IXAZOMIB-DEXAMETHASONE VS PHYSICIAN'S CHOICE IN PATIENTS WITH RELAPSED/REFRACTORY PRIMARY SYSTEMIC AL AMYLOIDOSIS (AL) BY PRIOR PROTEASOME INHIBITOR EXPOSURE IN THE PHASE 3 TOURMALINE-AL1 TRIAL
Author(s): ,
Efstathios Kastritis
Affiliations:
Department of Clinical Therapeutics,National and Kapodistrian University of Athens, School of Medicine,Athens,Greece
,
Angela Dispenzieri
Affiliations:
Division of Hematology,Mayo Clinic,Rochester,United States
,
Ashutosh D. Wechalekar
Affiliations:
National Amyloidosis Centre, the Royal Free London NHS Foundation Trust, University College London,London,United Kingdom
,
Stefan O. Schönland
Affiliations:
Department of Medicine V (Hematology, Oncology and Rheumatology),Amyloidosis Center Heidelberg, Heidelberg University Hospital,Heidelberg,Germany
,
Kihyun Kim
Affiliations:
Division of Hematology/Oncology, Department of Medicine,Samsung Medical Center, Sungkyunkwan University School of Medicine,Seoul,Korea, Republic Of
,
Vaishali Sanchorawala
Affiliations:
Amyloidosis Center, Boston University School of Medicine, Boston Medical Center,Boston,United States
,
Heather J. Landau
Affiliations:
Memorial Sloan Kettering Cancer Center,New York,United States
,
Fiona Kwok
Affiliations:
Clinical Haematology,Westmead Hospital,Sydney,Australia
,
Kenshi Suzuki
Affiliations:
Department of Hematology,Japanese Red Cross Medical Center,Tokyo,Japan
,
Raymond L. Comenzo
Affiliations:
John C. Davis Myeloma and Amyloid Program, Tufts Medical Center,Boston,United States
,
Giovanni Palladini
Affiliations:
Amyloidosis Research and Treatment Center, Foundation IRCCS Policlinico San Matteo, Department of Molecular Medicine, University of Pavia,Pavia,Italy
,
Deborah Berg
Affiliations:
Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited,Cambridge,United States
,
Guohui Liu
Affiliations:
Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited,Cambridge,United States
,
Arun Kumar
Affiliations:
Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited,Cambridge,United States
,
Douglas V. Faller
Affiliations:
Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited,Cambridge,United States
Giampaolo Merlini
Affiliations:
Amyloidosis Research and Treatment Center, Foundation IRCCS Policlinico San Matteo, Department of Molecular Medicine, University of Pavia,Pavia,Italy
(Abstract release date: 05/14/20) EHA Library. KASTRITIS E. 06/12/20; 294915; EP998
Dr. EFSTATHIOS KASTRITIS
Dr. EFSTATHIOS KASTRITIS
Contributions
Abstract

Abstract: EP998

Type: e-Poster

Background
The proteasome inhibitor (PI) bortezomib is commonly used in first-line therapy of AL, but new therapies are needed that are tolerable in the context of multi-organ dysfunction and that, in relapsed/refractory AL (RRAL), offer improved outcomes following prior bortezomib. Ixazomib is an oral PI, and in the international, multicenter TOURMALINE-AL1 trial (NCT01659658), the first phase 3 trial conducted in RRAL, while the first primary endpoint of hematologic overall response rate (ORR) was not met, all clinically relevant time-to-event endpoint data favored ixazomib plus dexamethasone (Ixa-Dex) vs physician’s choice (PC; Dispenzieri et al, ASH 2019).

Aims
We report subgroup analyses of ORR and time-to-event outcomes by prior PI exposure in TOURMALINE-AL1.

Methods
RRAL patients with major organ (cardiac and/or renal) involvement and 1–2 prior therapies were randomized (1:1) to Ixa-Dex (n=85) or PC (n=83), which comprised Dex plus lenalidomide (n=47), melphalan (n=24), cyclophosphamide (n=10), or thalidomide (n=2). Randomization was stratified by cardiac stage, relapsed vs refractory disease, and prior PI exposure. Patients could have prior exposure but not be refractory to PI therapy, and enrollment targeted ~50%/50% PI-exposed vs PI-naïve patients. The primary endpoints were hematologic ORR and 2-year rate of vital organ deterioration or death.

