A Study Comparing Once-weekly vs Twice-weekly Carfilzomib in Combination With Lenalidomide and Dexamethasone in Subjects With Relapsed or Refractory Multiple Myeloma
- Conditions
- Relapsed or Refractory Multiple Myeloma
- Interventions
- Registration Number
- NCT03859427
- Lead Sponsor
- Amgen
- Brief Summary
Compare efficacy of 56 mg/m2 carfilzomib administered once-weekly in combination with lenalidomide and dexamethasone (KRd 56 mg/m2) to 27 mg/m2 carfilzomib administered twice-weekly in combination with lenalidomide and dexamethasone (KRd 27 mg/m2) in subjects with relapsed or refractory multiple myeloma (RRMM) with 1 to 3 prior lines of therapy.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 454
Multiple myeloma with documented relapse or progression after most recent myeloma treatment. Subjects refractory to the most recent line of therapy are eligible, unless last treatment contained proteasome inhibitor (PI) or lenalidomide and dexamethasone. Refractory is defined as disease that is nonresponsive or progresses within 60 days of last therapy.
Subjects must have at least PR to at least 1 line of prior therapy.
Subjects must have received at least 1 but not more than 3 prior lines of therapy for multiple myeloma (induction therapy followed by stem cell transplant and consolidation maintenance therapy will be considered as 1 line of therapy).
Prior therapy with a PI or the combination of lenalidomide and dexamethasone are allowed if the patient had at least a PR to the most recent treatment with a PI or lenalidomide and dexamethasone, neither PI or lenalidomide and dexamethasone containing treatment were ceased due to toxicity, the patient has not relapsed within 60 days of discontinuation of the PI or lenalidomide and dexamethasone containing treatment. A history of prior neuropathy is permitted if this was not grade 3, grade 4 or grade 2 with pain and if not resolved within the 14 days before enrollment, is less than or equal to grade 2 without pain. Patients are permitted to have received single agent lenalidomide as maintenance therapy within 60 days of enrollment.
Previous treatment with a lenalidomide and dexamethasone containing regimen is allowed, as long as the subject did not progress during the first 3 months after initiating lenalidomide and dexamethasone containing therapy.
Measurable disease with at least 1 of the following assessed within 21 days prior to randomization:
- Immunoglobulin G (IgG) multiple myeloma: serum monoclonal protein (M-protein) level ≥ 1.0 g/dL
- Immunoglobulin A (IgA), Immunoglobulin D (IgD), Immunoglobulin E (IgE) multiple myeloma: serum M-protein level ≥ 0.5 g/dL
- Urine M-protein ≥ 200 mg per 24 hours
- In subjects without measurable serum or urine M-protein, serum-free light chain (SFLC) ≥ 100 mg/L (involved light chain) and an abnormal serum kappa lambda ratio
Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 ≤ 2
Other inclusion criteria may apply
Waldenström macroglobulinemia.
Multiple myeloma of Immunoglobulin M (IgM) subtype.
Plasma cell leukemia (> 2.0 × 10^9 /L circulating plasma cells by standard differential).
Uncontrolled hypertension, defined as a subject whose blood pressure is greater than or equal to 160 mmHg systolic or greater than or equal to 100 mmHg diastolic when taken in accordance with the European Society of Hypertension/European Society of Cardiology 2018 guidelines (Section 12.10; Williams et al, 2018).
Active congestive heart failure (New York Heart Association Class III to IV), symptomatic ischemia, uncontrolled arrhythmias, screening ECG with corrected QT interval (QTc) of > 470 msec, pericardial disease, or myocardial infarction within 4 months prior to randomization.
Calculated or measured creatinine clearance < 30 mL/min (calculation must be based on the Cockcroft and Gault formula) within 28 days prior to randomization.
