The Experts below are selected from a list of 4080 Experts worldwide ranked by ideXlab platform
Maria-victoria Mateos - One of the best experts on this subject based on the ideXlab platform.
-
subcutaneous Daratumumab in patients with relapsed or refractory multiple myeloma part 2 of the open label multicenter dose escalation phase 1b study pavo
Haematologica, 2020Co-Authors: Jesus F Sanmiguel, Saad Z Usmani, Lotfi Benboubker, Niels W C J Van De Donk, Torben Plesner, Jonathan L. Kaufman, Philippe Moreau, Maria-victoria Mateos, Albert Oriol, Peter HellemansAbstract:: Intravenous Daratumumab is approved for the treatment of multiple myeloma. In Part 1 of the PAVO study, a mix-and-deliver subcutaneous formulation of Daratumumab with recombinant human hyaluronidase PH20 (rHuPH20) was well tolerated, with low rates of infusion-related reactions and similar efficacy to intravenous Daratumumab. Part 2 of PAVO evaluated a concentrated, pre-mixed co-formulation of Daratumumab and rHuPH20 (DARA SC). Patients with ≥2 prior lines of therapy, including a proteasome inhibitor and immunomodulatory drug, received Daratumumab (1800 mg) and rHuPH20 (30,000 U) in 15 mL subcutaneously over 3-5 minutes per the approved intravenous monotherapy dosing schedule. Primary endpoints were Daratumumab trough concentration at the end of weekly dosing (just prior to the Cycle 3 Day 1 dose) and safety. Twenty-five patients were enrolled in PAVO Part 2. DARA SC achieved Daratumumab trough concentrations similar to or greater than intravenous Daratumumab 16 mg/kg. The adverse event profile of DARA SC was consistent with intravenous Daratumumab, with no new safety concerns and a lower infusion-related reaction rate. At a median follow-up of 14.2 months, the overall response rate was 52%, median duration of response was 15.7 months, and median progression-free survival was 12.0 months. DARA SC 1800 mg was well tolerated in relapsed/refractory multiple myeloma, with a low infusion-related reaction rate and reduced administration time. Daratumumab serum concentrations following DARA SC were consistent with intravenous dosing, and deep and durable responses were observed. Based on these results, ongoing studies are investigating DARA SC in multiple myeloma and other conditions. (ClinicalTrials.gov identifier: 02519452).
-
subcutaneous versus intravenous Daratumumab in patients with relapsed or refractory multiple myeloma columba a multicentre open label non inferiority randomised phase 3 trial
The Lancet Haematology, 2020Co-Authors: Maria-victoria Mateos, Hareth Nahi, Ivan Spicka, Wojciech Legiec, Sebastian Grosicki, Vladimir I Vorobyev, Vania T M Hungria, Sibirina Korenkova, Nizar J. BahlisAbstract:Summary Background 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. Methods 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 . Findings 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]). Interpretation 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. Funding Janssen Research & Development.
-
Daratumumab based regimens are highly effective and well tolerated in relapsed or refractory multiple myeloma regardless of patient age subgroup analysis of the phase 3 castor and pollux studies
Haematologica, 2020Co-Authors: Maria-victoria Mateos, Shinsuke Iida, Jacob P. Laubach, Andrew Spencer, Ajay K Nooka, Ludek Pour, Katja Weisel, Michele Cavo, Gordon Cook, Lotfi BenboubkerAbstract:The phase 3 POLLUX and CASTOR studies demonstrated superior benefit of Daratumumab plus lenalidomide/dexamethasone or bortezomib/dexamethasone in relapsed/refractory multiple myeloma. Efficacy and safety of Daratumumab was analyzed according to age groups of 65 to 74 years and ≥75 years. Patients received ≥1 prior line of therapy. In POLLUX, patients received lenalidomide/dexamethasone ± Daratumumab (16 mg/kg weekly, cycles 1-2; every two weeks, cycles 3-6; monthly until progression). In CASTOR, patients received eight cycles of bortezomib/dexamethasone ± Daratumumab (16 mg/kg weekly, cycles 1-3; every three weeks, cycles 4-8; monthly until progression). Patients aged >75 years received dexamethasone 20 mg weekly. For patients aged ≥75 years in POLLUX (median follow-up: 25.4 months), Daratumumab/lenalido-mide/dexamethasone prolonged progression-free survival versus lenalido-mide/dexamethasone (median: 28.9 versus 11.4 months; hazard ratio, 0.27; 95% confidence interval, 0.10-0.69; P=0.0042) and increased overall response rate (93.1% versus 76.5%; P=0.0740). Neutropenia was the most common grade 3/4 treatment-emergent adverse event (Daratumumab: 44.8%; control: 31.4%). Infusion-related reactions occurred in 12 (41.4%) patients. For patients aged ≥75 years in CASTOR (median follow-up: 19.4 months), Daratumumab/bortezomib/dexamethasone prolonged progression-free survival versus bortezomib/dexamethasone (median: 17.9 versus 8.1 months; hazard ratio, 0.26; 95% confidence interval, 0.10-0.65; P=0.0022) and increased overall response rate (95.0% versus 78.8%; P=0.1134). Thrombocytopenia was the most common grade 3/4 treatment-emergent adverse event (Daratumumab: 45.0%; control: 37.1%). Infusion-related reactions occurred in 13 (65.0%) patients. Similar findings were reported for patients aged 65 to 74 years in both studies. Taken together, this subgroup analysis of efficacy and safety of Daratumumab was largely consistent with the overall populations.
