Study Comparing Carfilzomib, Lenalidomide, and Dexamethasone (CRd) vs Lenalidomide and Dexamethasone (Rd) in Subjects With Relapsed Multiple Myeloma
- Conditions
- Relapsed Multiple Myeloma
- Interventions
- Registration Number
- NCT01080391
- Lead Sponsor
- Amgen
- Brief Summary
The primary objective was to compare progression-free survival in adults with relapsed multiple myeloma who are receiving CRd vs participants receiving Rd in a randomized multicenter setting.
- Detailed Description
This is a Phase 3, randomized, open-label, multicenter study comparing two treatment regimens for adults with relapsed multiple myeloma. Eligible subjects will be randomized in a 1:1 ratio to receive either the control Rd or CRd. Randomization will be stratified by β2 microglobulin levels (\< vs ≥ 2.5 mg/L), prior bortezomib (no vs yes), and prior lenalidomide (no vs yes). Participants will receive the treatment determined by randomization in 28-day cycles until disease progression or unacceptable toxicity (whichever occurs first).
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 792
-
Symptomatic multiple myeloma
-
Measurable disease, as defined by one or more of the following (assessed within 21 days prior to randomization):
- Serum M-protein ≥ 0.5 g/dL
- Urine Bence-Jones protein ≥ 200 mg/24 hours
- For immunoglobulin A (IgA) patients whose disease can only be reliably measured by serum quantitative immunoglobulin (qIgA) ≥ 750 mg/dL (0.75 g/dL)
-
Prior treatment with at least one, but no more than three, regimens for multiple myeloma
-
Documented relapse or progressive disease on or after any regimen
-
Achieved a response to at least one prior regimen
-
Age ≥ 18 years
-
Life expectancy ≥ 3 months
-
Eastern Cooperative Oncology Group (ECOG) performance status 0-2
-
Adequate hepatic function, with serum alanine aminotransferase (ALT) ≤ 3.5 times the upper limit of normal and serum direct bilirubin ≤ 2 mg/dL (34 µmol/L) within 21 days prior to randomization
-
Absolute neutrophil count ≥ 1.0 × 10^9/L within 21 days prior to randomization
-
Hemoglobin ≥ 8 g/dL (80 g/L) within 21 days prior to randomization
-
Platelet count ≥ 50 × 10^9/L (≥ 30 × 10^9/L if myeloma involvement in the bone marrow is > 50%) within 21 days prior to randomization
-
Creatinine clearance (CrCl) ≥ 50 mL/minute within 21 days prior to randomization
-
Written informed consent in accordance with federal, local, and institutional guidelines
-
Females of childbearing potential must agree to ongoing pregnancy testing and to practice contraception
-
Male subjects must agree to practice contraception
-
If previously treated with bortezomib (alone or in combination), progression during treatment
-
If previously treated with a lenalidomide and dexamethasone (len/dex) combination:
- Progression during the first 3 months of initiating treatment
- Any progression during treatment if the len/dex combination was the subject's most recent line of therapy
-
Discontinuation of previous lenalidomide or dexamethasone due to intolerance; subjects intolerant to bortezomib are not excluded
-
Prior carfilzomib treatment
-
POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)
-
Waldenström's macroglobulinemia or IgM myeloma
-
Plasma cell leukemia (> 2.0 × 10^9/L circulating plasma cells by standard differential)
-
Chemotherapy or investigational agent within 3 weeks prior to randomization or antibody therapy within 6 weeks prior to randomization
-
Radiotherapy to multiple sites or immunotherapy/antibody therapy within 28 days prior to randomization; localized radiotherapy to a single site within 7 days prior to randomization
-
Corticosteroid therapy at a dose equivalent to dexamethasone > 4 mg/day within 21 days prior to randomization
-
Pregnant or lactating females
-
Major surgery within 21 days prior to randomization
-
Acute active infection requiring treatment (systemic antibiotics, antivirals, or antifungals) within 14 days prior to randomization
-
Known human immunodeficiency virus infection
-
Active hepatitis B or C infection
-
