Stem Cell Transplant and Lenalidomide With and Without Bortezomib in Treating Patients With Multiple Myeloma

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT02257515
First received: October 2, 2014
Last updated: October 29, 2014
Last verified: October 2014

October 2, 2014
October 29, 2014
June 2010
December 2017   (final data collection date for primary outcome measure)
PFS [ Time Frame: Time from randomization or until evidence of progression, assessed at 3 years ] [ Designated as safety issue: No ]
The treatment arms will be compared with a log rank test stratified on risk status, and using a two-sided level significance level of 0.0167 adjusted for sequential monitoring.
Same as current
Complete list of historical versions of study NCT02257515 on ClinicalTrials.gov Archive Site
  • PFS [ Time Frame: Time from randomization or until evidence of progression, assessed up to 4 years ] [ Designated as safety issue: No ]
    The treatment arms will be compared with a log rank test stratified on risk status, and using a two-sided level significance level of 0.0167 adjusted for sequential monitoring.
  • Proportion of subjects who achieve CR on maintenance assessed using the International Uniform Response Criteria [ Time Frame: Assessed up to 4 years ] [ Designated as safety issue: No ]
  • Overall survival [ Time Frame: From randomization to death, loss to follow-up or the end of the study, whichever comes first, assessed up to 4 years ] [ Designated as safety issue: No ]
    The Kaplan-Meier estimate of survival will be estimated separately for each treatment-group and risk status.
  • Proportion of patients developing grade 3 or higher toxicity, graded according to the CTCAE [ Time Frame: Up to 4 years ] [ Designated as safety issue: Yes ]
    Safety data will be described in a variety of ways, both graphical and tabular, and incidence will be compared across time points and treatment arms.
  • Proportion of patients in each arm with definite and probable viral, fungal and bacterial infections [ Time Frame: Up to 4 years ] [ Designated as safety issue: No ]
    Tabulated for each patient.
  • Treatment-related mortality defined as death occurring in a patient from causes other than disease relapse or progression [ Time Frame: Up to 4 years ] [ Designated as safety issue: No ]
    An extension of the sequential probability ratio test (SPRT) will be used to test event rates, with the null and alternative hypotheses for the test. The binomial SPRT for each guideline can be represented graphically.
  • Proportion of patients who do not proceed to their second or, if applicable, third phase of treatment or who discontinue consolidation or maintenance at any time point due to toxicity, noncompliance or other reasons [ Time Frame: Up to 4 years ] [ Designated as safety issue: No ]
    An extension of the SPRT will be used to test event rates, with the null and alternative hypotheses for the test. The binomial SPRT for each guideline can be represented graphically.
  • Health-related quality of life evaluated using the Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) [ Time Frame: Up to 4 years ] [ Designated as safety issue: No ]
Same as current
Not Provided
Not Provided
 
Stem Cell Transplant and Lenalidomide With and Without Bortezomib in Treating Patients With Multiple Myeloma
A Trial of Single Autologous Transplant With or Without Consolidation Therapy Versus Tandem Autologous Transplant With Lenalidomide Maintenance for Patients With Multiple Myeloma

This phase III randomized trial studies three treatment strategies after a single autologous transplant for patients with multiple myeloma (MM): second autologous transplant with the same conditioning regimen followed by maintenance with lenalidomide; maintenance alone; or consolidation with lenalidomide, bortezomib and dexamethasone combination followed by lenalidomide maintenance. Lenalidomide may stop the growth of MM by blocking blood flow to the tumor. Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. It is not yet known which treatment is more effective in treating MM.

PRIMARY OBJECTIVES:

I. To compare progression free survival (PFS) between the two single transplant arms and between each single transplant arm and the tandem transplant arm.

SECONDARY OBJECTIVES:

I. Comparing PFS between treatment arms at one, two and four years after randomization.

II. Comparing rates of very good partial responses or better (very good partial response [VGPR], near complete response [nCR], complete response [CR] and stringent complete response [sCR]) after the first and second year from randomization.

III. Comparing the rate of CR conversion for patients not in CR at initiation of maintenance at 3 months, 6 months, 1, 2 and 3 years after initiation of maintenance.

