Carfilzomib and Melphalan Before Stem Cell Transplant in Treating Patients With Multiple Myeloma

• Sponsor: Mayo Clinic (Other)
• Overall Status: Completed
• CT.gov ID: NCT01842308
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 50
• Locations: 2
• Arm: 1
• Actual Duration (Months): 76.8
• Patients Per Site: 25
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
DS Stage I Plasma Cell Myeloma; DS Stage II Plasma Cell Myeloma; DS Stage III Plasma Cell Myeloma; Refractory Plasma Cell Myeloma	Procedure: Autologous Bone Marrow Transplantation; Procedure: Autologous Hematopoietic Stem Cell Transplantation; Drug: Carfilzomib; Other: Laboratory Biomarker Analysis; Drug: Melphalan	Phase 1/Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. 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:

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

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

TERTIARY OBJECTIVES:

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

2. 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 50 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1/2 Trial of Carfilzomib and Melphalan and Conditioning for Autologous Stem Cell Transplantation for Multiple Myeloma (CARAMEL)
• Actual Study Start Date: Jun 4, 2013
• Actual Primary Completion Date: Oct 11, 2017
• Actual Study Completion Date: Oct 28, 2019

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Treatment CONDITIONING: Patients receive carfilzomib 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.

Procedure: Autologous Bone Marrow Transplantation; Undergo autologous stem cell transplant; Other Names: ABMT Autologous Bone Marrow Transplant Autologous Marrow Transplantation ; Procedure: Autologous Hematopoietic Stem Cell Transplantation; Undergo autologous stem cell transplant; Other Names: Autologous Hematopoietic Cell Transplantation Autologous Stem Cell Transplantation ; Drug: Carfilzomib; Given IV; Other Names: Kyprolis PR-171 ; Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Melphalan; Given IV; Other Names: Alanine Nitrogen Mustard CB-3025 L-PAM L-Phenylalanine mustard L-Sarcolysin L-Sarcolysin Phenylalanine mustard L-Sarcolysine Melphalanum Phenylalanine Mustard Phenylalanine Nitrogen Mustard Sarcoclorin Sarkolysin WR-19813

Outcome Measures

Primary Outcome Measures

1. Determine Maximum Tolerated Dose by the Number of Patients With a DLT Per Dose Level [Up to day 30]

   Will be defined as the dose level below the lowest dose that induces dose-limiting toxicity(DLT) in at least one-third of patients. For this study, a DLT is any of the following during the first 2 cycles of treatment; Absolute neutrophil count engraftment* delayed beyond day 21 or Platelet engraftment* delayed beyond day 30, grade 3+ related sensory or motor neuropathy, or grade 4+ related non-neurologic or non-hematologic adverse event(excluding nausea, vomiting, and diarrhea. Reported below are the number of patients who experienced a DLT.

2. Percentage of Patients With Complete Responses, Defined as a Complete Response Noted as the Objective Status on Two Consecutive Evaluations (Phase II) [Up to 5 years]

   The percentage of successes will be estimated by the number of successes divided by the total number of evaluable patients. Exact binomial 95% confidence intervals for the true success percentages will be calculated.

Secondary Outcome Measures

1. Adverse Event Rate, Graded According to National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 [Up to 5 years]

   These results are reported in the adverse events section. The maximum grade for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed to determine patterns. Additionally, the relationship of the adverse event(s) to the study treatment will be taken into consideration.

2. Complete Response Rate at Day 100 [At day 100]

   Complete response rate (CRR) is defined as the percentage of complete responses estimated by the total number of patients who achieve a complete response by day 100 post-transplant divided by the total number of evaluable patients. Exact binomial 95% confidence intervals for the true complete response rate at day 100 will be calculated.