Other exclusion criteria may apply
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Carfilzomib once-weekly Carfilzomib Carfilzomib, lenalidomide, dexamethasone (KRd) regimen using once-weekly carfilzomib 56 mg/m2 Carfilzomib once-weekly Lenalidomide Carfilzomib, lenalidomide, dexamethasone (KRd) regimen using once-weekly carfilzomib 56 mg/m2 Carfilzomib twice-weekly Carfilzomib Carfilzomib, lenalidomide, dexamethasone (KRd) regimen using twice-weekly carfilzomib 27 mg/m2 Carfilzomib once-weekly Dexamethasone Carfilzomib, lenalidomide, dexamethasone (KRd) regimen using once-weekly carfilzomib 56 mg/m2 Carfilzomib twice-weekly Lenalidomide Carfilzomib, lenalidomide, dexamethasone (KRd) regimen using twice-weekly carfilzomib 27 mg/m2 Carfilzomib twice-weekly Dexamethasone Carfilzomib, lenalidomide, dexamethasone (KRd) regimen using twice-weekly carfilzomib 27 mg/m2
- Primary Outcome Measures
Name Time Method Overall Response Rate (ORR) Per International Myeloma Working Group Uniform Response Criteria (IMWG-URC) Cycle 1 Day 1 up to approximately 12 months (cycle = 28 days); median treatment duration for the twice-weekly arm was 47.00 weeks and for the once-weekly arm was 47.14 weeks. ORR was defined as the percentage of participants with a best overall response of stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR) per IMWG-URC. CR: negative immunofixation on serum and urine, soft tissue plasmacytomas disappearance, \< 5% plasma cells in bone marrow (BM). sCR: CR and normal serum free light chain ratio and no clonal cells in BM by immunohistochemistry. VGPR: Serum and urine M-protein detectable by immunofixation or ≥ 90% reduction in serum M-protein (urine M-protein level \< 100 mg/24-hours). PR: ≥ 50% reduction of serum M-protein and reduction in 24-hours urinary M-protein by ≥ 90% or to \< 200 mg/24-hours. The ORR 95% confidence intervals (CIs) were estimated using the Clopper-Pearson method.
- Secondary Outcome Measures
Name Time Method Kaplan-Meier Estimate of Progression-free Survival (PFS) Rate at 12 Months 12 months PFS rate was defined as the percentage of participants without disease progression or death due to any cause at 12 months. The PFS rate at 12 months was estimated using the Kaplan-Meier method by Klein and Moeschberger (1997). 95% CIs were estimated using the method by Kalbfleisch and Prentice (1980). PFS data was censored for participants who met any one of the following: 1. no baseline/no post-baseline disease assessments; 2. starting new anti-myeloma therapy before documentation of progressive disease (PD) or death; 3. PD or death immediately after more than 1 consecutively missed disease assessment visit (PD or death immediately after \> 63 days without disease assessment visit); 4. alive without documentation of PD; 5. lost to follow-up or withdrawn consent.
Percentage of Participants Who Reported Convenience as Measured by the Patient-reported Convenience With Carfilzomib-dosing Schedule Question Day 28 of Cycle 4 Patient-reported convenience was measured by the Patient-reported Convenience with Carfilzomib-dosing Schedule Question. The items in the questionnaire were categorized as 'Convenient', which included responses of 'Very Convenient' and 'Convenient', and 'Inconvenient' which included responses of 'Inconvenient' and 'Very Inconvenient'. The 95% CIs were estimated using the Clopper-Pearson method.
Number of Participants With Treatment-emergent Adverse Events (TEAEs) Cycle 1 Day 1 up to end of Cycle 12 + 30 days, where each cycle was 28 days; median treatment duration (any study treatment) was 47.00 weeks in the twice-weekly KRd group and 47.14 weeks in the once-weekly KRd group An adverse event (AE) was any untoward medical occurrence in a clinical study participant irrespective of a causal relationship with the study treatment. TEAEs were AEs starting on or after the first dose of any study drug, and up to 30 days of the last dose of any study drug, excluding AEs reported after End of Study date.
Time to Response (TTR) Cycle 1 Day 1 up to approximately 12 months (cycle = 28 days); median treatment duration for the twice-weekly arm was 47.00 weeks and for the once-weekly arm was 47.14 weeks. TTR was defined as the time from randomization to the earliest date when confirmed sCR, CR, VGPR, or PR per IMWG-URC was first achieved.