IV. Comparing overall survival between treatment arms at one, two, three and four years after randomization.

V. Comparing grade >= 3 toxicities, graded according to the Common Terminology Criteria for Adverse Events (CTCAE), after each autologous transplantation, consolidation and yearly until completion of maintenance.

VI. Comparing the incidence of infections after each autologous transplantation, consolidation and yearly until completion of maintenance.

VII. Comparing transplant related mortality (TRM) at one, two, three and four years after randomization.

VIII. Comparing the rate of non compliance with protocol therapy (autologous transplantations, consolidation and maintenance) yearly until completion of maintenance.

IX. Comparing quality of life after each autologous transplantations, consolidation and yearly until completion of maintenance.

OUTLINE: Patients are randomized to 1 of 3 treatment arms.

ARM A (TANDEM AUTOLOGOUS TRANSPLANT):

CONDITIONING REGIMEN: Patients receive melphalan intravenously (IV) on day -2 or -1 and between 60-180 days after first autologous transplant.

TRANSPLANTATION: Patients undergo first autologous peripheral blood stem cell transplant (PBSCT) on day 0 and second autologous PBSCT after second conditioning with melphalan.

MAINTENANCE THERAPY: Patients receive lenalidomide orally (PO) beginning 60-180 days after second autologous PBSCT and continuing for 3 years.

ARM B (LENALIDOMIDE MAINTENANCE ONLY):

CONDITIONING REGIMEN: Patients receive melphalan IV on day -2 or -1.

TRANSPLANTATION: Patients undergo autologous PBSCT on day 0.

MAINTENANCE THERAPY: Patients receive lenalidomide PO beginning 60-180 days after autologous PBSCT and continuing for 3 years.

ARM C (CONSOLIDATION THERAPY):

CONDITIONING REGIMEN: Patients receive melphalan IV on day -2 or -1.

TRANSPLANTATION: Patients undergo autologous PBSCT on day 0.

CONSOLIDATION THERAPY: Patients receive dexamethasone PO on days 1, 8, and 15, lenalidomide PO on days 1-14, and bortezomib IV over 3-5 seconds or subcutaneously (SC) on days 1, 4, 8, and 11. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.

MAINTENANCE THERAPY: Patients receive lenalidomide PO beginning 60-180 days after autologous PBSCT and continuing for 3 years.

After completion of study treatment, patients are followed up annually for at least 4 years.

Interventional
Phase 3
Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
  • Refractory Multiple Myeloma
  • Stage I Multiple Myeloma
  • Stage II Multiple Myeloma
  • Stage III Multiple Myeloma
  • Drug: lenalidomide
    Given PO
    Other Names:
    • CC-5013
    • IMiD-1
    • Revlimid
  • Drug: dexamethasone
    Given PO
    Other Names:
    • Aeroseb-Dex
    • Decaderm
    • Decadron
    • DM
    • DXM
  • Drug: bortezomib
    Given IV
    Other Names:
    • LDP 341
    • MLN341
    • VELCADE
  • Other: quality-of-life assessment
    Ancillary studies
    Other Name: quality of life assessment
  • Drug: melphalan
    Given IV
    Other Names:
    • Alkeran
    • CB-3025
    • L-PAM
    • L-phenylalanine mustard
    • L-Sarcolysin
  • Procedure: autologous-autologous tandem hematopoietic stem cell transplantation
    Undergo autologous PBSCT
  • Procedure: autologous hematopoietic stem cell transplantation
    Undergo autologous PBSCT
  • Procedure: peripheral blood stem cell transplantation
    Undergo autologous PBSCT
    Other Names:
    • PBPC transplantation
    • PBSC transplantation
    • peripheral blood progenitor cell transplantation
    • transplantation, peripheral blood stem cell
  • Active Comparator: Arm A (tandem autologous transplant)

    CONDITIONING REGIMEN: Patients receive melphalan IV on day -2 or -1 and between 60-180 days after first autologous transplant.

    TRANSPLANTATION: Patients undergo first autologous PBSCT on day 0 and second autologous PBSCT after second conditioning with melphalan.

    MAINTENANCE THERAPY: Patients receive lenalidomide PO beginning 60-180 days after second autologous PBSCT and continuing for 3 years.