3. Progression Free Percentage at 1 and 2 Years Post Registration [At 1 year and 2 years]

   Progression is an Increase of 25% from lowest value in any of the following (A "25% increase" refers to M protein, FLC and bone marrow results and does not refer to bone lesions, soft tissue plasmacytoma or hypercalcemia. The lowest value does not need to be a confirmed value. If the lowest serum Mprotein is ≥ 5 g/dL, an increase in serum M-protein of ≥ 1 g/dL is sufficient to define disease progression.), (In the case where a value is felt to be a spurious result per physician discretion (for example, a possible lab error), that value will not be considered when determining the lowest value.): Serum M-protein (absolute increase must be ≥ 0.5 g/dL) and/or Urine M-protein (absolute increase must be ≥ 200 mg/24 hrs) and/or If the only measurable disease is FLC, the difference between involved and uninvolved FLC levels (absolute increase must be>10 mg/dL) and/or If the only measurable disease is BM, bone marrow PC percentage (absolute increase must be ≥ 10%) (Bone marrow criteria for PD

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic in Florida	Jacksonville	Florida	United States	32224-9980
2	Mayo Clinic	Rochester	Minnesota	United States	55905

Sponsors and Collaborators

• Mayo Clinic
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Suzanne Hayman, Mayo Clinic

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Sep 27, 2018

More Information

Publications

None provided.

• Responsible Party: Mayo Clinic
• ClinicalTrials.gov Identifier: NCT01842308
• Other Study ID Numbers: MC1185; NCI-2013-00550; MC1185; P30CA015083
• First Posted: Apr 29, 2013
• Last Update Posted: Sep 1, 2020
• Last Verified: Oct 1, 2019

• Additional relevant MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell; Melphalan; Mechlorethamine; Nitrogen Mustard Compounds

Study Results

Participant Flow

Arm/Group Title	Phase 1: Dose Level 3	Phase 1: Dose Level 2	Phase 1: Dose Level 1	Phase 1: Dose Level 0	Phase 2: Dose Level 3
Arm/Group Description	CONDITIONING: Patients receive 56 mg/m^2 carfilzomib IV over 30 minutes on days -6, -5, -2, and -1. Patients also receive 100mg/m^2 melphalan IV over 1 hour on days -4 and -3. TRANSPLANT: Patients undergo autologous stem cell transplant on day 0. Autologous Bone Marrow Transplantation: Undergo autologous stem cell transplant. Autologous Hematopoietic Stem Cell. Transplantation: Undergo autologous stem cell transplant, Carfilzomib: Given IV. Laboratory Biomarker Analysis: Correlative studies, Melphalan: Given IV	CONDITIONING: Patients receive 45 mg/m^2 carfilzomib IV over 30 minutes on days -6, -5, -2, and -1. Patients also receive 100mg/m^2 melphalan IV over 1 hour on days -4 and -3. TRANSPLANT: Patients undergo autologous stem cell transplant on day 0. Autologous Bone Marrow Transplantation: Undergo autologous stem cell transplant. Autologous Hematopoietic Stem Cell. Transplantation: Undergo autologous stem cell transplant, Carfilzomib: Given IV. Laboratory Biomarker Analysis: Correlative studies, Melphalan: Given IV	CONDITIONING: Patients receive 36 mg/m^2 carfilzomib IV over 30 minutes on days -6, -5, -2, and -1. Patients also receive 100mg/m^2 melphalan IV over 1 hour on days -4 and -3. TRANSPLANT: Patients undergo autologous stem cell transplant on day 0. Autologous Bone Marrow Transplantation: Undergo autologous stem cell transplant. Autologous Hematopoietic Stem Cell. Transplantation: Undergo autologous stem cell transplant, Carfilzomib: Given IV. Laboratory Biomarker Analysis: Correlative studies, Melphalan: Given IV	CONDITIONING: Patients receive 27 mg/m^2 carfilzomib IV over 30 minutes on days -6, -5, -2, and -1. Patients also receive 100mg/m^2 melphalan IV over 1 hour on days -4 and -3. TRANSPLANT: Patients undergo autologous stem cell transplant on day 0. Autologous Bone Marrow Transplantation: Undergo autologous stem cell transplant. Autologous Hematopoietic Stem Cell. Transplantation: Undergo autologous stem cell transplant, Carfilzomib: Given IV. Laboratory Biomarker Analysis: Correlative studies, Melphalan: Given IV	CONDITIONING: Patients receive 56 mg/m^2 carfilzomib IV over 30 minutes on days -6, -5, -2, and -1. Patients also receive 100mg/m^2 melphalan IV over 1 hour on days -4 and -3. TRANSPLANT: Patients undergo autologous stem cell transplant on day 0. Autologous Bone Marrow Transplantation: Undergo autologous stem cell transplant. Autologous Hematopoietic Stem Cell. Transplantation: Undergo autologous stem cell transplant, Carfilzomib: Given IV. Laboratory Biomarker Analysis: Correlative studies, Melphalan: Given IV
Period Title: Overall Study
STARTED	6	3	3	2	36
COMPLETED	6	3	3	2	35
NOT COMPLETED	0	0	0	0	1

