ev. 5/14 Cancer esearch Group Schema NDUCTON 1, 3 rm Step 0 P E - E G S T T O Step 1 N D O M Z T O Stratification: ntent to stem cell transplant at progression: Yes or No Bortezomib 1.3 mg/m2 SQ or V days 1, 4, 8, 11 Cycles 1-8 1.3 mg/m2 SQ or V days 1 and 8 Cycles 9-12 Lenalidomide 25 mg PO daily days 1-14 2 Dexamethasone 20 mg PO days 1, 2, 4, 5, 8, 9, 11, 12 Cycles 1-4 10 mg PO days 1, 2, 4, 5, 8, 9, 11, 12 Cycles 5-8 10 mg PO days 1, 2, 8 and 9 Cycles 9-12 epeat cycles every 3 weeks for a total of 12 cycles NDUCTON rm B 1, 3 Carfilzomib 20 mg/m2 V days 1, 2; 36 mg/m2 days 8, 9, 15, 16 Cycle 1 36 mg/m2 V days 1, 2, 8, 9, 15, 16 Cycles 2-9 Step 2 Lenalidomide 25 mg PO daily days 1-21 2 O N D O M Stratification: MNTENNCE 1,3 rm C Lenalidomide 15 mg PO daily days 1-21 4 epeat cycles every 4 weeks for a total of 24 cycles nduction arm: Vd (rm ) or Cd (rm B) Z MNTENNCE 1,3 rm D Lenalidomide T 15 mg PO daily days 1-21 4 epeat cycles every 4 weeks until progression or excessive toxicity Observation Until disease progression N 5 N Dexamethasone 40 mg PO days 1, 8, 15, 22 Cycles 1-4 20 mg PO days 1, 8, 15, 22 Cycles 5-9 N epeat cycles every 4 weeks for a total of 9 cycles ccrual Goal: 756 patients with newly diagnosed, standard risk myeloma (see section 3.1.2 for definition of standard risk) 1. Patients can mobilize stem cells any time following 4 cycles (rm ) or 3 cycles (rm B) of induction therapy. f stem cells are harvested, interruption of treatment cycles for up to 35 days is allowed for completion of stem cell collection. While stem cell collection is strongly encouraged for transplant eligible patients, it is not required for protocol participation. ev. 5/14 2. n patients with creatinine clearance of 30-59 ml/min, starting dose of lenalidomide should be reduced to 10 mg. f the clearance improves to = 60 ml/min, the dose can be increased to 25 mg provided the patient has not experienced any of the toxicities that would require a dose reduction for lenalidomide. 3. t discretion of enrolling MD if considered appropriate, patients randomized to rm (Vd) can receive bortezomib injections under care of a local oncologist, returning to the enrolling institution only at the beginning of each cycle. Patients randomized to rm B (Cd) are required to receive Carfilzomib injections at the enrolling institution. During maintenance and observation (rms C and D), patients will have to be seen at the enrolling institution once every three months. 4. n patients with creatinine clearance of 30-59 ml/min, starting dose of lenalidomide should be reduced to 10 mg. f the clearance improves to = 60 ml/min, the dose can be increased to 15 mg provided the patient has not experienced any of the toxicities that would require a dose reduction for lenalidomide. 5. Submission of pre-study specimens per patient consent. 7
Cancer esearch Group ev. 5/14 3. Selection of Patients Each of the criteria in the checklist that follows must be met in order for a patient to be considered eligible for this study. Use the checklist to confirm a patient s eligibility. For each patient, this checklist must be photocopied, completed and maintained in the patient s chart. n calculating days of tests and measurements, the day a test or measurement is done is considered Day 0. Therefore, if a test is done on a Monday, the Monday four weeks later would be considered Day 28. Patient No. Patient s nitials (L, F) Physician Signature and Date NOTE: ll questions regarding eligibility should be directed to the study chair or study chair liaison. NOTE: nstitutions may use the eligibility checklist as source documentation if it has been reviewed, signed, and dated prior to registration/randomization by the treating physician. NOTE: This study involves pre-registration (see Section 4). Bone marrow and peripheral blood specimens are to be submitted for defined laboratory research studies and future undefined research studies as outlined in Section 10 per patient consent. 3.1 Step 1 andom ization 3.1.1 ge 18 years. 3.1.2 Patients must be diagnosed with symptomatic standard-risk multiple myeloma (S-MM) within 90 days prior to registration as defined by all of the following (except GEP70 status if unknown): ev. 9/14, 9/15 No evidence of t(14;16) by FSH testing on bone marrow or not available: please circle: yes or no or N date of test No evidence of t(14:20) by FSH testing on bone marrow or not available: please circle: yes or no or N date of test No evidence of deletion 17p by FSH testing on bone marrow; please circle yes or no date of test NOTE: f the FSH result states that no gh abnormality is present, both t(14;16) and t(14;20) can be considered negative. n 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). f 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. 19
Cancer esearch Group Standard isk GEP70 signature within the past 90 days (only if GEP has been done and results are available. NOTE: GEP testing is NOT a requirement for the study). f the test has been done, patients found to have a GEP70 status of High-isk will not be eligible. GEP70 Test Done? Yes No (skip remainder) GEP70 Status Standard-isk? Yes No Serum LDH 2 x ULN within the past 28 days Serum LDH: (U/L) ULN (U/L) No more than 20% circulating plasma cells on WBC differential or 2,000 plasma cells/microliter of peripheral blood within the past 90 days Plasma cell %: Plasma cells: (/microl) 3.1.3 Patients must have measurable or evaluable disease as defined by having one or more of the following, obtained within 28 days prior to randomization: 1g/dL monoclonal protein (M-protein) on serum protein electrophoresis 200 mg/24 hrs of monoclonal protein on a 24 hour urine protein electrophoresis nvolved free light chain 10 mg/dl or 100 g/l ND abnormal serum immunoglobulin kappa to lambda free light chain ratio (< 0.26 or > 1.65) Monoclonal bone marrow plasmacytosis 30% (evaluable disease) SPEP, UPEP, serum FLC assay and bone marrow biopsy and or aspirate are required to be performed within 28 days prior to randomization. Serum M-protein by SPEP (g/dl) Urine M-protein measurement by 24 hr UPEP (mg/24hr) 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. Serum Free Light Chain ssay Kappa FLC (mg/dl) or (mg/l); 20
ev. 2/15 Cancer esearch Group Lambda FLC (mg/dl) or (mg/l); kappa/lambda ratio 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 200mg/24 hr. Plasma cell % on Bone Marrow % 3.1.4 The following laboratory levels must be obtained within 28 days prior to randomization: 3.1.4.1 Hemoglobin 8 g/dl. Hemoglobin: 3.1.4.2 Untransfused platelet count 75,000 cells/mm 3. Platelet: 3.1.4.3 bsolute neutrophil count 1000 cells/mm 3. NC: 3.1.4.4 Calculated creatinine clearance 30 ml/min Creatinine clearance: 3.1.4.5 Bilirubin 1.5 mg/dl. Bilirubin: 3.1.4.6 SGPT (LT) and SGOT (ST) < 2.5 times the upper limit of normal. SGPT (LT): SGOT (ST): nstitutional ULN: nstitutional ULN: 3.1.5 Patients must have received no more than one cycle (4 weeks or less) of prior chemotherapy and no more than 160mg 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. 3.1.6 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. 21
Cancer esearch Group NOTE: Concurrent use after registration on the study should be restricted to the equivalent of prednisone 10 mg per day. 3.1.7 Patients must not have active, uncontrolled seizure disorder. Patients must have had no seizures in the last 6 months. 3.1.8 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. 3.1.9 ECOG performance status 0, 1, or 2. (PS 3 allowed if secondary to pain) 3.1.10 Patients with monoclonal gammopathy of undetermined significance or asymptomatic multiple myeloma are not eligible. 3.1.11 Patients must not have Grade 2 or higher peripheral neuropathy by CTCE 4.0. 3.1.12 Patients must not have active, uncontrolled infection. 3.1.13 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 fulldose anticoagulation. 3.1.14 Patients should not have New York Heart ssociation classification or V heart failure or myocardial infarction within the previous 6 months. 3.1.15 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). 3.1.16 Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mu/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 T THE SME TME, 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. ll patients must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure. See ppendix V: isks of Fetal Exposure, Pregnancy Testing Guidelines and cceptable Birth Control Methods. Female of childbearing potential (Y/N)? 22
Cancer esearch Group 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. 3.1.17 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. 3.1.18 The following patients will be excluded as this study involves an agent that may have genotoxic, mutagenic and teratogenic effects. 3.1.18.1 Pregnant women 3.1.18.2 Nursing women 3.1.19 HV infection is not excluded. Known HV positive patients must meet the following criteria: CD4 cell count 350/mm 3 No history of DS-related illness Not currently prescribed zidovudine or stavudine 3.1.20 Patient enrolling to this study must agree to register to the mandatory evssist program, and be willing and able to comply with the requirements of evssist. 3.2 Step 2 andom ization 3.2.1 Patients must not have experienced progression on Step 1 induction therapy. 3.2.2 Step 2 registration must be within 28 days of completing Step 1 therapy. Date Step 1 Therapy Completed: 3.2.3 Patients must not have received any non-protocol therapy outside of the assigned induction therapy. 3.2.4 ECOG performance status 0, 1, or 2. (PS 3 allowed if secondary to pain). 3.2.5 ny adverse event related to Step 1 therapy must have resolved to grade 2 or less. 3.2.6 Patient must have adequate laboratory levels as follows (within 28 days prior to randomization to Step 2) 3.2.6.1 Hemoglobin 8 g/dl. Hemoglobin: 3.2.6.2 Platelet count 75,000 cells/mm 3. Platelet: 23
Cancer esearch Group 3.2.6.3 bsolute neutrophil count 1000 cells/mm 3. NC: 3.2.6.4 Calculated creatinine clearance 30 ml/min. Creatinine clearance: 3.2.6.5 Bilirubin 1.5 mg/dl. Bilirubin: 3.2.6.6 SGPT (LT) and SGOT (ST) < 2.5 times the upper limit of normal. SGPT (LT): SGOT (ST): nstitutional ULN: nstitutional ULN: 3.2.7 Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mu/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 T THE SME TME, 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. ll patients must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure. See ppendix V: isks of Fetal Exposure, Pregnancy Testing Guidelines and cceptable Birth Control Methods. Female of childbearing potential (Y/N)? 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. 24
Cancer esearch Group 3.2.8 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. 3.2.9 The following patients will be excluded as this study involves an agent that may have genotoxic, mutagenic and teratogenic effects. 3.2.9.1 Pregnant women 3.2.9.2 Nursing women 3.2.10 Patient enrolling to this study must agree to register to the mandatory evssist program and be willing and able to comply with the requirements of evssist. 25