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NCT01208662 · CITED IN SOURCE DOCUMENTS

Randomized Trial of Lenalidomide, Bortezomib, Dexamethasone vs High-Dose Treatment With SCT in MM Patients up to Age 65

An NCI or FDA source cites this study. A citation does not establish that it applies to an individual diagnosis.

Phase
PHASE3
Status at capture
ACTIVE NOT RECRUITING
Registry last update
2026-01-22

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.

Open the original ClinicalTrials.gov record → · Download preserved record

What did the study report?

Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.

flow

Participant flow

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baseline

Baseline characteristics

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outcome · POSTED

Median Progression-Free Survival (PFS)

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outcome · POSTED

Partial Response (PR) Rate

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outcome · POSTED

Very Good Partial Response (VGPR) Rate

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outcome · POSTED

Complete Response (CR) Rate

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outcome · POSTED

Median Duration of Response: Partial Response (DOR PR)

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outcome · POSTED

5-Year Time to Progression (TTP)

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outcome · POSTED

5-Year Overall Survival (OS)

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outcome · POSTED

Grade 3 or Higher Treatment-Related Non-Hematologic Adverse Event (AE) Rate

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outcome · POSTED

5-year Cumulative Incidence of Second Primary Malignancy (SPM)

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outcome · POSTED

Median Treatment Duration

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outcome · POSTED

Median Maintenance Treatment Duration

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outcome · POSTED

Subsequent Therapy Rate

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outcome · POSTED

Change From Baseline on the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-NTX)

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outcome · POSTED

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

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outcome · POSTED

Quality-Adjusted Life Years (QALYs)

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outcome · POSTED

Next Generation Sequencing (NGS) Minimal Residual Disease Negative (MRD-) Rate at Maintenance Start

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outcome · POSTED

Median Event Free Survival (EFS)

