Celgene High Risk Multiple Myeloma (MM) Revlimid Induction and Maintenance Therapy

Lenalidomide and Low Dose Dexamethasone Induction Therapy Followed by Low Dose Melphalan, Prednisone, Lenalidomide and Bortezomib Sequential Maintenance Therapy for Newly Diagnosed High-risk Multiple Myeloma

The purpose of this study is to evaluate the effectiveness of induction therapy with lenalidomide and low dose dexamethasone followed by sequential low dose bortezomib followed by low dose Melphalan and Prednisone, then followed by low dose lenalidomide for multiple cycles in subjects with high risk Multiple Myeloma (MM). The primary objective is to evaluate the efficacy as measured by the progression free survival (PFS) at 2 years of low dose sequential therapy following four cycles of induction therapy with lenalidomide/low-dose dexamethasone in subjects with symptomatic high risk multiple myeloma, who have received no prior treatment. A total of 35 subjects were estimated to be accrued to this Phase II trial over a period of subjects who are still progression-free at 2 years. Two years will be as measured from date of registration to the trial. Progression will include disease progression (DP) as well as death due to any cause. Data will be analyzed and reported by the PI after 1 and 2 years of initiation of the study. All subsequent data collected may be analyzed and reported in a follow-up clinical report. The PI and independent reviewers will meet to review the efficacy and safety data and determine a risk/benefit analysis in this subject population.

Study design: A total of 35 subjects who were newly diagnosed, high risk Multiple Myeloma (high risk defined by the presence of one or more of the following: t(4;14), t(14;16), deletion of 17p13 (p53) by FISH, deletion of chromosome 13 or aneuploidy on metaphase analysis) were estimated to be accrued to this Phase II trial over a period of about 3 years.

The primary objective is to estimate the proportion of subjects who are still progression-free at 2 years. Two years is measured from date of registration to the trial. Progression will include disease progression as well as death due to any cause. Time to response, defined only for the responders, is defined as the time from the date of initiation of treatment to the first documentation of a confirmed response. Duration of response among subjects achieving a sustained complete response (sCR), complete response (CR), very good partial response (VGPR) or partial response (PR) will be defined as the length of the interval from initial PR to time of disease progression. Progression free survival (PFS) is defined for all subjects as the time from the date of initiation of treatment to the date of first documentation of relapse, progression, or death due to any cause. Time to progression (TTP) is defined for all subjects as the time from initiation of treatment to disease progression with deaths owing to causes other than progression not counted as events, but censored (Durie et al., 2006). Overall survival (OS) is defined as the time from the date of initiation of treatment to the date of death due to any cause. The Garban et al. trial found a 2-year progression-free rate of about 0.60 in 212 similar subjects. If a 2-year rate of 0.60 were to be observed in this trial, we would consider the treatment a success. A rate of 0.60 has an exact 80% confidence interval (CI) of 0.48 - 0.71.

True 2-year Probability of observing Progression-free a rate ≥ 0.60 0.48 0.11 0.52 0.22 0.56 0.38 0.60 0.57 0.64 0.75 0.68 0.88 0.72 0.95

DOSING REGIMEN(S):

Induction therapy: Lenalidomide 25 mg daily on Days 1-21 followed by 7 day rest and Dexamethasone 40 mg by mouth (po) daily on Days 1, 8, 15 and 22 every 28 days for 4 cycles. Subjects will receive 325 mg aspirin for deep vein thrombosis (DVT) prophylaxis.

Following induction therapy: Stem cell collection and cryopreservation - Subjects who achieve sCR, CR,VGPR and PR, are eligible for future stem cell transplant procedure.

Maintenance sequential therapy - Subjects who achieve >PR following induction therapy will receive repeating triplet cycles of alternating low dose therapy:

• Subjects will receive 325 mg aspirin for DVT prophylaxis.
• Cycle 1, 4, 7, etc - bortezomib 1.3 mg/m2 on day 1 and 8 of a 28-day cycle
• Cycle 2, 5, 8 etc- Melphalan 6 mg/m2 po daily on Days 1-7 days and Prednisone 60 mg/m2 po daily on Days 1-7 of a 28-day cycle
• Cycle 3, 6, 9, etc. Lenalidomide 10 mg po daily on Days 1-21 of a 28 day cycle.

Subjects will continue sequential alternating triplet cycles until time of progression or discontinuation due to poor tolerance or toxicity. Subjects who complete 24 months of maintenance therapy will be removed from study. Subjects who have achieved > stable disease (SD) from maintenance may continue for longer than 24 months after discussion with their physicians.

Efficacy/response assessments (including skeletal survey, quantification of M-protein, immunoglobulins, bone marrow aspiration, biopsy & morphology, serum free-light chain assay, and immunofixation of serum & urine) are scheduled to occur within 7 days after completion of Cycle 2 and 4 during induction and then every third cycle during maintenance starting at the end of Cycle 3 (+/- 14 days). Efficacy assessments will also be done at discontinuation.

Subjects will be assessed for disease response according to the modified and updated European Group for Blood and Bone marrow Transplant (EBMT) criteria (Durie 2006, Blade 1998). Response categories are listed in Appendix 15.3.

Data from all subjects who receive any study drug will be included in the safety analyses. Subjects who entered the study and did not take any of the study drug and had this confirmed, will not be evaluated for safety. The severity of the toxicities will be graded according to the National Cancer Institute's (NCI) common terminology criteria for adverse events (CTCAE) v3.0. Safety evaluation will be based on the incidence, intensity and type of adverse events: Karnofsky performance score (KPS) and clinically significant changes in the subject's physical examination findings, vital sign measurements, and clinical laboratory results. Exposure to study drug and reasons for discontinuation of study treatment will be tabulated.

Analyses: The proportion of subjects progression-free at the times of full restaging (i.e., at 6, 12, 18, 24, 36 months) will be calculated with 80% confidence intervals and descriptively compared to the rates in the Garban et al. paper. Time-to-progression (TTP) will be estimated with the Kaplan-Meier method. The percentage of subjects achieving a sCR, CR, VGPR or PR, will be tabulated, and the sCR+CR+VGPR+PR disease rate will be estimated with exact 80% confidence interval. Duration of response among subjects achieving a sCR, CR, VGPR or PR, will be defined as the length of the interval from initial response to progression; duration of response will be tabulated. All toxicities will be tabulated by type and grade.

An interim analysis will be conducted on the first 17 subjects accrued to this trial in order to determine whether the trial should be closed due to insufficient effectiveness. Although 2-year progression-free is the primary endpoint, response (sCR, CR, VGPR, or PR) will be used in the interim analysis as a surrogate endpoint since it can be evaluated much sooner than progression. The response rate of newly diagnosed patients with MM varies across published Phase II and III trials from 40% to 90%. When it becomes obvious that less than 8 of the first 17 subjects on induction therapy will be responders (e.g., if only 3 of the first 13 subjects respond), the study will close.

Inclusion Criteria:

1. Understand and voluntarily sign an informed consent form.

2. Age 18 years or older at the time of signing the consent.

3. Able to adhere to the study visit schedule and other protocol requirements.

4. Multiple myeloma (MM) diagnosed according to the following standard criteria:

   • Monoclonal plasma cells in bone marrow ≥10% and/or presence of biopsy-proven plasmacytoma
   • Monoclonal protein present in serum and/or urine Myeloma-related organ dysfunction (1 or more) (C) Calcium elevation in blood (serum calcium >10.5 mg/L or ULN) (R) Renal insufficiency (SCr >2 mg/dL) (A) Anemia (hemoglobin <10 g/dL or 2g <normal) (B) Lytic bone lesions or osteoporosis

5. Measurable disease requiring systemic therapy.

6. High risk multiple myeloma defined by the presence of one or more of the following:

   • Deletion of chromosome 13 by metaphase analysis (standard cytogenetics)
   • deletion of 17p13 (p53) by Fluorescence in situ hybridization (FISH) or metaphase analysis
   • t(4;14) by FISH
   • t(14;16) by FISH
   • t(8;14) by FISH
   • t(14;20) by FISH
   • hypodiploidy detected by FISH or metaphase analysis
   • any complex cytogenetic abnormality detected by metaphase analysis, with the exception of hyperdiploidy

7. No previous treatment with systemic therapy or radiation therapy lasting more than 4 weeks duration.

8. At least 7 days since date of last radiation or systemic treatment for MM.

9. Eastern Cooperative Oncology Group (ECOG) performance status of < or =2 at study entry.(0=Fully active; 1=Restricted but ambulatory; 2=Ambulatory but unable to work)

10. All study participants must be registered into the mandatory RevAssist® program, and willing and able to comply with the requirements.

11. Females of childbearing potential (FCBP) must have negative pregnancy test with a sensitivity of >/=50 milli-International unit (mIU)/mL within 10-14 days prior to and within 24 hours of prescribing lenalidomide and must use 2 acceptable methods of birth control, one highly effective method and one other effective method AT THE SAME TIME, >4 weeks before taking lenalidomide. FCBP must also agree to ongoing pregnancy testing. Men must agree not to father a child and agree to use a latex condom even if he has had a successful vasectomy, if partner is FCBP.

12. Disease free of prior malignancies for >5 years with exception of currently treated basal cell, squamous cell carcinoma of the skin, or carcinoma "insitu" of the cervix or breast

13. Able to take 325 mg aspirin daily as prophylactic anticoagulation for the duration of protocol therapy.

14. Receive concomitant therapy with bisphosphonates if bony lesions are present at time of enrollment.

Exclusion criteria

1. Any serious medical condition, laboratory abnormality, or psychiatric illness to prevent the subject from signing the consent.

2. Pregnant or breast feeding females.

3. Any condition which places the subject at unacceptable risk or confounds the ability to interpret data from the study.

4. Abnormal laboratory test results within these ranges:

   • Absolute neutrophil count < 1.0 x 109/L
   • Platelet count < 50 x 109/L (Subjects with severe pancytopenia (not meeting the above criteria) due to myeloma involvement of > 70% bone marrow are eligible)
   • Serum creatinine > 2.5 mg/dL or ≥ 3.0 mg/dL if due to multiple myeloma.
   • Total bilirubin > 2.0 mg/dl

5. History of allergy to any of the study medications, their analogues, or excipients in the various formulations

6. Concurrent use of other anti-cancer agents or treatments.

7. Known HIV positivity

8. Known Active Hepatitis A, B or C

9. Erythema nodosum characterized by a desquamating rash while taking thalidomide or similar drug.