Expiration of National Cancer Institute (NCI) funding of the study.

This is a Phase Ib/II safety and efficacy trial of single agent ABC294640, an inhibitor of sphingosine kinase 2 and dihydroceramide desaturase, in refractory or relapsed multiple myeloma (MM). Cohorts of patients with refractory or relapsed MM who have previously been treated with proteasome inhibitors and immunomodulatory agents will receive increasing doses of oral ABC294640. The starting dosage for ABC294640 will be 250 mg bis in die (BID) which is known to be safely tolerated as a single agent, and the ABC294640 dose will be escalated to two additional dose cohorts of 500 and 750 mg BID using Bayesian model average continual reassessment method (BMA-CRM) for dose finding. It is expected that 18 patients will be used to determine the maximum tolerated dose (MTD) for ABC294640 in refractory or relapsed MM. Up to 56 additional patients will be treated on the phase II portion of the study at the MTD or maximum dose used in phase I, with interim stopping rules for futility.

Pharmacokinetic (PK) and pharmacodynamic (PD) assessments of ABC294640 will be conducted on Day 1 of Cycle 1. Bone marrow biopsy will be obtained prior to the initiation of ABC294640, at the end of cycle #3 and at the end of cycle #6. In addition to serum protein electrophoresis (SPEP), urine protein electrophoresis (UPEP) and serum free light chain measurement, correlative studies will be performed to measure sphingosine kinase 2 (SK2) activity, sphingosine metabolites, and additional biomarkers in CD138+ myeloma cells.

Objectives for Phase 1b:

Primary Objectives • To assess safety and determine the maximum tolerated dose (MTD) of single agent ABC294640 in patients with refractory or relapsed multiple myeloma (MM) who have been previously treated with proteasome inhibitors and immunomodulatory agents.

Secondary Objectives

• To assess the antitumor activity of single agent ABC294640 in patients with refractory or relapsed MM after 3 cycles of treatment.
• To determine the pharmacokinetics of ABC294640 following administration of the drug.
• To describe the effects of ABC294640 on plasma levels of sphingosine 1-phosphate and IL-6 (interleukin - 6) in patients with refractory or relapsed MM.
• To assess pharmacodynamic markers (SK2 mRNA (messenger ribonucleic acid) level or activity, sphingolipid metabolites, c-Myc, Mcl-1 and pS6) in bone marrow CD138+ myeloma cells.

Objectives for Phase 2:

Primary Objectives

• Assess overall treatment response rate and overall survival in patients with relapsed or refractory MM treated with single-agent ABC294640.

Secondary Objectives

• To assess the treatment response of ABC294640 in patients with refractory or relapsed MM after 3 cycles of treatment.
• To determine if pharmacodynamic markers (SK2 mRNA or activity, sphingolipid metabolites, c-Myc, Mcl-1 and pS6) in bone marrow CD138+ myeloma cells predict tumor response to the treatment with ABC294640.

The projected ABC294640 doses for the escalation phase are: 250, 500, and 750 mg BID orally continuously as determined in the single agent trial for ABC294640. The dose will be given under fasting conditions (at least 1 hour before or 2 hours after eating). Each cycle of treatment is 28 days.

Patients will be monitored for safety and pharmacodynamics effects weekly in Cycle 1, biweekly for Cycles 2-4, and monthly for subsequent cycles.

Myeloma treatment response will be assessed as follows:

• Serum protein electrophoresis (SPEP), urine protein electrophoresis (UPEP) and serum free light chains before each cycle.
• Skeletal survey at screening, then every year or at the end of study if the study ends before the anniversary.
• Bone marrow biopsy and aspirates at the last day of cycle #3 and cycle #6 (± 7 days).

For the phase II portion of the study, patients will be treated with single agent ABC294640 at the MTD determined from the phase Ib study (or highest dose used, if MTD is not reached) until disease progression or intolerable toxicity occurs.

