Clinical trial NCT01208662: Randomized Trial of Lenalidomide, Bortezomib, Dexamethasone vs High-Dose Treatment With SCT in MM Patients up to Age 65
Official title: A Randomized, Phase III Study Comparing Conventional Dose Treatment Using a Combination of Lenalidomide, Bortezomib, and Dexamethasone (RVD) to High-Dose Treatment With Peripheral Stem Cell Transplant in the Initial Management of Myeloma in Patients Up to 65 Years of Age
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Multiple Myeloma
Keywords: Lenalidomide
Bortezomib
Dexamethasone
Stem Cell Transplant
Myeloma
Multiple Myeloma
Lead sponsor: Dana-Farber Cancer Institute
Sponsor class: OTHER
Collaborators: name: Celgene Corporation
name: Millennium Pharmaceuticals, Inc.
name: Massachusetts General Hospital
name: Cape Cod Hospital
name: Beth Israel Deaconess Medical Center
name: Emory University
name: University of Michigan
name: Fox Chase Cancer Center
name: Memorial Sloan Kettering Cancer Center
name: Fred Hutchinson Cancer Center
name: Barbara Ann Karmanos Cancer Institute
name: Duke University
name: University of California, San Francisco
name: University of Chicago
name: M.D. Anderson Cancer Center
name: UNC Lineberger Comprehensive Cancer Center
name: Roswell Park Cancer Institute
name: Stanford University
name: University of Mississippi Medical Center
name: Icahn School of Medicine at Mount Sinai
name: Wake Forest University Health Sciences
name: University of Arizona
name: OHSU Knight Cancer Institute
name: Eastern Maine Medical Center
name: University of California, San Diego
name: University of Alabama at Birmingham
name: University of Pittsburgh Medical Center
name: Ochsner Health System
name: University of Texas Southwestern Medical Center
name: State University of New York - Downstate Medical Center
name: Newton-Wellesley Hospital
name: Baylor College of Medicine
name: City of Hope Medical Center
name: University of Florida
name: Northwell Health
name: H. Lee Moffitt Cancer Center and Research Institute
name: Vanderbilt University Medical Center
name: Ohio State University
name: Huntsman Cancer Institute
name: Columbia University
First posted: 2010-09-24
Enrollment: 729
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: In this research study, we are looking to explore the drug combination, lenalidomide, bortezomib and dexamethasone alone or when combined with autologous stem cell transplantation to see what side effects it may have and how well it works for treatment of newly diagnosed multiple myeloma. Specifically, the objective of this trial is to determine if, in the era of novel drugs, high dose therapy (HDT) is still necessary in the initial management of multiple myeloma in younger patients. In this study, HDT as compared to conventional dose treatment would be considered superior if it significantly prolongs progression-free survival by at least 9 months or more, recognizing that particular subgroups may benefit more compared to others.

Detailed description: The drugs, lenalidomide, bortezomib, and dexamethasone, are approved by the FDA. They have not been approved in the combination for multiple myeloma or any other type of cancer. Bortezomib is currently approved by the FDA for the treatment of multiple myeloma. Lenalidomide is approved for use with dexamethasone for patients with multiple myeloma who have received at least one prior therapy and for the treatment of certain types of myelodysplastic syndrome (another type of cancer affecting the blood). Dexamethasone is commonly used, either alone, or in combination with other drugs, to treat multiple myeloma. Please note that Bortezomib and Lenalidomide are provided to patients participating in this trial at no charge. Melphalan and cyclophosphamide, the drugs used during stem cell collection and transplant, are also approved by the FDA. Melphalan is an FDA-approved chemotherapy for multiple myeloma and is used as a high-dose conditioning treatment prior to stem cell transplantation. Cyclophosphamide is used, either alone, or in combination with other drugs, to treat multiple myeloma. These drugs have been used in other multiple myeloma studies and information from those studies suggests that this combination of therapy may help to treat newly diagnosed multiple myeloma.

After screening procedures determine if a patient is eligible for this research study, the patient will be randomized into one of the study groups: lenalidomide, bortezomib and dexamethasone without autologous stem cell transplantation, followed by lenalidomide maintenance (Arm A) or lenalidomide, bortezomib and dexamethasone with autologous stem cell transplantation, followed by lenalidomide maintenance (Arm B). There is an equal chance of being placed in either group. Randomization was stratified by International Staging System (ISS) disease stage (I, II, or III) and cytogenetics (high-risk \[presence of 17p deletion, t(4;14), or t(14;16) on fluorescence in-situ hybridization\], standard-risk \[absence of high-risk abnormalities\], or undetermined \[test failure\]) assessed locally in a screening bone marrow sample, with positivity cut-offs per institutional standards.

