Study on the Effect of Ibrutinib on High Risk Smoldering Multiple Myeloma Patients

Inclusion Criteria Disease Related

1. High risk SMM, defined as follows by Mayo Clinic criteria:

   1. Bone marrow plasma cells between 10% and 60%
   2. Serum M-protein ≥ 3 g/dL \[except IgA ≥ 2 g/dL\] or urine M-protein \> 500 mg per 24 hours
   3. Serum free light chain ratio \< 0.126 or \> 8; an involved to uninvolved ratio of ≥ 100 is permitted
   4. Measurable disease, defined as: M-protein ≥ 1 g/dL OR Bence-Jones protein (BJP) \> 200 mg/24 hr OR involved free light chain \> 100 mg/dL
2. Diagnosed with SMM within the last 4 years

Laboratory

1. Adequate hematologic function independent of transfusion and growth factor support for at least 7 days prior to screening, with the exception of pegylated G-CSF (pegfilgrastim) and darbopoetin which require at least 14 days prior to screening defined as:

   * Absolute neutrophil count \> 750 cells/mm3 (1.0 x 109/L).
   * Platelet count \> 75,000 cells/mm3 (75 x 109/L).
2. Adequate hepatic and renal function defined as:

   * Serum aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3.0 x upper limit of normal (ULN).
   * Estimated creatinine clearance ≥ 30 ml/min (Cockcroft-Gault)
   * Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin, in which case the total bilirubin should be \< 3 x ULN)
3. PT/INR \< 1.5 x ULN and PTT (aPTT) \< 1.5 x ULN

   Demographic
4. Men and women ≥ 18 years of age
5. Eastern Cooperative Oncology Group (ECOG) performance status of \< 2

Exclusion Criteria Disease-Related

1. No end organ damage attributable to a plasma cell disorder, defined as having ANY of the following:

   1. Hypercalcemia: Serum calcium \> 1 mg/dL above the upper limit of normal or \> 11 mg/dL
   2. Renal insufficiency: Serum creatinine \> 2 mg/dL or creatinine clearance \< 30 mL per min
   3. Anemia: Hemoglobin value \> 2 g/dL below the upper limit of normal or a hemoglobin value \< 10 g/dL
   4. Bone lesions: One or more lytic lesions on skeletal radiography, CT, MRI, PET-CT, or PET-MRI
2. Bone marrow plasma cells \< 10% or \> 60%
3. Has received prior anti-myeloma therapy of any type
4. Has received prior bisphosphonate therapy
5. Has received an investigational drug, investigational vaccine, or has used an investigational medical device within 4 weeks or 4 half-lives, whichever is longer, before Cycle 1, Day 1 of study therapy
6. Osteoporosis, defined as having a T-score on DEXA of ≤ -2.5

Concurrent Conditions

1. History of other malignancies, except:

   * Malignancy treated with curative intent and with no known active disease present for ≥ 3 years before the first dose of study drug and felt to be at low risk for recurrence by treating physician
   * Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
   * Adequately treated carcinoma in situ without evidence of disease
2. Concurrent systemic immunosuppressant therapy (eg, cyclosporine A, tacrolimus, etc). Any use of corticosteroids EITHER for \> 14 days OR at dosages \> 20 mg/day of prednisone or equivalent is prohibited.
3. Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug
4. Recent infection requiring systemic treatment that was completed ≤ 14 days before the first dose of study drug
5. Known bleeding disorders (eg, von Willebrand's disease) or hemophilia
6. History of stroke or intracranial hemorrhage within 6 months prior to enrollment
7. Known HIV, HCV or HBV infection. Subjects who are positive for hepatitis B core antibody or hepatitis B surface antigen must have a negative polymerase chain reaction (PCR) result before enrollment. Those who are PCR positive will be excluded.
8. Any uncontrolled active systemic infection
9. Major surgery within 4 weeks of first dose of study drug
10. Any life-threatening illness, medical condition, or organ system dysfunction that, in the investigators' opinion, could compromise the subject's safety or put the study outcomes at undue risk