Carfilzomib and Melphalan Before Stem Cell Transplant in Treating Patients With Multiple Myeloma
Carfilzomib and Melphalan Before Stem Cell Transplant in Treating Patients With Multiple Myeloma
This phase I/II trial studies the side effects and best dose of carfilzomib when given
 together with melphalan and to see how well they work in treating patients with multiple
 myeloma before stem cell transplant. Carfilzomib may stop the growth of cancer cells by
 blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as
 melphalan, work in different ways to stop the growth of cancer cells, either by killing the
 cells or by stopping them from dividing. Giving carfilzomib together with melphalan may kill
 more cancer cells.
PRIMARY OBJECTIVES:

 I. To determine the maximum tolerated dose (MTD) of carfilzomib that can be added to high
 dose melphalan as part of conditioning chemotherapy for myeloma. (Phase I) II. To determine
 the efficacy of the combination in patients with myeloma undergoing stem cell
 transplantation, as defined by achievement of complete response (CR). (Phase II)

 SECONDARY OBJECTIVES:

 I. To examine the toxicities associated with addition of carfilzomib to high dose melphalan
 in patients with multiple myeloma (MM).

 II. To determine the progression free rate at 1 and 2 years post registration.

 TERTIARY OBJECTIVES:

 I. To determine the proportion of patients achieving a minimal residual disease (MRD)
 negative status.

 II. To assess the HevyLite assay prior to and during treatment.

 OUTLINE: This is a phase I, dose-escalation study of carfilzomib followed by a phase II
 study.

 CONDITIONING: Patients receive carfilzomib intravenously (IV) over 30 minutes on days -6, -5,
 -2, and -1. Patients also receive melphalan IV over 1 hour on days -4 and -3.

 TRANSPLANT: Patients undergo autologous stem cell transplant on day 0.

 After completion of study treatment, patients are followed up at day 30, day 100, and then
 every 90 days for up to 5 years.
Inclusion Criteria:

 -  Serum creatinine =< 2 mg/dL

 -  Absolute neutrophil count >= 1000/uL

 -  Platelet count >= 50,000/uL

 -  Hemoglobin >= 8.0 g/dL

 -  Diagnosis of symptomatic MM

 -  Measurable disease of multiple myeloma at the time of baseline values for disease
 assessment as defined by at least one of the following:

 -  Serum monoclonal protein >= 1.0 g/dL

 -  >= 200 mg of monoclonal 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

 -  Bone marrow plasma cells >= 30%

 -  NOTE: For patients with no relapse prior to transplant, measurable disease at the
 time of diagnosis

 -  NOTE: For patients who have had a disease relapse prior to transplant, measurable
 disease at the time of the most recent relapse immediately prior to transplant;
 NOTE: If the patient had treatment for the relapsed disease prior to transplant,
 the patient must have measurable disease at the time of relapse prior to this
 therapy

 -  Patient is considered for autologous stem cell transplantation with full dose
 melphalan (200 mg/m^2)

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

 -  Recovered from toxicity of previous chemotherapy (excludes grade 1 neurotoxicity and
 hematological toxicity)

 -  Provide informed written consent

 -  Ejection fraction >= 45%

 -  Corrected pulmonary diffusion capacity of greater than or equal to 50%

 -  Forced expiratory volume in 1 second (FEV1) >= 50%

 -  Forced vital capacity (FVC) >= 50%

 -  Negative pregnancy test performed =< 7 days prior to registration, for women of
 childbearing potential only

 -  Willing to return to Mayo Clinic Rochester, Mayo Clinic Arizona, Mayo Clinic Florida
 for treatment

 -  Note: During the active monitoring phase of a study (i.e., active treatment and
 observation), participants must be willing to return to the consenting
 institution for follow-up

 -  Willing to provide blood and bone marrow samples for correlative research purposes

 Exclusion Criteria:

 -  Prior autologous or allogeneic bone marrow/peripheral blood stem cell transplant

 -  More than two prior regimens for therapy of MM

 -  Myocardial infarction within 6 months prior to enrollment, or has New York Heart
 Association (NYHA) class III or IV heart failure, uncontrolled angina, severe
 uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute
 ischemia or active conduction system abnormalities; NOTE: Prior to study entry, any
 electrocardiogram (ECG) abnormality at screening has to be documented by the
 investigator as not medically relevant

 -  Seroreactivity for human immunodeficiency virus (HIV), human T-lymphotropic virus
 (HTLV) I or II, hepatitis B virus (HBV), hepatitis C virus (HCV)

 -  Other active malignancy < 2 years prior to registration; EXCEPTIONS: Non-melanotic
 skin cancer or carcinoma-in-situ of the cervix; NOTE: If there is a history or prior
 malignancy, they must not be receiving other specific treatment for their cancer

 -  Any of the following:

 -  Pregnant women or women of reproductive capability who are unwilling to use
 effective contraception

 -  Nursing women

 -  Men who are unwilling to use a condom (even if they have undergone a prior
 vasectomy) while having intercourse with any woman, while taking the drug and for
 28 days after stopping treatment

 -  Other co-morbidity, which would interfere with patient's ability to participate in the
 trial, e.g. uncontrolled infection, uncompensated lung disease

 -  Concurrent chemotherapy, radiotherapy, or any ancillary therapy considered
 investigational; NOTE: Bisphosphonates are considered to be supportive care rather
 than therapy, and are thus allowed while on protocol treatment

 -  Known allergies to any of the components of the investigational treatment regimen or
 required ancillary treatments