Myocardial infarction within 4 months prior to randomization, New York Hear Association (NYHA) Class III or IV heart failure, uncontrolled angina, history of severe coronary artery disease, severe uncontrolled ventricular arrhythmias, sick sinus syndrome, or electrocardiographic evidence of acute ischemia or Grade 3 conduction system abnormalities unless subject has a pacemaker
-
Uncontrolled hypertension or uncontrolled diabetes within 14 days prior to randomization
-
Other malignancy, including myelodysplastic syndromes (MDS), within the past 3 years with the exception of a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) carcinoma in situ of the cervix or breast; c) prostate cancer of Gleason Grade 6 or less with stable prostate-specific antigen levels; or d) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder or benign tumors of the adrenal or pancreas
-
Significant neuropathy (Grades 3-4, or Grade 2 with pain) within 14 days prior to randomization
-
Known history of allergy to Captisol® (a cyclodextrin derivative used to solubilize carfilzomib)
-
Contraindication to any of the required concomitant drugs or supportive treatments, including hypersensitivity to all anticoagulation and antiplatelet options, antiviral drugs, or intolerance to hydration due to preexisting pulmonary or cardiac impairment
-
Ongoing graft-vs-host disease
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Subjects with pleural effusions requiring thoracentesis or ascites requiring paracentesis within 14 days prior to randomization
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Any other clinically significant medical disease or condition that, in the Investigator's opinion, may interfere with protocol adherence or a subject's ability to give informed consent
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Lenalidomide and Dexamethasone (Rd) Dexamethasone Treatment was administered in cycles repeated every 28 days. Lenalidomide 25 mg was administered orally on days 1 to 21 and dexamethasone 40 mg was administered orally or IV on days 1, 8, 15, and 22. Lenalidomide and Dexamethasone (Rd) Lenalidomide Treatment was administered in cycles repeated every 28 days. Lenalidomide 25 mg was administered orally on days 1 to 21 and dexamethasone 40 mg was administered orally or IV on days 1, 8, 15, and 22. Carfilzomib, Lenalidomide, and Dexamethasone (CRd) Lenalidomide Treatment was administered in cycles every 28 days. Carfilzomib 20 mg/m² was administered intravenously (IV) on days 1 and 2 of cycle 1, escalating to 27 mg/m² on days 8, 9, 15, and 16 of cycle 1 and continuing on days 1, 2, 8, 9, 15, and 16 of cycle 2 through cycle 12 and then from cycle 13 through cycle 18, 27 mg/m² on days 1, 2, 15, and 16. Lenalidomide 25 mg was administered orally on days 1 to 21 from cycle 1 through cycle 18 and from cycle 19 and higher. Dexamethasone 40 mg was administered orally or IV on days 1, 8, 15, and 22 from cycle 1 through cycle 18 and from cycle 19 and higher. Carfilzomib, Lenalidomide, and Dexamethasone (CRd) Dexamethasone Treatment was administered in cycles every 28 days. Carfilzomib 20 mg/m² was administered intravenously (IV) on days 1 and 2 of cycle 1, escalating to 27 mg/m² on days 8, 9, 15, and 16 of cycle 1 and continuing on days 1, 2, 8, 9, 15, and 16 of cycle 2 through cycle 12 and then from cycle 13 through cycle 18, 27 mg/m² on days 1, 2, 15, and 16. Lenalidomide 25 mg was administered orally on days 1 to 21 from cycle 1 through cycle 18 and from cycle 19 and higher. Dexamethasone 40 mg was administered orally or IV on days 1, 8, 15, and 22 from cycle 1 through cycle 18 and from cycle 19 and higher. Carfilzomib, Lenalidomide, and Dexamethasone (CRd) Carfilzomib Treatment was administered in cycles every 28 days. Carfilzomib 20 mg/m² was administered intravenously (IV) on days 1 and 2 of cycle 1, escalating to 27 mg/m² on days 8, 9, 15, and 16 of cycle 1 and continuing on days 1, 2, 8, 9, 15, and 16 of cycle 2 through cycle 12 and then from cycle 13 through cycle 18, 27 mg/m² on days 1, 2, 15, and 16. Lenalidomide 25 mg was administered orally on days 1 to 21 from cycle 1 through cycle 18 and from cycle 19 and higher. Dexamethasone 40 mg was administered orally or IV on days 1, 8, 15, and 22 from cycle 1 through cycle 18 and from cycle 19 and higher.