Baseline Characteristics

Arm/Group Title	Phase 1; Dose Level 3	Phase 1; Dose Level 2	Phase 1; Dose Level 1	Phase 1; Dose Level 0	Phase 2	Total
Arm/Group Description	CONDITIONING: Patients receive carfilzomib 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. Autologous Bone Marrow Transplantation: Undergo autologous stem cell transplant. Autologous Hematopoietic Stem Cell. Transplantation: Undergo autologous stem cell transplant, Carfilzomib: Given IV. Laboratory Biomarker Analysis: Correlative studies, Melphalan: Given IV	CONDITIONING: Patients receive carfilzomib 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. Autologous Bone Marrow Transplantation: Undergo autologous stem cell transplant. Autologous Hematopoietic Stem Cell. Transplantation: Undergo autologous stem cell transplant, Carfilzomib: Given IV. Laboratory Biomarker Analysis: Correlative studies, Melphalan: Given IV	CONDITIONING: Patients receive carfilzomib 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. Autologous Bone Marrow Transplantation: Undergo autologous stem cell transplant. Autologous Hematopoietic Stem Cell. Transplantation: Undergo autologous stem cell transplant, Carfilzomib: Given IV. Laboratory Biomarker Analysis: Correlative studies, Melphalan: Given IV	CONDITIONING: Patients receive carfilzomib 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. Autologous Bone Marrow Transplantation: Undergo autologous stem cell transplant. Autologous Hematopoietic Stem Cell. Transplantation: Undergo autologous stem cell transplant, Carfilzomib: Given IV. Laboratory Biomarker Analysis: Correlative studies, Melphalan: Given IV	CONDITIONING: Patients receive carfilzomib 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. Autologous Bone Marrow Transplantation: Undergo autologous stem cell transplant. Autologous Hematopoietic Stem Cell. Transplantation: Undergo autologous stem cell transplant, Carfilzomib: Given IV. Laboratory Biomarker Analysis: Correlative studies, Melphalan: Given IV	Total of all reporting groups
Overall Participants	6	3	3	2	35	49
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	52	61	61	55	61	60
Sex: Female, Male (Count of Participants)
Female	2 33.3%	1 33.3%	0 0%	0 0%	14 40%	17 34.7%
Male	4 66.7%	2 66.7%	3 100%	2 100%	21 60%	32 65.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%	0 0%	1 2.9%	1 2%
Not Hispanic or Latino	6 100%	3 100%	2 66.7%	2 100%	32 91.4%	45 91.8%
Unknown or Not Reported	0 0%	0 0%	1 33.3%	0 0%	2 5.7%	3 6.1%

Outcome Measures

1. Primary Outcome

Title	Determine Maximum Tolerated Dose by the Number of Patients With a DLT Per Dose Level
Description	Will be defined as the dose level below the lowest dose that induces dose-limiting toxicity(DLT) in at least one-third of patients. For this study, a DLT is any of the following during the first 2 cycles of treatment; Absolute neutrophil count engraftment* delayed beyond day 21 or Platelet engraftment* delayed beyond day 30, grade 3+ related sensory or motor neuropathy, or grade 4+ related non-neurologic or non-hematologic adverse event(excluding nausea, vomiting, and diarrhea. Reported below are the number of patients who experienced a DLT.
Time Frame	Up to day 30

Outcome Measure Data

Analysis Population Description

All phase 1 patients that began treatment.

