Exposure-Response Relationship of Daratumumab Efficacy and Safety in Patients with Relapsed or Refractory Multiple Myeloma (MM) after Prior Proteasome Inhibitors (PIs) and Immunomodulatory Drugs (IMiDs)

2015 ◽  
Vol 15 ◽  
pp. e79-e80
Author(s):  
X.S. Xu ◽  
X. Yan ◽  
T. Puchalski ◽  
S. Lonial ◽  
H.M. Lokhorst ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Proteasome Inhibitors ◽  
Immunomodulatory Drugs ◽  
Efficacy And Safety ◽  
Response Relationship ◽  
Refractory Multiple Myeloma ◽  
Exposure Response ◽  
Relationship Of

scholarly journals Refractory IgD Multiple Myeloma Treated with Daratumumab: A Case Report and Literature Review

2016 ◽  
Vol 2016 ◽  
pp. 1-4 ◽  
Author(s):  
Muhammad Husnain ◽  
Sandra Kurtin ◽  
Nikki Barkett ◽  
Irbaz Bin Riaz ◽  
Amit Agarwal
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Median Overall Survival ◽  
Overall Response Rate ◽  
Response Rate ◽  
Human Monoclonal Antibody ◽  
Proteasome Inhibitors ◽  
Recent Analysis ◽  
Immunomodulatory Drugs ◽  
Refractory Multiple Myeloma

Patients with relapsed and refractory multiple myeloma have poor prognosis. A recent analysis of patients with relapsed and refractory multiple myeloma who were refractory to both proteasome inhibitors and immunomodulatory drugs showed the median overall survival of 9 months only. Daratumumab is the first-in-class human monoclonal antibody against CD38 cells which was studied in phase I/II trials for treatment of these patients with relapsed refractory multiple myeloma. It showed an overall response rate of 36% and a median overall survival (OS) of 17 months in these patients. We report a case of 40-year-old man with immunoglobulin D (IgD) multiple myeloma whose disease was refractory to at least 5 different chemotherapy regimens including proteasome inhibitors and immunomodulatory drugs. The clinical studies assessing daratumumab did not include any patients with IgD myeloma which is a rare form of multiple myeloma and to our knowledge is the first study reporting use of daratumumab in IgD myeloma.

scholarly journals Rivaroxaban for Treatment of Pediatric Venous Thromboembolism. an Einstein-Jr Phase 3 Dose-Exposure-Response Evaluation

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 164-164
Author(s):  
Guy Young ◽  
Anthonie WA. Lensing ◽  
Paul Monagle ◽  
Christoph Male ◽  
Dagmar Kubitza
Keyword(s):  
Venous Thromboembolism ◽  
Similar Efficacy ◽  
Efficacy And Safety ◽  
Response Relationship ◽  
Phase 3 ◽  
Once Daily ◽  
Exposure Response ◽  
Suspension Formulation ◽  
Relationship Of ◽  
Repeat Imaging

