Combination Study for High Risk Multiple Myeloma Patients

This is a Phase 2, multicenter, open label, nonrandomized study with six patients safety
lead-in cohort to evaluate efficacy and safety of elotuzumab in combination with
pomalidomide, carfilzomib and dexamethasone among high risk relapsed and refractory multiple
myeloma patients.

This study will enroll previously treated patients that currently show evidence of
progressive disease and have been diagnosed with high risk multiple myeloma. Thirty-nine
patients will be enrolled in the study.

First, six patients will be enrolled and used as a lead-in cohort for the safety evaluation
and MTD re-determination (if necessary). The results of the safety lead-in cohort will be
evaluated after the 6th patient has completed one full cycle of treatment. Recruitment of
patients will be withheld during safety data analysis. Enrollment of the remaining 33
patients will be contingent upon safety committee's decision.

The study consists of: 1) a screening period; 2) up to eight 28-day treatment cycles; 3) a
final assessment to occur 28 days after the end of the last treatment cycle; and 4) a
follow-up period.

All drugs will be administered on a 28-day cycle schedule throughout the study. Subjects
eligible for this study will receive treatment with study drug for a maximum of eight 28-day
treatment cycles. Subjects are to be treated for 8 cycles of therapy without demonstrating
PD.

Inclusion Criteria:

- Subjects must be adults (age ≥ 18 years at the time of signing the informed consent
document) and must meet all of the following inclusion criteria to be enrolled in the
study:

1. ECOG/Zubrod performance status of 0-2 at study entry

2. Has a diagnosis of high-risk MM by showing any of the following a-f criteria: :

1. Presence of conventional cytogenetic markers such as deletion of 17p-p53,
translocations involving t(14;16) and t(14;20)

2. Plasma cell leukemia (PCL) (> 2.0 × 109/L circulating plasma cells by
standard differential)

3. Extramedullary MM

4. Doubling in levels of a MM markers in the past 3 months such as any of the
following criteria alone or in combination: i) Serum M-protein ≥ 1.0 g/dL,
or ii) Urine M-protein ≥ 400 mg/24 hours, or iii) Only in patients who do
not meet i or ii, then use serum free light chain (SFLC) > 200 mg/L
(involved light chain) and an abnormal kappa/lambda ratio

5. Refractoriness to their most recent lenalidomide-containing regimen and
proteasome inhibitor-containing regimen.

6. Renal failure related to MM with creatinine clearance (CrCl) >15 mL/min but
<30 mL/min as calculated by Cockcroft-Gault equation (Appendix 14.8).

3. Has previously received more than two lines of therapy including a
lenalidomide-containing regimen and proteasome inhibitor-containing regimen.

4. Currently demonstrating progressive disease

5. Life expectancy greater than 3 months

6. Laboratory test results within these ranges at Screening and confirmed at
enrollment prior to drug dosing on Cycle 1 Day 1:

- ANC ≥ 1.5 x 109/L; if the bone marrow is extensively infiltrated ( ≥ 70%
plasma cells) then ≥ 1.0 x 109/L

- Platelet count ≥ 75 x 109/L; if the bone marrow is extensively infiltrated (
≥ 70% plasma cells) then ≥ 50 x 109/L

- Hemoglobin ≥ 8 g/dL

7. Women of childbearing potential (WOCBP†) must have a negative serum or urine
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within
10-14 days prior to and again within 24 hours of starting study drug regimen

† A WOCBP (women of childbearing potential) is a sexually mature woman who: 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) WOCBP must agree to follow
instructions for method(s) of contraception for the duration of treatment with
study drug (s) plus 5 half-lives of study drug plus 30 days (duration of
ovulatory cycle) for a total of 120 days post-treatment completion. Subject 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, and at least 28 days before she
starts taking study drugs. WOCBP must also agree to ongoing pregnancy testing.
All subjects must be counseled at a minimum of every 28 days about pregnancy
precautions and risks of fetal exposure. See Section 10.3.5.2, Appendix 4 and
Appendix 5. Males who are sexually active with WOCBP must agree to follow
instructions for method(s) of contraception for the duration of treatment with
study drug plus 5 half-lives of the study drug plus 90 days (duration of sperm
turnover) for a total of 154 days post-treatment completion. Men must agree to
use a latex condom during sexual contact with a WOCBP even if they have had a
vasectomy. All subjects must be counseled at a minimum of every 28 days about
pregnancy precautions and risks of fetal exposure. See Section 10.3.5, Appendix 4
and Appendix 5

