Study of the Bruton's Tyrosine Kinase Inhibitor in Combination With Carfilzomib (Kyprolis™) 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 and 3 clinical trials. The current study is designed and intended to
determine the safety and efficacy of PCI-32765 in combination with carfilzomib (Kyprolis™)
with and without dexamethasone in subjects with relapsed or relapsed and refractory multiple
myeloma (MM).

Inclusion Criteria:

- Measurable disease of MM as defined by at least ONE of the following:

1. Serum monoclonal protein (SPEP) ≥1 g/dL

2. Urine M-protein ≥200 mg/24 hrs

3. Serum free light chain (SFLC): involved FLC ≥10 mg/dL (≥100 mg/L) AND abnormal
kappa to lambda serum free light chain ratio

- Relapsed or relapsed and refractory MM after receiving at least 2 previous therapies,
including an immunomodulator and bortezomib and had either no response or documented
disease progression (according to IMWG criteria) to the most recent treatment regimen

- Adequate hematologic, hepatic, and renal function

- ECOG performance status of 0-2

Inclusion Criteria for Phase 2 Sub-study Cohort:

- Must meet all inclusion criteria defined in main study and in addition the following
criteria must be met:

- Subject must have received a regimen containing carfilzomib in combination with
dexamethasone as their most recent line of therapy and have:

1. Achieved less than a partial response ( without evidence of progression disease (PD).

OR

2. Disease progression following an initial confirmed response of MR or better to
the combination (according to IMWG response criteria).

Exclusion Criteria:

- Subject must not have primary refractory disease

- Plasma cell leukemia, primary amyloidosis or POEMS syndrome

- Unable to swallow capsules or disease significantly affecting gastrointestinal
function

- Requires anti-coagulation with warfarin or a vitamin K antagonist

- Requires treatment with strong CYP3A inhibitors

Exclusion Criteria for Phase 2 Sub-study Cohort:

- Must not meet any exclusion criteria defined in main study except for exclusion
criteria "Subject must not have primary refractory disease" which is related to prior
carfilzomib