Phase II Study of Thalidomide, Clarithromycin, Lenalidomide, and Dexamethasone for Newly Diagnosed Multiple Myeloma

This phase II study is a treatment program for patients with newly diagnosed multiple
myeloma. Up to 25 patients will be enrolled. Patients who sign consent and fulfill all
eligibility criteria will be enrolled to receive the following treatment plan:

T-BiRD Therapy:

Cycles 1-4

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

- Clarithromycin (500mg twice daily for each 28 day cycle)

- Lenalidomide (25 mg daily days 1-21 of every 28 day cycle) and

- Dexamethasone (40 mg daily on day 1, 8, 15 and 22 of each 28 day cycle)

- Prophylactic medications will be given.

After completing 4 cycles

- Patients who demonstrate progression of disease will be taken off study.

- Patients who achieve maximum response (either by achievement of complete remission or
stable disease plateau) will be transitioned to maintenance therapy.

- Patients who achieve VGPR or PR with acceptable toxicity will be given T-BiRD for an
additional 2 cycles: cycles 5 and 6.

Upon completion of 6 cycles of T-BiRD,

- Patients who achieve maximum response (either by achievement of complete remission or
stable disease plateau) will be transitioned to maintenance therapy.

- Patients without disease progression or maximum response (either by achievement of
complete remission or stable disease plateau) will receive BiRD therapy

- Patients with disease progression will be taken off study.

BiRD therapy will consist of the following:

- Clarithromycin (500mg twice daily for each 28 day cycle)*

- Lenalidomide (25mg daily days 1-21 of every 28 day cycle)*

- Dexamethasone (40mg on days 1, 8, 15, 22 of each 28 day cycle)*

- Prophylactic medications will be continued.

- Patients who finished T-BiRD therapy at reduced doses of clarithromycin,
lenalidomide or dexamethasone will start BiRD therapy at the same doses of
clarithromycin, lenalidomide and dexamethasone on which they ended T-BiRD therapy.

Patients who progress on BiRD will reinitiate T-BiRD as follows:

- Thalidomide (100mg/daily for days 1-28 for each 28 day cycle)

- Clarithromycin (500mg twice daily for each 28 day cycle)*

- Lenalidomide (25mg/daily for days 1-21 of each 28 day cycle)*

- Dexamethasone (40mg days 1, 8, 15, 22 of each 28 day cycle)*

- Prophylactic medications will be continued

- Patients who continue to show disease progression after two cycles of T-BiRD will be
taken off study.

- Patients who finished BiRD therapy at reduced doses of clarithromycin, lenalidomide
or dexamethasone will start T-BiRD therapy at the same doses of clarithromycin,
lenalidomide and dexamethasone on which they ended BiRD therapy.

Transition to maintenance therapy:

Patients who achieve a resolution of monoclonal gammopathy as detected on serum
immunofixation or achieve a plateau of disease (no change in quantitative M-spike as detected
on serum immunofixation) for > 2 cycles on either BiRD or T-BiRD therapy will be transitioned
to maintenance therapy. Maintenance therapy will be comprised of:

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

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

- Prophylactic medications will be continued

- Patients who finished induction therapy with BiRD or T-BiRD at reduced doses
lenalidomide or dexamethasone will start maintenance therapy at the same doses
lenalidomide and dexamethasone 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.

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) and female of childbearing potential will have their
pregnancy testing done, see APPENDIX III. 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).

- Newly diagnosed myeloma.

- No anti-myeloma therapy within 14 days prior to initiation of study treatment except
for corticosteroids with a maximum allowed dosage equivalent to three pulses of
dexamethasone (40mg daily for 4 days equals one pulse). 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.

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

- 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
RevAssist® and the 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.

- 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, clarithromycin, lenalidomide, or thalidomide.

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