-
Subcutaneous delivery of Daratumumab in relapsed or refractory multiple myeloma
Blood, 2019Co-Authors: Saad Z Usmani, Torben Plesner, Jonathan L. Kaufman, Philippe Moreau, Maria-victoria Mateos, Albert Oriol, Ajai Chari, Niels W.c.j. Van De Donk, Hareth Nahi, Lotfi BenboubkerAbstract:Daratumumab, a human monoclonal antibody targeting CD38, is approved as monotherapy and in combination regimens for patients with multiple myeloma (MM). Currently, Daratumumab is administered IV. The phase 1b PAVO (MMY1004) study evaluated subcutaneously administered Daratumumab in combination with the recombinant human hyaluronidase PH20 enzyme (rHuPH20) in patients with relapsed or refractory MM. Part 1 of the study, reported here, evaluated a mix-and-deliver (MD) formulation of Daratumumab and rHuPH20 (DARA-MD) administered by subcutaneous infusion. Patients received subcutaneous Daratumumab according to the approved IV monotherapy dosing schedule at 1200 mg (n = 8) or 1800 mg (n = 45). Primary end points were safety and pharmacokinetic (PK) variables. The most common treatment-emergent adverse events with DARA-MD 1200 mg were thrombocytopenia, upper respiratory tract infection, insomnia, and decreased appetite (37.5% each). Anemia (33.3%), upper respiratory tract infection, pyrexia, and diarrhea (26.7% each) were the most common treatment-emergent adverse events with DARA-MD 1800 mg. One patient in the 1200-mg dose group (12.5%) and 11 patients in the 1800-mg dose group (24.4%) experienced infusion-related reactions, which were generally grade 1/2 and typically occurred at the first infusion. The 1800 mg dose achieved similar or greater serum concentrations compared with the 16 mg/kg IV dose. Overall response rates of 25.0% and 42.2% were achieved with 1200-mg and 1800-mg DARA-MD, respectively. Subcutaneous administration of DARA-MD was well tolerated in patients with relapsed or refractory MM, with the 1800-mg dose exhibiting PK concentrations and responses consistent with IV Daratumumab in a similar patient population. This study was registered at www.clinicaltrials.gov as #NCT02519452.
-
Daratumumab plus bortezomib melphalan and prednisone for untreated myeloma
The New England Journal of Medicine, 2017Co-Authors: Maria-victoria Mateos, Meletios A. Dimopoulos, Michele Cavo, Kenshi Suzuki, Andrzej J Jakubowiak, Stefan Knop, Chantal Doyen, Paulo Sergio Lucio, Zsolt Nagy, Polina KaplanAbstract:Abstract Background The combination of bortezomib, melphalan, and prednisone is a standard treatment for patients with newly diagnosed multiple myeloma who are ineligible for autologous stem-cell transplantation. Daratumumab has shown efficacy in combination with standard-of-care regimens in patients with relapsed or refractory multiple myeloma. Methods In this phase 3 trial, we randomly assigned 706 patients with newly diagnosed multiple myeloma who were ineligible for stem-cell transplantation to receive nine cycles of bortezomib, melphalan, and prednisone either alone (control group) or with Daratumumab (Daratumumab group) until disease progression. The primary end point was progression-free survival. Results At a median follow-up of 16.5 months in a prespecified interim analysis, the 18-month progression-free survival rate was 71.6% (95% confidence interval [CI], 65.5 to 76.8) in the Daratumumab group and 50.2% (95% CI, 43.2 to 56.7) in the control group (hazard ratio for disease progression or death,...
Don M. Benson - One of the best experts on this subject based on the ideXlab platform.
-
Fratricide of NK Cells in Daratumumab Therapy for Multiple Myeloma Overcome by Ex Vivo–Expanded Autologous NK Cells
Clinical cancer research : an official journal of the American Association for Cancer Research, 2018Co-Authors: Yufeng Wang, Yibo Zhang, Tiffany Hughes, Jianying Zhang, Michael A. Caligiuri, Don M. BensonAbstract:Purpose: Daratumumab and its use in combination with other agents is becoming a new standard of care for the treatment of multiple myeloma. We mechanistically studied how Daratumumab acts on natural killer (NK) cells.Experimental Design: Quantities of NK cells in peripheral blood and/or bone marrow of patients with multiple myeloma or healthy donors were examined by flow cytometry. NK-cell apoptosis and the associated mechanism were assessed by flow cytometry and immunoblotting. Patients' NK cells were expanded in vitro using feeder cells. Combination treatment of Daratumumab and expanded NK cells was performed using an MM.1S xenograft animal model.Results: CD38-/low NK cells survived, whereas CD38+ NK cells were almost completely eliminated, in peripheral blood and bone marrow of Daratumumab-treated multiple myeloma patients. NK-cell depletion occurred due to Daratumumab-induced NK-cell fratricide via antibody-dependent cellular cytotoxicity. Consequently, CD38-/low NK cells were more effective for eradicating multiple myeloma cells than were CD38+ NK cells in the presence of Daratumumab. Blockade of CD38 with the F(ab)2 fragments of Daratumumab inhibited the antibody-mediated NK-cell fratricide. CD38-/low NK cells displayed a significantly better potential for expansion than CD38+ NK cells, and the expanded NK cells derived from the former population were more cytotoxic than those derived from the latter against multiple myeloma cells. Therefore, infusion of ex vivo-expanded autologous NK cells from Daratumumab-treated patients may improve the antibody therapy.Conclusions: We unravel a fratricide mechanism for Daratumumab-mediated NK-cell depletion and provide a potential therapeutic strategy to overcome this side effect in Daratumumab-treated patients with multiple myeloma. Clin Cancer Res; 24(16); 4006-17. ©2018 AACR.