Arm/Group Title	Phase 1: Dose Level 3	Phase 1: Dose Level 2	Phase 1: Dose Level 1	Phase 1: Dose Level 0
Arm/Group Description	CONDITIONING: Patients receive 56 mg/m^2 carfilzomib IV over 30 minutes on days -6, -5, -2, and -1. Patients also receive 100mg/m^2 melphalan IV over 1 hour on days -4 and -3. TRANSPLANT: Patients undergo autologous stem cell transplant on day 0. Autologous Bone Marrow Transplantation: Undergo autologous stem cell transplant. Autologous Hematopoietic Stem Cell. Transplantation: Undergo autologous stem cell transplant, Carfilzomib: Given IV. Laboratory Biomarker Analysis: Correlative studies, Melphalan: Given IV	CONDITIONING: Patients receive 45 mg/m^2 carfilzomib IV over 30 minutes on days -6, -5, -2, and -1. Patients also receive 100mg/m^2 melphalan IV over 1 hour on days -4 and -3. TRANSPLANT: Patients undergo autologous stem cell transplant on day 0. Autologous Bone Marrow Transplantation: Undergo autologous stem cell transplant. Autologous Hematopoietic Stem Cell. Transplantation: Undergo autologous stem cell transplant, Carfilzomib: Given IV. Laboratory Biomarker Analysis: Correlative studies, Melphalan: Given IV	CONDITIONING: Patients receive 36 mg/m^2 carfilzomib IV over 30 minutes on days -6, -5, -2, and -1. Patients also receive 100mg/m^2 melphalan IV over 1 hour on days -4 and -3. TRANSPLANT: Patients undergo autologous stem cell transplant on day 0. Autologous Bone Marrow Transplantation: Undergo autologous stem cell transplant. Autologous Hematopoietic Stem Cell. Transplantation: Undergo autologous stem cell transplant, Carfilzomib: Given IV. Laboratory Biomarker Analysis: Correlative studies, Melphalan: Given IV	CONDITIONING: Patients receive 27 mg/m^2 carfilzomib IV over 30 minutes on days -6, -5, -2, and -1. Patients also receive 100mg/m^2 melphalan IV over 1 hour on days -4 and -3. TRANSPLANT: Patients undergo autologous stem cell transplant on day 0. Autologous Bone Marrow Transplantation: Undergo autologous stem cell transplant. Autologous Hematopoietic Stem Cell. Transplantation: Undergo autologous stem cell transplant, Carfilzomib: Given IV. Laboratory Biomarker Analysis: Correlative studies, Melphalan: Given IV
Measure Participants	6	3	3	2
Count of Participants [Participants]	1 16.7%	0 0%	0 0%	0 0%

2. Primary Outcome

Title	Percentage of Patients With Complete Responses, Defined as a Complete Response Noted as the Objective Status on Two Consecutive Evaluations (Phase II)
Description	The percentage of successes will be estimated by the number of successes divided by the total number of evaluable patients. Exact binomial 95% confidence intervals for the true success percentages will be calculated.
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

All patients that received dose level 3 treatment, including phase 1: dose level 3 patients.

Arm/Group Title	Dose Level 3
Arm/Group Description	CONDITIONING: Patients receive 56 mg/m^2 carfilzomib 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. Autologous Bone Marrow Transplantation: Undergo autologous stem cell transplant. Autologous Hematopoietic Stem Cell. Transplantation: Undergo autologous stem cell transplant, Carfilzomib: Given IV. Laboratory Biomarker Analysis: Correlative studies, Melphalan: Given IV
Measure Participants	41
Number (95% Confidence Interval) [percentage of patients]	21.95

3. Secondary Outcome

Title	Adverse Event Rate, Graded According to National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0
Description	These results are reported in the adverse events section. The maximum grade for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed to determine patterns. Additionally, the relationship of the adverse event(s) to the study treatment will be taken into consideration.
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