- Primary Outcome Measures
Name Time Method Progression-free Survival (PFS) From randomization through the data cutoff date of 16 June 2014. Median follow-up time was approximately 31 months. Kaplan-Meier estimate of median time from randomization to progressive disease (PD) or all-cause death. PD was assessed using International Myeloma Working Group-Uniform Response Criteria (IMWG-URC). One or more conditions were required to meet PD: 2 consecutive rising serum or urine M-protein from central lab; documented new bone lesion(s) or soft tissue plasmacytoma(s) or increased size of existing bone lesion(s) or plasmacytoma(s); or confirmed hypercalcemia due solely to plasma cell proliferative disorder (local lab greater than 11.5 mg/dL on 2 separate occasions). Censoring conditions (censoring dates) were: no post-baseline disease assessment (DA) (randomization date); started non-protocol systemic anticancer treatment before PD or death (last DA date before such treatment); died or had PD after more than 1 missed DA (last DA date without PD before the first missed visit); or were alive and without documentation of PD, including lost to follow-up without PD (last DA date).
- Secondary Outcome Measures
Name Time Method Disease Control Rate From randomization through the data cutoff date of 16 June 2014. Median follow-up time was approximately 31 months. Disease control rate was defined as the percentage of participants who achieved a best response of stringent complete response (sCR), complete response (CR), very good partial response (VGPR), partial response (PR), minimal response (MR), or stable disease (SD) lasting ≥ 8 weeks according to International Myeloma Working Group - Uniform Response Criteria (IMWG-URC) (MR was determined using European Group for Blood and Marrow Transplantation criteria).
Quality of Life Core Module (QLQ-C30) Global Health Status/Quality of Life Scores Cycle 1 Day 1 (Baseline), Day 1 of Cycles 3, 6, 12, 18 Health-related quality of life was assessed with the use of the European Organization for Research and Treatment of Cancer Quality of Life Core Module (QLQ-C30) questionnaire, a validated instrument in multiple myeloma patients. Scores range from 0 to 100, with higher scores indicating better health related quality of life.
Overall Survival From randomization through the data cutoff date of 28 April 2017 for the final analysis of overall survival; median follow up time was 67.1 months in each treatment group. Overall survival (OS) was defined as the duration from randomization to death due to any cause. Participants who were still alive were censored at the date when the participant was last known to be alive or the data cutoff date, whichever occurred earlier.
Overall Response Rate From randomization through the data cutoff date of 16 June 2014. Median follow-up time was approximately 31 months. Overall response rate is defined as the percentage of participants who achieved either a confirmed stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR) as their best response based on the Independent Review Committee (IRC) assessed response outcome. Response was determined using the International Myeloma Working Group - Uniform Response Criteria (IMWG-URC).
Duration of Response From randomization through the data cutoff date of 16 June 2014. Longest follow-up time was approximately 42 months. Duration of response (DOR) was calculated for participants who achieved a best response of stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR). Duration of response was defined as the time in months from the initial start of response (PR or better) to the earlier of documented progressive disease (PD) or death due to any cause. Participants who had not progressed or died were censored according to the censoring rules defined previously for PFS.
Duration of Disease Control From randomization through the data cutoff date of 16 June 2014. Longest follow-up time was approximately 46 months. Duration of disease control (DDC) was calculated for participants who achieved disease control. DDC was defined as the time in months from randomization to the earlier of documented progressive disease (PD) or death due to any cause. Participants who had not progressed or died were censored according to the censoring rules defined previously for PFS.