Background: Venous thromboembolism (VTE) in children occurs with increasing frequency predominantly as a result of hospital-acquired thrombosis leading to a substantial rise in the use of anticoagulant medications in children. Only one anticoagulant (dalteparin, a subcutaneously administered agent) is licensed for use in children, but the evidence to support the use of anticoagulants in children is lacking. While several direct oral anticoagulants have been licensed and are in widespread use in adults, as of yet, none have been licensed for children and child-appropriate formulations are not commercially available. The EINSTEIN-Jr. program is a comprehensive clinical development program aimed at providing data to support the use (and eventual licensure) of rivaroxaban for children with VTE. The recently completed randomized EINSTEIN-Jr. phase 3 study showed similar efficacy and safety for rivaroxaban compared to standard anticoagulation for treatment of pediatric VTE. This abstract reports the results of the dose-exposure-response relationship of rivaroxaban from this study. The pediatric rivaroxaban dosing regimens were established based on phase 1 and 2 data in children and through pharmacokinetic (PK) modeling and has been previously reported. Methods: Rivaroxaban treatment with tablets or the newly-developed granules-for-oral suspension formulation was bodyweight-adjusted and administered once-daily, twice-daily or thrice-daily for children with bodyweights of ≥30, 12-<30, and <12kg, respectively. In children weighing <12kg, the lower range of the adult exposure range was targeted to avoid excessive concentrations at the end of the dosing interval. Previously, these regimens were confirmed for children weighing ≥20kg but only predicted in those <20kg. Based on sparse blood sampling, the 24-hour area under the plasma concentration-time curve [AUC(0-24)ss] and trough [Ctrough,ss] and maximum [Cmax,ss] steady-state plasma concentrations were derived using population PK modeling. Exposure-response graphs were generated to evaluate the potential relationship of individual PK parameters with recurrent VTE, change in thrombus burden at repeat imaging, and bleeding or adverse events. A taste and texture questionnaire was collected from suspension recipients. Results: Between November, 2014 and September, 2018, a total of 365 children were allocated to receive rivaroxaban in the following age groups: birth-<0.5 years (n=13); 0.5-<2 years (n=21); 2-<6 years (n=44); 6-<12 years (n=65); and 12-<18 years (n=173). Of these, 316 (94.3%) were evaluable for PK analyses. A total of 121 (38.3%) children received the rivaroxaban tablet formulation and 195 (61.7%) the suspension formulation. Symptomatic recurrent VTE occurred in 2 children (0.6%) during rivaroxaban treatment. Repeat imaging outcomes in the asymptomatic children were classified as normalized in 124 (39.2%), improved in 125 (39.6%), no relevant change in 16 (5.1%), and deteriorated in 1 (0.3%). In 48 children (15.2%) the result of repeat imaging was uncertain. No major bleeding events occurred with rivaroxaban treatment, whereas clinically relevant non-major bleeding and trivial bleeding were observed in 10 (3.2%) and 111 (35.1%) children, respectively. With respect to the dose-exposure relationship, the vast majority of the individual values were within the 5th-95th percentile for AUC(0-24)ss, Cmax,ss and Ctrough,ss (see figure below on the left). With respect to exposure-response relationship, no clustering was observed for any of the PK parameters with respect to efficacy, bleeding (shown in the figure below on the right), or adverse event outcomes. The results were similar for the tablet and suspension formulation. Acceptability and palatability of the suspension were favorable. Conclusion: Treatment of children with bodyweight-adjusted rivaroxaban regimens resulted in exposures similar to those previously observed in adults receiving 20 mg once daily dosing and the level of exposure was not related to the efficacy, bleeding, or adverse events. Based on this analysis and in conjunction with the previously demonstrated similar efficacy and safety of rivaroxaban compared with standard anticoagulation, we conclude that the bodyweight-adjusted pediatric rivaroxaban regimens with either tablets or suspension are validated and provide a new alternative treatment option for VTE in children. Figure Disclosures Young: Novo Nordisk: Consultancy, Honoraria; Spark: Consultancy, Honoraria; Shire/Takeda: Consultancy, Honoraria; Uniqure: Consultancy, Honoraria; Bioverativ/Sanofi: Consultancy, Honoraria; CSL Behring: Consultancy, Honoraria; Freeline: Consultancy, Honoraria; Genentech/Roche: Consultancy, Honoraria, Research Funding; Grifols: Consultancy, Honoraria; Kedrion: Consultancy, Honoraria. Lensing:Bayer: Employment. Male:Bristol Myers Squibb: Consultancy; Boehringer Ingelheim: Consultancy; Bayer: Consultancy. Kubitza:Bayer: Employment. OffLabel Disclosure: Pediatric treatment of VTE for a drug approved only in adults.

scholarly journals Efficiency of pomalidomide therapy in patients with multiple myeloma refractory to lenalidomide

2019 ◽  
Vol 14 (1) ◽  
pp. 8-13
Author(s):  
I. G. Rekhtina ◽  
L. P. Mendeleeva
Keyword(s):  
Multiple Myeloma ◽  
Proteasome Inhibitors ◽  
Antitumor Drugs ◽  
Low Doses ◽  
Efficacy And Safety ◽  
Refractory Multiple Myeloma ◽  
Highly Effective ◽  
Promising Treatment

Currently, there has been a marked increase in the number of opportunities for relapsed and refractory multiple myeloma treatment due toemergence of new target drugs. These include pomalidomide, a 3rd generation immunomodulator capable of treating double refractory multiple myeloma (to lenalidomide and bortezomib). Efficacy and safety of pomalidomide combined with low doses of dexamethasone have beenestablished in MM-003 and STRATUS trials. The summary presents the data on opportunities to further enhance the efficacy of pomalidomide combined with other antitumor drugs in patients with relapsed and refractory multiple myeloma who previously received 4–5 lines of therapy. It has been shown that triplets based on pomalidomide and dexamethasone combined with cyclophosphamide, bendamustine, daratumumab, carfilzomib, elotuzumab are highly effective in double refractory multiple myeloma patients. A combination of pomalidomide with proteasome inhibitors is a promising treatment provided that there is no refractoriness to bortezomib.