-
fratricide of nk cells in Daratumumab therapy for multiple myeloma overcome by ex vivo expanded autologous nk cells
Clinical Cancer Research, 2018Co-Authors: Yufeng Wang, Yibo Zhang, Tiffany Hughes, Jianying Zhang, Michael A. Caligiuri, Don M. BensonAbstract:Purpose: Daratumumab and its use in combination with other agents is becoming a new standard of care for the treatment of multiple myeloma. We mechanistically studied how Daratumumab acts on natural killer (NK) cells.Experimental Design: Quantities of NK cells in peripheral blood and/or bone marrow of patients with multiple myeloma or healthy donors were examined by flow cytometry. NK-cell apoptosis and the associated mechanism were assessed by flow cytometry and immunoblotting. Patients' NK cells were expanded in vitro using feeder cells. Combination treatment of Daratumumab and expanded NK cells was performed using an MM.1S xenograft animal model.Results: CD38-/low NK cells survived, whereas CD38+ NK cells were almost completely eliminated, in peripheral blood and bone marrow of Daratumumab-treated multiple myeloma patients. NK-cell depletion occurred due to Daratumumab-induced NK-cell fratricide via antibody-dependent cellular cytotoxicity. Consequently, CD38-/low NK cells were more effective for eradicating multiple myeloma cells than were CD38+ NK cells in the presence of Daratumumab. Blockade of CD38 with the F(ab)2 fragments of Daratumumab inhibited the antibody-mediated NK-cell fratricide. CD38-/low NK cells displayed a significantly better potential for expansion than CD38+ NK cells, and the expanded NK cells derived from the former population were more cytotoxic than those derived from the latter against multiple myeloma cells. Therefore, infusion of ex vivo-expanded autologous NK cells from Daratumumab-treated patients may improve the antibody therapy.Conclusions: We unravel a fratricide mechanism for Daratumumab-mediated NK-cell depletion and provide a potential therapeutic strategy to overcome this side effect in Daratumumab-treated patients with multiple myeloma. Clin Cancer Res; 24(16); 4006-17. ©2018 AACR.
-
Ninety-Minute Daratumumab Infusion Is Safe in Multiple Myeloma
Blood, 2017Co-Authors: Hallie Barr, Don M. Benson, Jessica Dempsey, Allyson Waller, Ying Huang, Nita Williams, Nidhi Sharma, Ashley E. Rosko, Yvonne A. Efebera, Craig C. HofmeisterAbstract:Background: Daratumumab, an anti-CD38 monoclonal antibody, was first approved for the treatment of relapsed and refractory multiple myeloma (MM) in December of 2015. The approved initial infusion lasts at least 6.5 hours, second infusion for 4.5 hours and all subsequent infusions over 3.5 hours. The risk of infusion related reactions (IRRs) is very low after the second infusion, and the prolonged continued infusion time results in long days for patients. Because of our success infusing other monoclonal antibodies over shorter times, such as rituximab (Dotson et al Support Care Cancer, 2016), we hypothesized that shortening the Daratumumab infusion from 3.5 hours to 90 minutes beginning with the third infusion would not increase the incidence of IRRs. Methods: This is a single-center safety study of an accelerated Daratumumab infusion in patients receiving standard of care Daratumumab therapy. Patients were eligible once they received at least 2 prior doses of Daratumumab, administered per standard prescribing information. Previous IRR was not an exclusion criterion. The accelerated infusion was calculated to deliver 20% of the dose over the first 30 minutes, then the remaining 80% over 60 minutes, resulting in an estimated 90 minute infusion (Table 1). Patients who tolerated the infusion well were allowed to continue the accelerated rate. Premedication regimens were allowed to be altered based on previous tolerability. Simon9s two-stage optimal design was utilized to design the study based on the incidence of grade 3 or above IRR. With 80% power the design allows 7 patients to be treated in the first stage, and if no patients experienced ≥ grade 3 IRR, an additional 21 patients would be treated. Out of all 28 patients, if 2 or more experienced ≥ grade 3 IRR, the regimen would be declared as too toxic. The protocol was approved by the cancer institutional review board. Results: Baseline characteristics are listed in Table 2. Twenty eight patients were treated with Daratumumab utilizing the accelerated rate, 8 of which received the accelerated infusion with their third dose of Daratumumab. The premedication regimen varied patient-to-patient and did not impact tolerability of the accelerated infusion. There were 5 patients who did not receive any steroid premedication and 3 who received reduced doses ( Conclusion: An accelerated infusion rate of Daratumumab delivering 20% of the dose over 30 minutes and 80% over 60 minutes is feasible and well-tolerated in patients who have received 2 prior doses of Daratumumab at standard infusion rates. Starting with the third dose of Daratumumab therapy, the 90-minute infusion is now standard practice at our institution. Disclosures Hofmeister: Janssen: Research Funding; Roche: Research Funding; Bristol-Myers Squibb: Research Funding; Takeda: Research Funding; Karyopharm: Research Funding; Celgene: Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Thrassos: Honoraria, Membership on an entity9s Board of Directors or advisory committees.
