Exposure–safety–efficacy analysis of single-agent ixazomib, an oral proteasome inhibitor, in relapsed/refractory multiple myeloma: dose selection for a phase 3 maintenance study

Summary Background Ixazomib is the first oral, small molecule proteasome inhibitor to reach phase 3 trials. The current analysis characterized the exposure-safety and exposure-efficacy relationships of ixazomib in patients with relapsed/refractory multiple myeloma (MM) with a purpose of recommending an approach to ixazomib dosing for maintenance therapy. Methods Logistic regression was used to investigate relationships between ixazomib plasma exposure (area under the curve/day; derived from individual apparent clearance values from a published population pharmacokinetic analysis) and safety/efficacy outcomes (hematologic [grade ≥ 3 vs ≤ 2] or non-hematologic [grade ≥ 2 vs ≤ 1] adverse events [AEs], and clinical benefit [≥stable disease vs progressive disease]) using phase 1 data in relapsed/refractory MM (NCT00963820; N = 44). Results Significant relationships to ixazomib exposure were observed for five AEs (neutropenia, thrombocytopenia, rash, fatigue, and diarrhea) and clinical benefit (p 
Source: Investigational New Drugs - Category: Drugs & Pharmacology Source Type: research

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In conclusion, a pharmacodynamic model was successfully developed, which provides a quantitative, mechanism-based platform for probing bortezomib dosing-regimens. Further research is needed t o determine whether this model could be used to individualize bortezomib regimens to maximize antineoplastic efficacy and minimize thrombocytopenia during MM treatment.
Source: Journal of Pharmacokinetics and Pharmacodynamics - Category: Drugs & Pharmacology Source Type: research
CONCLUSIONS: This study provides the basis for studying the addition of JAK inhibitors to improve the efficacy of immunomodulatory agents with steroids for treating myeloma patients but perhaps can also be expanded for treating other cancer patients that are refractory to this class of drugs. PMID: 31937615 [PubMed - as supplied by publisher]
Source: Clinical Cancer Research - Category: Cancer & Oncology Authors: Tags: Clin Cancer Res Source Type: research
Abstract Nowadays, bortezomib, a proteasome inhibitor, is widely used in treatment of newly diagnosed or relapsed multiple myeloma. The aim of this study was to analyze efficiency of bortezomib retreatment in patients with relapsed or refractory multiple myeloma. From 2004 to 2016, 283 patients were retrospectively evaluated at all hematological centers in the Czech Republic. Bortezomib was administered at the standard dosing and in combined therapy with corticosteroids, chemotherapy or thalidomide. Before bortezomib retreatment, 61% of patients received previous lenalidomide treatment, 40.6% autologous transplant...
Source: Neoplasma - Category: Cancer & Oncology Authors: Tags: Neoplasma Source Type: research
ConclusionVenetoclax therapy in a real-world cohort offered modest benefits in heavily pretreated patients. Adverse events were observed at a greater incidence than in the clinical trials. A wide heterogeneity of venetoclax dose escalation, multiagent combinations, and timing of initiation were identified and require investigation in subsequent clinical trials.
Source: Clinical Lymphoma Myeloma and Leukemia - Category: Cancer & Oncology Source Type: research
In conclusion, sequential therapy with VMP followed by Rd is effective and mostly feasible for transplant-ineligible NDMM. The study is registe red as UMIN000034815.
Source: Annals of Hematology - Category: Hematology Source Type: research
CONCLUSION: This study showed that blockade of the CXCR4-CXCL12 axis by ulocuplumab is safe with acceptable adverse events and leads to a high response rate in combinationwith lenalidomide and dexamethasone in patients with relapsed/refractory myeloma, making CXCR4-inhibitors a promising class of anti-myeloma drugs that should be further explored in clinical trials. PMID: 31672767 [PubMed - as supplied by publisher]
Source: Clinical Cancer Research - Category: Cancer & Oncology Authors: Tags: Clin Cancer Res Source Type: research
In conclusion, modified VRD-lite had similar efficacy with, but better tolerability than, twVRD in transplant-eligible patients. PMID: 31673952 [PubMed - as supplied by publisher]
Source: International Journal of Hematology - Category: Hematology Authors: Tags: Int J Hematol Source Type: research
This study is registered with the ISRCTN registry, number ISRCTN49407852, and clinicaltrialsregister.eu, number 2009–010956–93, and has completed recruitment.FindingsBetween Nov 15, 2010, and July 28, 2016, 583 patients were enrolled to the intensification randomisation, representing 48% of the 1217 patients who achieved partial or minimal response after initial induction therapy. 289 patients were assigned to CVD treatment and 294 patients to no treatment. After a median follow-up of 29·7 months (IQR 17·0–43·5), median progression-free survival was 30 months (95% CI 25–36) with...
Source: The Lancet Haematology - Category: Hematology Source Type: research
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Source: Journal of Bone and Mineral Research - Category: Orthopaedics Authors: Tags: Original Article Source Type: research
Risk stratification of multiple myeloma (MM) at diagnosis allows prognostication and drives therapeutic decisions and currently the International staging system (ISS) and the Revised International staging system (RISS) are routinely utilized. Increased red blood cell distribution width (RDW), anemia, and thrombocytopenia have been shown to predict worse progression-free (PFS) and overall survival (OS). We hypothesized that the hematopoietic indices including mean corpuscular volume (MCV), hemoglobin (Hgb), and platelet (Plt) count may reflect the impact of the tumor cells on the marrow microenvironment and examined its abi...
Source: Clinical Lymphoma, Myeloma and Leukemia - Category: Hematology Authors: Source Type: research
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