Clinical trial NCT01311687: A Phase 3, Multicenter, Randomized, Open-Label Study to Compare the Efficacy and Safety of Pomalidomide in Combination With Low-Dose Dexamethasone Versus High-Dose Dexamethasone in Subjects With Refractory Multiple Myeloma or Relapsed and Refractory Multiple Myeloma and Companion Study
Official title: A Phase 3, Muticenter, Randomized, Open-label Study to Compare the Efficacy and Safety of Pomalidomide in Combination With Low-dose Dexamethasone Versus High-dose Dexamethasone in Subjects With Refractory or Relapsed and Refractory Multiple Myeloma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Multiple Myeloma
Keywords: Myeloma
Multiple Myeloma
Relapsed Multiple Myeloma
Relapsed and Refractory Multiple Myeloma
Refractory Myeloma
Resistant Multiple Myeloma
Treatment-resistant Multiple Myeloma
Pomalidomide
Lenalidomide-resistant
Bortezomib-resistant
Lead sponsor: Celgene
Sponsor class: INDUSTRY
First posted: 2011-03-09
Enrollment: 455
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to compare efficacy and safety of pomalidomide in combination with low-dose dexamethasone versus high-dose dexamethasone in subjects with refractory or relapsed and refractory multiple myeloma.


Eligibility criteria: Inclusion Criteria:

* Must be ≥ 18 years of age
* Subjects must have documented diagnosis of multiple myeloma and have measurable disease
* Subjects must have undergone prior treatment with ≥ 2 treatment lines of anti-myeloma therapy
* Subjects must have either refractory or relapsed and refractory disease defined as documented disease progression during or within 60 days of completing their last myeloma therapy
* All subjects must have received at least 2 consecutive cycles of prior treatment that included lenalidomide and bortezomib
* All subjects must have failed treatment with both lenalidomide and bortezomib in one of the following ways: 1) Documented progressive disease on or within 60 days of completing treatment with lenalidomide and/or bortezomib, or 2) In case of prior response \[≥ partial response (PR)\] to lenalidomide or bortezomib, subjects must have relapsed within 6 months after stopping treatment with lenalidomide and/or bortezomib-containing regimens, or 3) Subjects who have not had a ≥ minimal response (MR) and have developed intolerance/toxicity after a minimum of two cycles of lenalidomide- and/or bortezomib-containing regimen
* Patients must have received adequate prior alkylator therapy
* Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2
* Females of childbearing potential (FCBP) must not become pregnant for 28 days prior to initiation of study drug, during the study, and for 28 days after discontinuation
* Females must agree to abstain from breastfeeding during study participation and 28 days after study drug discontinuation
* Males must agree to use a latex condom during any sexual during the study and for 28 days following discontinuation from this study
* Males must also agree to refrain from donating semen or sperm while on pomalidomide and for 28 days after discontinuation from this study

Exclusion Criteria:

* Any of the following laboratory abnormalities:

  * Absolute neutrophil count (ANC) \< 1,000/μL
  * Platelet count \< 75,000/ μL for subjects in whom \< 50% of bone marrow nucleated cells are plasma cells
  * Creatinine clearance \< 45 mL/min
  * Corrected serum calcium \> 14 mg/dL
  * Hemoglobin ≤ 8 g/dL
  * Serum glutamic oxaloacetic transaminase (SGOT)/ aspartate aminotransferase (AST) or transaminase, serum glutamic pyruvic (SGPT)/ alanine aminotransferase (ALT) \> 3.0 x upper limit of normal (ULN)
  * Serum total bilirubin \> 2.0 mg/dL
* Previous therapy with pomalidomide
* Hypersensitivity to thalidomide, lenalidomide, or dexamethasone
* Resistance to high-dose dexamethasone used in the last line of therapy
* Peripheral neuropathy ≥ Grade 2
* Subjects who received an allogeneic bone marrow or allogeneic peripheral blood stem cell transplant
* Subjects who are planning for or who are eligible for stem cell transplant
* Subjects with any one of the following: 1) Congestive heart failure, 2) Myocardial infarction within 12 months prior to starting study treatment, 3) Unstable or poorly controlled angina pectoris, including Prinzmetal variant angina pectoris
* Subjects who received any of the following within the last 14 days of initiation of study treatment: 1) Plasmapheresis, 2) Major surgery, 3) Radiation therapy, 4) Use of any anti-myeloma drug therapy
* Use of any investigational agents within 28 days or 5 half-lives (whichever is longer) of treatment
* Subjects with conditions requiring chronic steroid or immunosuppressive treatment
* Any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study
* Incidence of gastrointestinal disease that may significantly alter the absorption of pomalidomide
* Subjects unable or unwilling to undergo antithrombotic prophylactic treatment
* Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subjects from signing the informed consent form
* Pregnant or breastfeeding females
* Known human immunodeficiency virus (HIV) positivity or active infectious hepatitis A, B, or C

Primary outcomes:
measure: Progression-free Survival (PFS) - Primary Analysis
timeFrame: From randomization until the data cut-off date of 07 September 2012. Maximum duration of follow-up for PFS assessments was 57 weeks.
