Study of the Bruton's Tyrosine Kinase Inhibitor in Subjects With Relapsed or Relapsed and Refractory Multiple Myeloma

Bruton's tyrosine kinase (Btk) is an enzyme that is present in hematopoietic cells other than
T cells and is necessary for downstream signal transduction from various hematopoietic
receptors including the B cell receptor as well as some Fc, chemokine, and adhesion
receptors, and is crucial for both B cell development and osteoclastogenesis. Although
down-regulated in normal plasma cells, Btk is highly expressed in the malignant cells from
many myeloma patients and some cell lines. PCI 32765 is a potent and specific inhibitor of
Btk currently in Phase 2 clinical trials. The current study is designed and intended to
determine the effects of PCI-32765 in subjects with MM.

Inclusion Criteria:

- Diagnosis of symptomatic MM with measurable disease, defined here as having at least
one of the following:

1. Serum monoclonal protein (M-protein) ≥0.5 g/dL as determined by serum protein
electrophoresis (SPEP)

2. Urine M-protein ≥200 mg/24 hrs

3. Serum free light chain (FLC) assay: involved FLC level ≥10 mg/dL (≥100 mg/L)
provided serum FLC ratio is abnormal

- Relapsed or relapsed and refractory MM after receiving at least 2 but no more than 5
previous lines of therapy, 1 of which must be an immunomodulator.

- Refractory myeloma (to most recent treatment) is defined as disease that is
nonresponsive while on treatment or progressive disease within 60 days after the
completion of preceding treatment. Nonresponsive disease is defined as either failure
to achieve minimal response or development of progressive disease while on therapy.

- Men and women ≥18 years of age.

- ECOG performance status of ≤ 1.

Exclusion Criteria:

- Subject must not have primary refractory disease defined as disease that is
nonresponsive in subjects who have never achieved a minor response (MR) or better with
any therapy.

- Polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS)
syndrome, osteosclerotic myeloma, or Crow-Fukase syndrome.

- Plasma cell leukemia.

- Primary amyloidosis.

- Certain exclusions on prior therapy.

- ANC <0.75 x 10^9/L independent of growth factor support.

- Platelets <50 x 10^9/L) independent of transfusion support.

- AST or ALT ≥3.0 x upper limit of normal (ULN).

- Total bilirubin >2.5 x ULN, unless due to Gilbert's syndrome.

- Creatinine >2.5 mg/dL.

- Unable to swallow capsules or disease significantly affecting gastrointestinal
function.

- Requires anti-coagulation with warfarin or a vitamin K antagonist. Requires treatment
with strong CYP3A4/5 inhibitors.