Saad Z Usmani - One of the best experts on this subject based on the ideXlab platform.
-
Daratumumab subcutaneous formulation for the treatment of multiple myeloma
Expert opinion on biological therapy, 2020Co-Authors: Barry Paul, Shebli Atrash, Manisha Bhutani, Peter M. Voorhees, Issam Hamadeh, Saad Z UsmaniAbstract:Intravenous Daratumumab has shown unprecedented anti-myeloma activity when used as a single agent or in combination with other myeloma therapies. Recently, a subcutaneous formulation of Daratumumab...
-
subcutaneous Daratumumab in patients with relapsed or refractory multiple myeloma part 2 of the open label multicenter dose escalation phase 1b study pavo
Haematologica, 2020Co-Authors: Jesus F Sanmiguel, Saad Z Usmani, Lotfi Benboubker, Niels W C J Van De Donk, Torben Plesner, Jonathan L. Kaufman, Philippe Moreau, Maria-victoria Mateos, Albert Oriol, Peter HellemansAbstract:: Intravenous Daratumumab is approved for the treatment of multiple myeloma. In Part 1 of the PAVO study, a mix-and-deliver subcutaneous formulation of Daratumumab with recombinant human hyaluronidase PH20 (rHuPH20) was well tolerated, with low rates of infusion-related reactions and similar efficacy to intravenous Daratumumab. Part 2 of PAVO evaluated a concentrated, pre-mixed co-formulation of Daratumumab and rHuPH20 (DARA SC). Patients with ≥2 prior lines of therapy, including a proteasome inhibitor and immunomodulatory drug, received Daratumumab (1800 mg) and rHuPH20 (30,000 U) in 15 mL subcutaneously over 3-5 minutes per the approved intravenous monotherapy dosing schedule. Primary endpoints were Daratumumab trough concentration at the end of weekly dosing (just prior to the Cycle 3 Day 1 dose) and safety. Twenty-five patients were enrolled in PAVO Part 2. DARA SC achieved Daratumumab trough concentrations similar to or greater than intravenous Daratumumab 16 mg/kg. The adverse event profile of DARA SC was consistent with intravenous Daratumumab, with no new safety concerns and a lower infusion-related reaction rate. At a median follow-up of 14.2 months, the overall response rate was 52%, median duration of response was 15.7 months, and median progression-free survival was 12.0 months. DARA SC 1800 mg was well tolerated in relapsed/refractory multiple myeloma, with a low infusion-related reaction rate and reduced administration time. Daratumumab serum concentrations following DARA SC were consistent with intravenous dosing, and deep and durable responses were observed. Based on these results, ongoing studies are investigating DARA SC in multiple myeloma and other conditions. (ClinicalTrials.gov identifier: 02519452).
-
Subcutaneous delivery of Daratumumab in relapsed or refractory multiple myeloma
Blood, 2019Co-Authors: Saad Z Usmani, Torben Plesner, Jonathan L. Kaufman, Philippe Moreau, Maria-victoria Mateos, Albert Oriol, Ajai Chari, Niels W.c.j. Van De Donk, Hareth Nahi, Lotfi BenboubkerAbstract:Daratumumab, a human monoclonal antibody targeting CD38, is approved as monotherapy and in combination regimens for patients with multiple myeloma (MM). Currently, Daratumumab is administered IV. The phase 1b PAVO (MMY1004) study evaluated subcutaneously administered Daratumumab in combination with the recombinant human hyaluronidase PH20 enzyme (rHuPH20) in patients with relapsed or refractory MM. Part 1 of the study, reported here, evaluated a mix-and-deliver (MD) formulation of Daratumumab and rHuPH20 (DARA-MD) administered by subcutaneous infusion. Patients received subcutaneous Daratumumab according to the approved IV monotherapy dosing schedule at 1200 mg (n = 8) or 1800 mg (n = 45). Primary end points were safety and pharmacokinetic (PK) variables. The most common treatment-emergent adverse events with DARA-MD 1200 mg were thrombocytopenia, upper respiratory tract infection, insomnia, and decreased appetite (37.5% each). Anemia (33.3%), upper respiratory tract infection, pyrexia, and diarrhea (26.7% each) were the most common treatment-emergent adverse events with DARA-MD 1800 mg. One patient in the 1200-mg dose group (12.5%) and 11 patients in the 1800-mg dose group (24.4%) experienced infusion-related reactions, which were generally grade 1/2 and typically occurred at the first infusion. The 1800 mg dose achieved similar or greater serum concentrations compared with the 16 mg/kg IV dose. Overall response rates of 25.0% and 42.2% were achieved with 1200-mg and 1800-mg DARA-MD, respectively. Subcutaneous administration of DARA-MD was well tolerated in patients with relapsed or refractory MM, with the 1800-mg dose exhibiting PK concentrations and responses consistent with IV Daratumumab in a similar patient population. This study was registered at www.clinicaltrials.gov as #NCT02519452.
