Carfilzomib in Treating Patients With Multiple Myeloma in First Relapse or Refractory to First-Line Therapy
Carfilzomib in Treating Patients With Multiple Myeloma in First Relapse or Refractory to First-Line Therapy
This phase II trial studies how well carfilzomib works in treating patients with multiple
 myeloma in first relapse or refractory to first-line therapy. Carfilzomib may stop the growth
 of cancer cells by blocking some of the enzymes needed for cell growth.
PRIMARY OBJECTIVES:

 I. To assess the overall response rate of carfilzomib after 8 cycles of treatment in patients
 with first-relapsed myeloma.

 SECONDARY OBJECTIVES:

 I. To assess the overall response rate to single agent carfilzomib after 4 cycles of
 treatment.

 II. To assess progression-free survival (PFS). III. To assess time to progression (TTP). IV.
 To assess duration of response (DOR). V. To assess toxicities.

 TERTIARY OBJECTIVES:

 I. To examine the effect of carfilzomib alone or in combination with dexamethasone on the
 following biologic end points and their correlation with response: measurements of bone
 remodeling (sodium fluoride F 18 positron emission tomography [PET], serum markers of bone
 remodeling and the bone marrow osteoblastic and osteoclastic differentiation and function)
 with the measurement of disease response and proteasome activity in the bone marrow
 microenvironment.

 II. To describe recapture of response after progression in the maintenance phase.

 OUTLINE:

 TREATMENT PHASE (COURSES 1-8): Patients receive carfilzomib intravenously (IV) over 30
 minutes on days 1, 2, 8, 9, 15, and 16. Treatment repeats every 28 days for 8 courses in the
 absence of disease progression or unacceptable toxicity. Patients achieving less than partial
 response (PR) also receive dexamethasone orally (PO) or IV weekly in courses 4-8.

 MAINTENANCE PHASE (COURSES 9-14): Patients receive carfilzomib IV over 30 minutes on days 1,
 2, 15, and 16. Patients who received dexamethasone in the Treatment Phase continue to receive
 dexamethasone PO or IV weekly. Treatment repeats every 28 days for 6 courses in the absence
 of disease progression or unacceptable toxicity.

 After completion of study treatment, patients are followed up at 30 days and then every 3
 months.
Inclusion Criteria:

 -  Multiple myeloma (MM) in first relapse or refractory to first line therapy; the
 previous line of therapy should include either an immunomodulatory agent or a
 proteasome inhibitor

 -  Refractory disease is defined as =< 25% response or progression during therapy or
 within 60 days after completion

 -  The number of prior lines of anti-myeloma therapy will be determined as follows:

 -  Induction chemotherapy for peripheral-blood stem cell harvest followed by
 planned mobilization and subsequent high-dose chemotherapy with autologous
 stem cell transplant (ASCT) is considered one therapy regardless of the
 induction regimen

 -  Planned maintenance therapy after stem cell transplantation or other
 induction therapy is not considered a separate line of therapy, as long as
 there is no evidence of progression in the time between the induction or
 transplantation and the initiation of maintenance therapy

 -  Two ASCTs within 6 months of each other is considered as one line unless
 different agents were used in the high-dose therapy-conditioning regimens

 -  If the same regimen is repeated after a 6-month interval, they are
 considered to be two separate therapeutic lines

 -  If cyclophosphamide is used for reasons other than planned stem cell
 mobilization, its use is considered to be a separate line of therapy

 -  Dose modification of steroid and altering choices of steroid (i.e. from
 dexamethasone to prednisone) due to side effects, is not considered a line
 of therapy, as long as there is no evidence of progression

 -  If a regimen was stopped for more than 2 months, its re-initiation is
 counted as another line of therapy

 -  Presence of existing lytic bone lesions either by skeletal X-ray, computed tomography
 (CT) scan or magnetic resonance imaging (MRI) scan

 -  Measurable MM disease, defined as one of the following:

 -  A monoclonal immunoglobulin (Ig) concentration on serum electrophoresis of >= 0.5
 g/dL for an IgG myeloma, >= 0.1 g/dL for an IgD myeloma or >= 0.5 g/dL for an IgA
 myeloma