measure: Progression-free Survival (PFS) With a Later Cut-off Date
timeFrame: From randomization until the data cut-off date of 01 March 2013. Maximum duration of follow-up for PFS assessments was 74 weeks.
Secondary outcomes:
measure: Number of Participants With Adverse Events (AEs)
timeFrame: From first dose of study drug through to 30 days after the last dose as of the end of the study (29 August 2017); maximum time on treatment was 297, 269, and 239 weeks in the Pomalidomide + LD-Dex, HD-Dex, and cross-over groups respectively.
measure: Overall Survival - Primary Analysis
timeFrame: From randomization until the data cut-off date of 07 September 2012. Maximum time on follow-up for survival was 70 weeks.
measure: Overall Survival With a Later Cut-off Date
timeFrame: From randomization until the data cut-off date of 01 March 2013. Maximum time on follow-up for survival was 93 weeks.
measure: Overall Survival Based on the Final Dataset
timeFrame: From randomization until the data cut-off date of 29 August 2017. Maximum time on follow-up for survival was 324 weeks.
measure: Percentage of Participants With an Objective Response According to International Myeloma Working Group (IMWG) Uniform Response Criteria
timeFrame: From randomization until the data cut-off date of 01 March 2013. Maximum time on follow-up was 93 weeks.
measure: Percentage of Participants With Objective Response According to European Group for Blood and Marrow Transplantation (EBMT) Criteria
timeFrame: From randomization until the data cut-off date of 01 March 2013. Maximum time on follow-up was 93 weeks.
measure: Time to Progression
timeFrame: From randomization until the data cut-off date of 01 March 2013. Maximum time on follow-up was 93 weeks.
measure: Time to Response
timeFrame: From randomization until the data cut-off date of 01 March 2013. Maximum time on follow-up was 93 weeks.
measure: Duration of Response
timeFrame: From randomization until the data cut-off date of 01 March 2013. Maximum time on follow-up was 93 weeks.
measure: Time to the First Hemoglobin Improvement
timeFrame: From randomization until the data cut-off date of 01 March 2013. Maximum time on follow-up was 93 weeks.
measure: Time to Improvement in Bone Pain
timeFrame: From randomization until the data cut-off date of 01 March 2013. Maximum time on follow-up was 93 weeks.
measure: Time to Improvement in Renal Function
timeFrame: From randomization until the data cut-off date of 01 March 2013. Maximum time on follow-up was 93 weeks.
measure: Time to Improvement in Eastern Cooperative Oncology Group (ECOG) Performance Status
timeFrame: From randomization until the data cut-off date of 01 March 2013. Maximum time on follow-up was 93 weeks.
measure: Change From Baseline in the European Organization for Research and Treatment of Cancer Cancer Quality of Life Questionnaire for Patients With Cancer (EORTC QLQ-C30) Global Health Status Domain
timeFrame: Day 1 of Cycle 1 (Baseline), and Day 1 of Cycles 2, 3, 4, 5 and 6
measure: Change From Baseline in the EORTC QLQ-C30 Physical Functioning Domain
timeFrame: Day 1 of Cycle 1 (Baseline), and Day 1 of Cycles 2, 3, 4, 5 and 6
measure: Change From Baseline in the EORTC QLQ-C30 Emotional Functioning Domain
timeFrame: Day 1 of Cycle 1 (Baseline), and Day 1 of Cycles 2, 3, 4, 5 and 6
measure: Change From Baseline in the EORTC QLQ-C30 Fatigue Domain
timeFrame: Day 1 of Cycle 1 (Baseline), and Day 1 of Cycles 2, 3, 4, 5 and 6
measure: Change From Baseline in the EORTC QLQ-C30 Pain Domain
timeFrame: Day 1 of Cycle 1 (Baseline), and Day 1 of Cycles 2, 3, 4, 5 and 6
measure: Change From Baseline in the European Organization for Research and Treatment of Cancer QoL Questionnaire for Patients With Multiple Myeloma (EORTC QLQ-MY20) Disease Symptoms
timeFrame: Day 1 of Cycle 1 (Baseline), and Day 1 of Cycles 2, 3, 4, 5 and 6
measure: Change From Baseline in the EORTC QLQ-MY20 Side Effects Domain
timeFrame: Day 1 of Cycle 1 (Baseline), and Day 1 of Cycles 2, 3, 4, 5 and 6
measure: Change From Baseline in the European Quality of Life-5 Dimensions (EQ-5D) Utility Index Score
timeFrame: Day 1 of Cycle 1 (Baseline), and Day 1 of Cycles 2, 3, 4, 5 and 6
measure: Time to First Worsening of Quality of Life (QOL) Domains
timeFrame: Assessed on Day 1 of the first 6 treatment cycles.