All patients that received treatment

Arm/Group Title	Phase 1: Dose Level 3	Phase 1: Dose Level 2	Phase 1: Dose Level 1	Phase 1: Dose Level 0	Phase 2: Dose Level 3
Arm/Group Description	CONDITIONING: Patients receive 56 mg/m^2 carfilzomib IV over 30 minutes on days -6, -5, -2, and -1. Patients also receive 100mg/m^2 melphalan IV over 1 hour on days -4 and -3. TRANSPLANT: Patients undergo autologous stem cell transplant on day 0. Autologous Bone Marrow Transplantation: Undergo autologous stem cell transplant. Autologous Hematopoietic Stem Cell. Transplantation: Undergo autologous stem cell transplant, Carfilzomib: Given IV. Laboratory Biomarker Analysis: Correlative studies, Melphalan: Given IV	CONDITIONING: Patients receive 45 mg/m^2 carfilzomib IV over 30 minutes on days -6, -5, -2, and -1. Patients also receive 100mg/m^2 melphalan IV over 1 hour on days -4 and -3. TRANSPLANT: Patients undergo autologous stem cell transplant on day 0. Autologous Bone Marrow Transplantation: Undergo autologous stem cell transplant. Autologous Hematopoietic Stem Cell. Transplantation: Undergo autologous stem cell transplant, Carfilzomib: Given IV. Laboratory Biomarker Analysis: Correlative studies, Melphalan: Given IV	CONDITIONING: Patients receive 36 mg/m^2 carfilzomib IV over 30 minutes on days -6, -5, -2, and -1. Patients also receive 100mg/m^2 melphalan IV over 1 hour on days -4 and -3. TRANSPLANT: Patients undergo autologous stem cell transplant on day 0. Autologous Bone Marrow Transplantation: Undergo autologous stem cell transplant. Autologous Hematopoietic Stem Cell. Transplantation: Undergo autologous stem cell transplant, Carfilzomib: Given IV. Laboratory Biomarker Analysis: Correlative studies, Melphalan: Given IV	CONDITIONING: Patients receive 27 mg/m^2 carfilzomib IV over 30 minutes on days -6, -5, -2, and -1. Patients also receive 100mg/m^2 melphalan IV over 1 hour on days -4 and -3. TRANSPLANT: Patients undergo autologous stem cell transplant on day 0. Autologous Bone Marrow Transplantation: Undergo autologous stem cell transplant. Autologous Hematopoietic Stem Cell. Transplantation: Undergo autologous stem cell transplant, Carfilzomib: Given IV. Laboratory Biomarker Analysis: Correlative studies, Melphalan: Given IV	CONDITIONING: Patients receive 56 mg/m^2 carfilzomib IV over 30 minutes on days -6, -5, -2, and -1. Patients also receive 100mg/m^2 melphalan IV over 1 hour on days -4 and -3. TRANSPLANT: Patients undergo autologous stem cell transplant on day 0. Autologous Bone Marrow Transplantation: Undergo autologous stem cell transplant. Autologous Hematopoietic Stem Cell. Transplantation: Undergo autologous stem cell transplant, Carfilzomib: Given IV. Laboratory Biomarker Analysis: Correlative studies, Melphalan: Given IV
Measure Participants	6	3	3	2	35
Count of Participants [Participants]	6 100%	3 100%	3 100%	2 100%	35 100%

4. Secondary Outcome

Title	Complete Response Rate at Day 100
Description	Complete response rate (CRR) is defined as the percentage of complete responses estimated by the total number of patients who achieve a complete response by day 100 post-transplant divided by the total number of evaluable patients. Exact binomial 95% confidence intervals for the true complete response rate at day 100 will be calculated.
Time Frame	At day 100

Outcome Measure Data

Analysis Population Description

All patients treated at dose level 3

Arm/Group Title	Dose Level 3
Arm/Group Description	CONDITIONING: Patients receive 56 mg/m^2 carfilzomib 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. Autologous Bone Marrow Transplantation: Undergo autologous stem cell transplant. Autologous Hematopoietic Stem Cell. Transplantation: Undergo autologous stem cell transplant, Carfilzomib: Given IV. Laboratory Biomarker Analysis: Correlative studies, Melphalan: Given IV
Measure Participants	41
Number (95% Confidence Interval) [percentage of patients]	17.07