-
Rapid Infusion Daratumumab Is Safe and Well Tolerated in Clinical Practice
Blood, 2018Co-Authors: Issam Hamadeh, Justin R. Arnall, Shebli Atrash, Manisha Bhutani, Peter M. Voorhees, Ekaterina Kachur, Reed Friend, Allison Martin, Megan Jagosky, Saad Z UsmaniAbstract:Introduction: Daratumumab is an anti-CD38 monoclonal antibody, currently FDA approved for treatment of newly diagnosed transplant ineligible multiple myeloma (MM) in combination with melphalan, prednisone and bortezomib, in combination with lenalidomide-dexamethasone and bortezomib-dexamethasone for early relapse MM, and in combination with pomalidomide-dexamethasone and monotherapy for relapsed/refractory MM (RRMM). Recent data demonstrated the feasibility of infusing Daratumumab at an accelerated rate over 90 minutes from Cycle1 day 15 onwards [1], reducing the standard infusion time of 3-4 hours. Considering these data, all Daratumumab protocols at our institution were updated to implement the rapid infusion protocol in routine clinical practice. Herein, we report the safety profile of rapid Daratumumab infusion at our center. Methods: Retrospective chart review was performed from April 2016 through July 2018 to identify patients who completed at least one cycle of Daratumumab or any Daratumumab containing regimen for RRMM or amyloidosis at the Levine Cancer Institute (LCI). LCI includes a large infusion center at the main tertiary center and several other small infusion centers distributed throughout the states of North and South Carolina. Patients were divided into two cohorts; cohort 1 included patients who received Daratumumab administered at the standard infusion rate recommended by manufacturer, whereas cohort 2 received rapid infusion Daratumumab following the institution-wide implementation of the rapid infusion protocol in March 2018. Cohort 2 patients started on Daratumumab received the first two doses of cycle 1 at the standard infusion rate followed by a 90-minute infusion with third and subsequent doses. Furthermore, 20% of dose was given over 30 minutes and the remaining 80% over 60 minutes (overall duration: 90 minutes). Patients in both cohorts were pre-medicated with: acetaminophen, diphenhydramine, dexamethasone and montelukast (for first two doses of first cycle), given 30 minutes prior to initiating Daratumumab. The primary endpoint was to compare rates of infusion related reactions between the rapid and standard Daratumumab infusion protocols using Fischer9s exact test. Data collected included but not limited to: patient demographics, comorbidities, plasma cell disorder, pre-medications, type and management of infusion reactions, as well as post-infusion monitoring if documented. Results: A total of 73 RRMM (37 in cohort 1 and 36 in cohort 2) and 6 amyloidosis patients (3 in each cohort) were included in this study. Baseline characteristics are shown in table 1. Overall, there was no statistically significant difference in the rates of infusion related reactions between the rapid and standard infusion cohorts (2.6% vs. 5.0%, p=0.6). Of 39 patients in cohort 2, 8 patients received rapid infusion Daratumumab on day 15 (3rd dose) of first cycle, whereas remaining received a median of 7 cycles (range: 2-30) before the switch was commenced. Among those 8 patients where Daratumumab was started on day 15, only 1 developed an infusion related reaction. Notably, this patient had a history of prior exposure, and subsequently Daratumumab was administered at the rapid infusion rate on day 1 instead of day 15, approximately 4 months later. All infusion reactions reported in both cohorts were grade 1 which were managed according to institutional guidelines followed by resumption of infusion at lower rates. Conclusion and future directions: Our findings indicate that rapid Daratumumab infusion beyond day 8 of cycle 1 is a safe, tolerable and convenient option for RRMM and amyloidosis patients. Additional studies are underway to evaluate cost benefits of rapid infusion Daratumumab as well as patient/provider satisfaction. References: Barr H, Dempsey J, Waller A, et al. Ninety-minute Daratumumab Infusion is Safe in Multiple Myeloma. Leukemia. March 2018. DOI:10.1038/s41375-018-0120-2 Disclosures Voorhees:Novartis: Consultancy, Other: served on an IRC; Oncopeptides: Consultancy, Membership on an entity9s Board of Directors or advisory committees, Other: served on an IRC; Janssen: Consultancy, Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity9s Board of Directors or advisory committees, Other: served on an IRC; TeneoBio: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Amgen Inc.: Speakers Bureau; BMS: Consultancy, Membership on an entity9s Board of Directors or advisory committees. Usmani:Abbvie, Amgen, Celgene, Genmab, Merck, MundiPharma, Janssen, Seattle Genetics: Consultancy; Amgen, BMS, Celgene, Janssen, Merck, Pharmacyclics,Sanofi, Seattle Genetics, Takeda: Research Funding.