Trial Locations
- Locations (126)
Providence St. Joseph Medical Center
🇺🇸Burbank, California, United States
Stanford University
🇺🇸Stanford, California, United States
Weill Cornell Medical College
🇺🇸New York, New York, United States
Cancer Care Manitoba
🇨🇦Winnipeg, Manitoba, Canada
Rambam Medical Center
🇮🇱Haifa, Israel
Indiana University Health Melvin and Bren Simon Cancer Center
🇺🇸Indianapolis, Indiana, United States
Rush University Medical Center
🇺🇸Chicago, Illinois, United States
The University of Texas, MD Anderson Cancer Center
🇺🇸Houston, Texas, United States
Fred Hutchinson Cancer Research Center
🇺🇸Seattle, Washington, United States
AZ Sint-Jan AV
🇧🇪Brugge, Belgium
Institut Jules Bordet
🇧🇪Bruxelles, Belgium
Cliniques Universitaires Saint-Luc
🇧🇪Bruxelles, Belgium
Military Medical Academy Multiprofile Hospital for Active Treatment
🇧🇬Sofia, Bulgaria
John Theurer Cancer Center at Hackensack University Medical Center
🇺🇸Hackensack, New Jersey, United States
Princess Margaret Hospital
🇨🇦Toronto, Ontario, Canada
Sir Mortimer B. Davis - Jewish General Hospital
🇨🇦Montreal, Quebec, Canada
Azienda Ospedallera Niguarda Ca Granda
🇮🇹Milano, Italy
Azienda Ospedaliera Pisana Ospendale Santa Chiara - Main
🇮🇹Pisa, Italy
University Clinical Centre, Department of Hematologii Transplantologii
🇵🇱Gdansk, Poland
Multiprofile Hospital for Active Treatment "Sveta Marina"
🇧🇬Varna, Bulgaria
Medizinische Universitat Wien
🇦🇹Wien, Austria
Wilhelminspital der Stadt Wien, Zentrum fur Onkologie und Hamatologie
🇦🇹Wien, Austria
University Multiprofile Hospital for Active Treatment, "Dr. Georgi Stranski"
🇧🇬Pleven, Bulgaria
Hospital Antoine Beclere
🇫🇷Clamart, France
Universitatsklinikum Munster
🇩🇪Munster, Germany
Hadassah Medical Center, Ein Kerem
🇮🇱Jerusalem, Israel
Azienda Ospedaliera Citta della Salute e della Scienza di Torino
🇮🇹Torino, Italy
Cancer and Blood Disease Center
🇺🇸Lecanto, Florida, United States
Tom Baker Cancer Centre
🇨🇦Calgary, Alberta, Canada
Associates in Oncology and Hematology
🇺🇸Chattanooga, Tennessee, United States
UZ Brussel
🇧🇪Brussels, Belgium
UZ Leuven
🇧🇪Leuven, Belgium
University Multiprofile Hospital for Active Treatment "Sveti Georgi"
🇧🇬Plovdiv, Bulgaria
University of Dusseldorf
🇩🇪Dusseldorf, Germany
Universitat Heidelberg
🇩🇪Heidelberg, Germany
University General Hospital of Patras
🇬🇷Patras, Greece
Petz Aladar County Teaching Hospital
🇭🇺Gyor, Hungary
Kaposi Mor County Teaching Hospital
🇭🇺Kaposvar, Hungary
University of Pecs
🇭🇺Pecs, Hungary
St. Istvan and St. Laszlo Hospital of Budapest
🇭🇺Budapest, Hungary
General Hospital, Health Sciences Centre
🇨🇦St John's, Newfoundland and Labrador, Canada
McGill University Health Center, Royal Victoria Hospital
🇨🇦Montreal, Quebec, Canada
CH de Mulhouse, Hopital Emile Muller
🇫🇷Mulhouse, France
Western Gailee Hospital - Nahariya
🇮🇱Nahariya, Israel
