Bortezomib or Carfilzomib with Lenalidomide and Dexamethasone in Treating Patients with Newly Diagnosed Multiple Myeloma

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Basic Trial Information

PhaseTypeAgeTrial IDs
Phase IIIBiomarker/Laboratory analysis, Supportive care, Treatment18 and overE1A11
NCI-2012-02608, ECOG-E1A11, NCT01863550

Trial Description

Summary

This randomized phase III trial studies bortezomib, lenalidomide, and dexamethasone to see how well they work compared to carfilzomib, lenalidomide, and dexamethasone in treating patients with newly diagnosed multiple myeloma. Bortezomib and carfilzomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Lenalidomide may help the immune system kill abnormal blood cells or cancer cells. Drugs used in chemotherapy, such as dexamethasone, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether bortezomib, lenalidomide, and dexamethasone are more or less effective than carfilzomib, lenalidomide, and dexamethasone in treating patients with multiple myeloma

Further Study Information

PRIMARY OBJECTIVES:

I. To compare the overall survival between two strategies of lenalidomide maintenance following induction with a proteasome inhibitor–IMiD (lenalidomide) combination: limited duration of maintenance (24 months) versus indefinite maintenance therapy until disease progression.

SECONDARY OBJECTIVES:

I. To compare the progression-free survival between two strategies of lenalidomide maintenance following induction with a proteasome inhibitor–IMiD combination: limited duration of maintenance (24 months) or indefinite maintenance therapy until disease progression.

II. To compare progression-free survival between bortezomib, lenalidomide, and dexamethasone (VRd) and carfilzomib, lenalidomide, and dexamethasone (CRd) induction followed by lenalidomide maintenance in patients with newly diagnosed symptomatic multiple myeloma.

III. To compare induction rates of response between VRd and CRd arms.

IV. To evaluate time to progression, duration of response and overall survival between VRd and CRd induction therapy.

V. To compare induction rates of toxicity between VRd and CRd arms.

VI. To evaluate toxicity during lenalidomide maintenance.

TERTIARY OBJECTIVES:

I. To compare the short and long-term health-related quality of life impact between two strategies of lenalidomide maintenance following induction with a proteasome inhibitor–IMiD combination: limited duration of maintenance (24 months) versus indefinite maintenance therapy until disease progression.

II. To compare the impact on health-related quality of life between VRd and CRd induction therapy.

III. To evaluate the association between early induction response and change in health-related quality of life.

IV. To describe changes in health-related quality of life during the induction, active maintenance and observation phases.

V. To evaluate correlation between treatment adherence during maintenance and health-related quality of life.

VI. To compare induction minimal residual disease negativity rates between VRd and CRd arms.

VII. To compare minimal residual disease negativity rates between two strategies of lenalidomide maintenance following induction with a proteasome inhibitor–IMiD combination: limited duration of maintenance (24 months) versus indefinite maintenance therapy until disease progression.

VIII. To describe changes in minimal residual disease during the induction and active maintenance phases and explore association with response.

OUTLINE:

INDUCTION: Patients are randomized to 1 of 2 treatment arms.

ARM A: Patients receive bortezomib subcutaneously (SC) or intravenously (IV) on days 1, 4, 8, and 11 of courses 1-8 and days 1 and 8 of courses 9-12; lenalidomide orally (PO) daily on days 1-14; and dexamethasone PO daily on days 1, 2, 4, 5, 8, 9, 11, and 12 of courses 1-8 and days 1, 2, 8, and 9 of courses 9-12. Treatment repeats every 3 weeks for 12 courses in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive carfilzomib IV over 30 minutes on days 1, 2, 8, 9, 15, and 16; lenalidomide PO daily on days 1-21; and dexamethasone PO on days 1, 8, 15, and 22. Treatment repeats every 4 weeks for 9 courses in the absence of disease progression or unacceptable toxicity.

MAINTENANCE: After completion of induction therapy, patients are then randomized to 1 of 2 maintenance treatment arms.

ARM C: Patients receive lenalidomide PO daily on days 1-21. Treatment repeats every 4 weeks for 24 courses in the absences of disease progression or unacceptable toxicity.

ARM D: Patients receive lenalidomide PO daily on days 1-21. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years, every 6 months for 3 years, and then annually for 10 years.