Patient-reported Treatment Satisfaction as Measured by the Cancer Therapy Satisfaction Questionnaire (CTSQ) Cycle 5 Day 1, Cycle 12 Day 1, and safety follow-up (30 days after last dose) The CTSQ measures treatment satisfaction in individuals with cancer and includes a domain for satisfaction with therapy. The satisfaction with therapy scores ranges from 0 to 100 points, with 100 points indicating greatest satisfaction.
Analysis was based on ANCOVA model. The dependent variable of the models were the scale scores measured at each visit. The model included effects of intercept, scale score measured at cycle 2 day 1 visit, treatment arm, and randomization stratification factors.Kaplan-Meier Estimate of Duration of Response (DOR) Cycle 1 Day 1 up to approximately 12 months (cycle = 28 days); median treatment duration for the twice-weekly arm was 47.00 weeks and for the once-weekly arm was 47.14 weeks. For participants who achieved a PR or better, i.e., sCR, CR, VGPR, or PR per IMWG-URC, the DOR was defined as the time from the earliest date when a PR or better was first achieved, and subsequently confirmed, to the earliest date of confirmed PD or death due to any cause. Median DOR was estimated using the Kaplan-Meier method. 95% CIs were estimated using the method by Klein and Moeschberger (1997) with log-log transformation. For those alive and who had not experienced PD by analysis time, DOR was censored for participants who met any one of the following: 1. no baseline/no post-baseline disease assessments; 2. starting new anti-myeloma therapy before documentation of PD or death; 3. PD or death immediately after more than 1 consecutively missed disease assessment visit (PD or death immediately after \> 63 days without disease assessment visit); 4. alive without documentation of PD; 5. lost to follow-up or withdrawn consent.
Percentage of Participants With Minimal Residual Disease Negativity (MRD[-]) by IRC Per IMWG-URC at 12 Months Cycle 1 Day 1 up to 12 months (cycle = 28 days) The percentage of participants with achievement of MRD\[-\] at 12 months (± 4 weeks) from randomization, as assessed by next generation sequencing method at a 10\^-5 threshold. MRD negativity results from BM samples obtained at 8 to 13 months from randomization and prior to new anti-myeloma therapy or disease progression were considered in the calculation. The 95% CIs for percentages were estimated using the Clopper-Pearson method.
Kaplan-Meier Estimate of Time to Progression (TTP) Cycle 1 Day 1 up to approximately 12 months (cycle = 28 days); median treatment duration for the twice-weekly arm was 47.00 weeks and for the once-weekly arm was 47.14 weeks. TTP was defined as the duration from randomization for the first documented disease progression per IMWG-UCR. Median TTP was estimated using the Kaplan-Meier method. 95% CIs were estimated using the method by Klein and Moeschberger (1997) with log-log transformation. TTP was censored for participants who had no confirmed PD at the last non non-evaluable (non-NE), post-baseline disease assessment or the earlier of the following, where applicable: 1. the last non-NE, post-baseline disease assessment prior to start of a new anti-myeloma treatment, or 2. the last non-NE, post-baseline assessment followed \> 63 days later by disease progression; otherwise, at randomization.
Percentage of Participants Who Achieved Minimal Residual Disease Negative Complete Response (MRD[-]CR) by Independent Review Committee (IRC) Per IMWG-URC Cycle 1 Day 1 up to approximately 12 months (cycle = 28 days); median treatment duration for the twice-weekly arm was 47.00 weeks and for the once-weekly arm was 47.14 weeks. MRD\[-\]CR was defined as achievement of CR or better by IRC per IMWG-URC and achievement of MRD negativity as assessed by next generation sequencing method at a 10\^-5 threshold over the duration of the study. The 95% CIs for percentages were estimated using the Clopper-Pearson method.
