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

The purpose of this research study is to test whether the drug ibrutinib (trademark name: IMBRUVICA®) is effective at preventing the development of multiple myeloma in people who currently have smoldering myeloma. The researchers conducting this trial) have reason to believe that ibrutinib can delay the development of multiple myeloma, thus giving people who currently have smoldering myeloma a longer period of time when they feel healthy and well.

Smoldering myeloma is an abnormal condition that is considered to be an early phase of the disease multiple myeloma. In this disorder, there is an abnormal growth of plasma cells, which is a type of blood cell found in the bone marrow. This growth is not as severe in people with smoldering myeloma as it is in multiple myeloma, so people with smoldering myeloma do not have any symptoms and tend to feel well. However, they have a higher risk of developing multiple myeloma than people in the general population.

Some people with smoldering myeloma are at an especially high risk of developing myeloma - 50% of these people will develop multiple myeloma 2 years after they are diagnosed with smoldering myeloma. The investigators identify these people by looking at the amount of myeloma in the bone marrow (called "bone marrow plasma cell percentage") and the amount of myeloma protein (called "serum protein electrophoresis" and "serum free light chain assay") in the blood. To be considered high risk, individuals must have highly abnormal levels for these tests.

Based upon current guidelines, people with smoldering myeloma do not require any treatment. However, known is that many of these people will develop multiple myeloma in the near future. Currently there have been no proven and effective way of preventing these people from developing multiple myeloma, which remains an incurable disease.

This is a phase 2, open-label, single center, prospective pilot study designed to assess the efficacy of ibrutinib in subjects with high risk smoldering multiple myeloma.

All enrolled subjects will be treated with ibrutinib 560 mg (4 capsules, each containing 140 mg) taken PO daily for 12 cycles (28 days each). If a subject demonstrates benefit from ibrutinib, therapy may be extended beyond 12 cycles to a maximum of 2 years. Subjects who progress and meet criteria for symptomatic multiple myeloma will be withdrawn from study.

An initial cohort of 15 subjects will be accrued. If 4 or more patients progress to symptomatic myeloma in one year, then the study will be reviewed with the FDA to determine whether to employ a higher dose of ibrutinib, or to stop for futility. Otherwise, 21 additional patients will be accrued for a total sample size of 36.

Eligibility Criteria:
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