Carfilzomib, Pomalidomide, and Dexamethasone in Treating Patients With High-Risk Multiple Myeloma

PRIMARY OBJECTIVE:

I. To determine the ≥ complete response (CR) rates with carfilzomib, pomalidomide and
dexamethasone (CPD) consolidation and maintenance.

SECONDARY OBJECTIVES:

I. To determine the improved progression free survival (PFS) with CPD consolidation and
maintenance among high-risk patients.

II. To determine the best response rates (very good partial response rate [VGPR], stringent
complete response [sCR] rate) with CPD consolidation and maintenance.

II. To evaluate the safety of the CPD combination as consolidative and maintenance regimen.

III. To characterize safety in subjects who receive CPD consolidation and maintenance.

IV. To evaluate the duration of response (DOR).

V. To evaluate the overall survival (OS) in high-risk patients.

VI. To evaluate the minimal residual disease (MRD) detection with CPD consolidation and
maintenance.

OUTLINE:

CONSOLIDATION: Patients receive carfilzomib intravenously (IV) over 30 minutes on days 1, 2,
8, 9, 15, and 16, pomalidomide orally (PO) daily on days 1-21, and dexamethasone PO daily on
days 1, 2, 8, 9, 15, and 16. Treatment repeats every 28 days for up to 2 courses in the
absence of disease progression or unacceptable toxicity.

MAINTENANCE: Patients receive carfilzomib IV over 30 minutes on days 1, 8, and 15,
pomalidomide PO daily on days 1-21, and dexamethasone PO daily on days 1, 8, and 15. Courses
repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months.

Inclusion Criteria:

- Patients must meet the following criteria on screening examination to be eligible to
participate in the study; all laboratory assessments should be performed within 21
days of initiation of protocol therapy unless otherwise specified; subject is, in the
investigator's opinion, willing and able to comply with the protocol requirements

- Subject has given voluntary signed written informed consent before performance of any
study-related procedure that is not part of normal medical care, with the
understanding that consent may be withdrawn by the subject at any time without
prejudice to their future medical care

- Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 1

- Subject is a transplant-eligible patient that have undergone autologous stem cell
transplant (ASCT) within one year of their diagnosis and have achieved ≥ partial
response (PR) based on International Myeloma Working Group (IMWG) standard criteria

- Patients with high risk disease defined as

- Presence of del(17p); t(4;14); t(14;16); by fluorescence in situ hybridization
(FISH) or by cytogenetics (CTG)

- Plasma cell leukemia at diagnosis with ≥ 20% circulating plasma cells on
peripheral blood

- Subject agrees to refrain from blood donations during therapy on study and for 90 days
after therapy is completed

- Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy
test with a sensitivity of at least 50 milli-International units (mIU)/mL within 10-14
days prior to and again within 24 hours of starting pomalidomide and must either
commit to continued abstinence from heterosexual intercourse or begin TWO acceptable
methods of birth control, one highly effective method and one additional effective
method AT THE SAME TIME, at least 28 days before she starts taking pomalidomide
through 90 days after the last dose of study drug; FCBP must also agree to ongoing
pregnancy testing; men must agree to use a latex condom during sexual contact with a
FCBP even if they have had a vasectomy from the time of signing the informed consent
form through 90 days after the last dose of study drug; all patients must be
registered in and must comply with all requirements of the pomalidomide Risk
Evaluation and Mitigation Strategies (REMS) program; male subjects should refrain from
sperm donation for at least 90 days after the last dose of carfilzomib or pomalidomide

- FCBP refers to sexually mature female, regardless of sexual orientation or
whether they have undergone tubal ligation, who: 1) has not undergone a
hysterectomy or bilateral oophorectomy; or 2) has not been naturally menopausal
for at least 24 consecutive months

Exclusion Criteria:

- Diagnosed with smoldering multiple myeloma (MM), monoclonal gammopathy of undetermined
significance, Waldenstrom's macroglobulinemia, polyneuropathy, organomegaly,
endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome, amyloidosis
or standard risk myeloma or secondary plasma cell leukemia

- High risk patients that did not achieve ≥ PR after stem cell transplant

- Participant has ≥ grade 2 peripheral neuropathy on clinical examination within 21 days
before initiation of protocol therapy

- Creatinine clearance < 30 mL/min (either actual or calculated value), within 21 days
of initiation of protocol therapy; the Cockcroft-Gault formula should be used for
calculating creatinine clearance values

- Platelet count < 75,000 cells/mm³ at time of screening evaluation; transfusion may not
be used to meet platelet eligibility criteria within 7 days of obtaining screening
evaluation

- Participants with an absolute neutrophil count (ANC) < 1000 cells/mm³ at time of
screening evaluation; growth factors may not be used to meet ANC eligibility criteria
within 14 days of obtaining screening evaluation

- Participants with hemoglobin level < 8.0 g/dL, at time of screening; transfusion may
not be used to meet eligibility criteria within 7 days of obtaining screening
evaluation

- Bilirubin > 1.5 x institutional upper limit of normal (ULN), within 21 days of
initiation of protocol therapy

- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]),
alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]), or
alkaline phosphatase > 3 x institutional ULN, within 21 days of initiation of protocol
therapy

- Other ongoing or prior anti-myeloma therapy; patients may be receiving concomitant
therapy with bisphosphonates and low dose corticosteroids (e.g., prednisone up to but
no more than 10 mg p.o. once daily [q.d.] or its equivalent) for symptom management
and comorbid conditions; doses of corticosteroid should be stable for at least 7 days
prior to study treatment)

- Known significant cardiac abnormalities including:

- Congestive heart failure, New York Heart Association (NYHA) class III or IV

- Uncontrolled angina, arrhythmia or hypertension

- Myocardial infarction within the past six months

- Any other uncontrolled or severe cardiovascular condition

- Prior cerebrovascular event with residual neurologic deficit

- Serious, intercurrent illness including, but not limited to, clinically relevant
active infection, known active hepatitis B or C viral infection, known human
immunodeficiency virus (HIV) infection, uncontrolled diabetes mellitus, or serious
co-morbid medical conditions such as chronic restrictive pulmonary disease, and
cirrhosis

- Any condition, including laboratory abnormalities, that in the opinion of the
investigator places the subject at unacceptable risk if he/she were to participate in
the study

- Prior malignancy (within the last 5 years) except for adequately treated basal cell or
squamous cell skin cancer, or in situ cervical cancer

- Known hypersensitivity to acyclovir or similar anti-viral drug

- Known intolerance to steroid therapy

- Contraindication or prior intolerance to thromboembolic prophylaxis with aspirin,
warfarin or low-molecular weight heparin

- Participants with known central nervous system (CNS) disease

- Poor tolerability or known allergy to any of the study drugs or compounds of similar
chemical or biologic composition to dexamethasone, boron or mannitol

- Female participants pregnant or breast-feeding

- Participants who have undergone major surgery ≤ 4 weeks prior to starting study drug
or who have not recovered from side effects of the surgery

- Participants with any significant history of non-compliance to medical regimens or
unwilling or unable to comply with the instructions given to him/her by the study
staff