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adverse events

Adverse events

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more info

Limitations, agreements, and source contact

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Who could take part
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
healthy Volunteers
false
maximum Age
65 Years
minimum Age
18 Years
sex
ALL
std Ages
  1. ADULT
  2. OLDER_ADULT
Treatment arms and interventions
arm Groups
  1. description
    All participants received one cycle of Lenalidomide (R), bortezomib (V) and dexamethasone (D) and then were randomized. All participants then received two additional RVD cycles, followed by stem-cell collection. RVD Alone participants received five additional RVD cycles. Maintenance in both arms comprised daily lenalidomide 10 mg, escalated to 15 mg if tolerated, until disease progression, unacceptable toxicity, or withdrawal from treatment or study. After finishing protocol-specified treatment, off-study salvage transplantation was recommended but not mandated for RVD Alone participants at relapse. RVD cycle duration=21 days R: 25 mg oral on days 1-14 V: 1.3 mg per square meter of body surface area IV or subcutaneous on days 1, 4, 8, and 11 D: 20 mg oral (cycles 1-3) or 10 mg (cycles 4-8) on days 1, 2, 4, 5, 8, 9, 11, and 12
    intervention Names
    1. Drug: Lenalidomide
    2. Drug: Bortezomib
    3. Drug: Dexamethasone
    label
    RVD Alone
    type
    EXPERIMENTAL
  2. description
    All participants received one cycle of Lenalidomide (R), bortezomib (V) and dexamethasone (d) and then were randomized. All participants then received two additional RVD cycles, followed by stem-cell collection. RVD plus autologous stem cell transplant (ASCT) participants received high-dose melphalan (200 mg/m2, adjusted for ideal body weight) ASCT and, upon recovery (\~day 60), two additional RVD cycles. Maintenance in both arms comprised daily lenalidomide 10 mg, escalated to 15 mg if tolerated, until disease progression, unacceptable toxicity, or withdrawal from treatment or study. After finishing protocol-specified treatment, RVD plus ASCT participants could undergo a second transplant. RVD cycle duration=21 days R: 25 mg oral on days 1-14 V: 1.3 mg per square meter of body surface area IV or subcutaneous on days 1, 4, 8, and 11 D: 20 mg oral (cycles 1-3) or 10 mg (cycles 4-8) on days 1, 2, 4, 5, 8, 9, 11, and 12
    intervention Names
    1. Drug: Lenalidomide
    2. Drug: Bortezomib
    3. Drug: Dexamethasone
    4. Procedure: Autologous Stem Cell Transplant
    label
    RVD plus ASCT
    type
    ACTIVE_COMPARATOR
interventions
  1. arm Group Labels
    1. RVD Alone
    2. RVD plus ASCT
    description
    oral administration
    name
    Lenalidomide
    other Names
    1. CC-5013
    type
    DRUG
  2. arm Group Labels
    1. RVD Alone
    2. RVD plus ASCT
    description
    intravenous or, following protocol amendment, subcutaneous administration
    name
    Bortezomib
    other Names
    1. PS-341
    2. Velcade
    type
    DRUG
  3. arm Group Labels
    1. RVD Alone
    2. RVD plus ASCT
    description
    oral administration Dose of 20 mg/day for first 3 cycles. Dose of 10 mg/day for remaining cycles.
    name
    Dexamethasone
    other Names
    1. Decadron
    type
    DRUG
  4. arm Group Labels
    1. RVD plus ASCT
    description
    Autologous refers to stem cells that are harvested from the participant to be a source of new blood cells after high-dose chemotherapy with melphalan.
    name
    Autologous Stem Cell Transplant
    other Names
    1. Peripheral Blood Stem Cell (PBSC) Transplant
    type
    PROCEDURE
Study design
allocation
RANDOMIZED
intervention Model
PARALLEL
masking Info
masking
NONE
primary Purpose
TREATMENT
Enrollment
count
729
type
ACTUAL
Registered outcome plans (not posted results)
primary Outcomes
  1. description
    PFS was estimated using the Kaplan-Meier (KM) method and defined as time from randomization to the earlier of disease progression (PD) as determined by central review or death from any cause (events). Patients who started non-protocol therapy (NPT) were censored at the date of NPT initiation if available or date treatment ended if date of NPT was missing. Deaths occurring beyond 1 year from the date last known progression-free are not counted as events and censored at date of last disease evaluation. Patients who had not started NPT, progressed, or died were censored at the date of last disease evaluation. PD was based upon the International Myeloma Working Group (IMWG) uniform response criteria. \[Kumar S, et al Lancet Oncol 2016;17(8):e328-e346\].
    measure
    Median Progression-Free Survival (PFS)
    time Frame
    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
  1. description
    The PR rate is the percentage of participants achieving PR or better on treatment and was evaluated based on the IMWG criteria. PR was defined as \> 50% reduction of serum M-protein and reduction in 24-h urinary M-protein by \> 90% or to \< 200mg per 24 hours. If the serum and urine M-protein are unmeasurable, a \> 50% decrease in the difference between involved and uninvolved free light chain levels is required in place of the M-protein criteria. If serum and urine M-protein are unmeasurable, and serum free light assay is also unmeasurable, \>50% reduction in plasma cells is required in place of M-protein, provided baseline bone marrow plasma cell percentage was \> 30%. In addition to the above listed criteria, if present at baseline, a \> 50% reduction in the size of soft tissue plasmacytomas was also required. Exact (Clopper-Pearson) confidence limits of 98.2857% represents Bonferroni adjustment for 7 tests (1-0.05/7) per statistical analysis plan for key secondary outcomes.
    measure
    Partial Response (PR) Rate
    time Frame
    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.