8. Able to take aspirin (acetylsalicylic acid, ASA) at 81 or 325 mg/daily as
prophylactic anticoagulation (subjects intolerant to ASA may use warfarin or low
molecular weight heparin)

9. Written informed consent in accordance with federal, local, and institutional
guidelines

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

Exclusion Criteria:

- Subjects meeting any of the following exclusion criteria are not to be enrolled in the
study:

1. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein,
and skin changes) 19

2. Waldenström's macroglobulinemia

3. Received the following prior therapy:

1. Elotuzumab

2. Chemotherapy within 3 weeks of study drugs (6 weeks for nitrosourea,
melphalan or monoclonal antibodies)

3. Corticosteroids (>10 mg/daily prednisone or equivalent) within 3 weeks of
study drugs

4. Immunomodulatory therapy within one week before study drugs

5. Antibody therapy within 3 weeks before study drugs

6. Extensive radiation therapy (total maximum radiation doses of 50Gy to any
individual site or 30Gy for the disseminated MM of bone) within 3 weeks
before study drugs. Receipt of localized radiation therapy does not preclude
enrollment.

7. Cytotoxic chemotherapy with approved or investigational anticancer
therapeutics within 3 weeks prior to first dose

8. Use of any other experimental drug or therapy within 3 weeks of study drugs

4. Received the following transplant therapies:

1. Less than 12 weeks from auto transplant

2. Less than 16 weeks from allo transplant

3. Less than 4 weeks since any plasmapheresis

5. Major surgery within 4 weeks prior to first dose

6. Impaired cardiac function or clinically significant cardiac diseases, including
any one of the following:

1. Myocardial infarction within last 6 months prior to enrollment

2. Active congestive heart failure (New York Heart Association (NYHA) Class III
or IV) heart failure

3. Uncontrolled angina and/or hypertension

4. Clinically significant pericardial disease

5. Severe uncontrolled ventricular arrhythmias

6. Echocardiogram or MUGA evidence of LVEF below institutional normal within 28
days prior to enrollment

7. Electrocardiographic evidence of acute ischemia or active conduction system
abnormalities. Prior to study entry, any ECG abnormality at Screening has to
be documented by the investigator as not medically relevant.

7. Known or suspected amyloidosis

8. Severe hypercalcemia, i.e., serum calcium ≥ 12 mg/dL (3.0 mmol/L) corrected for
albumin

9. Acute active infection requiring systemic antibiotics, antiviral), or antifungal
agents

10. Known positivity for human immunodeficiency virus (HIV)

11. Known active hepatitis A,B or C virus infection

12. Known active tuberculosis (TB) including subjects with latent TB or with the risk
factor for activation of latent TB.

13. Patients with known cirrhosis

14. Secondary non-hematologic malignancy within the past 3 years, except:

1. Adequately treated basal cell or squamous cell skin cancer

2. Carcinoma in situ of the cervix

3. Prostate cancer < Gleason score 6 or less with stable prostate-specific
antigen (PSA) levels over 12 months

4. Breast carcinoma in situ with full surgical resection

5. Treated medullary or papillary thyroid cancer

15. Patients with myelodysplastic syndrome

16. Prior cardio vascular accident (CVA) with persistent neurological deficit

17. Significant neuropathy (Grades 3 to 4) within 14 days prior to first dose

18. Peripheral neuropathy with pain ≥ G2 within 14 days prior to first dose

19. Women who are pregnant and/or breast feeding

20. Known hypersensitivity to dexamethasone

21. Known history of allergy to Captisol® (a cyclodextrin derivative used to
solubilize carfilzomib)

22. Known hypersensitivity to compounds of similar chemical or biological composition
to thalidomide

23. The development of erythema nodosum if characterized by a desquamating rash while
taking thalidomide or similar drugs

24. Hypersensitivity to any of the required concomitant drugs or supportive
treatments, including hypersensitivity to antiviral drugs.

25. Ongoing graft-versus-host disease.

26. Pleural effusions requiring thoracentesis or ascites requiring paracentesis
within 14 days prior to enrollment.

27. Uncontrolled diabetes within 2 weeks prior to enrollment.

28. Any other clinically significant medical disease or psychiatric condition that,
in the Investigator's opinion, may interfere with protocol adherence or a
patient's ability to give informed consent