Study to Determine Efficacy and Safety of Lenalidomide Plus Low-dose Dexamethasone Versus Melphalan, Prednisone, Thalidomide in Patients With Previously Untreated Multiple Myeloma
Condition: Multiple Myeloma
MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell
Intervention: Lenalidomide and low-dose dexamethasone; Lenalidomide plus low-dose dexamethasone given for 18 four-week cycles; Melphalan, Prednisone and Thalidomide
Intervention description: Lenalidomide - oral, 2.5mg, 5mg, 10mg, 15mg 20mg, or 25 mg capsules, given either days 1-21 of each 28 day cycles or given every other day for 21 days until documentation of PD.
Dexamethasone - oral 4mg tablets for a total dose of 20mg or 40 mg given days 1,8,15 and 22 of each 28 day cycle up to disease progression; lenalidomide - oral, 2.5mg, 5mg, 10mg, 15mg, 20 mg or 25 mg capsules given on days 1-21 of each 28 day cycle or every other day for 21 days for 18 cycles.
Dexamethasone - oral 4mg tablets for a total dose of 20mg or 40 mg given days 1,8,15 and 22 of each 28 day cycle for 18 cycles; Melphalan - oral, 2mg tablets dosed at either 0.25mg/kg, 0.125 mg/kg, 0.20mg/kg or 0.10mg/kg on days 1-4 of each 42 day cycle up to 12 cycles Prednisone - oral, 5mg, 10mg, 20 mg and 50 mg tablets dosed at 2mg/kg daily days 1-4 of each 42 day cycle for up to 12 cycles Thalidomide - oral, 50mg, 100mg and 200 mg capsules dosed at either 100mg or 200 mg daily on days 1-41 of each 42 day cycle for up to 12 cycles
Intervention MeSH terms: Thalidomide; Dexamethasone; Dexamethasone acetate; Prednisone; Lenalidomide; Melphalan; BB 1101
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 1623.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: newly diagnosed multiple myeloma; Lenalidomide; Revlimid; phase III

Summary:

      The purpose of this study is to compare the safety and efficacy of Lenalidomide plus low dose
      dexamethasone to that of the combination of melphalan, prednisone and thalidomide.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Must understand and voluntarily sign informed consent form

          2. Age ≥ 18 years at the time of signing consent

          3. Previously untreated, symptomatic multiple myeloma as defined by the 3 criteria below:

               -  MM diagnostic criteria (all 3 required):

               -  Monoclonal plasma cells in the bone marrow ≥10% and/or presence of a
                  biopsy-proven plasmacytoma

               -  Monoclonal protein present in the serum and/or urine

               -  Myeloma-related organ dysfunction (at least one of the following) [C] Calcium
                  elevation in the blood (serum calcium >10.5 mg/dl or upper limit of normal) [R]
                  Renal insufficiency (serum creatinine >2 mg/dl) [A] Anemia (hemoglobin <10 g/dl
                  or 2 g < laboratory normal) [B] Lytic bone lesions or osteoporosis

             AND have measurable disease by protein electrophoresis analyses as defined by the
             following:

               -  IgG multiple myeloma: Serum monoclonal paraprotein (M-protein) level ≥ 1.0 g/dl
                  or urine M-protein level ≥ 200 mg/24 hours

               -  IgA multiple myeloma: Serum M-protein level ≥ 0.5 g/dl or urine M-protein level ≥
                  200 mg/24 hours

               -  IgM multiple myeloma (IgM M-protein plus lytic bone disease documented by
                  skeletal survey plain films): Serum M-protein level ≥ 1.0 g/dl or urine M-protein
                  level ≥ 200mg/24hours

               -  IgD multiple myeloma: Serum M-protein level ≥ 0.05 g/dl or urine M-protein level
                  ≥ 200 mg/24 hours

               -  Light chain multiple myeloma: Serum M-protein level ≥ 1.0 g/dl or urine M-protein
                  level ≥ 200 mg/24 hours

             AND are at least 65 years of age or older or, if younger than 65 years of age, are not
             candidates for stem cell transplantation because:

               -  The patient declines to undergo stem cell transplantation or

               -  Stem cell transplantation is not available to the patient due to cost or other
                  reasons

          4. ECOG performance status of 0, 1, or 2

          5. Able to adhere to the study visit schedule and other protocol requirements

          6. Females of child-bearing potential (FCBP)^2:

               1. Must agree to undergo two medically supervised pregnancy tests prior to starting
                  study therapy with either Rd or MPT. The first pregnancy test will be performed
                  within 10-14 days prior to the start of Rd or MPT and the second pregnancy test
                  will be performed within 24 hours prior to the start of Rd or MPT. She must also
                  agree to ongoing pregnancy testing during the course of the study and after the
                  end of study therapy. This applies even if the patient practices complete and
                  continued sexual abstinence.