Change From Baseline in EORTC QLQ-C30 Role Functioning Scale Baseline (Cycle 1 Day 1), Cycle 3 Day 1, Cycle 5 Day 1, Cycle 7 Day 1, Cycle 9 Day 1, Cycle 12 Day 1, and safety follow-up (30 days after last dose) The QLQ-C30 role function is one of the functional domains of the EORTC QLQ-C30 self-reported instrument and the role functioning score ranges from 0-100 points, with 100 points indicating the best possible functioning. A positive change from baseline indicated an improvement in functioning.
Kaplan-Meier Estimate of Overall Survival (OS) Cycle 1 Day 1 up to approximately 12 months (cycle = 28 days); median treatment duration for the twice-weekly arm was 47.00 weeks and for the once-weekly arm was 47.14 weeks. OS was defined as the time from randomization to the date of death due to any cause. Median OS was estimated using the Kaplan-Meier method. 95% CIs were estimated using the method by Klein and Moeschberger (1997) with log-log transformation. Participants still alive or lost to follow-up or withdrawn consent from study by the analysis time were censored at the date on which the participant was last known to be alive.
Change From Baseline in European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire (EORTC QLQ)-Core 30 (C30) Physical Functioning Scale Baseline (Cycle 1 Day 1), Cycle 3 Day 1, Cycle 5 Day 1, Cycle 7 Day 1, Cycle 9 Day 1, Cycle 12 Day 1, and safety follow-up (30 days after last dose) The QLQ-C30 physical function is one of the functional domains of the EORTC QLQ-C30 self-reported instrument and the physical functioning score score ranges from 0-100 points, with 100 points indicating the best possible functioning. A positive change from baseline indicated an improvement in functioning.
Trial Locations
- Locations (108)
Oncology Consultants PA
🇺🇸Houston, Texas, United States
Gelre Ziekenhuizen
🇳🇱Apeldoorn, Netherlands
Spaarne Gasthuis
🇳🇱Hoofddorp, Netherlands
General University Hospital of Patras Panagia i Voithia
🇬🇷Patra, Greece
General Hospital of Thessaloniki Georgios Papanikolaou
🇬🇷Thessaloniki, Greece
Oncology Hematology Care Inc
🇺🇸Cincinnati, Ohio, United States
Vilnius University Hospital Santaros Clinic Public Institution
🇱🇹Vilnius, Lithuania
Fundeni Clinical Institute
🇷🇴Bucharest, Romania
Spitalul Clinic Colentina
🇷🇴Bucuresti, Romania
Spitalul Clinic Dr Gavril Curteanu Oradea
🇷🇴Oradea, Romania
Spitalul Clinic Municipal de Urgenta Timisoara
🇷🇴Timisoara, Romania
Juntendo University Hospital
🇯🇵Bunkyo-ku, Tokyo, Japan
Spitalul Universitar de Urgenta Bucuresti
🇷🇴Bucharest, Romania
Spitalul Clinic Judetean de Urgenta Sibiu
🇷🇴Sibiu, Romania
Institutul Clinic Fundeni
🇷🇴Bucharest, Romania
Spitalul Clinic Coltea
🇷🇴Bucharest, Romania
Institutul Oncologic Prof Dr Ion Chiricuta
🇷🇴Cluj-Napoca, Romania
Japanese Red Cross Medical Center
🇯🇵Shibuya-ku, Tokyo, Japan
Institutul Regional de Oncologie Iasi
🇷🇴Iasi, Romania
Helsingin Yliopistollinen Keskussairaala
🇫🇮Helsinki, Finland
New York Oncology Hematology, PC
