follicular Lymphoma: Final Results of the Randomized, Open-Label, Crossover, PrefMab Study

Introduction: Rituximab (R) plus chemotherapy (chemo) is standard of care for patients (pts) with diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). A subcutaneous (SC) formulation of R (R-SC) that has a non-inferior pharmacokinetic profile to the intravenous (IV) formulation (R-IV) and similar efficacy and safety in DLBCL and FL pts is now available for clinical use. The randomized, open-label, crossover, Phase 3b PrefMab study (NCT01724021) aimed to explore pt preference and treatment satisfaction for the SC vs IV formulation of R. In the primary analysis (data cut-off, January 19, 2015; Rummel et al. Ann Oncol 2017), a strong pt preference for R-SC over R-IV administration was demonstrated (81% vs 11% at Cycle 8; primary endpoint). In addition, on the Rituximab Administration Satisfaction Questionnaire, median scores were higher for R-SC vs R-IV for ‘Impact on Activities of Daily Living’, ‘Convenience of Therapy’, ‘Satisfaction with Therapy’, and ‘Psychological Impact’. No new safety signals were reported. Here, we present the final analysis of the PrefMab study, which was performed after all pts had completed at least 24 months' follow-up (data cut-off, December 20, 2016) with a focus on long-term pt outcomes and safety.Methods: Pts aged 18-80 yrs with previously untreated CD20+ DLBCL or FL were randomized 1:1 to receive one of two 8-cycle schedules of R in combination with 6-8 cycles of chemo (CHOP, CVP, or bendamustine, as per local practice): Sequence A (n=372), 1 cycle R-IV (375mg/m2) then 3 cycles R-SC (1400mg) then 4 cycles R-IV; Sequence B (n=371), 4 cycles R-IV then 4 cycles R-SC. Maintenance therapy was not mandated by the study protocol; however, pts with FL could receive maintenance at the investigator's discretion. Secondary endpoints reported here include overall (OR) and complete response (CR) rates (assessed according to Cheson 1999 criteria) and investigator-assessed progression-free (PFS), event-free (EFS), disease-free, and overall survival. Safety was also assessed by treatment-emergent adverse event (AE) reporting. Efficacy was analyzed in all randomized pts, safety in all pts who received ≥1 dose of R.Results: Of 743 randomized pts, 740 received study treatment (465 pts with DLBCL [63%], 273 with FL [37%], and 2 other [0.3%]). Demographics and baseline characteristics are presented in Table 1. The median age of pts with DLBCL was 61 yrs and of pts with FL was 59 yrs. The majority of pts with DLBCL and FL received CHOP chemo (Table 1). OR rates were >90% in both DLBCL and FL pts (Table 2). CR rates were 55.1% in pts with DLBCL and 44.4% in pts with FL (Table 2). PFS rates at 3 yrs were 79% in DLBCL pts and 91% in FL pts. Other time-to-event endpoints are presented in Table 2. EFS was shorter in FL pts than DLBCL pts; however, because R maintenance was considered a non-protocol-specified anti-lymphoma therapy, FL pts were censored at the time of starting maintenance therapy. Treatment sequence had no impact on response rates or time-to-event endpoints. Pharmacokinetic serum-level data will be presented.Of pts who received ≥2 cycles of treatment, 653/712 (92%) experienced ≥1 AE on or after Cycle 2. AEs were generally balanced according to administration route and diagnosis, although a higher rate of grade ≥3 AEs and serious AEs occurred in DLBCL pts compared with FL (Table 3). Most AEs occurred in Cycle 1, during which all pts received R-IV (pts with AE in Cycle 1: Arm A, 71%; Arm B, 69%). No administration-related reactions (ARRs) occurred at a frequency of ≥2% in pts receivingR-SC or R-IV on or after Cycle 2. There were no differences in rates of ARRs according to IV or SC administration. FL pts were more likely to experience an ARR than DLBCL pts. At the end of the study, 104 pts had died (85 DLBCL; 19 FL). Fatal AEs related to R, according to the investigator's judgment, included oropharyngeal candidiasis, pneumonia, septic shock, febrile neutropenia, and myocardial infarction (1 case each).Conclusions: In addition to the strong pt preference for SC dosing and improved satisfaction observed in the primary analysis, these findings confirm that R-SC is an efficacious and well-tolerated treatment option in DLBCL and FL pts. Overall, outcomes did not appear to be impacted by treatment sequence. [Display omitted] DisclosuresRummel:Roche: Honoraria, Other: PrefMab is sponsored by F. Hoffmann-La Roche Ltd. Third-party Medical Writing assistance, under the direction of Mathias Rummel, was provided by Lynda McEvoy of Gardiner-Caldwell Communications, and was funded by F. Hoffmann-La Roche Ltd, Research Funding. Brugger:AstraZeneca: Employment, Equity Ownership. Re:Gilead: Membership on an entity's Board of Directors or advisory committees. Task:Genentech: Employment, Equity Ownership. McIntyre:Roche: Employment, Equity Ownership. Meier:Roche: Employment. Osborne:Roche: Employment. Smith:Roche: Employment. Grigg:Roche: Other: Funding to attend ASH 2016.

