Combination Study for High Risk Multiple Myeloma Patients

Inclusion Criteria:

• Subjects must be adults (age ≥ 18 years at the time of signing the informed consentdocument) and must meet all of the following inclusion criteria to be enrolled in thestudy:

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: :
3. Presence of conventional cytogenetic markers such as deletion of 17p-p53,translocations involving t(14;16) and t(14;20)
4. Plasma cell leukemia (PCL) (> 2.0 × 109/L circulating plasma cells bystandard differential)
5. Extramedullary MM
6. Doubling in levels of a MM markers in the past 3 months such as any of thefollowing 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 donot meet i or ii, then use serum free light chain (SFLC) > 200 mg/L (involved light chain) and an abnormal kappa/lambda ratio
7. Refractoriness to their most recent lenalidomide-containing regimen andproteasome inhibitor-containing regimen.
8. 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).
9. Has previously received more than two lines of therapy including alenalidomide-containing regimen and proteasome inhibitor-containing regimen.
10. Currently demonstrating progressive disease
11. Life expectancy greater than 3 months
12. Laboratory test results within these ranges at Screening and confirmed atenrollment 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 urinepregnancy 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 beennaturally postmenopausal for at least 24 consecutive months (i.e., has had mensesat any time in the preceding 24 consecutive months) WOCBP must agree to followinstructions for method(s) of contraception for the duration of treatment withstudy drug (s) plus 5 half-lives of study drug plus 30 days (duration ofovulatory cycle) for a total of 120 days post-treatment completion. Subject musteither commit to continued abstinence from heterosexual intercourse or begin TWOacceptable methods of birth control, one highly effective method and oneadditional effective method AT THE SAME TIME, and at least 28 days before shestarts taking study drugs. WOCBP must also agree to ongoing pregnancy testing.All subjects must be counseled at a minimum of every 28 days about pregnancyprecautions and risks of fetal exposure. See Section 10.3.5.2, Appendix 4 andAppendix 5. Males who are sexually active with WOCBP must agree to followinstructions for method(s) of contraception for the duration of treatment withstudy drug plus 5 half-lives of the study drug plus 90 days (duration of spermturnover) for a total of 154 days post-treatment completion. Men must agree touse a latex condom during sexual contact with a WOCBP even if they have had avasectomy. All subjects must be counseled at a minimum of every 28 days aboutpregnancy precautions and risks of fetal exposure. See Section 10.3.5, Appendix 4and Appendix 5
8. Able to take aspirin (acetylsalicylic acid, ASA) at 81 or 325 mg/daily asprophylactic anticoagulation (subjects intolerant to ASA may use warfarin or lowmolecular weight heparin)
9. Written informed consent in accordance with federal, local, and institutionalguidelines
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 thestudy:

1. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein,and skin changes) 19
2. Waldenström's macroglobulinemia
3. Received the following prior therapy:
4. Elotuzumab
5. Chemotherapy within 3 weeks of study drugs (6 weeks for nitrosourea,melphalan or monoclonal antibodies)
6. Corticosteroids (>10 mg/daily prednisone or equivalent) within 3 weeks ofstudy drugs
7. Immunomodulatory therapy within one week before study drugs
8. Antibody therapy within 3 weeks before study drugs
9. Extensive radiation therapy (total maximum radiation doses of 50Gy to anyindividual site or 30Gy for the disseminated MM of bone) within 3 weeksbefore study drugs. Receipt of localized radiation therapy does not precludeenrollment.
10. Cytotoxic chemotherapy with approved or investigational anticancertherapeutics within 3 weeks prior to first dose
11. Use of any other experimental drug or therapy within 3 weeks of study drugs
12. Received the following transplant therapies:
13. Less than 12 weeks from auto transplant
14. Less than 16 weeks from allo transplant
15. Less than 4 weeks since any plasmapheresis
16. Major surgery within 4 weeks prior to first dose
17. Impaired cardiac function or clinically significant cardiac diseases, includingany one of the following:
18. Myocardial infarction within last 6 months prior to enrollment
19. Active congestive heart failure (New York Heart Association (NYHA) Class IIIor IV) heart failure
20. Uncontrolled angina and/or hypertension
21. Clinically significant pericardial disease
22. Severe uncontrolled ventricular arrhythmias
23. Echocardiogram or MUGA evidence of LVEF below institutional normal within 28days prior to enrollment
24. Electrocardiographic evidence of acute ischemia or active conduction systemabnormalities. Prior to study entry, any ECG abnormality at Screening has tobe documented by the investigator as not medically relevant.
25. Known or suspected amyloidosis
26. Severe hypercalcemia, i.e., serum calcium ≥ 12 mg/dL (3.0 mmol/L) corrected foralbumin
27. Acute active infection requiring systemic antibiotics, antiviral), or antifungalagents
28. Known positivity for human immunodeficiency virus (HIV)
29. Known active hepatitis A,B or C virus infection
30. Known active tuberculosis (TB) including subjects with latent TB or with the riskfactor for activation of latent TB.
31. Patients with known cirrhosis
32. Secondary non-hematologic malignancy within the past 3 years, except:
33. Adequately treated basal cell or squamous cell skin cancer
34. Carcinoma in situ of the cervix
35. Prostate cancer < Gleason score 6 or less with stable prostate-specificantigen (PSA) levels over 12 months
36. Breast carcinoma in situ with full surgical resection
37. Treated medullary or papillary thyroid cancer
38. Patients with myelodysplastic syndrome
39. Prior cardio vascular accident (CVA) with persistent neurological deficit
40. Significant neuropathy (Grades 3 to 4) within 14 days prior to first dose
41. Peripheral neuropathy with pain ≥ G2 within 14 days prior to first dose
42. Women who are pregnant and/or breast feeding
43. Known hypersensitivity to dexamethasone
44. Known history of allergy to Captisol® (a cyclodextrin derivative used tosolubilize carfilzomib)
45. Known hypersensitivity to compounds of similar chemical or biological compositionto thalidomide
46. The development of erythema nodosum if characterized by a desquamating rash whiletaking thalidomide or similar drugs
47. Hypersensitivity to any of the required concomitant drugs or supportivetreatments, including hypersensitivity to antiviral drugs.
48. Ongoing graft-versus-host disease.
49. Pleural effusions requiring thoracentesis or ascites requiring paracentesiswithin 14 days prior to enrollment.
50. Uncontrolled diabetes within 2 weeks prior to enrollment.
51. Any other clinically significant medical disease or psychiatric condition that,in the Investigator's opinion, may interfere with protocol adherence or apatient's ability to give informed consent