Rabin Medical Center
🇮🇱Petach Tikva, Israel
The Chaim Sheba Medical Center
🇮🇱Ramat Gan, Israel
University of Alberta, Cross Cancer Institute
🇨🇦Edmonton, Alberta, Canada
Hopital Saint-Antoine
🇫🇷Paris, France
University of Hamburg-Eppendorf
🇩🇪Hamburg, Germany
Cancer Institut Universitaire de Toulouse-Oncopole (iUCT)
🇫🇷Toulouse, France
Specialized Hospital for Active Treatment of Hematological Diseases
🇧🇬Sofia, Bulgaria
Hopitaux de Brabois
🇫🇷Vandoeuvre-Les-Nancy, France
Universitatsklinikum Wurzburg
🇩🇪Wurzburg, Germany
Bekes County Pandy Kalman Hospital
🇭🇺Gyula, Hungary
State Higher Educational Institution: St Petersburg State Medical University n.a.I.P Pavlov
🇷🇺St. Petersburg, Russian Federation
Vancouver General Hospital
🇨🇦Vancouver, British Columbia, Canada
Mayo Clinic
🇺🇸Rochester, Minnesota, United States
Froedtert & Medical College of Wisconsin
🇺🇸Milwaukee, Wisconsin, United States
St. Bartholomew's Hospital
🇬🇧London, United Kingdom
Royal Marsden Hospital
🇬🇧Sutton, United Kingdom
St. Georges Hospital
🇬🇧London, United Kingdom
Ziekenhuisnetwerk Antwerpen - AZ Stuivenberg
🇧🇪Antwerpen, Belgium
Federal State Budgetary Scientific Institution: N.N. Blokhin Russian Cancer Research Center
🇷🇺Moscow, Russian Federation
Zamojski Non-Public Hospital
🇵🇱Zamosc, Poland
Coltea Clinical Hospital
🇷🇴Bucharest, Romania
Bucharest University Emergency Hospital
🇷🇴Bucharest, Romania
Regional Institute of Iasi
🇷🇴Iasi, Romania
FSBI: Russian Research Institute of Hematology and Blood Transfusion under the Ferderal Agency for M&B
🇷🇺St. Petersburg, Russian Federation
Clinical Hospital Center Bezanijska Kosa
🇷🇸Belgrade, Serbia
Military Medical Academy, Clinic of Hematology
🇷🇸Belgrade, Serbia
Clinical Center Nis, Clinic of Hematology
🇷🇸Nis, Serbia
Clinical Center of Vojvodina, Clinic of Hematology
🇷🇸Novi Sad, Serbia
Moscow State Medical Institution Municipal City Clinical Hospital n.a. S.P. Botkin
🇷🇺Moscow, Russian Federation
Fundeni Clinical Institute, "Stefan Berceanu" Center for Hematology and Bone Marrow Transplantation
🇷🇴Bucharest, Romania
State Medical Institution Komi Republican Oncological Center
🇷🇺Syktyvkar, Komi Republic, Russian Federation
Maria Sklodowska-Curie Institute of Oncology
🇵🇱Warszawa, Poland
First Republican Clinical Hospital under the Ministry of Healthcare of the Republic of Udmurtia
🇷🇺Izhevsk, Russian Federation
Federal State Budget Institution: Hematology Research Center under MoH
🇷🇺Moscow, Russian Federation
SHEI: First St. Petersburg State Medical University N.a.I.P Pavlov under MoH, Clinic of Bone Marrow Transplant
🇷🇺St. Petersburg, Russian Federation
Federal State Budget Institute: Federal Almalov Medical Research Centre under Ministry of Healthcare
🇷🇺St. Petersburg, Russian Federation
Clinical Center of Serbia, Clinic of Hematology
🇷🇸Belgrade, Serbia
Sahlgrenska Universitetssjukhuset
