This study is an open label phase I/II trial to investigate the safety and efficacy of Cabozantinib for patients with relapsed or refractory myeloma.

Inclusion Criteria:

• MSKCC confirmed diagnosis of multiple myeloma that has relapsed or is resistant after therapy with at least one immunomodulatory drug (i.e. lenalidomide, thalidomide) and at least one proteasome inhibitor.
• Age ≥ 18 years old.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.

The subject has organ and marrow function as follows:

• Absolute neutrophil count (ANC) ≥ 1500/mm3 (G-CSF is allowed).
• Platelets ≥ 50,000/mm3 or 30,000 (if marrow infiltrated with myeloma; no platelet transfusions are allowed in the 7 days prior to screening)
• Hemoglobin ≥ 8 g/dL (with transfusions). Bilirubin ≤ 1.5 × the upper limit of normal (ULN).
• Serum creatinine ≤ 1.5 × ULN or calculated creatinine clearance ≥ 50 mL/min.
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × ULN if no liver involvement, or ≤ 5 × ULN with liver involvement.
• Lipase < 1.5 x the upper limit of normal.
• Patient must be able/willing to undergo bone marrow aspirate and biopsy.
• Subjects with brain metastasis or CNS disease are considered eligible if the subject has not received radiation therapy for brain metastasis within 2 weeks of enrollment and has been on a stable dose of steroids for 2 or more weeks.
• Sexually active subjects (men and women) must agree to use medically accepted barrier methods of contraception (e.g. male condom, female condom, or diaphragm with spermicidal gel) during the course of the study and for 4 months after the last dose of study drug(s), even if oral contraceptives are also used. All subjects of reproductive potential must agree to use both a barrier method and a second method of birth control.
• Women of childbearing potential must have a negative pregnancy test at screening. Women of childbearing potential include women who have experienced menarche and who have not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or are not postmenopausal. Postmenopause is defined as:
• Amenorrhea ≥ 12 consecutive months without another cause OR
• A documented serum follicle-stimulating hormone (FSH) level > 35 mIU/mL (for women with irregular menstrual periods and on hormone replacement therapy)

Exclusion Criteria:

• The subject has received cytotoxic chemotherapy (including investigational cytotoxic chemotherapy) or biologic agents (e.g., cytokines or antibodies) within 2 weeks, or nitrosoureas/ mitomycin C within 6 weeks before the first dose of study treatment.

• The subject has received radiation therapy within 14 days of the first dose of study treatment.

• The subject has received prior treatment with a small molecule kinase inhibitor or a hormonal therapy (including investigational kinase inhibitors or hormones) within 14 days or five half-lives of the compound or active metabolites, whichever is longer, before the first dose of study treatment.

• The subject has not recovered from toxicity due to all prior therapies (i.e., return to pretherapy baseline or to Grade 0 or 1).

• The subject has prothrombin time (PT)/ International Normalized Ratio (INR) or partial thromboplastin time (PTT) test results at screening that are ≥1.3 ×ULN.

• The subject has uncontrolled significant intercurrent illness including, but not limited to, ongoing or active infection, uncontrolled congestive heart failure, unstable angina pectoris within 6 months, stroke within 6 months, myocardial infarction within 6 months, or uncontrolled cardiac arrhythmias, uncontrolled hypertension.

• Corrected QTc of greater than 500msec.

• The subject is pregnant or breastfeeding.

• The subject has a previously identified allergy or hypersensitivity to components of the study treatment formulation.

• The subject requires concomitant treatment, in therapeutic doses, with anticoagulants such as warfarin or warfarin-related agents, heparin, thrombin or Factor Xa inhibitors, or antiplatelet agents (e.g., clopidogrel). Low dose aspirin (≤ 81 mg/day), low-dose warfarin (≤ 1 mg/day), and prophylactic low molecular weight heparin (LMWH) are permitted.

• The subject has experienced any of the following within 6 months before the first dose of study treatment:

  1. clinically-significant hematemesis or gastrointestinal bleeding
  2. hemoptysis of ≥ 0.5 teaspoon (2.5ml) of red blood
  3. any other signs indicative of pulmonary hemorrhage The subject has radiographic evidence of cavitating pulmonary lesion(s)

• The subject has tumor in contact with, invading or encasing major blood vessels

• Gastrointestinal disorders particularly those associated with a high risk of perforation or fistula formation including:

• Any of the following at the time of screening i) intra-abdominal tumor/metastases invading GI mucosa ii) active peptic ulcer disease, iii) inflammatory bowel disease (including ulcerative colitis and Crohn's disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis iv) malabsorption syndrome

Any of the following within 6 months before the first dose of study treatment:

i) history of abdominal fistula ii) gastrointestinal perforation iii) bowel obstruction or gastric outlet obstruction iv) intra-abdominal abscess. Note: Complete resolution of an intra-abdominal abscess must be confirmed prior to initiating treatment with cabozantinib even if the abscess occurred more that 6 months ago.

• History of major surgery as follows:

  1. Major surgery within 3 months of the first dose of cabozantinib. Major surgery within 6 months of the first dose of cabozantinib if there are complications related to wound healing.
  2. Minor surgery within 1 month of the first dose of cabozantinib if there were no wound healing complications or within 3 months of the first dose of cabozantinib if there were wound complications (particularly when associated with delayed or incomplete healing) within 28 days. Note: Complete healing following abdominal surgery must be confirmed prior to initiating treatment with cabozantinib even if surgery occurred more that 28 days ago.

• Other disorders associated with a high risk of fistula formation including PEG tube placement within 3 months before the first dose of study therapy or concurrent evidence of intraluminal tumor involving the trachea and esophagus.

• Concurrent malignancy except for treated non-melanoma skin cancer and cervical carcinoma in situ.

• The subject requires chronic concomitant treatment of strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, and St. John's Wort).

1 year