Carfilzomib and Stem Cell Transplant for Plasma Cell Myeloma

Background:

- Despite very significant progress in therapy for plasma cell myeloma (PCM) in the last
decade, the disease remains mostly incurable.

- High-dose chemotherapy followed by autologous hematopoietic cell transplantation (AHCT)
continues to be a critical component of early treatment for PCM, but it is clear that
the disease is not eradicated by the present high-dose therapy strategy, while
intensifying the preparative regimen has, to this day, resulted in either no
improvement in disease control or increased toxicity.

- Carfilzomib (CFZ) is a newer proteasome inhibitor with increased activity and a safer
toxicity profile than bortezomib in PCM. The favorable toxicity profile makes it a
likely candidate for increasing anti-PCM drug exposure in the early post-AHCT period.

Objectives:

Primary Objectives

-Evaluate feasibility and toxicity of an increasing number of doses of CFZ administered in
the early period post-AHCT for PCM

Secondary Objective

- Evaluate the immune reconstitution post-AHCT following CFZ therapy

- Evaluate the effects of the addition of CFZ in the early post-AHCT period on the
response rate at day 100 post-AHCT

Eligibility:

- Newly diagnosed subjects with PCM following induction therapy

- Subjects with documentation of persistent/refractory disease who have received no more
than 2 salvage regimens following relapse and who have not undergone AHCT

- Adequate organ functions with no major co-morbidity

- Age greater than 18 years and less than or equal to 75 years

Design:

- Phase I/II study on the backbone of high-dose melphalan on day -2 pre-AHCT

- Addition of an increasing number of doses of CFZ in the early post-AHCT period
introduced in a step-wise fashion in 3 successive cohorts of 3 to 15 subjects:

Cohort 1: add CFZ 20 mg/m^2 on days +1, +2

Cohort 2 : add CFZ 20 mg/m^2 on days: +1, +2, +8, +9

Cohort 3: add CFZ 20 mg/m^2 on days: +1, +2, +8, +9 and add an early post-AHCT consolidation
following

engraftment: CFZ 20 mg/m^2 given on days 42-43 then CFZ 56 mg/m^2 given on days 49-50,
56-57, then on days 70-71, 77-78 and 84-85

-Dose-limiting toxicity, incidence of engraftment failure and treatment-related mortality
are the objects of early stopping rules for safety purposes

- INCLUSION CRITERIA:

Multiple myeloma criteria for newly or recently diagnosed subjects

- Presence of clonal plasma cells in the bone marrow greater than or equal to 10% or a
documented clonal plasmacytoma (either by immuno-histochemistry or by Ig gene
rearrangement), AND

- Presence of an M-component; an M-component (immunoglobulin G (IgG) or immunoglobulin
A (IgA)) in serum greater than or equal to 1g/dl or in urine greater or equal to 200
mg/24 h.

ALTERNATIVELY, if the M-component criterion is not met:

- An abnormal serum free light chain (FLC) ratio on the serum FLC assay, or if the FLC
ratio is normal,

- Baseline bone marrow must have 10% or greater clonal plasma cells

AND, IN ADDITION, presence of one or more of the following attributable to the disease (in
the presence or absence of an M-component):

- Calcium elevation greater than 11.5 mg/dl (2.65 mmol/l)

- Renal insufficiency: serum creatinine greater than 2 mg/dl (177 mmol/l) or less than
60ml/min.

- Hemoglobin less than 10 g/dl (12.5 mmol/l) or 2 g/dl (1.25 mmol/l) below lower normal

- Bone disease (lytic lesions or osteopenia)

- Other evidence of disease activity: repeated infections, secondary amyloidosis,
hyperviscosity, hypogammablobulinemia

Criteria for subjects with persistent or recurrent disease

Subjects with recurrent or persistent disease are eligible if:

- Criteria for initiating therapy for plasma cell myeloma (PCM) had been present at the
time of initiation of therapy or there is clear clinical indication for salvage
therapy.

- They have not undergone an autologous transplant for the treatment of PCM

- They have received no more than two salvage regimens for the treatment of recurrent
or persistent PCM (each regimen may include more than one cycle)

Other eligibility criteria

-Age > 18 years and less than or equal to 75 years.

In subjects between 65 and 75 years of age, physiologic age and co-morbidity will be
thoroughly evaluated before enrolling. Specifically, any history of cardiovascular
pathology or symptoms not clearly fitting the exclusion criteria of Section 2.1.2 will
prompt an evaluation by a Clinical Center Cardiologist and eligibility will be considered
on a case-by-case basis.

- Karnofsky performance status of 70% or greater (Eastern Cooperative Oncology Group
(ECOG) 0 or 1)

- Ejection fraction (EF) by multi-gated acquisition scan (MUGA) or 2-D echocardiogram
within institution normal limits. In case of low ejection fraction (EF), the subject
may remain eligible after a stress echocardiogram is performed if the EF is more than
35% and if the increase in EF with stress is estimated at 10% or more.

- creatinine clearance > 25ml/min (measured on a 24 hour urine collection)

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than or
equal to 3 x upper limit of normal

- Bilirubin less than or equal to1.5 (except if due to Gilbert's disease)

- Corrected carbon dioxide diffusing capacity (DLCO) greater than or equal to 40% on
pulmonary function tests

EXCLUSION CRITERIA:

- Prior allogeneic or autologous stem cell transplantation

- Prior treatment with Carfilzomib (CFZ) is not an exclusion

- History of recent (< 6 months) cerebrovascular accident

- History of documented recent (< 6 months) pulmonary embolus

- Clinically significant cardiac pathology:

- Myocardial infarction within 6 months prior to enrollment,

- Class III or IV heart failure according to New York Heart Association (NYHA),

- Uncontrolled angina,

- Severe uncontrolled ventricular arrhythmias, or

- Electrocardiographic evidence of acute ischemia or active conduction abnormalities
felt to pose a significant cardiac riks by a Cardiology consultant

- Patients with a history of coronary artery bypass grafting or angioplasty will
receive a cardiology evaluation and be considered on a case-by-case basis.

- Human immunodeficiency virus (HIV) seropositive

- Acute active infection requiring treatment (systemic antibiotics, antivirals, or
antifungals) within 14 days prior to enrollment

- Active hepatitis B or C infection

- Uncontrolled hypertension or uncontrolled diabetes within 14 days prior to enrollment

- Major surgery within 21 days prior to enrollment

- Non-hematologic malignancy within the past 3 years with the exception of a)
adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid
cancer; b) carcinoma in situ of the cervix or breast; c) prostate cancer of Gleason
Grade 6 or less with stable prostate-specific antigen levels; or d) cancer considered
cured by surgical resection or unlikely to impact survival during the duration of the
study, such as localized transitional cell carcinoma of the bladder or benign tumors
of the adrenal or pancreas

- Significant neuropathy (Grades 3 4, or Grade 2 with pain) within 14 days prior to
randomization

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

- Patients known or found to be pregnant

- Female patients of childbearing age who are unwilling to practice contraception

- Patients may be excluded at the discretion of the principal investigator (PI) if it
is deemed that allowing participation would represent an unacceptable medical or
psychiatric risk.

- Patients must be able to give informed consent