Inclusion Criteria:

• At least 18 years of age.
• Patients must have WM or MM previously treated with at least 1 and no more than 5 prior therapies.
• Treatment with prior autologous transplant is permitted. If a transplant is used as consolidation following chemotherapy, without intervening disease progression, it will be considered 1 line of treatment with the preceding chemotherapy.
• Patients with MM must have a monoclonal protein in the serum of greater than or equal to 1 g/dL or monoclonal light chain in the urine protein electrophoresis of greater than or equal to 200 mg/ 24 hours, or measurable plasmacytoma.
• Patients with WM must have an immunoglobulin M (IgM) paraprotein with a minimum IgM level of > 2 times the upper limit of normal, have detectable lymphoplasmacytic (LPL) cells in the bone marrow, and be symptomatic for WM.
• ECOG Performance Status (PS) of 0, 1, or 2.

• The following laboratory values obtained prior to registration:

  • Absolute neutrophil count (ANC) greater than or equal to 1000/microL
  • Platelet (PLT) count greater than or equal to 75,000/microL
  • Total bilirubin less than or equal to 1.5 x upper limit of normal (ULN) (if total is elevated check direct and, if normal, patient is eligible)
  • Aspartate transaminase (AST) less than or equal to 3 x ULN
  • Creatinine less than or equal to 1.5 x ULN
  • Hemoglobin (Hgb) greater than or equal to 8.0 g/dL.
• Expected survival of greater than 12 weeks.
• The ability to provide informed consent.
• Male and female patients with reproductive potential must use an approved contraceptive method, if appropriate (for example, intrauterine device [IUD], birth control pills, or barrier device) during and for 3 months after discontinuation of study treatment. Women with childbearing potential must have a negative serum pregnancy test less than or equal to 3 days prior to study enrollment

Exclusion Criteria:

• Prior allogeneic hematopoietic stem cell transplant.
• Are unable to discontinue use of non-EIAEDs, for example carbamazepine, phenobarbital, and phenytoin. Patients on anti-coagulant therapy should be monitored. Ongoing treatment with therapeutic doses of Coumadin is prohibited. However, prophylactic, low dose (less than or equal to 2mg daily) Coumadin for DVT is allowed. In such cases, PT/INR should be closely monitored.
• Have ECG abnormalities including baseline 12-lead ECG with QTc interval of greater than 450 msec in males or greater than 470 msec in females, or QRS duration of greater than 100 msec. Patients who have a congenital long-QT-syndrome in their own or family medical history should be excluded at the investigator's discretion.
• Have an uncontrolled infection.
• Have prior treatment with BCNU 6 weeks, alkylating agent 4 weeks, or other cytotoxic chemotherapy agents 4 weeks prior to registration in this trial. Have prior treatment with biologic therapy less than or equal to 12 weeks or corticosteroids less than or equal to 2 weeks prior to registration in this trial. However, treatment with less than or equal to 10 mg of prednisone as a chronic therapy is allowed.
• Have radiation therapy less than or equal to 2 weeks prior to treatment in this trial.
• Are pregnant or breast-feeding.
• Are being treated with concurrent chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy considered investigational.
• Are known to be HIV positive.
• Were previously treated with enzastaurin.
• Patients who are unable to swallow tablets.
• Have received treatment within the last 30 days with a drug that has not received regulatory approval for any indication at the time of study entry.
• Concurrent malignancy that could complicate interpretation of response or safety evaluation. Non-melanoma skin cancer and carcinoma in situ of the cervix are not exclusions.