Population Pharmacokinetics and Exposure–Response Relationship of Carfilzomib in Patients With Multiple Myeloma

2016 ◽  
Vol 57 (5) ◽  
pp. 663-677 ◽  
Author(s):  
Ying Ou ◽  
Sameer Doshi ◽  
Anh Nguyen ◽  
Fredrik Jonsson ◽  
Sanjay Aggarwal ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Population Pharmacokinetics ◽  
Response Relationship ◽  
Exposure Response ◽  
Relationship Of

scholarly journals Population pharmacokinetic and exposure–response analyses of elotuzumab plus pomalidomide and dexamethasone for relapsed and refractory multiple myeloma

2021 ◽  
Author(s):  
Takafumi Ide ◽  
Mayu Osawa ◽  
Kinjal Sanghavi ◽  
Heather E. Vezina
Keyword(s):  
Multiple Myeloma ◽  
Progression Free Survival ◽  
Central Compartment ◽  
Peripheral Compartment ◽  
Population Pharmacokinetic ◽  
Parameter Estimates ◽  
Efficacy And Safety ◽  
Refractory Multiple Myeloma ◽  
Exposure Response ◽  
Grade 3

Abstract Purpose Elotuzumab plus pomalidomide/dexamethasone (E-Pd) demonstrated efficacy and safety in relapsed and refractory multiple myeloma (RRMM). The clinical pharmacology of elotuzumab [± lenalidomide/dexamethasone (Ld)] was characterized previously. These analyses describe elotuzumab population pharmacokinetics (PPK), the effect of Pd, and assess elotuzumab exposure–response relationships for efficacy and safety in patients with RRMM. Methods A previously established PPK model was updated with E-Pd data from the phase 2 ELOQUENT-3 study (NCT02654132). The dataset included 8180 serum concentrations from 440 patients with RRMM from 5 clinical trials. Elotuzumab PK parameter estimates were used to generate individual daily time-varying average concentrations (daily Cavg) for multi-variable time-to-event exposure–response analyses of progression-free survival (PFS) and time to the first occurrence of grade 3 + adverse events (AEs) in RRMM. Results Elotuzumab PK were well-described by a two-compartment model with parallel linear and Michaelis–Menten elimination from the central compartment (Vmax) and non-renewable target-mediated elimination from the peripheral compartment (Kint). Co-administration with Pd resulted in a 19% and 51% decrease in elotuzumab linear clearance and Kint, respectively, versus Ld; steady-state exposures were similar. Vmax increased with increasing serum M-protein. Hazard ratios (95% confidence intervals) for daily Cavg were 0.9983 (0.9969–0.9997) and 0.9981 (0.9964–0.9998) for PFS and grade 3 + AEs, respectively. Conclusions The PPK model adequately described the data and was appropriate for determining exposures for exposure–response analyses. There were no clinically relevant differences in elotuzumab exposures between Pd and Ld backbones. In ELOQUENT-3, increasing elotuzumab daily Cavg prolonged PFS without increasing grade 3 + AEs.

Exposure–Response Analysis for Selection of Optimal Dosage Regimen of Anifrolumab in Patients With Systemic Lupus Erythematosus

Rheumatology ◽  
2021 ◽  
Author(s):  
Yen Lin Chia ◽  
Linda Santiago ◽  
Bing Wang ◽  
Denison Kuruvilla ◽  
Shiliang Wang ◽  
...  
Keyword(s):  
Type I Interferon ◽  
Drug Clearance ◽  
Optimal Dosage ◽  
Type I ◽  
Efficacy And Safety ◽  
Response Relationship ◽  
Phase 3 ◽  
Optimal Dosage Regimen ◽  
Exposure Response ◽  
Selection Of

Abstract Objectives The randomized, double-blind, phase 2 b MUSE study evaluated the efficacy and safety of the type I interferon receptor antibody anifrolumab (300 mg or 1000 mg every 4 weeks) compared with placebo for 52 weeks in patients with chronic, moderate to severe SLE. Characterizing the exposure–response relationship of anifrolumab in MUSE will enable selection of its optimal dosage regimen in two phase 3 studies in patients with SLE. Methods The exposure–response relationship, pharmacokinetics (PK), and SLE Responder Index (SRI[4]) efficacy data were analysed using a population approach. A dropout hazard function was also incorporated into the SRI(4) model to describe the voluntary patient withdrawals during the 1-year treatment period. Results The population PK model found that type I IFN test–high patients, and patients with a higher body weight, had significantly greater clearance of anifrolumab. Stochastic clinical simulations demonstrated that doses <300 mg would lead to a greater-than-proportional reduction in drug exposure owing to type I interferon alpha receptor–mediated drug clearance (antigen-sink effect, more rapid drug clearance at lower concentrations) and suboptimal SRI(4) responses with wider confidence intervals. Conclusions Based on PK, efficacy, and safety considerations, anifrolumab 300 mg every 4 weeks was recommended as the optimal dosage for pivotal phase 3 studies in patients with SLE.