-
Deep sustained response to Daratumumab monotherapy associated with T-cell expansion in triple refractory myeloma
BMC, 2018Co-Authors: Saad Z Usmani, Imran Khan, Tineke Casneuf, Christopher Chiu, David Foureau, Lawrence J. Druhan, Katherine Rigby, Kate A SasserAbstract:Abstract Background Daratumumab, a human CD38 monoclonal antibody that has direct on-tumor and immunomodulatory mechanisms of action, demonstrated clinical benefit as monotherapy or in combination with established regimens in patients with multiple myeloma with one or more prior lines of therapy. Case presentation A male patient, who was 70 years of age at the time of diagnosis of multiple myeloma in 2011, relapsed after five lines of therapy, including autologous stem cell transplantation. The patient’s disease, which was considered high risk with a deletion of chromosome 17p, advanced quickly and was triple refractory 2 years after diagnosis leaving few treatment options. He was treated with Daratumumab monotherapy in the SIRIUS clinical trial resulting in a stringent complete response and clearance of minimal residual disease. The duration of the patient’s clinical response is now over 3.5 years without relapse, compared with a median of 7.6 months for similarly treated patients. The patient’s immunophenotype revealed CD8+ T-cell expansion, clonal expansion of the T-cell receptor repertoire, and decreases in regulatory T cells during Daratumumab therapy, suggesting a robust adaptive immune response. This immune response was still present 32 months into Daratumumab therapy. Conclusions The results from this case report showed that a patient with advanced multiple myeloma, who had exhausted all treatment options with existing regimens, mounted an ongoing, deep, and durable response to Daratumumab monotherapy. Further investigation of the immunologic profile provided additional patient-level evidence of an immunomodulatory mechanism of action of Daratumumab. Trial registration ClinicalTrials.gov Identifier number NCT01985126. Submitted 22 July 201
Ajai Chari - One of the best experts on this subject based on the ideXlab platform.
-
A comprehensive overview of Daratumumab and carfilzomib and the recently approved Daratumumab, carfilzomib and dexamethasone regimen in relapsed/refractory multiple myeloma
Expert review of hematology, 2020Co-Authors: Shambavi Richard, Joshua Richter, Sundar Jagannath, Hearn Jay Cho, Samir Parekh, Deepu Madduri, Ajai ChariAbstract:Introduction: Novel, effective regimens are needed in patients with relapsed and refractory myeloma (RRMM) who inevitably relapse after PI and IMID containing treatment. Areas covered: Pre-clinical data, early clinical and pivotal trials relevant to the development of the two backbone drugs of carfilzomib and Daratumumab, and the two important recent trials, EQUULEUS and CANDOR leading to the FDA approval of the combination regimen of Daratumumab, carfilzomib, and dexamethasone (DKd) for RRMM are detailed in this review. Expert opinion: EQUULEUS and CANDOR have established the efficacy of the DKd regimen in the landscape of bortezomib and lenalidomide refractory patients. The split dosing schedule of the first dose of Daratumumab was approved by the FDA based on EQUULEUS, significantly improving patient convenience. Subcutaneous Daratumumab is being evaluated in this combination to further improve tolerance and convenience. Further studies are needed to evaluate and optimally sequence the many effective and potent drugs available in RRMM.
-
Subcutaneous delivery of Daratumumab in relapsed or refractory multiple myeloma
Blood, 2019Co-Authors: Saad Z Usmani, Torben Plesner, Jonathan L. Kaufman, Philippe Moreau, Maria-victoria Mateos, Albert Oriol, Ajai Chari, Niels W.c.j. Van De Donk, Hareth Nahi, Lotfi BenboubkerAbstract:Daratumumab, a human monoclonal antibody targeting CD38, is approved as monotherapy and in combination regimens for patients with multiple myeloma (MM). Currently, Daratumumab is administered IV. The phase 1b PAVO (MMY1004) study evaluated subcutaneously administered Daratumumab in combination with the recombinant human hyaluronidase PH20 enzyme (rHuPH20) in patients with relapsed or refractory MM. Part 1 of the study, reported here, evaluated a mix-and-deliver (MD) formulation of Daratumumab and rHuPH20 (DARA-MD) administered by subcutaneous infusion. Patients received subcutaneous Daratumumab according to the approved IV monotherapy dosing schedule at 1200 mg (n = 8) or 1800 mg (n = 45). Primary end points were safety and pharmacokinetic (PK) variables. The most common treatment-emergent adverse events with DARA-MD 1200 mg were thrombocytopenia, upper respiratory tract infection, insomnia, and decreased appetite (37.5% each). Anemia (33.3%), upper respiratory tract infection, pyrexia, and diarrhea (26.7% each) were the most common treatment-emergent adverse events with DARA-MD 1800 mg. One patient in the 1200-mg dose group (12.5%) and 11 patients in the 1800-mg dose group (24.4%) experienced infusion-related reactions, which were generally grade 1/2 and typically occurred at the first infusion. The 1800 mg dose achieved similar or greater serum concentrations compared with the 16 mg/kg IV dose. Overall response rates of 25.0% and 42.2% were achieved with 1200-mg and 1800-mg DARA-MD, respectively. Subcutaneous administration of DARA-MD was well tolerated in patients with relapsed or refractory MM, with the 1800-mg dose exhibiting PK concentrations and responses consistent with IV Daratumumab in a similar patient population. This study was registered at www.clinicaltrials.gov as #NCT02519452.
-
Daratumumab-induced transient myopic shift
Elsevier, 2019Co-Authors: Maria A. Mavrommatis, Hoon Jung, Ajai Chari, Bart Barlogie, James G. ChelnisAbstract:Purpose: To describe an unprecedented case of transient myopic shift induced by a chemotherapeutic agent, Daratumumab. Observations: A 43-year-old emmetropic female with multiple myeloma experienced sudden onset of myopic shift during her first intravenous dose of Daratumumab, an increasingly common FDA-approved chemotherapeutic agent. Her myopia was corrected with -4D lenses in both eyes, and the patient reports cessation of symptoms and disuse of lenses after two days. Conclusions and importance: A number of medications have been documented to induce transitory myopic shift, and this report now includes Daratumumab among such agents. Further clinical findings regarding the mechanism and frequency of Daratumumab-induced myopic shift are needed to further develop our understanding of its tangential effect on the eye. Keywords: Transient myopia, Myopic shift, Multiple myeloma, Daratumuma
-
Daratumumab-induced transient myopic shift.
