S1304, Carfilzomib and Dexamethasone for Treating Patients With Relapsed or Refractory Myeloma

PRIMARY OBJECTIVES:

I. To evaluate and compare progression free survival (PFS) of two different doses of
carfilzomib with dexamethasone in multiple myeloma (MM) patients with relapsed and/or
refractory disease.

SECONDARY OBJECTIVES:

I. To evaluate and compare response rates (RR) for each arm. II. To evaluate response rates
(RR) for patients that relapse on low dose carfilzomib and subsequently cross-over to high
dose carfilzomib.

III. To evaluate the safety of this combination for this patient population. IV. To evaluate
overall survival (OS).

TERTIARY OBJECTIVES:

I. To explore the molecular variability in MM cells obtained from extramedullary bone marrow
relapse sites.

II. To explore the role of positron emission tomography (PET) scanning in assessing disease
burden and as a tool to assess treatment response.

III. To explore changes in left ventricular ejection fraction (LVEF) in patients with
relapsed or refractory multiple myeloma treated with low dose carfilzomib or high dose
carfilzomib plus dexamethasone.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive dexamethasone intravenously (IV) and low-dose carfilzomib IV over
2-10 minutes on days 1, 2, 8, 9, 15, and 16. Patients with progression cross-over to Arm II.

ARM II: Patients receive dexamethasone IV and high-dose carfilzomib IV over 30 minutes on
days 1, 2, 8, 9, 15, and 16.

Note that for the first course of treatment on both arms carfilzomib is given at a reduced
rate to assess toxicity.

In both arms, treatment repeats every 28 days for up to 12 courses in the absence of disease
progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 3 years from
initial registration.

Inclusion Criteria:

- REGISTRATION STEP 1: INITIAL RANDOMIZATION

- Patients must have a confirmed diagnosis of symptomatic multiple myeloma and must be
currently relapsed or refractory; all tests for establishing disease status must be
completed within 28 days prior to registration and documented on the Baseline Tumor
Assessment Form for Multiple Myeloma

- Patients must have measurable disease within 28 days prior to registration

- Patients must have received at least one prior regimen of chemotherapy for symptomatic
multiple myeloma; patients may not have more than six (6) previous regimens of therapy
for the disease; prior chemotherapy must have been completed at least 21 days prior to
registration; for study purposes, a regimen is defined as follows:

- An anti-myeloma therapy used at the time of initial diagnosis or documented
disease progression which is given with the intent to decrease disease burden

- Any maintenance therapy used after an Induction should be considered part of that
Induction regimen

- Use of any agent or combination of agents more than once during the patient's
disease history for separate documented disease progressions will be counted as
separate regimens (e.g., if a patient receives lenalidomide/bortezomib at initial
diagnosis and achieves response, but then progresses and receives
lenalidomide/bortezomib after progression, these count as 2 separate regimens)

- In cases of allogeneic or autologous stem cell transplant, the entire induction +
stem cell mobilization + conditioning + planned maintenance should be considered
one regimen

- Patients may not have received any prior carfilzomib treatment

- Patients must not be receiving any other concurrent therapy considered to be
investigational; patients must not be planning to receive any radiotherapy (except
localized radiation for palliative care); patients must not be planning to receive any
concurrent chemotherapy, immunotherapy, radiotherapy or other treatment with curative
intent

- Patients must have complete history and physical examination within 28 days prior to
registration

- Patients must have baseline PET scan within 28 days prior to registration; note that
images are submitted centrally for review

- Patients with non-secretory MM or known primary amyloidosis are not eligible

- Patients must have Zubrod performance status 0-2

- Patients must not have clinically significant illness including uncontrolled, active
infection requiring intravenous antibiotics, New York Heart Association (NYHA) class
III or class IV heart failure, unstable angina pectoris, myocardial infarction within
the past 6 months, or >= grade 3 cardiac arrhythmias

- Patients must have undergone an electrocardiogram (EKG) within 28 days prior to
registration

- Patients must have either echocardiogram (ECHO) with ejection fraction >= 45% within
28 days prior to registration

