Bendamustine + Pomalidomide + Dex in R/R Multiple Myeloma

PRIMARY ENDPOINTS:

Phase I • Determination of the MTD of the combination therapy

Phase II:

• Response rate (CR+PR)

SECONDARY ENDPOINTS:

- Overall Response Rate (ORR)

- Progression Free Survival (PFS)

- Time to Progression (TTP)

- Time to next therapy

A total of 56 patients may be enrolled in this study: Dose escalation phase: Up to 24
subjects; Dose expansion phase: Up to a maximum of 38 patients treated at the maximum
tolerated dose (MTD).

Study treatment will be administered starting at Cohort 1 for up to four sequential cohorts,
with 3-6 patients in each cohort. A standard 3+ 3 dose escalation schedule will be used. A
minimum of 3 patients will be entered within each cohort, to be expanded to 6 patients if
dose limiting toxicities (DLTs) are observed, to determine the MTD. Once the MTD is reached,
any additional patients will be enrolled at the MTD level.

Dose Escalation

- Cohort -1: bendamustine 120 mg/m2; pomalidomide 2mg; dexamethasone 40mg**

- Cohort 1 (initial dose): bendamustine 120/mg/m2; pomalidomide 3 mg; dexamethasone 40
mg**

- Cohort 2: bendamustine 120 mg/m2; pomalidomide 4 mg; dexamethasone 40 mg**

- Cohort 3: bendamustine 150 mg/m2; pomalidomide 4 mg; dexamethasone 40 mg**

- Cohort 4: bendamustine 180 mg/m2; pomalidomide 4 mg; dexamethasone 40 mg**

EVALUATION:

- For toxicity: 1 cycle (All patients will be considered evaluable for toxicity unless
they cannot complete the first cycle of therapy due to withdrawal of consent or disease
progression.)

- For efficacy: 2 cycles Intended treatment duration: Patients will continue on protocol
as long as they are receiving clinical benefit and will be removed for disease
progression (at the investigator's discretion the patient may be treated up to one cycle
after progression noted to confirm progression), adverse event/unacceptable toxicity or
side effect, or withdrawal of consent.

A DLT is defined as any of the following occurring during the first treatment cycle (28 days)
that are judged by the investigator to be at least possibly related to the study therapy:

Hematologic:

- Febrile neutropenia (ANC <1.0x109/L) with fever of 38.5 C. Subjects who enter the study
with lower counts (ANC <1.0x109/L) due to >5030%* marrow involvement will not be
evaluated for this portion of the DLT definition.

- Grade 4 neutropenia (ANC < 0.5x109/L) for more than 7 days despite GCSF support.
Subjects who enter the study with lower counts (ANC <1.0x109/L) due to >5030%* marrow
involvement will not be evaluated for this portion of the DLT definition.

- Grade 4 thrombocytopenia (platelets count <25.0x109/L) lasting >7 days despite dose
delay. Subjects who enter the study with lower counts (platelets <50.0x109/L) due to
>5030%* marrow involvement will not be evaluated for this portion of the DLT definition.

- Grade 3-4 thrombocytopenia associated with bleeding

- Any hematologic toxicity requiring a dose reduction within Cycle 1

- Inability to receive Day 1 dose of Cycle 2 due to drug related toxicity persisting from
Cycle 1 greater than 14 days

Non-hematologic:

- Any > Grade 3 toxicity determined by the Investigator to be related to pomalidomide or
bendamustine (with the exception of thrombotic events and as noted below).

- > Grade 3 nausea, vomiting, or diarrhea, despite the use of maximal
antiemetic/antidiarrheal therapy

- > Grade 3 neuropathy with pain

- >Grade 3 venous thromboembolic events.

- Any Grade 4 rash related to the agents will be considered a DLT.

- A Grade 3 rash related to the agents that has not resolved to < Grade 2 within a 10 day
period despite steroids therapy will be considered a DLT.

- If an event is attributed to progressive disease, it will not be counted as a DLT.

- Any non-hematologic toxicity requiring a dose reduction within Cycle 1

- Delay in ability to receive Day 1 dose of Cycle 2 due to drug related toxicity
persisting from Cycle 1 greater than 14 days

INCLUSION CRITERIA:

Patients must meet all of the following inclusion criteria to be eligible to enroll in this
study.

1. Cytopathologically or histologically confirmed diagnosis of multiple myeloma

2. Relapsed or refractory to most recent therapy (i.e. < 25% response, progression during
therapy or within 60 days after completion).

3. Refractory to prior lenalidomide therapy (i.e. history of progression on therapy using
full or maximally tolerated dose of lenalidomide for >/= two cycles).

4. Measurable disease:

- Serum M protein > 0.5 g/dL or

- Urine Bence Jones protein >200 mg/24 hr or

- Elevated Free Light Chain per International Myeloma Working Group (IMWG)
criteria, and abnormal ratio

5. Evidence of progression/relapse

6. Over 18

7. Life expectancy of more than 3 months

8. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2

9. Total bilirubin < 2 times the upper limit of normal (ULN), and aspartate
aminotransferase (AST) and alanine aminotransferase (ALT) < 3 times ULN

10. Serum creatinine <3 mg/dL

11. • Absolute neutrophil count (ANC) >1.0 x 109/L or <1.0 x 109/L but > 0.75 due to >30%*
marrow involvement (without granulocyte and granulocyte/macrophage colony stimulating
factor (GCSF and GMCSF) for >1 week and of pegylated GCSF for >2 weeks)

- Hemoglobin >8 g/dL

- Platelet count >75.0 x 109/L or < 75.0 x 109/L but >50.0 x 109/L due to >30%*
marrow involvement (without platelet transfusions for >1 week)

- Transfusions allowed if clinically indicated

12. Agree to take enteric coated aspirin 81 mg daily

13. Consent

14. Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy
test and abstain from sex or begin TWO acceptable methods of birth control >28 days
before pomalidomide dose, and agree to ongoing pregnancy testing.

15. Male patients must abstain from sex or use a latex condom and not donate sperm while
taking pomalidomide and for 1 week after stopping drug.

16. Register with POMALYST REMS™ and comply with their requirements.

EXCLUSION CRITERIA:

1. Patients with known sensitivity to immunomodulatory drugs (IMiDs)

2. Use of experimental drugs or therapy within 21 days of study-related drug therapy.

3. Exposure to chemotherapy or steroids within 14 days of study-related drug therapy.

4. Prior use of pomalidomide.

5. Radiation therapy within 14 days of screening.

6. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and
skin changes).

7. Plasma cell leukemia.

8. Waldenström's macroglobulinemia.

9. Major surgery within 21 days prior to first dose.

10. Pregnant or lactating females.

11. Congestive heart failure, symptomatic ischemia, conduction abnormalities uncontrolled
or myocardial infarction in the last six months.

12. Uncontrolled hypertension

13. Acute active infection requiring systemic antibiotics, antivirals, or antifungals
within 14 days prior to first dose.

14. Active treatment or intervention for other malignancy or need active treatment within
8 months of starting study treatment.

15. Serious psychiatric or medical conditions that interfere with treatment

16. Significant neuropathy (Grade 3, Grade 4) at first dose and/or within 14 days before
enrollment

17. Contraindication to required concomitant drugs

18. Patients with primary systemic amyloidosis