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. 2023 Aug 29:63:102167.
doi: 10.1016/j.eclinm.2023.102167. eCollection 2023 Sep.

Ixazomib, daratumumab and low-dose dexamethasone in intermediate-fit patients with newly diagnosed multiple myeloma: an open-label phase 2 trial

Kaz Groen  1   2 , Claudia A M Stege  1   2 , Kazem Nasserinejad  3   4 , Koen de Heer  5 , Roel J W van Kampen  6 , Rineke B L Leys  7 , Noortje Thielen  8 , Matthijs Westerman  9 , Ka-Lung Wu  10 , Inge Ludwig  11 , Djamila E Issa  12 , Gerjo A Velders  13 , Marie-Christiane Vekemans  14 , Gert-Jan Timmers  15 , Fransien de Boer  16 , Lidwine W Tick  17 , Annelies Verbrugge  3 , Danny Buitenhuis  3 , Sonia M Cunha  3 , Ellen van der Spek  18 , Esther G M de Waal  19 , Maaike Sohne  20 , Pieter Sonneveld  21 , Inger S Nijhof  20 , Saskia K Klein  22   23 , Niels W C J van de Donk  1   2 , Mark-David Levin  24 , Paula F Ypma  25 , Sonja Zweegman  1   2
Affiliations

Ixazomib, daratumumab and low-dose dexamethasone in intermediate-fit patients with newly diagnosed multiple myeloma: an open-label phase 2 trial

Kaz Groen et al. EClinicalMedicine. .

Abstract

Background: The outcome of non-transplant eligible newly diagnosed multiple myeloma (NDMM) patients is heterogeneous, partly depending on frailty level. The aim of this study was to prospectively investigate the efficacy and safety of Ixazomib-Daratumumab-low-dose dexamethasone (Ixa-Dara-dex) in NDMM intermediate-fit patients.

Methods: In this phase II multicenter HOVON-143 study, IMWG Frailty index based intermediate-fit patients, were treated with 9 induction cycles of Ixa-Dara-dex, followed by maintenance with ID for a maximum of 2 years. The primary endpoint was overall response rate on induction treatment. Patients were included from October 2017 until May 2019. Trial Registration Number: NTR6297.

Findings: Sixty-five patients were included. Induction therapy resulted in an overall response rate of 71%. Early mortality was 1.5%. At a median follow-up of 41.0 months, median progression-free survival (PFS) was 18.2 months and 3-year overall survival 83%. Discontinuation of therapy occurred in 77% of patients, 49% due to progression, 9% due to toxicity, 8% due to incompliance, 3% due to sudden death and 8% due to other reasons. Dose modifications of ixazomib were required frequently (37% and 53% of patients during induction and maintenance, respectively), mainly due to, often low grade, polyneuropathy. During maintenance 23% of patients received daratumumab alone. Global quality of life (QoL) improved significantly and was clinically relevant, which persisted during maintenance treatment.

Interpretation: Ixazomib-Daratumumab-low-dose dexamethasone as first line treatment in intermediate-fit NDMM patients is safe and improves global QoL. However, efficacy was limited, partly explained by ixazomib-induced toxicity, hampering long term tolerability of this 3-drug regimen. This highlights the need for more efficacious and tolerable regimens improving the outcome in vulnerable intermediate-fit patients.

Funding: Janssen Pharmaceuticals, Takeda Pharmaceutical Company Limited.

Keywords: Daratumumab; Elderly; IMWG frailty index; Intermediate-fit; Ixazomib; Multiple myeloma.

PubMed Disclaimer

Conflict of interest statement

Claudia Stege. Speaker's Bureau: Sanofi, Celgene/Bristol Myers Squibb, Takeda. Consulting or Advisory Role: Sanofi, Janssen. Marie-Christiane Vekemans. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Amgen, Janssen, Takeda, Bristol Myers Squibb/Celgene. Consulting or Advisory Role: Amgen, Celgene-Bristol Myers Squibb, Janssen, Takeda, Sanofi, Pfizer, GlaxoSmithKline, Menarini. Ka-Lung Wu. Consulting or Advisory Role: Pfizer, Janssen, Bristol Myers Squibb. Niels W. C. J. van de Donk. Consulting or Advisory Role: Janssen, Celgene, Bristol Myers Squibb, Novartis, Amgen, Servier, Takeda, Bayer, Roche, Pfizer, Abbvie, Adaptive. Research Funding: Janssen, Celgene, Amgen, Novartis, Bristol Myers Squibb, Cellectis. Gert Jan Timmers. Participation on an Advisory Board: Novartis. Travel, Accommodations, Expenses: Novartis, Janssen. Ellen van der Spek. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Janssen. Pieter Sonneveld. Participation on a Data Safety Monitoring Board or Advisory Board: Celgene, Janssen, Amgen, Bristol Myers Squibb, Karyopharm Therapeutics, Pfizer. Research Funding: Janssen, Amgen, Bristol Myeres Squibb/Celgene, Karyopharm Therapeutics, Pfizer. Inger S. Nijhof. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Janssen, Celgene/Bristol Myers Squibb, Sanofi. Mark-David Levin. Support for attending meetings and/or travel: Janssen, Takeda. Paula F. Ypma. Payment or honoraria for presentations: Janssen. Support for attending meetings and/or travel: Janssen. Sonja Zweegman. Consulting or Advisory Role: Janssen-Cilag, Takeda, Celgene/Bristol Myers Squibb, Sanofi, Oncopeptides (no personal funding). Research Funding: Janssen, Takeda. No other potential conflicts of interest were reported.

Figures

Fig. 1
Fig. 1
CONSORT diagram—patient flow and causes of treatment discontinuation. Consort diagram of the number of intermediate-fit patients participating in the HOVON 143 study, flow through the induction and maintenance phase and timing and reason for treatment discontinuation. Reasons for treatment discontinuation: – Toxicity: 1cardiac decompensation; 2PNP grade 3 with pain; 3acute renal failure; 4 PNP grade 2; 5 Orthostatic hypotension grade 3 – Intercurrent death: I sudden death; II unknown cause of death – Other reasons: a hypothyroidism related to amiodarone; b increase in M-protein not formally meeting criteria of progressive disease (PD); c progressive vascular dementia; d Squamous cell carcinoma grade 3; e PNP grade 2 and increase in M-protein (not formally meeting criteria of PD) during COVID19 pandemic; f Physician decision (increasing M-protein not formally meeting criteria of PD).
Fig. 2
Fig. 2
Survival outcomes of intermediate-fit patients A) Progression-free survival (PFS), B) overall survival (OS), C) progression-free survival 2 (PFS2) and D) event-free survival (EFS). For further specification of EFS reasons, please be referred to Table S2 in the Supplemental data. No differences in PFS, OS or EFS were observed between patient subgroups defined intermediate-fit based on age 76–80 vs based on another frailty parameter (comorbidities or iADL dependency) (Figure S1).
Fig. 2
Fig. 2
Survival outcomes of intermediate-fit patients A) Progression-free survival (PFS), B) overall survival (OS), C) progression-free survival 2 (PFS2) and D) event-free survival (EFS). For further specification of EFS reasons, please be referred to Table S2 in the Supplemental data. No differences in PFS, OS or EFS were observed between patient subgroups defined intermediate-fit based on age 76–80 vs based on another frailty parameter (comorbidities or iADL dependency) (Figure S1).
See this image and copyright information in PMC

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