5. Secondary Outcome

Title	Progression Free Percentage at 1 and 2 Years Post Registration
Description	Progression is an Increase of 25% from lowest value in any of the following (A "25% increase" refers to M protein, FLC and bone marrow results and does not refer to bone lesions, soft tissue plasmacytoma or hypercalcemia. The lowest value does not need to be a confirmed value. If the lowest serum Mprotein is ≥ 5 g/dL, an increase in serum M-protein of ≥ 1 g/dL is sufficient to define disease progression.), (In the case where a value is felt to be a spurious result per physician discretion (for example, a possible lab error), that value will not be considered when determining the lowest value.): Serum M-protein (absolute increase must be ≥ 0.5 g/dL) and/or Urine M-protein (absolute increase must be ≥ 200 mg/24 hrs) and/or If the only measurable disease is FLC, the difference between involved and uninvolved FLC levels (absolute increase must be>10 mg/dL) and/or If the only measurable disease is BM, bone marrow PC percentage (absolute increase must be ≥ 10%) (Bone marrow criteria for PD
Time Frame	At 1 year and 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dose Level 3
Arm/Group Description	CONDITIONING: Patients receive 56 mg/m^2 carfilzomib 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. Autologous Bone Marrow Transplantation: Undergo autologous stem cell transplant. Autologous Hematopoietic Stem Cell. Transplantation: Undergo autologous stem cell transplant, Carfilzomib: Given IV. Laboratory Biomarker Analysis: Correlative studies, Melphalan: Given IV
Measure Participants	41
1 year	90.24
2 years	75.61

