Carfilzomib + High Dose Melphalan as Preparative Regimen for Autologous Hematopoietic Stem Cell Transplantation

This is a phase 1/2a trial. Since this is an AHSCT conditioning regimen trial, only one cycle
of therapy will be administered for each subject.

PHASE 1 The phase 1 component has a typical 3+3 design.

- Initially up to three subjects will be enrolled in each cohort starting at cohort 0 in
the table below.

- If no dose limiting toxicity (DLT) is noted among the 3 initial subjects, 3 additional
patients will be accrued at the subsequent cohort.

- If 1/3 subjects experience DLT, 3 additional subjects will be accrued at the cohort. If
no additional DLT occur, accrual will continue at the subsequent cohort.

- If 2 or more subjects experience DLT in a given cohort, the dose will be considered
higher than the maximum tolerated dose (MTD) and the immediately lower dose will be
considered the MTD.

- If accrual is completed in cohort 4 with 0/3 or 1/6 DLT, the MTD will be considered "not
reached" and cohort 4 will be expanded in the phase 2 of the trial.

- If 2 subjects experience DLTs in cohort 0, patients will be accrued in cohort -1, one
subject at a time, with the subsequent subject only being accrued once the current
subject has completed the DLT period (transplant day 30). The doses in cohort -1 will be
considered the MTD if 0/3 or 1/6 subjects experience DLT.

- If ≥ 2 subjects experience DLT in cohort -1 the study will be interrupted without
proceeding to phase 2a and the combination of carfilzomib and high dose melphalan will
be considered too toxic.

PHASE 2 Once the MTD for the combination of carfilzomib and high dose melphalan with AHSCT is
found, there will be expansion of the MTD cohort so that 28 individuals will be treated at
the MTD of carfilzomib and high dose melphalan.

Screening - Subjects likely to meet eligibility criteria will be offered participation in the
study after the investigator verifies with the registration system that there is a current
available slot (phase 1). Subjects will sign informed consent prior to any protocol
associated procedure. Screening procedures are outlined in Table 3 and will 1) ensure that
subject meets all the eligibility criteria, 2) obtain disease assessment to allow efficacy
measurements, 3) assess baseline toxicity and 4) provide initial biological samples for
pharmacodynamic and correlative studies.

Treatment- Subjects will receive the appropriate dose of carfilzomib (according to assigned
cohort in phase 1 and at the determined MTD in phase 2) on days -3 and -2. Carfilzomib will
be infused over 30 minutes. On day -2, with 60 to 120 minutes of the end of infusion of
carfilzomib, subjects will receive 200 mg/m2 of intravenous melphalan as an intravenous push
or a fast infusion. Prophylaxis of chemotherapy induced nausea and vomiting will follow
institutional guidelines.

Infusion of autologous cells- Infusion of autologous hematopoietic stem cells will occur on
day 0 and follow institutional SOP.

Follow up phase - On day 1 following HSCT patients will receive pegfilgrastim 6 mg
subcutaneously as per institutional standard of care aiming at faster engraftment. The follow
up phase will last 100 days and will consist of standard post transplantation supportive care
and monitoring of adverse events (AE's). For the phase 1 component of the study,
dose-limiting toxicities will be captured during the first 30 days after transplantation (DLT
period). Patients without progression may continue with carfilzomib maintenance therapy.

Patients will either be randomized in blocks of two to either maintenance therapy Arm 1= AB
(two cycles of A followed by two cycles of B), or maintenance therapy Arm 2= BA (two cycles
of B followed by two cycles of A). Maintenance regimen A will consist of carfilzomib 36 mg/m2
infused over 30 minutes on days 1,8,15. Maintenance regimen B will consist of carfilzomib 36
mg/m2 infused over 30 minutes on days 1, 2, 15 and 16. Each cycle will have 4 week duration.
The first four maintenance therapy cycles will be dictated by a randomized assignment at time
of study registration to maintenance therapy. For both maintenance therapy arms, a patient
preference questionnaire will be administered to the patient upon completion of the 4th
cycle. The remaining 8 cycles (cycles 5-12) will be administered according to the regimen
schedule preferred by the patient as documented on the patient preference questionnaire.

Disease assessment- Disease assessment will occur at day 100 (+/- 7 days) and will consist of
serum protein electrophoresis, serum and urine immunofixation, 24h urine protein
electrophoresis, serum free light chains, bone marrow aspiration and biopsy, complete blood
counts and metabolic panel.

Inclusion Criteria:

1. Age ≥ 18 years and ≤ 70 years

2. Life expectancy ≥ 12 months

3. Eastern Cooperative Oncology Group (ECOG) performance status 0-2

4. Diagnosis of symptomatic multiple myeloma, relapsed after initial therapy.

5. At least minimal response (defined as 25% decrease in the M protein in serum or urine)
to the most recent treatment regimen.

6. Evaluable disease prior to most recent treatment regimen as defined by at least one of
the following:

- Serum monoclonal (M) protein ≥0.5 g/dl by protein electrophoresis

- 200 mg of M protein in the urine on 24 hour electrophoresis

- Serum immunoglobulin free light chain ≥10 mg/dL AND abnormal serum immunoglobulin
kappa to lambda free light chain ratio

- Monoclonal bone marrow plasmacytosis ≥30%

7. Adequate hepatic function, with serum ALT ≤ 3.5 times the upper limit of normal and
serum direct bilirubin ≤ 2 mg/dL (34 µmol/L) within 14 days prior to start of therapy

8. Hemoglobin ≥ 8 g/dL (80 g/L) within 14 days prior to registration (subjects may be
receiving red blood cell [RBC] transfusions in accordance with institutional
guidelines)

9. Creatinine clearance (CrCl) ≥ 40 mL/minute within 14 days prior to registration,
either measured or calculated using a standard formula (eg, Cockcroft and Gault).

10. Prior storage of at least 2 x 106 CD34+ cells/kg available for autologous
transplantation. During the phase 1 component of the study, at least the same amount
of cells is required as "back up" in the unlikely event of non-engraftment.

11. Subjects may have had a prior AHSCT for the treatment of MM as long as it was
performed greater than 12 months from study registration.

12. Subjects must meet institutional general eligibility criteria for autologous
transplantation.

13. Written informed consent in accordance with federal, local, and institutional
guidelines.

14. Female of childbearing potential (FCBP) must agree to ongoing pregnancy testing and to
practice contraception.

15. Male subjects must agree to practice contraception.

Exclusion Criteria:

1. Pregnant or lactating females.

2. Major surgery within 30 days prior to start of treatment.

3. Acute active infection requiring treatment (systemic antibiotics, antivirals, or
antifungals) within 14 days prior to registration.

4. Known human immunodeficiency virus infection.

5. Active hepatitis B or C infection.

6. Unstable angina or myocardial infarction within 4 months prior to registration, NYHA
Class III or IV heart failure, uncontrolled angina, history of severe coronary artery
disease, severe uncontrolled ventricular arrhythmias, sick sinus syndrome, or
electrocardiographic evidence of acute ischemia or Grade 3 conduction system
abnormalities unless subject has a pacemaker.

7. Uncontrolled hypertension or uncontrolled diabetes within 14 days prior to
registration.

8. Nonhematologic 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.

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

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

11. Subjects with pleural effusions requiring thoracentesis or ascites requiring
paracentesis within 14 days prior to registration.

12. Any other clinically significant medical disease or condition that, in the
Investigator's opinion, may interfere with protocol adherence or a subject's ability
to give informed consent.