               2. Must commit to either continued abstinence from heterosexual intercourse (which
                  must be reviewed on a monthly basis) or agree to use and be able to comply with
                  effective contraception without interruption, 28 days prior to starting study
                  drug, during the study therapy (including during periods of dose interruptions),
                  and for 28 days after discontinuation of study therapy.

          7. Male Patients:

               1. Must agree to use a condom during sexual contact with a FCBP, even if they have
                  had a vasectomy, throughout study drug therapy, during any dose interruption and
                  after cessation of study therapy.

               2. Must agree to not donate semen during study drug therapy and for a period after
                  end of study drug therapy.

               3. Must practice complete abstinence or agree to use a condom during sexual contact
                  with a pregnant female or a female of childbearing potential while participating
                  in the study, during dose interruptions and for at least 28 days following study
                  drug discontinuation, even if he has undergone a successful vasectomy.

          8. All patients must:

               1. Have an understanding that the study drug could have a potential teratogenic
                  risk.

               2. Agree to abstain from donating blood while taking study drug therapy and
                  following discontinuation of study drug therapy.

               3. Agree not to share study medication with another person. All FCBP and male
                  patients must be counseled about pregnancy precautions and risks of fetal
                  exposure.

        Exclusion Criteria:

          1. Previous treatment with anti-myeloma therapy (does not include radiotherapy,
             bisphosphonates, or a single short course of steroid [i.e., less than or equal to the
             equivalent of dexamethasone 40 mg/day for 4 days; such a short course of steroid
             treatment must not have been given within 14 days of randomization]).

          2. Any serious medical condition that places the patient at an unacceptable risk if he or
             she participates in this study. Examples of such a medical condition are, but are not
             limited to, patient with unstable cardiac disease as defined by: Cardiac events such
             as MI within the past 6 months, NYHA heart failure class III-IV, uncontrolled atrial
             fibrillation or hypertension; patients with conditions requiring chronic steroid or
             immunosuppressive treatment, such as rheumatoid arthritis, multiple sclerosis and
             lupus, that likely need additional steroid or immunosuppressive treatments in addition
             to the study treatment.

          3. Pregnant or lactating females.

          4. Any of the following laboratory abnormalities:

               -  Absolute neutrophil count (ANC) < 1,000/µL (1.0 x 109/L)

               -  Untransfused platelet count < 50,000 cells/µL (50 x 10^9/L)

               -  Serum SGOT/AST or SGPT/ALT > 3.0 x upper limit of normal (ULN)

          5. Renal failure requiring hemodialysis or peritoneal dialysis.

          6. Prior history of malignancies, other than multiple myeloma, unless the patient has
             been free of the disease for ≥ 3 years. Exceptions include the following:

               -  Basal cell carcinoma of the skin

               -  Squamous cell carcinoma of the skin

               -  Carcinoma in situ of the cervix

               -  Carcinoma in situ of the breast

               -  Incidental histological finding of prostate cancer (TNM stage of T1a or T1b)

          7. Patients who are unable or unwilling to undergo antithrombotic therapy.

          8. Peripheral neuropathy of > grade 2 severity.

          9. Known HIV positivity or active infectious hepatitis, type A, B, or C. Primary AL
             (immunoglobulin light chain) amyloidosis and myeloma complicated by amyloidosis.

               -  1 A variety of other types of end organ dysfunctions can occasionally occur and
                  lead to a need for therapy. Such dysfunction is sufficient to support
                  classification as myeloma if proven to be myeloma-related.

               -  2 A FCBP is a sexually mature woman who: 1) has not undergone a hysterectomy or
                  bilateral oophorectomy or 2) has not been naturally postmenopausal (i.e.,
                  amenorrhea following cancer therapy does not rule out childbearing potential) for
                  at least 24 consecutive months (i.e., has had menses at any time in the preceding
                  24 consecutive months).