Adverse Events

Time Frame	5 years
Adverse Event Reporting Description	The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting. All eligible patients that have initiated treatment will be considered evaluable for assessing adverse event rate(s). The maximum grade for each type of adverse event will be recorded for each patient.
Arm/Group Title	Phase 1; Dose Level 3		Phase 1; Dose Level 2		Phase 1; Dose Level 1		Phase 1; Dose Level 0		Phase 2
Arm/Group Description	CONDITIONING: Patients receive carfilzomib 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. Autologous Bone Marrow Transplantation: Undergo autologous stem cell transplant. Autologous Hematopoietic Stem Cell. Transplantation: Undergo autologous stem cell transplant, Carfilzomib: Given IV. Laboratory Biomarker Analysis: Correlative studies, Melphalan: Given IV		CONDITIONING: Patients receive carfilzomib 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. Autologous Bone Marrow Transplantation: Undergo autologous stem cell transplant. Autologous Hematopoietic Stem Cell. Transplantation: Undergo autologous stem cell transplant, Carfilzomib: Given IV. Laboratory Biomarker Analysis: Correlative studies, Melphalan: Given IV		CONDITIONING: Patients receive carfilzomib 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. Autologous Bone Marrow Transplantation: Undergo autologous stem cell transplant. Autologous Hematopoietic Stem Cell. Transplantation: Undergo autologous stem cell transplant, Carfilzomib: Given IV. Laboratory Biomarker Analysis: Correlative studies, Melphalan: Given IV		CONDITIONING: Patients receive carfilzomib 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. Autologous Bone Marrow Transplantation: Undergo autologous stem cell transplant. Autologous Hematopoietic Stem Cell. Transplantation: Undergo autologous stem cell transplant, Carfilzomib: Given IV. Laboratory Biomarker Analysis: Correlative studies, Melphalan: Given IV		CONDITIONING: Patients receive carfilzomib 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. Autologous Bone Marrow Transplantation: Undergo autologous stem cell transplant. Autologous Hematopoietic Stem Cell. Transplantation: Undergo autologous stem cell transplant, Carfilzomib: Given IV. Laboratory Biomarker Analysis: Correlative studies, Melphalan: Given IV
All Cause Mortality
	Phase 1; Dose Level 3		Phase 1; Dose Level 2		Phase 1; Dose Level 1		Phase 1; Dose Level 0		Phase 2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/6 (0%)		0/3 (0%)		0/3 (0%)		0/2 (0%)		0/35 (0%)
Serious Adverse Events
	Phase 1; Dose Level 3		Phase 1; Dose Level 2		Phase 1; Dose Level 1		Phase 1; Dose Level 0		Phase 2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/6 (50%)		2/3 (66.7%)		1/3 (33.3%)		2/2 (100%)		16/35 (45.7%)
Blood and lymphatic system disorders
Anemia	0/6 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/2 (0%)	0	0/35 (0%)	0
Cardiac disorders
Atrial fibrillation	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/2 (50%)	1	1/35 (2.9%)	1
Sinus bradycardia	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/2 (0%)	0	1/35 (2.9%)	1
Supraventricular tachycardia	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/2 (0%)	0	1/35 (2.9%)	2
Gastrointestinal disorders
Abdominal pain	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/2 (0%)	0	1/35 (2.9%)	1
Colitis	0/6 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/2 (0%)	0	1/35 (2.9%)	1
Mucositis oral	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/2 (0%)	0	1/35 (2.9%)	1
Nausea	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/2 (0%)	0	4/35 (11.4%)	4
Vomiting	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/2 (0%)	0	3/35 (8.6%)	3
General disorders
Fatigue	1/6 (16.7%)	1	0/3 (0%)	0	0/3 (0%)	0	0/2 (0%)	0	0/35 (0%)	0
Fever	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/2 (0%)	0	1/35 (2.9%)	1
Hepatobiliary disorders
Cholecystitis	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/2 (0%)	0	1/35 (2.9%)	1
Infections and infestations
Infections and infestations - Other, specify	0/6 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/2 (0%)	0	0/35 (0%)	0
Upper respiratory infection	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/2 (50%)	1	0/35 (0%)	0
Injury, poisoning and procedural complications
Spinal fracture	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/2 (0%)	0	1/35 (2.9%)	1
Investigations
Alanine aminotransferase increased	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/2 (0%)	0	1/35 (2.9%)	1
Alkaline phosphatase increased	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/2 (0%)	0	1/35 (2.9%)	1
Aspartate aminotransferase increased	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/2 (0%)	0	2/35 (5.7%)	3
Blood bilirubin increased	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/2 (0%)	0	1/35 (2.9%)	1
Creatinine increased	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/2 (0%)	0	2/35 (5.7%)	2
White blood cell decreased	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/2 (0%)	0	1/35 (2.9%)	1
Metabolism and nutrition disorders
Dehydration	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/2 (0%)	0	1/35 (2.9%)	1