Real-world treatment patterns in relapsed/refractory multiple myeloma: Clinical and economic outcomes in patients treated with pomalidomide or daratumumab

2021 ◽  
pp. 107815522199553
Author(s):  
Joshua Richter ◽  
Vamshi Ruthwik Anupindi ◽  
Jason Yeaw ◽  
Suneel Kudaravalli ◽  
Stojan Zavisic ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Real World ◽  
Treatment Options ◽  
Proteasome Inhibitors ◽  
Economic Outcomes ◽  
Office Visits ◽  
Refractory Multiple Myeloma ◽  
Kaplan Meier ◽  
Real World Evidence ◽  
New Treatment

Introduction Real-world evidence on later line treatment of relapsed/refractory multiple myeloma (RRMM) is sparse. We evaluated clinical outcomes among RRMM patients in the 1-year following treatment with pomalidomide or daratumumab and compared economic outcomes between RRMM patients and non-MM patients. Patient and Methods Adult patients with ≥1 claim of pomalidomide or daratumumab were identified between January 2012 and February 2018 using IQVIA PharMetrics® Plus US claims database. Patients were required to have a diagnosis or treatment for MM and a claim of any immunomodulatory drugs and proteasome inhibitors before the index date. Mean time to new therapy, overall survival (OS) using Kaplan-Meier curve and adverse events (AEs) were reported over the 1-year post-index period. RRMM patients were also matched to a non-MM comparator cohort and economic outcomes were compared between the two cohorts. Results 289 RRMM patients were matched to 1,445 patients without MM. Most prevalent hematological AE was anemia (72.0%) and non-hematological AE was infections (75.4%). Mean (SD) time to a new treatment was 4.7 (5.3) months and median OS was 14.6 months. RRMM patients had significantly higher hospitalizations and physician office visits (Both P < .0001) compared to non-MM patients. Adjusting for baseline characteristics, patients with RRMM had 4.9 times (95% CI 3.8-6.4, P < .0001) the total healthcare costs compared with patients without MM. The major driver of total costs among RRMM patients was pharmacy costs (67.3%). Conclusion RRMM patients showed a high frequency of AEs, low OS, and a substantial economic burden suggesting need for effective treatment options.

scholarly journals The role of idecabtagene vicleucel in patients with heavily pretreated refractory multiple myeloma

2021 ◽  
Vol 12 ◽  
pp. 204062072110196
Author(s):  
Albert Oriol ◽  
Laura Abril ◽  
Anna Torrent ◽  
Gladys Ibarra ◽  
Josep-Maria Ribera
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Safety Profile ◽  
Proteasome Inhibitors ◽  
Clinical Development ◽  
Phase Iii ◽  
Acceptable Safety Profile ◽  
Refractory Multiple Myeloma ◽  
High Risk Patients ◽  
Risk Patients

The development of several treatment options over the last 2 decades has led to a notable improvement in the survival of patients with multiple myeloma. Despite these advances, the disease remains incurable for most patients. Moreover, standard combinations of alkylating agents, immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies targeting CD38 and corticoids are exhausted relatively fast in a proportion of high-risk patients. Such high-risk patients account for over 20% of cases and currently represent a major unmet medical need. The challenge of drug resistance requires the development of highly active new agents with a radically different mechanism of action. Several immunotherapeutic modalities, including antibody–drug conjugates and T-cell engagers, appear to be promising choices for patients who develop resistance to standard combinations. Chimeric antigen-receptor-modified T cells (CAR-Ts) targeting B-cell maturation antigen have demonstrated encouraging efficacy and an acceptable safety profile compared with alternative options. Multiple CAR-Ts are in early stages of clinical development, but the first phase III trials with CAR-Ts are ongoing for two of them. After the recent publication of the results of a phase II trial confirming a notable efficacy and acceptable safety profile, idecabtagene vicleucel is the first CAR-T to gain regulatory US Food and Drug Administration approval to treat refractory multiple myeloma patients who have already been exposed to antibodies against CD38, proteasome inhibitors, and immunomodulatory agents and who are refractory to the last therapy. Here, we will discuss the preclinical and clinical development of idecabtagene vicleucel and its future role in the changing treatment landscape of relapsed and refractory multiple myeloma.

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