    Interventions:
    • Drug: lenalidomide
    • Other: quality-of-life assessment
    • Drug: melphalan
    • Procedure: autologous-autologous tandem hematopoietic stem cell transplantation
    • Procedure: peripheral blood stem cell transplantation
  • Active Comparator: Arm B (lenalidomide maintenance only)

    CONDITIONING REGIMEN: Patients receive melphalan IV on day -2 or -1.

    TRANSPLANTATION: Patients undergo autologous PBSCT on day 0.

    MAINTENANCE THERAPY: Patients receive lenalidomide PO beginning 60-180 days after autologous PBSCT and continuing for 3 years.

    Interventions:
    • Drug: lenalidomide
    • Other: quality-of-life assessment
    • Drug: melphalan
    • Procedure: autologous hematopoietic stem cell transplantation
    • Procedure: peripheral blood stem cell transplantation
  • Active Comparator: Arm C (consolidation therapy)

    CONDITIONING REGIMEN: Patients receive melphalan IV on day -2 or -1.

    TRANSPLANTATION: Patients undergo autologous PBSCT on day 0.

    CONSOLIDATION THERAPY: Patients receive dexamethasone PO on days 1, 8, and 15, lenalidomide PO on days 1-14, and bortezomib IV over 3-5 seconds on days 1, 4, 8, and 11. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.

    MAINTENANCE THERAPY: Patients receive lenalidomide PO beginning 60-180 days after autologous PBSCT and continuing for 3 years.