- Patients must not have > grade 2 neuropathy and/or POEMS syndrome (plasma cell
dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and
skin changes)

- Total bilirubin =< 1.5 x upper limit of normal (ULN)

- Serum glutamic oxaloacetic transaminase (SGOT) and serum glutamate pyruvate
transaminase (SGPT) =< 3 x ULN

- Absolute neutrophil count (ANC) >= 1,000 cell/mm^3 without growth factor support
within 14 days prior to registration

- Platelets >= 50,000 cells/mm^3 for patients who have bone marrow plasmacytosis < 50%
or >= 30,000 cells/mm^3 for patients who have bone marrow plasmacytosis of >= 50%
within 14 days prior to registration

- Calculated or measured creatinine clearance >= 30 ml/min within 14 days prior to
registration

- Patients who are known to be human immunodeficiency virus positive (HIV+) are eligible
providing they meet all of the following additional criteria within 28 days prior to
registration:

- Cluster of differentiation (CD)4 cells >= 500/mm^3

- Viral load of < 50 copies HIV messenger ribonucleic acid (mRNA)/mm^3 if on
combination antiretroviral therapy (cART) or < 25,000 copies HIV mRNA if not on
cART

- No zidovudine or stavudine as part of cART

- Patients who are HIV+ and do not meet all of these criteria are not eligible for
this study

- Patients with known hepatitis B or hepatitis C infection must have viral load <
800,000 IU/L within 28 days prior to registration

- Patients must have baseline skeletal survey to document lytic lesions, osteopenia or
compression fracture within 28 days prior to registration

- Patients may have received palliative external beam radiation therapy (XRT) for local
disease control with no curative intent. XRT must be completed at least 7 days prior
to registration

- Patients must be offered participation in specimen submission for translational
medicine studies and banking; with patient consent, specimens must be submitted

- Patients must not be pregnant or nursing; women/men of reproductive potential must
have agreed to use an effective contraceptive method; a woman is considered to be of
"reproductive potential" if she has had menses at any time in the preceding 12
consecutive months; in addition to routine contraceptive methods, "effective
contraception" also includes heterosexual celibacy and surgery intended to prevent
pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy,
bilateral oophorectomy or bilateral tubal ligation; however, if at any point a
previously celibate patient chooses to become heterosexually active during the time
period for use of contraceptive measures outlined in the protocol, he/she is
responsible for beginning contraceptive measures

- No other prior malignancy is allowed except for the following: adequately treated
basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated
stage I or II cancer from which the patient is currently in complete remission, or any
other cancer from which the patient has been disease free for three years

- Patients or their legally authorized representative must be informed of the
investigational nature of this study and must sign and give written informed consent
in accordance with institutional and federal guidelines

- As a part of the Oncology Patient Enrollment Network (OPEN) registration process the
treating institution's identity is provided in order to ensure that the current
(within 365 days) date of institutional review board approval for this study has been
entered in the system

- REGISTRATION STEP 2: CROSSOVER

- Patient must have been eligible for and initially randomized to Arm 1 (low dose
carfilzomib), begun cycle 2 of treatment, and progressed prior to completing 12 cycles
of protocol therapy

- At least 14 days and no more than 28 days must have elapsed between the last day of
treatment on Arm 1 and registration to Arm 3

- Patients must have recovered from all non-hematologic toxicities to =< grade 2 and
from all hematologic toxicities to =< grade 3 prior to registration

- Patients must have begun cycle 2 (carfilzomib - 27 mg/m^2) and must not have received
any dose reduction for toxicity in the last cycle of treatment, immediately preceding
progression

- Patients must have serum protein electrophoresis (SPEP) and kappa and lambda light
chain testing performed within 14 days prior to registration in order to establish
baseline measurements

- Patients must not have ejection fraction decrease > 10% from baseline (as determined
by ECHO) or other ejection fraction decrease accompanied by other clinical
signs/symptoms of New York Heart Association (NYHA) class III or IV heart failure,
measured within 28 days prior to registration; if any question exists regarding
individual patient eligibility in this situation, contact the study chair for
determination