Eligibility criteria: Inclusion Criteria:

* Diagnosis of Multiple Myeloma, according to the International Myeloma Foundation 2003 Diagnostic Criteria
* Documented symptomatic myeloma, with organ damage related to myeloma with laboratory assessments performed within 21 days of registration
* Myeloma that is measurable by either serum or urine evaluation of the monoclonal component or by assay of serum free light chains.
* ECOG performance status \</= 2
* Negative HIV blood test
* Voluntary written informed consent

Exclusion Criteria:

* Pregnant or lactating female
* Prior systemic therapy for MM (localized radiotherapy allowed if at least 7 days before study entry, corticosteroids allowed if dose \</= equivalent of 160 mg dexamethasone over 2 weeks)
* Primary amyloidosis (AL) or myeloma complicated by amylosis
* Receiving any other investigational agents
* Known brain metastases
* Poor tolerability or allergy to any of the study drugs or compounds of similar composition
* Platelet count \<50,000/mm3, within 21 days of registration
* ANC \<1,000 cells/mm3, within 21 days of registration
* Hemoglobin \<8 g/dL, within 21 days of registration
* Hepatic impairment (\>/= 1.5 x institutional ULN or AST (SGOT), ALT (SGPT), or alkaline phosphatase \>2 x ULN). Patients with benign hyperbilirubinemia are eligible.
* Renal insufficiency (serum creatinine \>2.0 mg/dl or creatinine clearance \<50 ml/min, within 21 days of registration)
* Respiratory compromise (DLCO \< 50%)
* Clinical signs of heart or coronary failure or LVEF \< 40%. Myocardial infarction within 6 months prior to enrollment, NYHA Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conductive system abnormalities
* Intercurrent illness including, but not limited to ongoing or active severe infection, known infection with hepatitis B or C virus, poorly controlled diabetes, severe uncontrolled psychiatric disorder or psychiatric illness/social situations that would limit compliance with study requirements
* Previous history of another malignant condition except for basal cell carcinoma and stage I cervical cancer. If malignancy was experienced more than 2 years ago and confirmed as cured, these participants may be considered for the study on case by case basis with PI discussion.
* Inability to comply with an anti-thrombotic treatment regimen
* Peripheral neuropathy \>/= Grade 2