  2. description
    The VGPR rate is the percentage of participants achieving VGPR or better on treatment and was evaluated based on IMWG criteria. VGPR was defined as serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein plus urine M-protein level \<100mg per 24 hours.
    measure
    Very Good Partial Response (VGPR) Rate
    time Frame
    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.
  3. description
    The CR rate is the percentage of participants achieving CR or better on treatment and was evaluated based on IMWG criteria. CR was defined as the negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and \<5% plasma cells in bone marrow. Confirmation with repeat bone marrow biopsy was not needed.
    measure
    Complete Response (CR) Rate
    time Frame
    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.
  4. description
    DOR PR was estimated using the KM method and defined as the time from documented best response as CR to documented disease progression per IMWG criteria. Patients who have not progressed or died were censored at the date last known progression-free.
    measure
    Median Duration of Response: Partial Response (DOR PR)
    time Frame
    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.
  5. description
    TTP was estimated using the KM method and defined as time from randomization to time of documented IMWG disease progression or censoring time (time of last disease evaluation for those alive, time to death among those who died). Patients initiating non-protocol therapy prior to progression or death were censored at the date of non-protocol therapy in the TTP analysis. The 5-year TTP endpoint is a probability.
    measure
    5-Year Time to Progression (TTP)
    time Frame
    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.
  6. description
    OS was estimated using the KM method and defined as time from randomization to death due to any cause. Patients alive were censored at date last known alive. The 5-year OS endpoint is a probability.
    measure
    5-Year Overall Survival (OS)
    time Frame
    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.
  7. description
    Safety was evaluated throughout trial treatment, including ASCT, and through 30 days after receipt of the last dose of a trial drug. Treatment attribution and grade were based on the NCI CTCAE v4. The Grade 3 or Higher Treatment-Related Non-Hematologic AE Rate is percentage of participants who experienced any grade 3-5 treatment-related (possible, probable or definite attribution) non-hematologic adverse event based on CTCAEv4 as reported on case report forms. The difference in the rate of all grade 3 or higher toxicities was compared between the two groups using Fisher's exact test.
    measure
    Grade 3 or Higher Treatment-Related Non-Hematologic Adverse Event (AE) Rate
    time Frame
    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.
  8. description
    Second primary malignancy (SPM) is defined as the development of another new, unrelated cancer, regardless of treatment for previous malignancy attribution. The cumulative incidence of SPMs was estimated with death as a competing risk. SPMs were collected using an SAE form or MEDWATCH 3500A form, with intensity determined by using the NCI CTCAE version 4 as a guideline.
    measure
    5-year Cumulative Incidence of Second Primary Malignancy (SPM)
    time Frame
    5 years
  9. description
    Treatment duration estimated using the KM method is defined as the time from registration (C1) to the time off treatment (event) or censored at date of last treatment.
    measure
    Median Treatment Duration
    time Frame
    Up to 134 months
  10. description
    Maintenance treatment duration estimated using the KM method is defined as the time from start of maintenance to the time off maintenance (event) or censored at date of last maintenance treatment.
    measure
    Median Maintenance Treatment Duration
    time Frame
    Up to 128 months
  11. description
    Subsequent therapy rate was the percentage of participants who discontinued treatment and initiated subsequent non-protocol therapy.
    measure
    Subsequent Therapy Rate
    time Frame
    Up to 129 months
  12. description
    The FACT/GOG-NTX assessment consists of 11 questions that are all used to construct 1 subscale to summarize symptoms of peripheral neuropathy, including sensory, motor, and auditory problems and cold sensitivity. (https://www.facit.org/measures/FACT-GOG-NTX) Each question has 4 possible responses from 0 (Not at all) to 4 (Very Much) which are reverse-scored and summed. This sum is then scaled by the number of questions answered by multiplying by 11 and then dividing by the number of questions that are non-blank, in order to keep all final scores proportional to one another even if some questions are left blank. The aggregate score ranges from 0 to 44, with higher scores indicating less neurotoxicity and lower scores indicating more neurotoxicity. Change from baseline is the difference
    measure
    Change From Baseline on the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-NTX)
    time Frame
    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
Full study description
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.
Source references
references
  1. 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.
    pmid
    35660812
    type
    RESULT
  2. 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.
    pmid
    34549906
    type
    DERIVED
Source notices and limitations
    Discovery and provenance
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      source update dates
      1. context
        Updated: April 25, 2025
        datetime
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        April 25, 2025

    Preserved source evidence · Not medical advice