Other outcomes:
Locations:
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: East Melbourne
country: Australia
facility: Peter MacCallum Cancer Institute
state: Victoria
city: Frankston
country: Australia
facility: Frankston Hospital
state: Victoria
city: Brisbane
country: Australia
facility: Princess Alexandra Hospital
city: Camperdown
country: Australia
facility: Royal Prince Alfred Hospital
city: Melbourne
country: Australia
facility: Alfred hospital
city: Nedlands
country: Australia
facility: Sir Charles Gairdner Hospital
city: Waratah
country: Australia
facility: Calvary Mater Hospital
city: Wodonga
country: Australia
facility: Border Medical Oncology
city: Wollongong
country: Australia
facility: Wollongong Hospital
city: Gent
country: Belgium
facility: UZ Gent
city: Leuven
country: Belgium
facility: UZ Leuven
city: Yvoir
country: Belgium
facility: CHU UCL Mont-Godinne-Dinant asbl
city: Calgary
country: Canada
facility: Tom Baker Cancer Center
state: Alberta
city: Edmonton
country: Canada
facility: Cross Cancer Institute
state: Alberta
city: Vancouver
country: Canada
facility: British Columbia Cancer Agency
state: British Columbia
city: Halifax
country: Canada
facility: James Cancer Hospital
state: Nova Scotia
city: Hamilton
country: Canada
facility: Juravinski Cancer Centre
state: Ontario
city: London
country: Canada
facility: London Health Sciences Centre
state: Ontario
city: Toronto
country: Canada
facility: University Health Network
state: Ontario
city: Montreal
country: Canada
facility: Maisonneuve Rosemont
state: Quebec
city: Montreal
country: Canada
facility: Royal Victoria Hospital McGill Department of Oncology(RVH)
state: Quebec
city: Montreal
country: Canada
facility: Sir Mortimer B. Davis - Jewish Genl
state: Quebec
city: Praha 2
country: Czechia
facility: Charles University General Hospital
city: Aalborg
country: Denmark
facility: Hæmatologisk afd. B Aalborg Sygehus Syd
city: Arhus C
country: Denmark
facility: Aarhus University Hospital
city: Odense C
country: Denmark
facility: Odense Universitetshospital
city: Vejle
country: Denmark
facility: Vejle Hospital
city: Angers Cedex 01
country: France
facility: CHU d'Angers
city: Bayonne
country: France
facility: Centre Hospitalier de la cote basque
city: La Roche sur Yon
country: France
facility: Centre Hospitalier Departemental
city: Lille
country: France
facility: CHRU de Lille FR
city: Marseille Cedex 9
country: France
facility: Institut Paoli-Calmettes
city: Nantes Cedex 1
country: France
facility: CHRU Nantes
city: Paris, Cedex 10
country: France
facility: Hopital Saint-Louis
city: Paris
country: France
facility: CHU Hôpital St-Antoine
city: Pessac
country: France
facility: CHRU - Hopital du Haut Leveque
city: Pierre Bénite
country: France
facility: Centre Hospitalier Lyon Sud
city: Tours
country: France
facility: Hopital Bretonneau
city: Tulouse Cedex 9
country: France
facility: Hopital Purpan
city: Vandoeuvre
country: France
facility: CHU Nancy
city: Dresden
country: Germany
facility: Universitatsklinikum Carl Gustav Carus
city: Essen
country: Germany
facility: Universitatsklinikum Essen
city: Hamburg
country: Germany
facility: Askepios Klinik St. Georg
city: Heidelberg
country: Germany
facility: Universitatsklinikum Heidelberg
city: Jena
country: Germany
facility: Universitatsklinikum Jena
city: Leipzig
country: Germany
facility: Universitatsklinikum Leipzig
city: Tübingen
country: Germany
facility: University of Tubingen
city: Ulm
country: Germany
facility: Universitatsklinikum Ulm
city: Wuerzburg
country: Germany
facility: Universitatsklinikum Wurzburg
city: Athens
country: Greece
facility: Alexandra General Hospital of Athens
city: Bologna
country: Italy
facility: Azienda Ospedaliero-Universitaria di Bologna - Policlinico S.Orsola-Malpighi
city: Genova
country: Italy
facility: Clinica Ematologica- A.O.U. San Martino