🇺🇸Albany, New York, United States
Metropolitan Hospital
🇬🇷Athens, Greece
Texas Oncology-Denton
🇺🇸Denton, Texas, United States
Universitätsklinikum Carl Gustav Carus der Technischen Universität Dresden
🇩🇪Dresden, Germany
US Oncology Research Investigational Products Center
🇺🇸Fort Worth, Texas, United States
Robert A Moss Oncology
🇺🇸Fountain Valley, California, United States
Charité, Universitätsklinikum Berlin, Campus Benjamin Franklin
🇩🇪Berlin, Germany
University Hospital of Alexandroupolis
🇬🇷Alexandroupoli, Greece
Alexandra Hospital
🇬🇷Athens, Greece
Universitaetsklinikum Salzburg
🇦🇹Salzburg, Austria
Texas Oncology
🇺🇸San Antonio, Texas, United States
Fakultni nemocnice Olomouc
🇨🇿Olomouc, Czechia
Johannes Gutenberg Universitaet Mainz
🇩🇪Mainz, Germany
Universitatsklinikum Hamburg-Eppendorf
🇩🇪Hamburg, Germany
Centre Hospitalier Universitaire de Poitiers - Hopital la Miletrie
🇫🇷Poitiers Cedex, France
Rocky Mountain Cancer Centers Denver Midtown
🇺🇸Denver, Colorado, United States
Baptist MD Anderson Cancer Center
🇺🇸Jacksonville, Florida, United States
Oulun Yliopistollinen Sairaala
🇫🇮Oulu, Finland
Turun Yliopistollinen Keskussairaala
🇫🇮Turku, Finland
Hartford HealthCare Cancer Institute at The Hospital of Central Connecticut
🇺🇸Plainville, Connecticut, United States
University Multiprofile Hospital for Active Treatment Sveti Georgi EAD
🇧🇬Plovdiv, Bulgaria
Fakultni nemocnice Brno
🇨🇿Brno, Czechia
Advocate Lutheran General Hospital
🇺🇸Park Ridge, Illinois, United States
Fakultni nemocnice Hradec Kralove
🇨🇿Hradec Kralove, Czechia
Vseobecna fakultni nemocnice v Praze
🇨🇿Praha 2, Czechia
United States Oncology Regulatory Affairs Corporate Office
🇺🇸The Woodlands, Texas, United States
251 General Airforce Hospital
🇬🇷Athens, Greece
National Hospital Organization Kyushu Cancer Center
🇯🇵Fukuoka-shi, Fukuoka, Japan
Tesshokai Kameda General Hospital
🇯🇵Kamogawa-shi, Chiba, Japan
Regional Clinical Hospital
🇷🇺Krasnoyarsk, Russian Federation
Hyogo College of Medicine Hospital
🇯🇵Nishinomiya-shi, Hyogo, Japan
Osaka University Hospital
🇯🇵Suita-shi, Osaka, Japan
Moscow State Budget Healthcare Institution City clinical Hospital 52 of Moscow Healthcare Department
🇷🇺Moscow, Russian Federation
Specialized Hospital for Active Treatment of Hematology Diseases EAD
🇧🇬Sofia, Bulgaria
University Multiprofile Hospital for Active Treatment Sveti Ivan Rilski EAD
🇧🇬Sofia, Bulgaria
Centre Hospitalier Universitaire Archet 2
🇫🇷Nice cedex 3, France
Universitatsklinikum Koln
🇩🇪Köln, Germany
Centre Hospitalier Universitaire de Nantes
🇫🇷Nantes, France
Hopital Saint Louis
🇫🇷Paris, France
Centre Hospitalier Lyon Sud
🇫🇷Pierre-Benite, France
Hopital Pitie-Salpetriere
🇫🇷Paris, France
Institut de Cancerologie Strasbourg
🇫🇷Strasbourg, France
Institut Universitaire du Cancer Toulouse Oncopole
🇫🇷Toulouse cedex 9, France
Centre Hospitalier Universitaire de Nancy - Hopital de Brabois
🇫🇷Vandoeuvre les Nancy Cedex, France
Agios Savvas Anticancer Hospital
🇬🇷Athens, Greece
General Hospital Evangelismos
🇬🇷Athens, Greece
