The following criteria is provided for health care professionals.

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