city: Napoli
country: Italy
facility: Oncoematologia, Istituto Nazionale Tumori Fondazione G. Pascale
city: Orbassano
country: Italy
facility: AOU San Luigi Gonzaga
city: Padova
country: Italy
facility: Universita degli Studi di Padova
city: Placenza
country: Italy
facility: Hospital Clinic
city: Reggio Emilia
country: Italy
facility: Servizio di Ematologia, A.O. - Arcispedale S.Maria Nuova
city: Rome
country: Italy
facility: Univerita La Sapienza Dipartimento di Biotecnologie Cellulari ed Ematologia
city: Torino
country: Italy
facility: Azienda Ospedaliera San Giovanni Battista
city: Amsterdam
country: Netherlands
facility: VU University Medical Center
city: Rotterdam
country: Netherlands
facility: Erasmus Medical Center
city: Utrecht
country: Netherlands
facility: University Medical Center Utrecht
city: Moscow
country: Russian Federation
facility: State Institution Hematological Research, Centre of Russian Academy of Medical Science
city: Moscow
country: Russian Federation
facility: State Institution Moscow Regional Research Clinical Institute
city: Saint Petersburg
country: Russian Federation
facility: State Educational Institution, Saint Petersburg State Medical University
city: St. Petersburg
country: Russian Federation
facility: St. Petersburg Research Institute of Hematology and Blood Transfusion
city: Badalona (Barcelona)
country: Spain
facility: Hospital Universitari Germans Trias i Pujol
city: Barcelona
country: Spain
facility: Hospital Clinic Provincial de Barcelona
city: Madrid
country: Spain
facility: Hospital de La Princesa
city: Madrid
country: Spain
facility: Hospital 12 de Octubre
city: Salamanca
country: Spain
facility: Hospital Universitario de Salamanca
city: San Sebastián (Guipuzcoa)
country: Spain
facility: Hospital Donostia
city: Santander
country: Spain
facility: Hospital Universitario Marques de Valdecilla
city: Valencia
country: Spain
facility: Hospital de la Fe
city: Göteborg
country: Sweden
facility: Department of Hematology Hematology Centre
city: Lund
country: Sweden
facility: University Hospital in Lund
city: Stockholm
country: Sweden
facility: Karolinska University Hospital Huddinge
city: Stockholm
country: Sweden
facility: Karolinska University Hospital
city: Uppsala
country: Sweden
facility: Overlakare Medocomcentrum, hematologi
city: Berne
country: Switzerland
facility: Medizinische Universitatsklinik
city: Geneva
country: Switzerland
facility: Hopitaux Universitaires de Geneve-HUG
city: Zürich
country: Switzerland
facility: UniversitatSspital Zurich
city: Bournemouth
country: United Kingdom
facility: Royal Bournemouth Hospital
city: Leeds
country: United Kingdom
facility: St James's University Hospital
city: London
country: United Kingdom
facility: St.Bartholomew's Hospital
city: London
country: United Kingdom
facility: King's College Hospital
city: Newcastle Upon Tyne
country: United Kingdom
facility: Freeman Hospital
city: Nottingham
country: United Kingdom
facility: Nottingham City Hospital
city: Plymouth
country: United Kingdom
facility: Derriford Hospital
city: Sheffield
country: United Kingdom
facility: Royal Hallamshire HospitalSheffield Teaching Hospitals NHS Trust
city: Sutton-Surrey
country: United Kingdom
facility: The Royal Marsden Hospital
city: Wolverhampton
country: United Kingdom
facility: The Royal Wolverhampton Hospital NHS Trust
Study officials:
affiliation: Celgene
name: Lars Sternas, MD, PhD
role: STUDY_DIRECTOR
References:
citation: Moreau P, Weisel KC, Song KW, Gibson CJ, Saunders O, Sternas LA, Hong K, Zaki MH, Dimopoulos MA. Relationship of response and survival in patients with relapsed and refractory multiple myeloma treated with pomalidomide plus low-dose dexamethasone in the MM-003 trial randomized phase III trial (NIMBUS). Leuk Lymphoma. 2016 Dec;57(12):2839-2847. doi: 10.1080/10428194.2016.1180685. Epub 2016 May 13.