Subcutaneous daratumumab + bortezomib, cyclophosphamide, and dexamethasone (VCd) in patients with newly diagnosed light chain (AL) amyloidosis: Updated results from the phase 3 ANDROMEDA study.

8003 Background: Systemic AL amyloidosis is a plasma cell disease characterized by the deposition of insoluble amyloid fibrils causing organ dysfunction and death. Primary results from the ANDROMEDA study showed that addition of subcutaneous (SC) daratumumab (DARA) to the standard of care combination of bortezomib, cyclophosphamide, and dexamethasone (VCd) was superior to VCd alone, with higher rates of hematologic complete response (CR) and an acceptable safety profile. DARA-VCd was approved for newly diagnosed AL amyloidosis in January 2021. Here we present an update of the primary ANDROMEDA study results with longer follow-up. Methods: ANDROMEDA is a randomized, open-label, active-controlled phase 3 study. Adult patients (pts) with newly diagnosed AL amyloidosis were randomized 1:1 to DARA-VCd or VCd and were treated for 6 28-day Cycles (Cyc). Bortezomib (1.3 mg/m2), cyclophosphamide (300 mg/m2 maximum weekly dose 500 mg), and dexamethasone (40 mg) were given weekly. DARA SC was given weekly (Cyc 1–2) and every 2 weeks (wk) (Cyc 3–6). After Cyc 6, pts in the DARA-VCd group received DARA SC alone every 4 wk for up to 24 Cyc from first dose. Disease status was evaluated every 4 wk in Cyc 1–6 and every 8 wk after Cyc 7. The primary endpoint was overall hematologic CR rate in the intent-to-treat population. Secondary endpoints were major organ deterioration progression-free survival (PFS), organ response rate, time to hematologic response, survival, and safety. Results: Of 388 randomized pts, 195 were randomized to DARA-VCd and 193 to VCd. As of November 2020, the median treatment duration was 18.5 months (mo) for DARA-VCd and 5.3 mo for VCd; 78 pts (40%) in the DARA-VCd group were still on treatment. The overall hematologic CR rate continued to be higher with DARA-VCd than VCd (59% vs 19%; odds ratio [OR] 5.9; 95% CI 3.7–9.4; P&lt; 0.0001). More pts achieved a very good partial response or better (≥VGPR) with DARA-VCd than VCd (79% vs 50%; OR 3.7; 95% CI 2.4–5.9; P&lt; 0.0001). Among responders, median time from randomization to ≥VGPR was shorter for DARA-VCd than VCd (0.56 vs 0.82 mo). Cardiac response rates were higher with DARA-VCd than VCd at 6 mo (42% vs 22%) and at 12 mo (57% vs 28%); renal response rates were 54% vs 27% at 6 mo and 57% vs 27% at 12 mo. A total of 71 deaths occurred (DARA-VCd, n = 31; VCd, n = 40). From Cyc 7 onward in the DARA-VCd group, no grade 3/4 treatment-emergent adverse events occurred in ≥5% of pts. There were no systemic administration-related reactions with DARA-VCd after Cyc 6. Analysis of major organ deterioration PFS will be updated after ̃200 events have occurred. Conclusions: Updated results from the ANDROMEDA study reinforce the clinical superiority of DARA-VCd over VCd in pts with newly diagnosed AL amyloidosis. Based on its recent approval, DARA-VCd represents a new standard of care in AL amyloidosis. Clinical trial information: NCT03201965.

