Phase 3 Study (CLARION) of Carfilzomib, Melphalan, Prednisone (KMP) v Bortezomib, Melphalan, Prednisone (VMP) in Newly Diagnosed Multiple Myeloma (NDMM)

Facon, Thierry; Lee, Jae Hoon; Moreau, Philippe; Niesvizky, Rubén; Dimopoulos, Meletios A.; Osman, Muhtarjan; Aggarwal, Sanjay; Klippel, Zandra; Miguel, Jesús San

doi:10.1016/j.clml.2017.03.045

Cited by 33 publications

(27 citation statements)

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“…16,17,23 Most studies of the VMP regimen have utilized a fixed duration of treatment (often approximately 1 year) rather than extended or continuous therapy. 17,19,32,33 Furthermore, in the real-world clinical practice setting, early discontinuations due to toxicities are common.…”

Section: Discussionmentioning

confidence: 99%

A phase I/II dose-escalation study investigating all-oral ixazomib-melphalan-prednisone induction followed by single-agent ixazomib maintenance in transplant-ineligible newly diagnosed multiple myeloma

et al. 2018

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This phase I/II dose-escalation study investigated the all-oral ixazomib-melphalan-prednisone regimen, followed by single-agent ixazomib maintenance, in elderly, transplant-ineligible patients with newly diagnosed multiple myeloma. Primary phase I objectives were to determine the safety and recommended phase II dose of ixazomib-melphalan-prednisone. The primary phase II objective was to determine the complete plus very good partial response rate. In phase I, patients were enrolled to 4 arms investigating weekly or twice-weekly ixazomib (13 28-day cycles or nine 42-day cycles) plus melphalan-prednisone. In phase II, an expansion cohort was enrolled at the recommended phase II ixazomib dose. Of the 61 patients enrolled, 26 received the recommended phase II dose (ixazomib 4.0 mg [days 1, 8, 15] plus melphalan-prednisone 60 mg/m2 [days 1-4], 28-day cycles). Of the 61 enrolled patients, 36 (13 of 26 in the recommended phase II dose cohort) received single-agent ixazomib maintenance (days 1, 8, 15; 28-day cycles). In phase I, 10/38 patients reported dose-limiting toxicities in cycle 1, including grade 3 and/or 4 neutropenia (n=6) and thrombocytopenia (n=4). Complete plus very good partial response rate was 48% (48% at recommended phase II dose), including 28% (22%) complete response or better; responses deepened during maintenance in 34% (33%) of evaluable patients. After median follow up of 43.6 months, median progression-free survival was 22.1 months. Adverse events were mainly hematologic events, gastrointestinal events, and peripheral neuropathy. This study demonstrates the feasibility, tolerability, and activity of ixazomib-melphalan-prednisone induction and single-agent ixazomib maintenance in transplant-ineligible newly diagnosed multiple myeloma patients. clinicaltrials.gov identifier 01335685.

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Section: Discussionmentioning

confidence: 99%

A phase I/II dose-escalation study investigating all-oral ixazomib-melphalan-prednisone induction followed by single-agent ixazomib maintenance in transplant-ineligible newly diagnosed multiple myeloma

et al. 2018

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“…Further details of each study including ethical approval are described elsewhere. 2,10,21,22 Patients were eligible for entry into the pooled sample if they had completed the EORTC QLQ-C30 or QLQ-MY20 at baseline plus at least one other of the following time points: mid-treatment (MT), or end of treatment (EOT). MT was defined as Week 8-12, as while ENDEAVOR and CLARION both had PRO assessments common to both treatment arms at Week 12, the closest PRO assessment common to both arms in ASPIRE was at Week 8.…”

Section: Clinical Trial Datamentioning

confidence: 99%

Estimation of minimally important differences and responder definitions for EORTC QLQ‐MY20 scores in multiple myeloma patients

