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

Kaz Groen; Claudia A M Stege; Kazem Nasserinejad; Koen de Heer; Roel J W van Kampen; Rineke B L Leys; Noortje Thielen; Matthijs Westerman; Ka-Lung Wu; Inge Ludwig; Djamila E Issa; Gerjo A Velders; Marie-Christiane Vekemans; Gert-Jan Timmers; Fransien de Boer; Lidwine W Tick; Annelies Verbrugge; Danny Buitenhuis; Sonia M Cunha; Ellen van der Spek; Esther G M de Waal; Maaike Sohne; Pieter Sonneveld; Inger S Nijhof; Saskia K Klein; Niels W C J van de Donk; Mark-David Levin; Paula F Ypma; Sonja Zweegman

doi:10.1016/j.eclinm.2023.102167

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

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

Authors

Kaz Groen^{1

2}, Claudia A M Stege^{1

2}, Kazem Nasserinejad^{3

4}, Koen de Heer⁵, Roel J W van Kampen⁶, Rineke B L Leys⁷, Noortje Thielen⁸, Matthijs Westerman⁹, Ka-Lung Wu¹⁰, Inge Ludwig¹¹, Djamila E Issa¹², Gerjo A Velders¹³, Marie-Christiane Vekemans¹⁴, Gert-Jan Timmers¹⁵, Fransien de Boer¹⁶, Lidwine W Tick¹⁷, Annelies Verbrugge³, Danny Buitenhuis³, Sonia M Cunha³, Ellen van der Spek¹⁸, Esther G M de Waal¹⁹, Maaike Sohne²⁰, Pieter Sonneveld²¹, Inger S Nijhof²⁰, Saskia K Klein^{22

23}, Niels W C J van de Donk^{1

2}, Mark-David Levin²⁴, Paula F Ypma²⁵, Sonja Zweegman^{1

2}

Affiliations

¹ Department of Hematology, Amsterdam UMC, Vrije Universiteit Amsterdam, the Netherlands.
² Cancer Center Amsterdam, Treatment and Quality of Life, Amsterdam, the Netherlands.
³ HOVON Data Center, Department of Hematology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
⁴ Innovative Statistical Consulting, Therapeutics Development Team, Cytel Inc., Massachusetts, USA.
⁵ Department of Internal Medicine, Flevoziekenhuis, Almere, the Netherlands.
⁶ Department of Internal Medicine, Zuyderland Hospital, Sittard-Geleen, the Netherlands.
⁷ Department of Internal Medicine, Maasstad Hospital, Rotterdam, the Netherlands.
⁸ Department of Internal Medicine, Diakonessenhuis, Utrecht, the Netherlands.
⁹ Department of Internal Medicine, Northwest Clinics, Alkmaar, the Netherlands.
¹⁰ Department of Hematology, ZNA Stuivenberg, Antwerpen, Belgium.
¹¹ Department of Internal Medicine, Ziekenhuis Bernhoven, Uden, the Netherlands.
¹² Department of Internal Medicine, Jeroen Bosch Hospital, Den Bosch, the Netherlands.
¹³ Department of Internal Medicine, Gelderse Vallei, Ede, the Netherlands.
¹⁴ Department of Hematology, Cliniques Universitaires Saint-Luc, UCL, Brussels, Belgium.
¹⁵ Department of Internal Medicine, Amstelland Hospital, Amstelveen, the Netherlands.
¹⁶ Department of Internal Medicine, Ikazia Hospital, Rotterdam, the Netherlands.
¹⁷ Department of Internal Medicine, Maxima Medical Center, Eindhoven, the Netherlands.
¹⁸ Department of Internal Medicine, Rijnstate Hospital, Arnhem, the Netherlands.
¹⁹ Department of Internal Medicine, Medisch Centrum Leeuwarden, Leeuwarden, the Netherlands.
²⁰ Department of Internal Medicine, Antonius Ziekenhuis, Nieuwegein, the Netherlands.
²¹ Department of Hematology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
²² Department of Internal Medicine, Meander Medical Center, Amersfoort, the Netherlands.
²³ Department of Hematology, University Medical Center Groningen, Groningen, the Netherlands.
²⁴ Department of Internal Medicine, Albert Schweitzer Hospital, Dordrecht, the Netherlands.
²⁵ Department of Internal Medicine, Haga Hospital, Den Haag, the Netherlands.

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.