Transition from Intravenous to Subcutaneous Daratumumab Formulation in Clinical Practice

IntroductionDaratumumab is an anti-CD38 monoclonal antibody widely used for treating patients with newly diagnosed or relapsed/refractory multiple myeloma. The subcutaneous formulation of daratumumab was developed with the purpose of minimizing the treatment burden (to patients and health care system) associated with intravenous daratumumab. Given its recent approval, there is a knowledge gap regarding the best practices that should be instituted for safe administration of subcutaneous daratumumab. MethodsA retrospective chart review was performed from August 2020 until November 2020 to identify patients either switched to or treated upfront (daratumumab naive) with any subcutaneous daratumumab-based treatment regimen. All patients received appropriate premedications per institutional standards of care. The study end points were to report real-world data regarding administration-related reaction rates (at or following discharge from infusion center), as well as compare their incidence rates to those noted in the COLUMBA study (historical cohort). ResultsThe study included 58 patients, of whom 38% (n = 22) were daratumumab naive. The majority (84%, n = 49) received subcutaneous daratumumab in combination with various antimyeloma regimens. There were no cases of administration-related reactions at infusion center or after discharge irrespective of previous exposure to intravenous daratumumab. None of the patients included herein required rescue home medications or visited the emergency department within 24 to 48 hours after subcutaneous daratumumab administration. These translated into a significant difference in incidence of administration-related reactions compared with historical cohort (0% vs. 13%, P = .003). ConclusionSubcutaneous daratumumab was extremely well tolerated and could be safely administered without need for monitoring or rescue home medications.

Subcutaneous versus intravenous daratumumab in patients with relapsed or refractory multiple myeloma (COLUMBA): a multicentre, open-label, non-inferiority, randomised, phase 3 trial