citation: Miguel JS, Weisel K, Moreau P, Lacy M, Song K, Delforge M, Karlin L, Goldschmidt H, Banos A, Oriol A, Alegre A, Chen C, Cavo M, Garderet L, Ivanova V, Martinez-Lopez J, Belch A, Palumbo A, Schey S, Sonneveld P, Yu X, Sternas L, Jacques C, Zaki M, Dimopoulos M. Pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone alone for patients with relapsed and refractory multiple myeloma (MM-003): a randomised, open-label, phase 3 trial. Lancet Oncol. 2013 Oct;14(11):1055-1066. doi: 10.1016/S1470-2045(13)70380-2. Epub 2013 Sep 3.
citation: Siegel DS, Weisel KC, Dimopoulos MA, Baz R, Richardson P, Delforge M, Song KW, San Miguel JF, Moreau P, Goldschmidt H, Cavo M, Jagannath S, Yu X, Hong K, Sternas L, Zaki M, Palumbo A. Pomalidomide plus low-dose dexamethasone in patients with relapsed/refractory multiple myeloma and moderate renal impairment: a pooled analysis of three clinical trials. Leuk Lymphoma. 2016 Dec;57(12):2833-2838. doi: 10.1080/10428194.2016.1177181. Epub 2016 Jun 7.
citation: Weisel KC, Dimopoulos MA, Moreau P, Lacy MQ, Song KW, Delforge M, Karlin L, Goldschmidt H, Banos A, Oriol A, Alegre A, Chen C, Cavo M, Garderet L, Ivanova V, Martinez-Lopez J, Knop S, Yu X, Hong K, Sternas L, Jacques C, Zaki MH, San Miguel J. Analysis of renal impairment in MM-003, a phase III study of pomalidomide + low - dose dexamethasone versus high - dose dexamethasone in refractory or relapsed and refractory multiple myeloma. Haematologica. 2016 Jul;101(7):872-8. doi: 10.3324/haematol.2015.137083. Epub 2016 Apr 14.
citation: Dimopoulos MA, Weisel KC, Song KW, Delforge M, Karlin L, Goldschmidt H, Moreau P, Banos A, Oriol A, Garderet L, Cavo M, Ivanova V, Alegre A, Martinez-Lopez J, Chen C, Spencer A, Knop S, Bahlis NJ, Renner C, Yu X, Hong K, Sternas L, Jacques C, Zaki MH, San Miguel JF. Cytogenetics and long-term survival of patients with refractory or relapsed and refractory multiple myeloma treated with pomalidomide and low-dose dexamethasone. Haematologica. 2015 Oct;100(10):1327-33. doi: 10.3324/haematol.2014.117077. Epub 2015 Aug 6.
citation: San Miguel JF, Weisel KC, Song KW, Delforge M, Karlin L, Goldschmidt H, Moreau P, Banos A, Oriol A, Garderet L, Cavo M, Ivanova V, Alegre A, Martinez-Lopez J, Chen C, Renner C, Bahlis NJ, Yu X, Teasdale T, Sternas L, Jacques C, Zaki MH, Dimopoulos MA. Impact of prior treatment and depth of response on survival in MM-003, a randomized phase 3 study comparing pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone in relapsed/refractory multiple myeloma. Haematologica. 2015 Oct;100(10):1334-9. doi: 10.3324/haematol.2015.125864. Epub 2015 Jul 9.
citation: Weisel K, Dimopoulos M, Song KW, Moreau P, Palumbo A, Belch A, Schey S, Sonneveld P, Sternas L, Yu X, Amatya R, Gibson CJ, Zaki M, Jacques C, San Miguel J. Pomalidomide and Low-Dose Dexamethasone Improves Health-Related Quality of Life and Prolongs Time to Worsening in Relapsed/Refractory Patients With Multiple Myeloma Enrolled in the MM-003 Randomized Phase III Trial. Clin Lymphoma Myeloma Leuk. 2015 Sep;15(9):519-30. doi: 10.1016/j.clml.2015.05.007. Epub 2015 Jun 6.
citation: Song KW, Dimopoulos MA, Weisel KC, Moreau P, Palumbo A, Belch A, Schey S, Sonneveld P, Sternas L, Yu X, Amatya R, Monzini MS, Zaki M, Jacques C, San Miguel J. Health-related quality of life from the MM-003 trial of pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone in relapsed and/or refractory multiple myeloma. Haematologica. 2015 Feb;100(2):e63-7. doi: 10.3324/haematol.2014.112557. Epub 2014 Nov 25. No abstract available.