Inclusion Criteria:

1. Patient must have a diagnosis of symptomatic multiple myeloma, relapsed or refractory after previous treatment with a proteasome inhibitor (bortezomib or carfilzomib) and an immunomodulatory agent (thalidomide, lenalidomide or pomalidomide).

2. Have measurable disease as defined by at least one of the following:

   • Serum monoclonal (M) protein ≥1.0 g/dl by protein electrophoresis
   • >200 mg of M protein in the urine on 24 hour electrophoresis
   • Serum immunoglobulin free light chain ≥10 mg/dL AND abnormal serum immunoglobulin kappa to lambda free light chain ratio
   • Monoclonal bone marrow plasmacytosis ≥30%

3. Voluntary signed and dated institutional review board (IRB) approved informed consent form in accordance with regulatory and institutional guidelines.

4. Time interval from last systemic chemotherapy (not including low dose dexamethasone) more than 2 weeks prior to initiation of ABC294640. Patients receiving high dose dexamethasone defined as 40mg dexamethasone a day for 4 days will need 2 weeks washout prior to initiation of ABC294640

5. 18 years of age or older.

6. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.

7. Acceptable liver function:

   • Bilirubin ≤ 1.5 times upper limit of normal (CTCAE Grade 1 baseline)
   • AST (aminotransferase) (SGOT), ALT (alanine aminotransferase) (SGPT) ≤ 5 x ULN (CTCAE Grade 2 baseline)
   • Serum creatinine ≤1.5 XULN (1.5 times the upper limit of normal) (CTCAE Grade 1 baseline)

8. Acceptable hematologic status (with or without transfusion support):

   • Absolute neutrophil count ≥1000 cells/mm3,
   • Platelet count ≥50,000 (plt/mm3),
   • Hemoglobin ≥9 g/dL.

9. Urinalysis: No clinically significant abnormalities.

10. PT (partial thromboplastin) and PTT (partial thromboplastin time) ≤ 1.5 X ULN after correction of nutritional deficiencies that may contribute to prolonged PT/PTT.

11. As determined by the treating investigator, the patient must have well-controlled blood pressure, defined as systolic blood pressure <150mmHg (Millimeter of Mercury)and/or diastolic blood pressure <100 mmHg for the majority of measurements.

12. A negative pregnancy test (if female of child bearing potential).

13. For men and women of child-producing potential, willingness to use effective contraceptive methods during the study.

Exclusion Criteria:

1. Pregnant or nursing women.
2. Patients who are currently participating in any other clinical trial of an investigational product.
3. Major surgery within 30 days prior to start of treatment
4. Acute active infection requiring treatment (systemic antibiotics, antivirals, or antifungals) within 14 days prior to start of treatment
5. Known human immunodeficiency virus infection
6. Active hepatitis B or C infection with abnormal liver functions (i.e., LFTs (liver function test) > 2 x upper normal limits)
7. Unstable angina or myocardial infarction within 4 months prior to start of treatment, New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina, history of severe coronary artery disease, severe uncontrolled ventricular arrhythmias, sick sinus syndrome, or electrocardiographic evidence of acute ischemia or Grade 3 conduction system abnormalities unless subject has a pacemaker
8. Uncontrolled hypertension or uncontrolled diabetes within 14 days prior to start of treatment
9. Nonhematologic malignancy within the past 3 years with the exception of a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) carcinoma in situ of the cervix or breast; c) prostate cancer of Gleason Grade 6 or less with stable prostate-specific antigen levels; or d) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder
10. Subjects with pleural effusions requiring thoracentesis or ascites requiring paracentesis within 14 days prior to initiation of ABC294640
11. Any other clinically significant medical or psychiatric disease or condition, or social situation that, in the Investigator's opinion, may interfere with protocol adherence or a subject's ability to give informed consent

Patients with Refractory or Relapsed Multiple Myeloma Who have Previously Been Treated with Proteasome Inhibitors and Immunomodulatory Agents were treated with three doses of ABC294640.

Up to 20.5 weeks

Treatment emergent adverse events (TEAE) were any event not present before exposure to study medication or any event already present that worsens in either intensity or frequency following exposure to study drug.