American journal of ophthalmology case reports, 2018Co-Authors: Maria A. Mavrommatis, Hoon Jung, Ajai Chari, Bart Barlogie, James G. ChelnisAbstract:Abstract Purpose To describe an unprecedented case of transient myopic shift induced by a chemotherapeutic agent, Daratumumab. Observations A 43-year-old emmetropic female with multiple myeloma experienced sudden onset of myopic shift during her first intravenous dose of Daratumumab, an increasingly common FDA-approved chemotherapeutic agent. Her myopia was corrected with -4D lenses in both eyes, and the patient reports cessation of symptoms and disuse of lenses after two days. Conclusions and importance A number of medications have been documented to induce transitory myopic shift, and this report now includes Daratumumab among such agents. Further clinical findings regarding the mechanism and frequency of Daratumumab-induced myopic shift are needed to further develop our understanding of its tangential effect on the eye.
Torben Plesner - One of the best experts on this subject based on the ideXlab platform.
-
subcutaneous Daratumumab in patients with relapsed or refractory multiple myeloma part 2 of the open label multicenter dose escalation phase 1b study pavo
Haematologica, 2020Co-Authors: Jesus F Sanmiguel, Saad Z Usmani, Lotfi Benboubker, Niels W C J Van De Donk, Torben Plesner, Jonathan L. Kaufman, Philippe Moreau, Maria-victoria Mateos, Albert Oriol, Peter HellemansAbstract:: Intravenous Daratumumab is approved for the treatment of multiple myeloma. In Part 1 of the PAVO study, a mix-and-deliver subcutaneous formulation of Daratumumab with recombinant human hyaluronidase PH20 (rHuPH20) was well tolerated, with low rates of infusion-related reactions and similar efficacy to intravenous Daratumumab. Part 2 of PAVO evaluated a concentrated, pre-mixed co-formulation of Daratumumab and rHuPH20 (DARA SC). Patients with ≥2 prior lines of therapy, including a proteasome inhibitor and immunomodulatory drug, received Daratumumab (1800 mg) and rHuPH20 (30,000 U) in 15 mL subcutaneously over 3-5 minutes per the approved intravenous monotherapy dosing schedule. Primary endpoints were Daratumumab trough concentration at the end of weekly dosing (just prior to the Cycle 3 Day 1 dose) and safety. Twenty-five patients were enrolled in PAVO Part 2. DARA SC achieved Daratumumab trough concentrations similar to or greater than intravenous Daratumumab 16 mg/kg. The adverse event profile of DARA SC was consistent with intravenous Daratumumab, with no new safety concerns and a lower infusion-related reaction rate. At a median follow-up of 14.2 months, the overall response rate was 52%, median duration of response was 15.7 months, and median progression-free survival was 12.0 months. DARA SC 1800 mg was well tolerated in relapsed/refractory multiple myeloma, with a low infusion-related reaction rate and reduced administration time. Daratumumab serum concentrations following DARA SC were consistent with intravenous dosing, and deep and durable responses were observed. Based on these results, ongoing studies are investigating DARA SC in multiple myeloma and other conditions. (ClinicalTrials.gov identifier: 02519452).
-
controversy in the use of cd38 antibody for treatment of myeloma is high cd38 expression good or bad
Cells, 2020Co-Authors: Torben Plesner, Niels W.c.j. Van De Donk, Paul G. RichardsonAbstract:During a time span of just a few years, the CD38 antibody, Daratumumab, has been established as one of the most important new drugs for the treatment of multiple myeloma, both in the relapsed/refractory setting and, more recently, as a first-line treatment. Although much is known about the pleiotropic modes of action of Daratumumab, we are still not sure how to use it in an optimal manner. Daratumumab targets CD38 on myeloma cells and a high level of CD38 expression facilitates complement-mediated cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). Since the expression of CD38 by myeloma cells is downregulated during treatment with Daratumumab, it may seem reasonable to introduce a wash-out period and retreat with Daratumumab at a later time point when CD38 expression has recovered in order to gain the maximum benefit of Daratumumab’s capacity to kill myeloma cells by CDC, ADCC and ADCP. In other aspects, CD38 seems to serve as a survival factor for myeloma cells by facilitating protective myeloma cell–stromal-cell interactions, contributing to the formation of nanotubes that transfer mitochondria from the stromal cells to myeloma cells, boosting myeloma cell proliferation and survival and by generation of immunosuppressive adenosine in the bone marrow microenvironment. In addition, continuous exposure to Daratumumab may keep immune suppressor cells at a low level, which boosts the anti-tumor activity of T-cells. In fact, one may speculate if in the early phase of treatment of a myeloma patient, the debulking effects of Daratumumab achieved by CDC, ADCC and ADCP are more important while at a later stage, reprogramming of the patient’s own immune system and certain metabolic effects may take over and become more essential. This duality may be reflected by what we often observe when we watch the slope of the M-protein from myeloma patients responding to Daratumumab: A rapid initial drop followed by a slow decline of the M-protein during several months or even years. Ongoing and future clinical trials will teach us how to use Daratumumab in an optimal way.
