Inclusion Criteria:

• Subject was previously diagnosed with multiple myeloma based on standard diagnostic criteria, as follows.

• Major criteria:

  1. Plasmacytomas on tissue biopsy.
  2. Bone marrow plasmacytosis (> 30% plasma cells).
  3. Monoclonal immunoglobulin spike on serum electrophoresis immunoglobulin G (IgG) >3.5 g/dL or immunoglobulin A (IgA) > 2.0 g/dL; kappa or lambda light chain excretion > 1 g/day on 24 hour urine protein electrophoresis.

• Minor criteria:

  1. Bone marrow plasmacytosis (10 to 30% plasma cells).
  2. Monoclonal immunoglobulin present but of lesser magnitude than given under major criteria.
  3. Lytic bone lesions.
  4. Normal IgM < 50 mg/dL, IgA < 100 mg/dL or IgG < 600 mg/dL.

• Any of the following sets of criteria will confirm the diagnosis of multiple myeloma:

  • Any two of the major criteria.
  • Major criterion 1 plus minor criterion b, c, or d.
  • Major criterion 3 plus minor criterion a or c.
  • Minor criteria a, b, and c or a, b, and d.
• Patients must have relapsed or refractory disease (refractory is defined as progression during treatment or within 60 days after the completion of treatment) requiring 2nd or 3rd line therapy
• Patients refractory to a combination of lenalidomide and dexamethasone will not be eligible. Patients may have received lenalidomide and/or dexamethasone
• Patients with measurable disease defined as:
• Serum monoclonal protein greater than 0.5 g/dl and greater than 0.2 g/24 hr urine light chain excretion.
• Patients with lower M-protein values or non-secretory myeloma will be eligible if measurable disease can be established, such as serum Freelite chain ratio > 5x normal ratio limit, measurable soft tissue plasmacytoma greater than 2 cm, by either physical examination and/or applicable radiographs (i.e. MRI, CT-scan) and/or bone marrow involvement > 30%.
• Age ≥ 18 years at the time of signing informed consent document.
• All necessary baseline studies for determining eligibility must be obtained within 14 days prior to enrollment. (Pregnancy test must be within 7 days for women of childbearing potential.)
• Pre-study ECOG performance status 0-2. Patients with lower performance status based solely on bone pain will be eligible.
• Patients must have adequate liver functions: AST and ALT < 3 X upper limit of normal, alkaline phosphatase < 3.0 X upper limit of normal, except if attributed to tumor, and bilirubin < upper limit of normal
• Subject must be able to adhere to the study visit schedule and other protocol requirements.
• Subject must understand and voluntarily sign an informed consent document.
• Women of child-bearing potential (WCBP)—defined as a sexually mature woman who has not undergone a hysterectomy or who has not been naturally postmenopausal for at least 24 consecutive months (i.e., who has had menses any time in the preceding 24 consecutive months)—must have a negative serum or urine pregnancy test within 7 days prior to enrollment. In addition, all sexually active WCBP and male patients must agree to use adequate contraceptive methods (oral, injectable, or implantable hormonal contraceptive; tubal ligation; intra-uterine device; barrier contraceptive with spermicide; or vasectomized partner) throughout the study.
• Able to take aspirin (81 or 325 mg) daily as prophylactic anticoagulation (patients intolerant to ASA may use low molecular weight heparin).

Exclusion Criteria:

• Renal insufficiency (serum creatinine levels > 3 mg/dL)..
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to perifosine (miltefosine or edelfosine).
• Known hypersensitivity to thalidomide
• The development of erythema nodosum if characterized by a desquamating rash while taking thalidomide or similar drugs.
• Concomitant medications that include corticosteroids (except as indicated for other medical conditions or up to 100 mgs of hydrocortisone or equivalent as premedication for administration of certain medications or blood products), chemotherapy, or other therapy that is or may be active against myeloma within 2 weeks prior to Cycle 1 Day 1. Nitrosoureas must be discontinued 6 weeks prior to Cycle 1 Day 1.
• Subjects with hemoglobin < 8.0 g/dL.
• Patient has an absolute neutrophil count of <1.0 x 109/L within 14 days before enrollment.
• Peripheral neuropathy of grade 3 or greater. Patients with painful grade 2 neuropathy are also excluded.
• Patient has a platelet count of <75 x 109/L within 14 days before enrollment
• Any condition, including laboratory abnormalities, that in the opinion of the investigator places the subject at unacceptable risk if he/she were to participate in the study.
• WCBP who are pregnant or breast-feeding or men and women who are not using adequate contraception.
• Plasma cell leukemia at time of study entry.