Primary outcomes:
measure: Median Progression-Free Survival (PFS)
timeFrame: On treatment, disease was assessed every cycle up to maintenance and every 3 cycles on maintenance. In long-term follow-up, disease was assessed every 2 months until PD or death. Median (maximum) PFS follow-up was 70 and 129 months.
Secondary outcomes:
measure: Partial Response (PR) Rate
timeFrame: Disease was assessed every cycle up to maintenance and every 3 cycles on maintenance. Median treatment duration (months) from randomization 28.2 (RVD Alone) and 36.1 (RVD plus ASCT). Maximum treatment duration was 133.5 months in this study cohort.
measure: Very Good Partial Response (VGPR) Rate
timeFrame: Disease was assessed every cycle up to maintenance and every 3 cycles on maintenance. Median treatment duration (months) from randomization 28.2 (RVD Alone) and 36.1 (RVD plus ASCT). Maximum treatment duration was 134 months in this study cohort.
measure: Complete Response (CR) Rate
timeFrame: Disease was assessed every cycle up to maintenance and every 3 cycles on maintenance. Median treatment duration (months) from randomization 28.2 (RVD Alone) and 36.1 (RVD plus ASCT). Maximum treatment duration was 134 months in this study cohort.
measure: Median Duration of Response: Partial Response (DOR PR)
timeFrame: On treatment, disease was assessed every cycle up to maintenance and every 3 cycles on maintenance. In long-term follow-up, disease was assessed every 2 months until PD or death. Median (maximum) DOR PR follow-up was 62.9 and 122.9 months.
measure: 5-Year Time to Progression (TTP)
timeFrame: On treatment, disease was assessed every cycle up to maintenance and every 3 cycles on maintenance. In long-term follow-up, disease was assessed every 2 months until PD or death. Median TTP follow-up was 70 months. The probability estimate is at 5 years.
measure: 5-Year Overall Survival (OS)
timeFrame: In long-term follow-up, survival follow-up every 2 months until death. Median (maximum) OS follow-up was 76 and 129 months.The probability estimate is at 5 years.
measure: Grade 3 or Higher Treatment-Related Non-Hematologic Adverse Event (AE) Rate
timeFrame: AEs was assessed every cycle on treatment. Median treatment duration (months) from randomization 28.2 (RVD Alone) and 36.1 (RVD plus ASCT). Maximum treatment duration was 133.5 months in this study cohort.
measure: 5-year Cumulative Incidence of Second Primary Malignancy (SPM)
timeFrame: 5 years
measure: Median Treatment Duration
timeFrame: Up to 134 months
measure: Median Maintenance Treatment Duration
timeFrame: Up to 128 months
measure: Subsequent Therapy Rate
timeFrame: Up to 129 months
measure: Change From Baseline on the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-NTX)
timeFrame: Cycle 1 (Baseline), Cycle 2, Pre-Mobilization, Cycle 5 Arm A / Post Auto-HSCT Arm B, Cycle 8 Arm A /Cycle 5 Arm B, Maintenance Day 1, 2 years from baseline, 3 years from baseline
measure: Change From Baseline on the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire Core 30 (EORTC QLQ-C30): Global Health Status/Quality of Life (QoL) Sub-scale
timeFrame: Cycle 1 (Baseline), Cycle 2, Pre-Mobilization, Cycle 5 Arm A / Post Auto-HSCT Arm B, Cycle 8 Arm A /Cycle 5 Arm B, Maintenance Day 1, 2 years from baseline, 3 years from baseline
measure: Quality-Adjusted Life Years (QALYs)
timeFrame: Maximum observation of survival for this study cohort was 129.4 months.
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Tucson
country: United States
facility: Arizona Comprehensive Cancer Center
state: Arizona
city: Duarte
country: United States
facility: City of Hope
state: California
city: La Jolla
country: United States
facility: University of California at San Diego
state: California
city: San Francisco
country: United States
facility: University of California, San Francisco
state: California
city: Stanford
country: United States
facility: Stanford University
state: California
city: Denver
country: United States
facility: Colorado Blood Cancer Institute
state: Colorado
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Tampa
country: United States
facility: H. Lee Moffitt Cancer Center
state: Florida
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Boise
country: United States
facility: Mountain States Tumor Institute at St. Luke's Regional Medical Center
state: Idaho
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: New Orleans
country: United States
facility: Ochsner Foundation Clinic
state: Louisiana
city: Brewer
country: United States
facility: Eastern Maine Medical Center
state: Maine
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Hyannis
country: United States
facility: Cape Cod Healthcare
state: Massachusetts
city: Newton
country: United States
facility: Newton-Wellesley Hospital
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Detroit
country: United States
facility: Barbara Ann Karmanos Cancer Institute
state: Michigan
city: Jackson
country: United States
facility: University of Mississippi Medical Center
state: Mississippi
city: Concord
country: United States
facility: New Hampshire Oncology and Hematology
state: New Hampshire
city: Hooksett
country: United States
facility: New Hampshire Oncology and Hematology
state: New Hampshire
city: Laconia
country: United States
facility: New Hampshire Oncology and Hematology
state: New Hampshire
city: Brooklyn
country: United States
facility: State University of New York Downstate Medical Center
state: New York
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: Lake Success
country: United States
facility: North Shore Long Island Jewish Health System
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: New York
country: United States
facility: Mount Sinai Medical Center
state: New York
city: New York
country: United States
facility: Columbia University
state: New York
city: Rochester
country: United States
facility: University of Rochester Medical Center
state: New York
city: Chapel Hill
country: United States
facility: UNC Lineberger Comprehensive Cancer Center
state: North Carolina
city: Durham
country: United States
facility: Duke University
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest University
state: North Carolina
city: Columbus
country: United States
facility: Ohio State University Medical Center
state: Ohio
city: Portland
country: United States
facility: Oregon Health and Sciences
state: Oregon
city: Philadelphia
country: United States
facility: University of Pennsylvania Medical Center
state: Pennsylvania
city: Philadelphia
country: United States
facility: Fox Chase Cancer Center
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt University
state: Tennessee
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute
state: Utah
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research Center
state: Washington
Study officials:
affiliation: Dana-Farber Cancer Institute
name: Paul G. Richardson, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Richardson PG, Jacobus SJ, Weller EA, Hassoun H, Lonial S, Raje NS, Medvedova E, McCarthy PL, Libby EN, Voorhees PM, Orlowski RZ, Anderson LD Jr, Zonder JA, Milner CP, Gasparetto C, Agha ME, Khan AM, Hurd DD, Gowin K, Kamble RT, Jagannath S, Nathwani N, Alsina M, Cornell RF, Hashmi H, Campagnaro EL, Andreescu AC, Gentile T, Liedtke M, Godby KN, Cohen AD, Openshaw TH, Pasquini MC, Giralt SA, Kaufman JL, Yee AJ, Scott E, Torka P, Foley A, Fulciniti M, Hebert K, Samur MK, Masone K, Maglio ME, Zeytoonjian AA, Nadeem O, Schlossman RL, Laubach JP, Paba-Prada C, Ghobrial IM, Perrot A, Moreau P, Avet-Loiseau H, Attal M, Anderson KC, Munshi NC; DETERMINATION Investigators. Triplet Therapy, Transplantation, and Maintenance until Progression in Myeloma. N Engl J Med. 2022 Jul 14;387(2):132-147. doi: 10.1056/NEJMoa2204925. Epub 2022 Jun 5.
citation: Parmar H, Vesole DH, Biran N. From VAD to VRD: Is Transplant Still Needed in the Upfront Setting of Myeloma? Cancer J. 2021 May-Jun 01;27(3):190-195. doi: 10.1097/PPO.0000000000000522.