🇸🇪Goteborg, Sweden
Karolinska Universitetsjukhuset i Huddinge
🇸🇪Stockholm, Sweden
Royal Free Hampstead
🇬🇧London, United Kingdom
Karolinska Universitetssjukhuset Solna, Hematologiskt Centrum
🇸🇪Stockholm, Sweden
Nottingham University Hospitals (City Campus)
🇬🇧Nottingham, United Kingdom
The Royal Wolverhampton Hospital NHS Trust
🇬🇧Wolverhampton, United Kingdom
Hospital Clinic I Provincial
🇪🇸Barcelona, Spain
Hospital Universitario y Politeecnico La Fe
🇪🇸Valencia, Spain
Hospital Donostia
🇪🇸San Sebastian, Spain
Hospital Universitario de Salamanca
🇪🇸Salamanca, Spain
Hospital Universitario Germans Trias i Pujol
🇪🇸Badalona, Spain
Hospital Universitario Miguel Servet
🇪🇸Zaragoza, Spain
University of Szeged, Albert Szent-Gyorgi Clinical Center
🇭🇺Szeged, Hungary
Groupe Hospitalier Necker - Enfants Malades
🇫🇷Paris, France
Hopital Claude Huriez
🇫🇷Lille, France
St. Jude Hospital Yorba Linda dba; St. Joseph Heritage Healthcare
🇺🇸Santa Rosa, California, United States
Colorado Blood Cancer Institute
🇺🇸Denver, Colorado, United States
University of Kansas Cancer Center
🇺🇸Kansas City, Kansas, United States
The University of Michigan - Comprehensive Cancer Center
🇺🇸Ann Arbor, Michigan, United States
NYU Clinical Cancer Center
🇺🇸New York, New York, United States
The Don & Sybil Harrington Cancer Center
🇺🇸Amarillo, Texas, United States
Baylor Sammons Cancer Center
🇺🇸Dallas, Texas, United States
UT Southwestern Medical Center at Dallas
🇺🇸Dallas, Texas, United States
Scott and White Memorial Hospital
🇺🇸Temple, Texas, United States
University Hospital Hradec Kralove
🇨🇿Hradec Kralove, Czechia
University Hospital Brno, Department of Internal Medicine - Hematooncology
🇨🇿Brno, Czechia
University Hospital Kralovske Vinohrady - Prague
🇨🇿Praha 10, Czechia
University Hospital Olomouc
🇨🇿Olomouc, Czechia
General University Hospital Prague
🇨🇿Praha 2, Czechia
Clinique Victor Hugo - Centre Jean Bernard
🇫🇷Le Mans, France
CHU Nantes Hotel Dieu
🇫🇷Nantes, France
Krankenhaus Nordwest
🇩🇪Frankfurt am Main, Germany
Stiftungsklinikum Mittelrhein
🇩🇪Koblenz, Germany
LMU Klinikum der Universitat
🇩🇪Munchen, Germany
Alexandra Hospital
🇬🇷Athens, Greece
University of Debrecen, Medical and Health Science Center
🇭🇺Debrecen, Hungary
Kaplan Medical Center
🇮🇱Rehovot, Israel
Azienda Ospedllero Maggiore della Carita
🇮🇹Novara, Italy
Ospedale S. Eugenio
🇮🇹Roma, Italy
Erasmus MC, Department of Haematology
🇳🇱Rotterdam, Netherlands
Samodzielny Publ. Szp. Wojewodzki w Gorzow Wlkp.
🇵🇱Gorzow Wielkopolski, Poland
Independent Public Teaching Hospital of Medical University of Silesia in Katowice
🇵🇱Katowice, Poland
Nicolaus Copernicus Memorial Provincial Specialist Hospital in Lodz
🇵🇱Lodz, Poland
Szpital Wojewwodzki im. dr Ludwika Rydygiera w Suwalkach
🇵🇱Suwalki, Poland
Nicolaus Copernicus Municipal Specialist Hospital
🇵🇱Torun, Poland