Results
Of the 168 patients enrolled, 90 were PI-naïve and 78 PI-exposed; this included 46 and 39 patients in the Ixa-Dex arm, respectively, and 44 and 39 patients in the PC arm, per stratification. Among the PI-exposed patients, 28 and 27 in the Ixa-Dex and PC arms, respectively, had received bortezomib in their last prior line. The hematologic ORR was 63% vs 50% for Ixa-Dex vs PC (odds ratio [OR] 1.71; 95% confidence interval [CI] 0.74–3.96) in PI-naïve patients, and 41% vs 51% (OR 0.66; 95% CI 0.27–1.62) in PI-exposed patients. For time-to-event outcomes, hazard ratios (HRs) were 0.46–0.85 in favor of Ixa-Dex vs PC in both PI-naïve and PI-exposed patients (Table). 

Conclusion
Hematologic ORR was higher with Ixa-Dex vs PC in PI-naïve patients but lower in PI-exposed patients, although these differences were not statistically significant, and long-term clinically relevant outcomes favored Ixa-Dex in both groups. Based on HRs, the magnitude of benefit appeared similar or greater in PI-naïve vs PI-exposed patients. 

Session topic: 14. Myeloma and other monoclonal gammopathies - Clinical

Keyword(s): AL amyloidosis, Clinical trial, Phase III, Proteasome inhibitor

Abstract: EP998

Type: e-Poster

Background
The proteasome inhibitor (PI) bortezomib is commonly used in first-line therapy of AL, but new therapies are needed that are tolerable in the context of multi-organ dysfunction and that, in relapsed/refractory AL (RRAL), offer improved outcomes following prior bortezomib. Ixazomib is an oral PI, and in the international, multicenter TOURMALINE-AL1 trial (NCT01659658), the first phase 3 trial conducted in RRAL, while the first primary endpoint of hematologic overall response rate (ORR) was not met, all clinically relevant time-to-event endpoint data favored ixazomib plus dexamethasone (Ixa-Dex) vs physician’s choice (PC; Dispenzieri et al, ASH 2019).

Aims
We report subgroup analyses of ORR and time-to-event outcomes by prior PI exposure in TOURMALINE-AL1.

Methods
RRAL patients with major organ (cardiac and/or renal) involvement and 1–2 prior therapies were randomized (1:1) to Ixa-Dex (n=85) or PC (n=83), which comprised Dex plus lenalidomide (n=47), melphalan (n=24), cyclophosphamide (n=10), or thalidomide (n=2). Randomization was stratified by cardiac stage, relapsed vs refractory disease, and prior PI exposure. Patients could have prior exposure but not be refractory to PI therapy, and enrollment targeted ~50%/50% PI-exposed vs PI-naïve patients. The primary endpoints were hematologic ORR and 2-year rate of vital organ deterioration or death.

Results
Of the 168 patients enrolled, 90 were PI-naïve and 78 PI-exposed; this included 46 and 39 patients in the Ixa-Dex arm, respectively, and 44 and 39 patients in the PC arm, per stratification. Among the PI-exposed patients, 28 and 27 in the Ixa-Dex and PC arms, respectively, had received bortezomib in their last prior line. The hematologic ORR was 63% vs 50% for Ixa-Dex vs PC (odds ratio [OR] 1.71; 95% confidence interval [CI] 0.74–3.96) in PI-naïve patients, and 41% vs 51% (OR 0.66; 95% CI 0.27–1.62) in PI-exposed patients. For time-to-event outcomes, hazard ratios (HRs) were 0.46–0.85 in favor of Ixa-Dex vs PC in both PI-naïve and PI-exposed patients (Table). 

Conclusion
Hematologic ORR was higher with Ixa-Dex vs PC in PI-naïve patients but lower in PI-exposed patients, although these differences were not statistically significant, and long-term clinically relevant outcomes favored Ixa-Dex in both groups. Based on HRs, the magnitude of benefit appeared similar or greater in PI-naïve vs PI-exposed patients. 

Session topic: 14. Myeloma and other monoclonal gammopathies - Clinical

Keyword(s): AL amyloidosis, Clinical trial, Phase III, Proteasome inhibitor

By clicking “Accept Terms & all Cookies” or by continuing to browse, you agree to the storing of third-party cookies on your device to enhance your user experience and agree to the user terms and conditions of this learning management system (LMS).

Cookie Settings
Accept Terms & all Cookies