 -  Measurable urinary light chain secretion by quantitative analysis of >= 200 mg/24
 hours

 -  Involved serum free light chain (FLC) level >= 10 mg/dL, provided the serum FLC
 ratio is abnormal

 -  Patients with oligo- or non-secretory disease must have bone marrow involvement
 with at least 30% plasmacytosis on aspiration

 -  Life expectancy >= 3 months as determined by the treating physician

 -  Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 1 or 2

 -  Absolute neutrophil count (ANC) >= 1.0 × 10^9/L (without transfusion support and
 without hematological growth factor support within 2 weeks of cycle 1 day 1)

 -  Platelets >= 50 × 10^9/L; if the bone marrow contains >= 50% plasma cells, a platelet
 count of >= 30 × 10^9/L is allowed (without transfusion support and without
 hematological growth factor support within 2 weeks of cycle 1 day 1)

 -  Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) and/or
 alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT) =< 2.5 × the
 upper limit of normal (ULN)

 -  Bilirubin < 2.0 mg/dL

 -  Serum creatinine =< 3.0 mg/dL or a calculated creatinine clearance of at least 15
 mL/min (using the Cockcroft and Gault method)

 -  Adequate cardiac function defined as left ventricular ejection fraction (LVEF) >= 40%

 -  NOTE: 2-dimensional (2-D) transthoracic echocardiogram (ECHO) is the preferred
 method of evaluation

 -  Multigated acquisition scan (MUGA) is acceptable if ECHO is not available

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

 -  Females of childbearing potential (FCBP) must agree to ongoing pregnancy testing and
 to practice contraception; females are considered of childbearing potential unless
 they are surgically sterile (they have undergone a hysterectomy, bilateral tubal
 ligation, or bilateral oophorectomy) or they are naturally postmenopausal for at least
 12 consecutive months

 -  Male subjects must agree to practice contraception

 Exclusion Criteria:

 -  No primary amyloidosis

 -  No plasma cell leukemia (> 2.0 × 10^9/L circulating plasma cells by standard
 differential)

 -  No treatment with an investigational product or device within 21 days of cycle 1 day 1

 -  No history of allergic reaction/hypersensitivity to any of the study medications,
 their analogues or excipients in the various formulations

 -  No treatment with cytotoxic therapy or monoclonal antibodies within 21 days prior to
 cycle 1 day 1

 -  No treatment with a steroid intended to treat myeloma within 14 days prior to cycle 1
 day 1

 -  No autologous or allogeneic stem cell transplant within 3 months prior to cycle 1 day
 1

 -  No radiotherapy within 21 days prior to cycle 1 day 1; however, if the radiation
 portal covered =< 5% of the bone marrow reserve, the patient may be enrolled
 irrespective of the end date of radiotherapy

 -  No major surgery within 14 days and minor surgery within 7 days prior to cycle 1 day 1

 -  No pregnant or lactating females

 -  No acute active infection requiring treatment (systemic antibiotics, antivirals, or
 antifungals) within 14 days prior to cycle 1 day 1

 -  No known human immunodeficiency virus (HIV) infection

 -  No active hepatitis B or C infection

 -  No unstable angina or myocardial infarction within 4 months prior to cycle 1 day 1,
 New York Heart Association (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

 -  No uncontrolled hypertension or uncontrolled diabetes (as determined by the treating
 physician) within 14 days prior to cycle 1 day 1

 -  No 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

 -  No significant neuropathy (grades 3-4, or grade 2 with pain) within 14 days prior to
 cycle 1 day 1

 -  No known history of allergy to Captisol (a cyclodextrin derivative used to solubilize
 carfilzomib)

 -  No contraindication to any of the required concomitant drugs or supportive treatments,
 including hypersensitivity to all anticoagulation and antiplatelet options, antiviral
 drugs, or intolerance to hydration due to preexisting pulmonary or cardiac impairment

 -  No subjects with pleural effusions requiring thoracentesis or ascites requiring
 paracentesis within 14 days prior to cycle 1 day 1

 -  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