    Interventions:
    • Drug: lenalidomide
    • Drug: dexamethasone
    • Drug: bortezomib
    • Other: quality-of-life assessment
    • Drug: melphalan
    • Procedure: autologous hematopoietic stem cell transplantation
    • Procedure: peripheral blood stem cell transplantation
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Active, not recruiting
750
Not Provided
December 2017   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • INITIAL PATIENT ELIGIBILITY CRITERIA
  • Patients meeting the criteria for symptomatic MM
  • Patients who have received at least two cycles of any regimen as initial systemic therapy and are within 2 - 12 months of the first dose of initial therapy
  • Left ventricular ejection fraction at rest > 40%
  • Bilirubin < 1.5 x the upper limit of normal (Patients who have been diagnosed with Gilbert's Disease are allowed to exceed the defined bilirubin value of 1.5 x the upper limit of normal)
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2.5 x the upper limit of normal
  • Creatinine clearance of >= 40 mL/min, estimated or calculated
  • Diffusion capacity of the lung of carbon monoxide (DLCO), forced ejection volume in 1 second (FEV1), forced vital capacity (FVC) > 50% of predicted value (corrected for hemoglobin)
  • Patients with an adequate autologous graft defined as a cryopreserved peripheral blood stem cell (PBSC) graft containing >= 4 x 10^6 cluster of differentiation (CD)34+ cells/kg patient weight; he graft may not be CD34+ selected or otherwise manipulated to remove tumor or other cells; the graft can be collected at the transplanting institution or by a referring center; the autograft must be stored so that there are two products each containing at least 2 x 10^6 CD34+ cells/kg patient weight
  • Signed informed consent form
  • PATIENT ELIGIBILITY CRITERIA FOR SECOND AUTOLOGOUS TRANSPLANT (TREATMENT ARM A)
  • In order to be eligible to continue on protocol and receive their second transplant (preferably between 60-120 days, but at least 60 days or not longer than 180 days post first autologous transplant), patients must have recovered sufficiently from their first transplant; conditioning therapy for the second transplant must not start sooner than 60 days after the first autologous transplant
  • Mucositis and gastrointestinal symptoms resolved, off hyperalimentation and intravenous hydration
  • Liver and renal function tests within the inclusion criteria for initial autograft
  • Off antibiotics and amphotericin B formulations, voriconazole or other anti-fungal therapy for the treatment of proven, probable or possible infections (defined in accordance with the European Organization for Research and Treatment of Cancer/Mycoses Study Group [EORTC/MSG] criteria); patients who have completed treatment for an infection but are continuing antibiotics or anti-fungal therapy for prophylaxis are eligible to continue on protocol with approval of the medical monitor or one of the protocol chairs
  • Completed administration of any radiotherapy
  • Cardiac and pulmonary function within the inclusion criteria for initial autograft; evaluation is only required if clinically indicated
  • Creatinine clearance of >= 40 mL/min, estimated or calculated
  • Women who are pregnant (positive beta-HCG) or breastfeeding are ineligible to proceed to a second autologous transplant
  • Patients unable to meet criteria for a second transplant (NOTE: beyond 180 days after the first autotransplant) but are still eligible for maintenance therapy should proceed to maintenance
  • PATIENT ELIGIBILITY CRITERIA TO BEGIN LENALIDOMIDE, BORTEZOMIB, DEXAMETHASONE (RVD) CONSOLIDATION (TREATMENT ARM C)
  • Patients must have recovered sufficiently from their first transplant to be eligible for consolidation therapy (preferably between 60-120 days, but at least 60 days or not longer than 180 days post first autologous transplant)
  • Mucositis and gastrointestinal symptoms resolved, off hyperalimentation and intravenous hydration
  • Liver and renal function tests within the inclusion criteria for initial autograft
  • Off antibiotics and amphotericin B formulations, voriconazole or other anti-fungal therapy for proven, probable or possible infections (defined in accordance with the EORTC/MSG criteria); Patients who have been treated for an infection but are continuing antibiotics or anti-fungal therapy for prophylaxis are eligible to continue on protocol with approval of the medical monitor or one of the protocol chairs
  • Completed administration of any radiotherapy
  • Less than or equal to grade 2 sensory neuropathy within 14 days before start of consolidation
  • Platelet count >= 75 x10^9/L (without transfusion in previous 7 days)
  • Absolute neutrophil count (ANC) >= 1.5 x 10^9/L without filgrastim administration within 7 days, or pegfilgrastim within 14 days of starting consolidation
  • Requirements prior taking lenalidomide: Females of childbearing potential (FCBP); a female of childbearing potential is a sexually mature woman who: has not undergone a hysterectomy or bilateral oophorectomy; or has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months); must have a negative serum pregnancy test with a sensitivity of at least 50 mIU/mL within 10 - 14 days prior to and again within 24 hours of beginning treatment with lenalidomide (prescriptions must be filled within 7 days) and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 4 weeks before she starts taking lenalidomide; FCBP must also agree to ongoing pregnancy testing; women who are breastfeeding are ineligible to proceed to RVD consolidation; men must agree to use a latex condom during sexual contact with females of child bearing potential even if they have had a successful vasectomy; all patients must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure
  • Patients must be willing to begin DVT prophylaxis
  • Patients unable to meet criteria for consolidation (NOTE: within 180 days of the first autologous transplantation) or who develop unacceptable toxicity during consolidation should be started on maintenance therapy
  • During the transition period beginning April 30, 2012 and by June 30, 2012 and through the duration of the study, all study participants must be registered into the mandatory RevAssist® for study participants (RASP) program, and be willing and able to comply with the requirements of the RASP program
  • During the transition period beginning April 30, 2012 and by June 30, 2012 and through the duration of the study all study participants must receive counseling and complete phone surveys as required by the RASP program
  • PATIENT ELIGIBILITY CRITERIA TO BEGIN MAINTENANCE THERAPY (ALL TREATMENT ARMS)
  • Patients must have recovered sufficiently from their first or second transplant (preferably between 60-120 days, but at least 60 days or not longer than 180 days post autologous transplant - treatment Arms A and B) or completion of consolidation therapy (at least 84 days or less than 180 days from initiation of consolidation therapy or after completion of 4 cycles of RVD - treatment Arm C) in order to initiate lenalidomide maintenance therapy
  • Mucositis and gastrointestinal symptoms resolved, off hyperalimentation and intravenous hydration
  • Off antibiotics and amphotericin B formulations, voriconazole or other anti-fungal therapy for treatment of proven, probable or possible infections (defined in accordance with the EORTC/MSG criteria); patients who completed treatment for an infection but are continuing antibiotics or anti-fungal therapy for prophylaxis are eligible to continue on protocol with approval of the medical monitor or one of the protocol chairs
  • Completed administration of any radiotherapy
  • Platelet count >= 75 x 10^9/L (without transfusion in previous 7 days)
  • Absolute neutrophil count (ANC) >= 1.5 x 10^9/L without filgrastim administration within 7 days, or pegfilgrastim within 14 days of measurement
  • No contraindications to lenalidomide (patients who were previously exposed to lenalidomide and who either did not tolerate it or who developed severe adverse events that preclude future use of this medication)
  • Liver and renal function tests within the inclusion criteria for initial autograft
  • All study participants must be registered into the mandatory RevAssist for Study Participants (RASP) program, and be willing and able to comply with the requirements of the RASP program
  • All study participants must receive counseling and complete phone surveys as required by the RASP program
  • Females of childbearing potential (FCBP) must have a negative serum pregnancy test with a sensitivity of at least 50 mIU/mL within 10-14 days prior to and again within 24 hours of beginning treatment with lenalidomide (prescriptions must be filled within 7 days) and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 4 weeks before she starts taking lenalidomide; FCBP must also agree to ongoing pregnancy testing; men must agree to use a latex condom during sexual contact with females of child bearing potential even if they have had a successful vasectomy; all patients must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure; patients must be willing to begin DVT prophylaxis

