A Study of Carfilzomib Plus Dexamethasone in Subjects With Relapsed or Refractory Multiple Myeloma at US Community Oncology Centers

This is a phase 2, multicenter, open-label study in subjects with RRMM in US community
oncology centers. Subjects with 1-3 prior lines of therapy at study entry are eligible to be
screened for participation. Subjects refractory to their last line of treatment are eligible
to participate as long as their last line of treatment did not include a proteasome inhibitor
(PI). The study will consist of a screening period of up to 28 days for bone marrow
assessments and up to 21 days for all other assessments, up to 12 cycles of treatment, and a
30-day safety follow-up period following the last dose of study drug. During the treatment
period, all subjects will be treated with Kd 20/56 mg/m2 twice weekly for up to six 28-day
cycles followed by up to Kd 70 mg/m2 once weekly for another six 28-day cycles. After
discontinuation of study drugs, subjects will be followed for 30 days for safety.

Inclusion Criteria:

- Subject has provided informed consent prior to initiation of any study specific
activities/procedures.

- Males or females greater than or equal to 18 years of age.

- Relapsed MM after last treatment or refractory while receiving non-proteasome
inhibitor therapy.

- . Measurable disease with at least 1 of the following assessed within 21 days prior to
enrollment: immunoglobulin G (IgG) MM: serum monoclonal protein (M-protein) level ≥
1.0 g/dL IgA, IgD, IgE multiple myeloma: serum M protein level ≥ 0.5 g/dL urine
M-protein ≥ 200 mg per 24 hours in subjects without measurable serum or urine
M-protein, serum free light chain (SFLC) ≥ 100 mg/L (involved light chain) and an
abnormal serum kappa lambda ratio.

- Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 to 1.

- Subjects must have at least partial response (PR) to at least 1 line of prior therapy.

- Subjects must have received at least 1 but not more than 3 prior lines of therapy for
MM (induction therapy followed by stem cell transplant and consolidation/maintenance
therapy will be considered as 1 line of therapy; see Section 12.11).

- Prior therapy with a PI is allowed as long as the subject had at least a PR to most
recent therapy with PI, was not removed due to toxicity (except for neuropathy, see
criterion 213), did not relapse within 60 days from discontinuation of PI, and will
have at least a 6-month PI treatment-free interval from last dose received until
enrollment. (Subjects may receive maintenance therapy with drugs that are not PI
during this 6-month PI treatment-free interval).

Exclusion Criteria:

- Waldenström macroglobulinemia.

- Multiple myeloma of IgM subtype.

- POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and
skin changes).

- History of plasma cell leukemia.

- Primary amyloidosis (patients with multiple myeloma with asymptomatic deposition of
amyloid plaques found on biopsy would be eligible if all other criteria are met).

- Subjects with nephrotic range proteinuria (greater than or equal to 3 g albumin for 24
hours urine OR greater than or equal to 2 g albumin/1 g of creatinine on a random
urine specimen).

- Myelodysplastic syndrome.

- History of other malignancy within the past 5 years, with the following exceptions:
Malignancy treated with curative intent and with no known active disease present for
greater than or equal to 3 years before enrollment and felt to be at low risk for
recurrence by the treating physician. Adequately treated non-melanoma skin cancer or
lentigo maligna without evidence of disease. Adequately treated cervical carcinoma in
situ without evidence of disease. Adequately treated breast ductal carcinoma in situ
without evidence of disease. Prostatic intraepithelial neoplasia without evidence of
prostate cancer. Adequately treated urothelial papillary noninvasive carcinoma or
carcinoma in situ. Treated medullary or papillary thyroid cancer. Similar neoplastic
conditions with an expectation of greater than 95% five-year disease-free survival.

- Known HIV infection, hepatitis C infection (subjects with hepatitis C that achieve a
sustained virologic response following antiviral therapy are allowed), or hepatitis B
infection (subjects with hepatitis B surface antigen or core antibody that achieve
sustained virologic response with antiviral therapy directed at hepatitis B are
allowed).