Eligibility Criteria

Inclusion Criteria:

STEP I: Patients must have received no more than one cycle (4 weeks or less) of prior chemotherapy and no more than 160 mg of prior dexamethasone (or equivalent dose of prednisone) for treatment of symptomatic myeloma; they should not have been exposed to lenalidomide, bortezomib or carfilzomib for treatment of symptomatic myeloma; prior radiation therapy to symptomatic lesions is allowed provided 14 days is allowed between the completion of radiation therapy and start of protocol treatment

STEP I: Patients must be diagnosed with symptomatic standard-risk multiple myeloma (SR-MM) as defined by all of the following (except gene expression profile [GEP]70 status if unknown):

No evidence of t(14;16) by fluorescence in situ hybridization (FISH) testing on bone marrow or not available

No evidence of t(14:20) by FISH testing on bone marrow or not available

No evidence of deletion 17p by FISH testing on bone marrow

  • NOTE: If the FISH result states that no immunoglobulin heavy chain (IgH) abnormality is present, both t(14;16) and t(14;20) can be considered negative; in addition, if the patient has a t(11;14) or t(4;14) translocation present, they can be considered negative for t(14;16) and t(14;20); if testing for t(14;16) or t(14;20) could not be performed for lack of sufficient material or non-availability of the probe in the test panel, patients can be enrolled on the study

Standard Risk GEP70 signature within the past 90 days (only if GEP has been done and results are available)

Serum lactate dehydrogenase (LDH) =< 2 x upper limit of normal (ULN) within the past 28 days

No more than 20% circulating plasma cells on white blood cell (WBC) differential or 2,000 plasma cells/microliter of peripheral blood within the past 90 days

STEP II: Females of childbearing potential (FCBP)* must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL within 10-14 days prior to and again within 24 hours of starting lenalidomide 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 28 days 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 a FCBP 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

A female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) 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

STEP I: Patients must have measurable or evaluable disease as defined by having one or more of the following, obtained within 28 days prior to randomization:

>= 1 g/dL monoclonal protein (M-protein) on serum protein electrophoresis

>= 200 mg/24 hrs of monoclonal protein on a 24 hour urine protein electrophoresis

Involved free light chain >= 10 mg/dL or >= 100 g/L AND abnormal serum immunoglobulin kappa to lambda free light chain ratio (< 0.26 or > 1.65)

Monoclonal bone marrow plasmacytosis >= 30% (evaluable disease)

Serum protein electrophoresis (SPEP), urine protein electrophoresis (UPEP), and serum free light chain (FLC) assay and bone marrow biopsy and or aspirate are required to be performed within 28 days prior to randomization

  • NOTE: UPEP (on a 24-hour collection) is required, no substitute method is acceptable; urine must be followed monthly if the baseline urine M-spike is >= 200 mg/24 hr; please note that if both serum and urine M-components are present, both must be followed in order to evaluate response
  • NOTE: The serum free light chain test is required to be done if the patient does not have measurable disease in the serum or urine; measurable disease in the serum is defined as having a serum M-spike >= 1 g/dL; measurable disease in the urine is defined as having a urine M-spike >= 200 mg/24 hr

STEP I: Patients with monoclonal gammopathy of undetermined significance or asymptomatic multiple myeloma are not eligible

STEP I: Untransfused platelet count >= 75,000 cells/mm^3

STEP I: Bilirubin =< 1.5 mg/dL

STEP I: Calculated creatinine clearance >= 30 mL/min

STEP I: Patients must not have uncontrolled intercurrent illness including uncontrolled hypertension, symptomatic congestive heart failure, unstable angina, uncontrolled cardiac arrhythmia, uncontrolled psychiatric illness or social situation that would limit compliance with the study, or a prior history of Stevens Johnson syndrome

STEP I: Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2 (performance status [PS] 3 allowed if secondary to pain)

STEP I: Patients should not have New York Heart Association classification III or IV heart failure or myocardial infarction within the previous 6 months

STEP I: Sexually active males must be willing to use a condom (even if they have undergone a prior vasectomy) while having intercourse, while taking lenalidomide and for 4 weeks after stopping treatment

STEP I: Absolute neutrophil count >= 1000 cells/mm^3

STEP I: Hemoglobin >= 8 g/dL

STEP I: Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) and serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) < 2.5 times the upper limit of normal

STEP I: Patients must not have active, uncontrolled seizure disorder; patients must have had no seizures in the last 6 months

STEP I: Patient enrolling to this study must agree to register to the mandatory RevAssist® program, and be willing and able to comply with the requirements of RevAssist®

STEP I: The following patients will be excluded:

Pregnant women

Nursing women

STEP I: Patients must not have grade 2 or higher peripheral neuropathy by Common Terminology Criteria for Adverse Events (CTCAE) 4.0

STEP I: Patients must not have active, uncontrolled infection

STEP I: Human immunodeficiency virus (HIV) infection is not excluded; known HIV positive patients must meet the following criteria:

Cluster of differentiation (CD)4 cell count >= 350/mm^3

No history of acquired immune deficiency syndrome (AIDS)-related illness

Not currently prescribed zidovudine or stavudine

STEP II: Patient enrolling to this study must agree to register to the mandatory RevAssist® program and be willing and able to comply with the requirements of RevAssist®

STEP II: Sexually active males must be willing to use a condom (even if they have undergone a prior vasectomy) while having intercourse, while taking lenalidomide and for 4 weeks after stopping treatment

STEP II: The following patients will be excluded:

Pregnant women

Nursing women

STEP II: ECOG performance status 0, 1, or 2 (PS 3 allowed if secondary to pain)

STEP II: Any adverse event related to step 1 therapy must have resolved to grade 2 or less

STEP II: Absolute neutrophil count >= 1000 cells/mm^3

STEP II: SGPT (ALT) and SGOT (AST) < 2.5 times the upper limit of normal

STEP II: Step 2 registration must be within 28 days of completing step 1 therapy

STEP II: Patients must not have experienced progression on step 1 induction therapy

STEP II: Hemoglobin >= 8 g/dL

STEP II: Platelet count >= 75,000 cells/mm^3

STEP II: Calculated creatinine clearance >= 30 mL/min

STEP II: Bilirubin =< 1.5 mg/dL

STEP I: Patients with a history of prior malignancy are eligible provided they were treated with curative intent and do not require active therapy (currently treated basal cell, squamous cell carcinoma of the skin, or carcinoma “in situ” of the cervix or breast are not excluded)

STEP I: Females of childbearing potential (FCBP)* must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL within 10-14 days prior to and again within 24 hours of starting lenalidomide 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 28 days 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 a FCBP 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

A female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) 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

STEP I: Prior systemic glucocorticoid use for the treatment of non-malignant disorders is permitted; prior or concurrent topical or localized glucocorticoid therapy to treat non-malignant comorbid disorders is permitted; NOTE: concurrent use after registration on the study should be restricted to the equivalent of prednisone 10 mg per day

STEP I: Patients may have a history of current or previous deep vein thrombosis or pulmonary embolism but must be willing to take some form of anti-coagulation as prophylaxis if they are not currently on full-dose anticoagulation

STEP II: Patients must not have received any non-protocol therapy outside of the assigned induction therapy

Trial Contact Information

Trial Lead Organizations / Sponsors / Collaborators

ECOG-ACRIN Cancer Research Group

  • National Cancer Institute
Shaji K. Kumar, Principal Investigator

Trial Sites

U.S.A.

Colorado
Denver

Colorado Cancer Research Program CCOP

Keren Sturtz
Ph: 888-785-6789

Keren Sturtz
Principal Investigator

Florida
Pensacola

Sacred Heart Medical Oncology Group - Davis Highway

Tarek Eldawy (Mohamed)
Ph: 850-416-4611

Tarek Eldawy (Mohamed)
Principal Investigator

Illinois
Galesburg

Illinois CancerCare-Galesburg Cottage Plaza Office

Nguyet Anh Le-Lindqwister
Ph: 800-793-2262

Nguyet Anh Le-Lindqwister
Principal Investigator

Nebraska
Omaha

Missouri Valley Cancer Consortium

Gamini S. Soori
Ph: 402-991-8070ext202
Email: mwilwerding@mvcc.cc

Gamini S. Soori
Principal Investigator

Nevada
Las Vegas

Children's Specialty Center of Nevada II

John Allan Ellerton
Ph: 702-384-0013

John Allan Ellerton
Principal Investigator

Nevada Cancer Research Foundation CCOP

John Allan Ellerton
Ph: 702-384-0013

John Allan Ellerton
Principal Investigator

Wisconsin
Milwaukee

Aurora Cancer Care-Milwaukee South

Dhimant R. Patel
Ph: 800-252-2990

Dhimant R. Patel
Principal Investigator

Link to the current ClinicalTrials.gov record.
NLM Identifer NCT01863550

Note: Information about participating sites on pharmaceutical industry trials may be incomplete. Please visit the ClinicalTrials.gov record via the link above for more information about participating sites.