Exclusion Criteria:

  • Patients who never fulfill the criteria for symptomatic MM
  • Patients with purely non-secretory MM (absence of a monoclonal protein [M protein] in serum as measured by electrophoresis and immunofixation and the absence of Bence Jones protein in the urine defined by use of conventional electrophoresis and immunofixation techniques); patients with light chain MM detected in the serum by free light chain assay are eligible
  • Patients with plasma cell leukemia
  • Karnofsky performance score less than 70%
  • Patients with > grade 2 sensory neuropathy* (CTCAE); according to the CTCAE v3.0, grade 3 sensory neuropathy is sensory alteration or paresthesia that interferes with activities of daily living
  • Patients with uncontrolled bacterial, viral or fungal infections (currently taking medication and progression of clinical symptoms)
  • Patients seropositive for the human immunodeficiency virus (HIV)
  • Myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities; prior to study entry, any electrocardiogram (ECG) abnormality at screening has to be documented by the investigator as not medically relevant
  • Patient has hypersensitivity to bortezomib, boron or mannitol
  • Patient has received other investigational drugs with 14 days before enrollment
  • Patients with prior malignancies except resected basal cell carcinoma or treated cervical carcinoma in situ; cancer treated with curative intent < 5 years previously will not be allowed unless approved by the protocol officer or one of the protocol chairs; cancer treated with curative intent > 5 years previously is allowed
  • Female patients who are pregnant (positive beta-human chorionic gonadotropin [HCG]) or breastfeeding
  • Females of childbearing potential (FCBP)† or men who have sexual contact with FCBP unwilling to use contraceptive techniques during the length of lenalidomide maintenance therapy; † a female of childbearing potential is a sexually mature female who: has not undergone a hysterectomy or bilateral oophorectomy; or has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)
  • Prior allograft or prior autograft
  • Patients who have received mid-intensity melphalan (> 50 mg IV) as part of prior therapy
  • Patients unable or unwilling to provide informed consent
  • Prior organ transplant requiring immunosuppressive therapy
  • Patients with disease progression prior to enrollment
  • Patients who have received lenalidomide as initial therapy for MM and have experienced toxicities resulting in treatment discontinuation
  • Patients who experienced thromboembolic events while on full anticoagulation during prior therapy with lenalidomide or thalidomide
  • Patients unwilling to take deep vein thrombosis (DVT) prophylaxis
  • Patients who cannot undergo an intervention in any treatment arm due to a priori denial of medical costs coverage by third party payers
  • Patients unable or unwilling to return to the transplant center for their assigned treatments
Both
up to 70 Years
No
Contact information is only displayed when the study is recruiting subjects
United States
 
NCT02257515
NCI-2012-01011, NCI-2012-01011, CDR0000671722, BMT CTN 0702, BMTCTN-0702
Yes
National Cancer Institute (NCI)
National Cancer Institute (NCI)
Not Provided
Principal Investigator: Amrita Krishnan Blood and Marrow Transplant Clinical Trials Network
National Cancer Institute (NCI)
October 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP