Phase II Study of Dexamethasone, Thalidomide and Lenalidomide for Subjects With Relapsed or Refractory Multiple Myeloma
Phase II Study of Dexamethasone, Thalidomide and Lenalidomide for Subjects With Relapsed or Refractory Multiple Myeloma
Study Objectives

 1. To evaluate the efficacy of the combination of dexamethasone (Decadron®), thalidomide
 (Thalomid®), and lenalidomide (Revlimid®) as therapy for patients with relapsed or
 refractory multiple myeloma (MM) who have failed prior treatment with both lenalidomide
 and thalidomide when used as monotherapies.

 2. To evaluate the safety of the combination of lenalidomide, dexamethasone, and
 thalidomide as a therapy for patients with relapsed or refractory multiple myeloma.
This phase II study is a treatment program for patients with relapsed or refractory multiple
 myeloma who have had prior treatment with both thalidomide and lenalidomide in separate
 regimens each used as a single agent or in combination with corticosteroids. Up to 45
 patients will be enrolled. Patients who sign informed consent form and RevAssist® and
 S.T.E.P.S® patient agreement form and fulfill all eligibility criteria will be enrolled.

 DexTR therapy:

 Cycles 1-4

 -  Dexamethasone (40mg ) will be given on days 1-4, 9-12, 17-20 of a 28-day cycle.

 -  Thalidomide will be given 50mg daily on days 1-7, thereafter 100mg daily on days 8-28 of
 the first 28-day cycle. Thalidomide will then be given at 100mg/daily for days 1-28 of
 each subsequent cycle.

 -  Lenalidomide will be given 25mg daily for days 1-21 of each 28 day cycle.

 -  Prophylactic medications, such as medications for thrombosis risk, will be given.

 After completing 4 cycles:

 -  Patients who demonstrate disease progression at any time will be taken off study.

 -  Patients who achieve a resolution of monoclonal gammopathy as detected on serum
 immunofixation or achieve a plateau of disease (no change in M-spike as detected on
 serum protein electrophoresis) for > 2 cycles will be transitioned to maintenance
 therapy.

 -  Patients who continue to respond without achieving either a plateau or a CR will
 continue on induction therapy until plateau for >2 cycles or CR in the absence of
 untoward toxicity. These patients will be then transitioned to maintenance therapy.

 Maintenance therapy:

 Maintenance therapy will consist of:

 -  Dexamethasone 20mg weekly days 1, 8, 15, 22 out of a 28 day cycle)

 -  Lenalidomide 25 mg/daily days 1 - 21 out of a 28 day cycle. 15mg/daily on days 1-21 of a
 28 day cycle of lenalidomide will be given to patients with a creatinine clearance of <
 40cc/min*

 -  Patients who finished induction therapy with DexTR at a reduced dose of
 lenalidomide will start maintenance therapy at the same dose of lenalidomide on
 which they ended induction therapy. For patients with a creatinine clearance of <
 40cc / minute, the lenalidomide dose will be the lower of their last induction
 therapy dose or 15mg daily on days 1 - 21 out of a 28 day cycle.

 Serial clinic visits and laboratory measurements will be performed to monitor for treatment
 response. Those patients who demonstrate progression of disease at any point during DexTR
 therapy will be taken off study.

 At the end of every cycle (which may coincide with day 1 of the new cycle), response and
 toxicity will be evaluated. During cycle 1, patients will have lab work done weekly (CBC with
 differential and blood electrolytes). All patients will remain on study until disease
 progression or side effects become excessive. Patients who achieve a stable plateau and are
 on maintenance therapy as defined above may be taken off study if eligible to proceed to high
 dose chemotherapy and autologous stem cell transplantation.
Inclusion Criteria:

 -  Subject must voluntarily sign and understand written informed consent.

 -  Age > 18 years at the time of signing the consent form.

 -  Histologically confirmed Salmon-Durie stage II or III MM. Stage I MM patients will be
 eligible if they display poor prognostic factors (ß2M ≥5.5 mg/L, plasma cell
 proliferation index ≥5%, albumin of less then 3.0, and unfavorable cytogenetics).

 -  Relapsed or refractory myeloma as defined by Appendix II, table 1, progression of
 disease either after prior therapy or lack of response to currently used therapy.

 -  Prior treatment with prior lenalidomide and thalidomide as single agents or in
 combination with dexamethasone, but not in combination with each other.

 -  No anti-myeloma therapy within 14 days prior to initiation of study treatment.
 Patients may be receiving adjuvant antiresorptive therapy (i.e., pamidronate or
 zoledronic acid) as routine care.

 -  Measurable disease as defined by > 1.0 g/dL serum monoclonal protein, >0.1 g/dL serum
 free light chains, >0.2 g/24 hrs urinary M-protein excretion, and/or measurable
 plasmacytoma(s).

 -  Karnofsky performance status ≥70% (>60% if due to bony involvement of myeloma.

 -  All study participants must be registered into the mandatory RevAssist® and
 S.T.E.P.S.® programs, and be willing and able to comply with the requirements of the
 RevAssist® and S.T.E.P.S.® programs.

 -  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 prescribing lenalidomide and thalidomide (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.

 -  Able to take aspirin daily as prophylactic anticoagulation (patients intolerant to ASA
 may use warfarin or low molecular weight heparin).

 -  Life expectancy ≥ 3 months

 -  Subjects must meet the following laboratory parameters:

 -  Absolute neutrophil count (ANC) ≥1000 cells/mm3 (1.0 x 109/L)

 -  Platelets count ≥ 75,000/mm3 (75 x 109/L)

 -  Serum SGOT/AST <3.0 x upper limits of normal (ULN)

 -  Serum SGPT/ALT <3.0 x upper limits of normal (ULN)

 -  Serum creatinine <2.5 mg/dL (221 µmol/L)

 -  Serum total bilirubin <2.0 mg/dL (34 µmol/L)

 Exclusion Criteria:

 -  Patients with non-secretory MM (no measurable monoclonal protein, free light chains,
 and/or M-spike in blood or urine).

 -  Prior history of other malignancies (except for basal cell or squamous cell carcinoma
 of the skin or carcinoma in situ of the cervix or breast) unless disease free for ≥ 5
 years.

 -  Myocardial infarction within 6 months prior to enrollment , or NYHA(New York Hospital
 Association) Class III or IV heart failure, uncontrolled angina, severe uncontrolled
 ventricular arrhythmias, electrocardiographic evidence of acute ischemia or active
 conduction system abnormalities.

 -  Pregnant or lactating females are ineligible.

 -  Given the potential of the study drugs to trigger or worsen HIV viremia and the
 incidence of opportunistic infections inpatients infected with the HIV virus, HIV-1 or
 HIV-2 positive patients will be excluded. The interactions of HAART with study drugs
 have not been determined.

 -  Active hepatitis B or hepatitis C infection.

 -  Active viral or bacterial infections or any coexisting medical problem that would
 significantly increase the risks of this treatment program.

 -  Any coexisting medical problem or laboratory evaluation that, in the treating
 physician's or principal investigator's opinion, makes the patient unsuitable to
 participate in this clinical trial.

 -  Known hypersensitivity to dexamethasone, lenalidomide, or thalidomide.

 -  History of thromboembolic event within the past 6 months prior to enrollment.