- .Acute or chronic graft-versus-host disease (any grade).

- Acute active infection requiring systemic antibiotics, antifungal, antiviral (except
antiviral therapy directed at hepatitis B) agents within 14 days prior to enrollment.

- Known cirrhosis.

- Significant neuropathy (grades 3 to 4, or grade 2 with pain) within 14 days prior to
enrollment.

- Subjects with pleural effusions requiring thoracentesis or ascites requiring
paracentesis within 14 days prior to enrollment.

- Uncontrolled hypertension, defined as an average systolic blood pressure ≥ 160 mmHg or
diastolic ≥ 100 mmHg (see Section 12.12 for more details). Subjects with controlled
hypertension are eligible.

- Hepatic dysfunction within 21 days prior to enrollment (see Section 7.1.1.2.1):

bilirubin 1.5 times the upper limit of normal (ULN) aspartate aminotransferase (AST) or
alanine aminotransferase (ALT) 3 times the ULN

- Active congestive heart failure with or without reduced ejection fraction (NYHA Class
III to IV), symptomatic ischemia, uncontrolled arrhythmias, clinically significant
electrocardiogram (ECG) abnormalities, screening ECG with corrected QT interval (QTc)
of greater than 470 msec, pericardial disease, myocardial infarction within 4 months
prior to enrollment.

- Known chronic obstructive pulmonary disease.

- Known interstitial pneumonitis.

- Immunotherapy within 21 days prior to enrollment.

- Chemotherapy with approved anticancer therapeutic within 21 days prior to enrollment.

- Glucocorticoid therapy (prednisone greater than 30 mg/day or equivalent) within 14
days prior to enrollment.

- Focal radiation therapy within 7 days prior to enrollment. Radiation therapy to an
extended field involving a significant volume of bone marrow within 21 days prior to
enrollment (ie, prior radiation must have been to less than 30% of the bone marrow).

- Major surgery (except kyphoplasty) within 28 days prior to enrollment.

- Autologous or allogeneic stem cell transplant within 90 days prior to enrollment.

- Contraindication to dexamethasone.

- Known history of allergy to Captisol (a cyclodextrin derivative used to solubilize
carfilzomib).

- Intolerance to intravenous (IV) hydration.

- Currently receiving treatment in another investigational device or drug study, or less
than 30 days since ending treatment on another investigational device or drug
study(ies). Other investigational procedures while participating in this study are
excluded.

- Hepatic dysfunction within 21 days prior to enrollment: bilirubin greater than or
equal to 1.5 times the upper limit of normal (ULN); aspartate aminotransferase (AST)
or alanine aminotransferase (ALT) greater than or equal to 3 times the ULN.

- Left ventricular ejection fraction less than 40% assessed by transthoracic
echocardiogram.

- Severe valvular disease assessed by transthoracic echocardiogram.

- Severe right-ventricular dysfunction assessed by transthoracic echocardiogram.

- Right-ventricular systolic pressure greater than 40 mm Hg assessed by transthoracic
echocardiogram.

- Screening ANC should be independent of growth factor support for greater than or equal
to 1 week.

- Hemoglobin less than 80 g/L within 21 days prior to enrollment. Use of erythropoietic
stimulating factors and red blood cell (RBC) transfusions per institutional guidelines
is allowed, however most recent RBC transfusion may not have been done within 7 days
prior to obtaining screening hemoglobin.

- Platelet count < 50 x 109/L (≤ 30 x 109/L if myeloma involvement in the bone marrow is
> 50%) within 21 days prior to enrollment. Subjects should not have received platelet
transfusions for at least 1 week prior to obtaining the screening platelet count.

- Estimated GFR less than 30 mL/min/1.73 m2 (per the Chronic Kidney Disease Epidemiology
Collaboration formula, see Section 12.13) within 21 days prior to enrollment.