Intravenous daratumumab for treatment of patients with multiple myeloma involves a lengthy infusion that affects quality of life, and infusion-related reactions are common. Subcutaneous daratumumab is thought to be easier to administer and to cause fewer administration-related reactions. In this study (COLUMBA), we tested the non-inferiority of subcutaneous daratumumab to intravenous daratumumab. In this ongoing, multicentre (147 sites in 18 countries), open-label, non-inferiority, randomised, phase 3 trial, we recruited adult patients (age ≥18 years) if they had confirmed relapsed or refractory multiple myeloma according to International Myeloma Working Group criteria; received at least three previous lines of therapy, including a proteasome inhibitor and immunomodulatory drug, or were double refractory to both a proteasome inhibitor and immunomodulatory drug; and had an Eastern Cooperative Oncology Group performance status score of 2 or lower. Patients were randomly assigned (1:1) by a computer-generated randomisation schedule and balanced using randomly permuted blocks to receive daratumumab subcutaneously (subcutaneous group) or intravenously (intravenous group). Randomisation was stratified on the basis of baseline bodyweight (≤65 kg, 66-85 kg, >85 kg), previous therapy lines (≤four vs >four), and myeloma type (IgG vs non-IgG). Patients received 1800 mg of subcutaneous daratumumab co-formulated with 2000 U/mL recombinant human hyaluronidase PH20 or 16 mg/kg of intravenous daratumumab once weekly (cycles 1-2), every 2 weeks (cycles 3-6), and every 4 weeks thereafter (28-day cycles) until progressive disease or toxicity. The co-primary endpoints were overall response and maximum trough concentration (Ctrough; cycle 3, day 1 pre-dose). The non-inferiority margin for overall response was defined using a 60% retention of the lower bound (20·8%) of the 95% CI of the SIRIUS trial. Efficacy analyses were done by intention-to-treat population. The pharmacokinetic-evaluable population included all patients who received all eight weekly daratumumab doses in cycles 1 and 2 and provided a pre-dose pharmacokinetics blood sample on day 1 of cycle 3. The safety population included all patients who received at least one daratumumab dose. This trial is registered with ClinicalTrials.gov, NCT03277105. Between Oct 31, 2017, and Dec 27, 2018, 655 patients were screened, of whom 522 were recruited and randomly assigned (subcutaneous group n=263; intravenous group n=259). Three patients in the subcutaneous group and one in the intravenous group did not receive treatment and were not evaluable for safety. At a median follow-up of 7·5 months (IQR 6·5-9·3), overall response and Ctrough met the predefined non-inferiority criteria. An overall response was seen in 108 (41%) of 263 patients in the subcutaneous group and 96 (37%) of 259 in the intravenous group (relative risk 1·11, 95% CI 0·89-1·37). The geometric means ratio for Ctrough was 107·93% (90% CI 95·74-121·67), and the maximum Ctrough was 593 μg/mL (SD 306) in the subcutaneous group and 522 μg/mL (226) in the intravenous group. The most common grade 3 and 4 adverse events were anaemia (34 [13%] of 260 patients evaluable for safety in the subcutaneous group and 36 [14%] of 258 patients in the intravenous group), neutropenia (34 [13%] and 20 [8%]), and thrombocytopenia (36 [14%] and 35 [14%]). Pneumonia was the only serious adverse event in more than 2% of patients (seven [3%] in the subcutaneous group and 11 [4%] in the intravenous group). There was one death resulting from a treatment-related adverse event in the subcutaneous daratumumab group (febrile neutropenia) and four in the intravenous group (sepsis [n=2], hepatitis B reactivation [n=1], and Pneumocystis jirovecii pneumonia [n=1]). Subcutaneous daratumumab was non-inferior to intravenous daratumumab in terms of efficacy and pharmacokinetics and had an improved safety profile in patients with relapsed or refractory multiple myeloma. These data could contribute to the approval of the subcutaneous daratumumab formulation by regulatory bodies. Janssen Research & Development.

Japanese guidance for use of biologics for psoriasis (the 2019 version).

As the first biologics for psoriasis in Japan, infliximab and adalimumab, anti-tumor necrosis factor-α antibodies, became available in the field of dermatology in 2010, followed by ustekinumab, an anti-interleukin (IL)-12/IL-23p40 antibody, which was launched in Japan in 2011. Since 2015, three IL-17 inhibitors of secukinumab and ixekizumab, anti-IL-17A antibodies, and brodalumab, an anti-IL-17 receptor antibody, and two anti-IL-23p19 antibodies of guselkumab and risankizumab, have also been launched. It is important for physicians to select appropriate biologic therapy for each psoriatic patient after due consideration of disease factors, treatment factors and patient background factors, sharing such information with patients. The following can be listed as points to be considered for the selection of biologics: drug effects (e.g. strength of effectiveness, time to onset of effectiveness, effectiveness against arthritis, primary failure, secondary failure), safety (e.g. infections, administration-related reactions and relationships with other comorbidities), convenience for patients (e.g. hospital visit intervals, self-injection, maintenance therapy at clinics, feasibility of drug discontinuation/re-administration) and payment (medical costs) borne by patients. This guidance has been prepared with the aim of allowing dermatologists experienced in the treatment of psoriasis to use biologics appropriately according to the circumstances of individual patients after consideration of the above-mentioned factors.