Theagenion Cancer Hospital of Thessaloniki
🇬🇷Thessaloniki, Greece
Nagoya City University Hospital
🇯🇵Nagoya-shi, Aichi, Japan
Toyohashi Municipal Hospital
🇯🇵Toyohashi-shi, Aichi, Japan
Japanese Red Cross Society Himeji Hospital
🇯🇵Himeji-shi, Hyogo, Japan
Ogaki Municipal Hospital
🇯🇵Ogaki-shi, Gifu, Japan
Hitachi Ltd Hitachi General Hospital
🇯🇵Hitachi-shi, Ibaraki, Japan
National Hospital Organization Okayama Medical Center
🇯🇵Okayama-shi, Okayama, Japan
National Hospital Organization Sendai Medical Center
🇯🇵Sendai-shi, Miyagi, Japan
Kindai University Hospital
🇯🇵Osakasayama-shi, Osaka, Japan
University Hospital Kyoto Prefectural University of Medicine
🇯🇵Kyoto-shi, Kyoto, Japan
Niigata Cancer Center Hospital
🇯🇵Niigata-shi, Niigata, Japan
Japanese Red Cross Osaka Hospital
🇯🇵Osaka-shi, Osaka, Japan
Saitama Medical Center
🇯🇵Kawagoe-shi, Saitama, Japan
Tochigi Cancer Center
🇯🇵Utsunomiya-shi, Tochigi, Japan
The Cancer Institute Hospital of Japanese Foundation for Cancer Research
🇯🇵Koto-ku, Tokyo, Japan
Hospital of Lithuanian University of Health Sciences Kaunas Clinics Public Institution
🇱🇹Kaunas, Lithuania
VU Medisch Centrum
🇳🇱Amsterdam, Netherlands
SBHI of Republic of Karelia Republic Hosiptal n a V A Baranov
🇷🇺Petrozavodsk, Russian Federation
SBHI of Moscow city City clinical hospital na S P Botkin of Moscow city Healthcare department
🇷🇺Moscow, Russian Federation
Hospital Clinico Universitario de Salamanca
🇪🇸Salamanca, Castilla León, Spain
Univerzitna nemocnica Bratislava, Nemocnica sv Cyrila a Metoda
🇸🇰Bratislava, Slovakia
State Budget Educational Institution of High Professional Skills Samara State Medical University
🇷🇺Samara, Russian Federation
Hallands Sjukhus Halmstad
🇸🇪Halmstad, Sweden
Hospital Universitari Son Espases
🇪🇸Palma de Mallorca, Baleares, Spain
Hospital Universitari Germans Trias i Pujol
🇪🇸Badalona, Cataluña, Spain
Hospital Clinic i Provincial de Barcelona
🇪🇸Barcelona, Cataluña, Spain
Hospital Universitario Quironsalud Madrid
🇪🇸Pozuelo de Alarcon, Madrid, Spain
Clinica Universidad de Navarra
🇪🇸Pamplona, Navarra, Spain
Falu Lasarett
🇸🇪Falun, Sweden
Sahlgrenska Universitetssjukhuset
🇸🇪Goteborg, Sweden
Sunderby Sjukhus
🇸🇪Lulea, Sweden
Skanes Universitetssjukhus
🇸🇪Lund, Sweden
Gazi Universitesi Saglik Arastirma ve Uygulama Merkezi Gazi Hastanesi
🇹🇷Ankara, Turkey
Bagcilar Medipol Mega Universite Hastanesi
🇹🇷Istanbul, Turkey
Ankara Universitesi Tip Fakultesi Cebeci Arastirma ve Uygulama Hastanesi
🇹🇷Ankara, Turkey
Erciyes Universitesi Tip Fakultesi Mehmet Kemal Dedeman Hematoloji-Onkoloji Hastanesi
🇹🇷Kayseri, Turkey
Istanbul Universitesi Istanbul Tip Fakultesi
🇹🇷Istanbul, Turkey
Istanbul Florence Nightingale Hastanesi
🇹🇷Istanbul, Turkey
Dokuz Eylul Universitesi Arastirma Uygulama Hastanesi
🇹🇷Izmir, Turkey
National Hospital Organization Shibukawa Medical Center
🇯🇵Shibukawa-shi, Gunma, Japan
Centre Hospitalier Universitaire de Rennes
🇫🇷Rennes, France
Federal centre of heart, blood and endocrinology Almazova
🇷🇺Saint Petersburg, Russian Federation