-
Subcutaneous delivery of Daratumumab in relapsed or refractory multiple myeloma
Blood, 2019Co-Authors: Saad Z Usmani, Torben Plesner, Jonathan L. Kaufman, Philippe Moreau, Maria-victoria Mateos, Albert Oriol, Ajai Chari, Niels W.c.j. Van De Donk, Hareth Nahi, Lotfi BenboubkerAbstract:Daratumumab, a human monoclonal antibody targeting CD38, is approved as monotherapy and in combination regimens for patients with multiple myeloma (MM). Currently, Daratumumab is administered IV. The phase 1b PAVO (MMY1004) study evaluated subcutaneously administered Daratumumab in combination with the recombinant human hyaluronidase PH20 enzyme (rHuPH20) in patients with relapsed or refractory MM. Part 1 of the study, reported here, evaluated a mix-and-deliver (MD) formulation of Daratumumab and rHuPH20 (DARA-MD) administered by subcutaneous infusion. Patients received subcutaneous Daratumumab according to the approved IV monotherapy dosing schedule at 1200 mg (n = 8) or 1800 mg (n = 45). Primary end points were safety and pharmacokinetic (PK) variables. The most common treatment-emergent adverse events with DARA-MD 1200 mg were thrombocytopenia, upper respiratory tract infection, insomnia, and decreased appetite (37.5% each). Anemia (33.3%), upper respiratory tract infection, pyrexia, and diarrhea (26.7% each) were the most common treatment-emergent adverse events with DARA-MD 1800 mg. One patient in the 1200-mg dose group (12.5%) and 11 patients in the 1800-mg dose group (24.4%) experienced infusion-related reactions, which were generally grade 1/2 and typically occurred at the first infusion. The 1800 mg dose achieved similar or greater serum concentrations compared with the 16 mg/kg IV dose. Overall response rates of 25.0% and 42.2% were achieved with 1200-mg and 1800-mg DARA-MD, respectively. Subcutaneous administration of DARA-MD was well tolerated in patients with relapsed or refractory MM, with the 1800-mg dose exhibiting PK concentrations and responses consistent with IV Daratumumab in a similar patient population. This study was registered at www.clinicaltrials.gov as #NCT02519452.
-
Effects of Daratumumab on natural killer cells and impact on clinical outcomes in relapsed or refractory multiple myeloma.
Blood advances, 2017Co-Authors: Tineke Casneuf, Sagar Lonial, Imran Khan, Tahamtan Ahmadi, Amy Axel, Homer Adams, Christopher Chiu, Xiaoyu Yan, Torben PlesnerAbstract:Daratumumab, a human CD38 imunoglobulin G 1κ monoclonal antibody, has demonstrated clinical activity and a manageable safety profile in monotherapy and combination therapy clinical trials in relapsed and/or refractory multiple myeloma. CD38 is expressed at high levels on myeloma cells and, to a lesser extent, on immune effector cells, including natural killer (NK) cells, which are important for Daratumumab-mediated antibody-dependent cellular cytotoxicity (ADCC). Here, the pharmacodynamic effects of Daratumumab monotherapy on NK cells, and the effect of NK cell dynamics on Daratumumab efficacy and safety, were assessed. Daratumumab, like other CD38 antibodies, reduced NK-cell counts in peripheral blood mononuclear cells (PBMCs) of healthy donors in vitro. Data on NK-cell counts, clinical efficacy, and adverse events were pooled from two single-agent Daratumumab studies, GEN501 and SIRIUS. In Daratumumab-treated myeloma patients, total and activated NK-cell counts reduced rapidly in peripheral blood after the first dose, remained low over the course of treatment, and recovered after treatment ended. There was a clear maximum effect relationship between Daratumumab dose and maximum reduction in NK cells. Similar reductions were observed in bone marrow. PBMCs from Daratumumab-treated patients induced lysis by ADCC of CD38+ tumor cells in vitro, suggesting that the remaining NK cells retained cytotoxic functionality. There was no relationship between NK-cell count reduction and the efficacy or safety profile of Daratumumab. Furthermore, although NK cell numbers are reduced after Daratumumab treatment, they are not completely depleted and may still contribute to ADCC, clinical efficacy, and infection control.
-
clinical implications of complex pharmacokinetics for Daratumumab dose regimen in patients with relapsed refractory multiple myeloma
Clinical Pharmacology & Therapeutics, 2017Co-Authors: Xiaoyu Yan, Torben Plesner, Thomas A Puchalski, Sagar Lonial, Henk M Lokhorst, Imran Khan, Richard Jansson, Peter M. Voorhees, Kevin Liu, Tahamtan AhmadiAbstract:New therapeutic strategies are urgently needed to improve clinical outcomes in patients with multiple myeloma (MM). Daratumumab is a first-in-class, CD38 human immunoglobulin G1κ monoclonal antibody approved for treatment of relapsed or refractory MM. Identification of an appropriate dose regimen for Daratumumab is challenging due to its target-mediated drug disposition, leading to time- and concentration-dependent pharmacokinetics. We describe a thorough evaluation of the recommended dose regimen for Daratumumab in patients with relapsed or refractory MM.