Sully

Trigg

Bonner

et al. 2019

European J of Haematology

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Objectives: Thresholds for the minimally important difference (MID) or responder definition (RD) in health-related quality-of-life (HRQoL) scores are required to interpret the impact of an intervention or change in the trajectory of the condition which is meaningful to patients. This study aimed to establish MID and RD for the European Organisation for Research and Treatment of Cancer Quality of Life Multiple Myeloma questionnaire (EORTC QLQ-MY20).Methods: A novel mixed-methods approach was applied by utilizing both existing clinical trial data and prospective patient interviews. Anchor-based, distributionbased, and qualitative-based estimates of meaningful change were triangulated to form recommended RDs for each scale of the EORTC QLQ-MY20. Anchor-based MIDs were summarized using weighted correlation.Results: Recommended MIDs were as follows: Disease Symptoms (DS 10 points), Side Effects of Treatment (SE 10 points), Body Image (BI 13 points), and Future Perspective (FP 9 points). Recommended RDs were as follows: DS (16 improvement; 11 worsening), SE (6 improvement; 9 worsening), BI (33 improvement; 33 worsening), and FP (11 improvement; 11 worsening). Conclusions:The study generated estimates of the MID and RD for each scale of the EORTC QLQ-MY20. Published estimates will enable investigators and clinicians to adopt these as standard for interpretation and for hypothesis testing. Consequently, analyses from trials of different interventions can be more comparable. K E Y W O R D SEORTC QLQ-MY20, interpretation guidelines, meaningful change, minimally important difference, mixed methods, multiple myeloma, qualitative interviews, quality of life, responder definition Kate Sully and Andrew Trigg are contributed equally to this work.This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

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“…Studies evaluating the combination of CFZ with POM/DEX have also demonstrated comparable ORR in patients that are refractory to LEN and BTZ (Shah et al, 2015). In contrast, recent data has demonstrated that CFZ in combination with melphalan and prednisolone did not show any significant PFS benefit over BTZ with melphalan and prednisolone in newly diagnosed MM (Facon et al, 2017). This suggests that irreversible inhibition of the CT-L subunit of the proteasome is not sufficient to add clinical benefit over that observed with reversible CT-L inhibition in the newly diagnosed setting.…”

Section: Discussionmentioning

confidence: 99%

A phase 1 clinical trial evaluating marizomib, pomalidomide and low‐dose dexamethasone in relapsed and refractory multiple myeloma (NPI‐0052‐107): final study results

et al. 2017

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SummaryMarizomib (MRZ) is an irreversible, pan-subunit proteasome inhibitor (PI) in clinical development for relapsed/refractory multiple myeloma (RRMM) and glioma. This study analysed MRZ, pomalidomide (POM) and low-dose dexamethasone (Lo-DEX) [PMD] in RRMM to evaluate safety and determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D). Intravenous MRZ (0Á3-0Á5 mg/m 2 ) was administered over 2 h on days 1, 4, 8, 11; POM (3-4 mg) on days 1-21; and Lo-DEX (5 or 10 mg) on days 1, 2, 4, 5, 8, 9, 11, 12, 15, 16, 22 and 23 of every 28-day cycle. Thirty-eight patients were enrolled that had received a median of 4 (range 1-10) prior lines of therapy; all patients received prior lenalidomide and bortezomib. No dose-limiting toxicities (DLTs) were observed and 0Á5 mg/m 2 MRZ was determined to be the RP2D. The most common treatment-related ≥Grade 3 adverse events were: neutropenia (11/38 patients: 29%), pneumonia (4/38 patients 11%), anaemia (4/38 patients; 11%) and thrombocytopenia (4/38 patients; 11%). The overall response rate and clinical benefit rate was 53% (19/36) and 64% (23/36), respectively. In conclusion, PMD was well tolerated and demonstrated promising activity in heavily pre-treated, high-risk RRMM patients.

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Phase 3 Study (CLARION) of Carfilzomib, Melphalan, Prednisone (KMP) v Bortezomib, Melphalan, Prednisone (VMP) in Newly Diagnosed Multiple Myeloma (NDMM)

Cited by 33 publications

References 0 publications

A phase I/II dose-escalation study investigating all-oral ixazomib-melphalan-prednisone induction followed by single-agent ixazomib maintenance in transplant-ineligible newly diagnosed multiple myeloma

A phase I/II dose-escalation study investigating all-oral ixazomib-melphalan-prednisone induction followed by single-agent ixazomib maintenance in transplant-ineligible newly diagnosed multiple myeloma

Estimation of minimally important differences and responder definitions for EORTC QLQ‐MY20 scores in multiple myeloma patients

A phase 1 clinical trial evaluating marizomib, pomalidomide and low‐dose dexamethasone in relapsed and refractory multiple myeloma (NPI‐0052‐107): final study results

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