Hyperglycemia	0/6 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/2 (0%)	0	0/35 (0%)	0
Hypophosphatemia	0/6 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/2 (0%)	0	1/35 (2.9%)	2
Nervous system disorders
Presyncope	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/2 (0%)	0	2/35 (5.7%)	2
Syncope	1/6 (16.7%)	1	0/3 (0%)	0	0/3 (0%)	0	0/2 (0%)	0	2/35 (5.7%)	2
Psychiatric disorders
Confusion	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/2 (0%)	0	1/35 (2.9%)	1
Renal and urinary disorders
Acute kidney injury	1/6 (16.7%)	1	0/3 (0%)	0	0/3 (0%)	0	0/2 (0%)	0	0/35 (0%)	0
Respiratory, thoracic and mediastinal disorders
Dyspnea	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/2 (0%)	0	1/35 (2.9%)	1
Hypoxia	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/2 (0%)	0	2/35 (5.7%)	2
Sleep apnea	0/6 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/2 (0%)	0	0/35 (0%)	0
Vascular disorders
Hypertension	1/6 (16.7%)	1	0/3 (0%)	0	1/3 (33.3%)	1	0/2 (0%)	0	0/35 (0%)	0
Hypotension	0/6 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/2 (0%)	0	0/35 (0%)	0
Other (Not Including Serious) Adverse Events
	Phase 1; Dose Level 3		Phase 1; Dose Level 2		Phase 1; Dose Level 1		Phase 1; Dose Level 0		Phase 2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/6 (100%)		3/3 (100%)		3/3 (100%)		2/2 (100%)		35/35 (100%)
Blood and lymphatic system disorders
Anemia	6/6 (100%)	9	2/3 (66.7%)	2	3/3 (100%)	3	2/2 (100%)	3	31/35 (88.6%)	45
Febrile neutropenia	4/6 (66.7%)	4	0/3 (0%)	0	1/3 (33.3%)	1	0/2 (0%)	0	1/35 (2.9%)	1
Cardiac disorders
Atrial fibrillation	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/2 (0%)	0	1/35 (2.9%)	1
Cardiac disorders - Other, specify	1/6 (16.7%)	1	0/3 (0%)	0	0/3 (0%)	0	0/2 (0%)	0	0/35 (0%)	0
Gastrointestinal disorders
Abdominal pain	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/2 (0%)	0	1/35 (2.9%)	1
Diarrhea	1/6 (16.7%)	1	0/3 (0%)	0	0/3 (0%)	0	0/2 (0%)	0	6/35 (17.1%)	6
Dyspepsia	0/6 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/2 (0%)	0	0/35 (0%)	0
Esophagitis	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/2 (0%)	0	3/35 (8.6%)	3
Gastroesophageal reflux disease	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/2 (0%)	0	2/35 (5.7%)	2
Gastrointestinal disorders - Other, specify	1/6 (16.7%)	1	0/3 (0%)	0	0/3 (0%)	0	0/2 (0%)	0	0/35 (0%)	0
Mucositis oral	0/6 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/2 (0%)	0	3/35 (8.6%)	3
Nausea	1/6 (16.7%)	1	1/3 (33.3%)	1	0/3 (0%)	0	2/2 (100%)	3	8/35 (22.9%)	9
Vomiting	1/6 (16.7%)	1	1/3 (33.3%)	1	0/3 (0%)	0	1/2 (50%)	1	7/35 (20%)	8
General disorders
Fatigue	0/6 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	1/2 (50%)	1	15/35 (42.9%)	21
Fever	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/2 (0%)	0	2/35 (5.7%)	2
Pain	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/2 (0%)	0	1/35 (2.9%)	1
Infections and infestations
Infections and infestations - Other, specify	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/2 (50%)	1	0/35 (0%)	0
Lung infection	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/2 (0%)	0	1/35 (2.9%)	1
Investigations
Blood bilirubin increased	2/6 (33.3%)	2	0/3 (0%)	0	0/3 (0%)	0	0/2 (0%)	0	3/35 (8.6%)	5
CD4 lymphocytes decreased	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	2/2 (100%)	2	0/35 (0%)	0
Creatinine increased	4/6 (66.7%)	5	2/3 (66.7%)	4	1/3 (33.3%)	2	0/2 (0%)	0	14/35 (40%)	25
Lymphocyte count decreased	4/6 (66.7%)	7	3/3 (100%)	6	3/3 (100%)	6	2/2 (100%)	4	32/35 (91.4%)	76
Neutrophil count decreased	5/6 (83.3%)	6	3/3 (100%)	11	3/3 (100%)	3	2/2 (100%)	3	30/35 (85.7%)	66
Platelet count decreased	6/6 (100%)	14	3/3 (100%)	13	3/3 (100%)	8	2/2 (100%)	4	35/35 (100%)	100
Weight loss	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/2 (0%)	0	1/35 (2.9%)	1
White blood cell decreased	6/6 (100%)	11	3/3 (100%)	12	3/3 (100%)	4	2/2 (100%)	3	32/35 (91.4%)	82
Metabolism and nutrition disorders
Anorexia	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/2 (0%)	0	6/35 (17.1%)	6
Dehydration	1/6 (16.7%)	1	0/3 (0%)	0	1/3 (33.3%)	1	0/2 (0%)	0	2/35 (5.7%)	2
Hyperglycemia	1/6 (16.7%)	1	0/3 (0%)	0	1/3 (33.3%)	1	0/2 (0%)	0	5/35 (14.3%)	7
Hypoalbuminemia	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/2 (0%)	0	3/35 (8.6%)	3
Hypocalcemia	0/6 (0%)	0	1/3 (33.3%)	2	0/3 (0%)	0	0/2 (0%)	0	5/35 (14.3%)	6
Hypokalemia	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/2 (50%)	1	9/35 (25.7%)	10
Hyponatremia	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/2 (0%)	0	1/35 (2.9%)	1
Hypophosphatemia	2/6 (33.3%)	2	1/3 (33.3%)	1	0/3 (0%)	0	1/2 (50%)	1	12/35 (34.3%)	12
Musculoskeletal and connective tissue disorders
Bone pain	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/2 (0%)	0	1/35 (2.9%)	1
Pain in extremity	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/2 (0%)	0	1/35 (2.9%)	1
Nervous system disorders
Dizziness	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/2 (0%)	0	1/35 (2.9%)	1
Peripheral motor neuropathy	2/6 (33.3%)	6	0/3 (0%)	0	1/3 (33.3%)	3	0/2 (0%)	0	4/35 (11.4%)	8
Peripheral sensory neuropathy	3/6 (50%)	10	2/3 (66.7%)	4	2/3 (66.7%)	7	2/2 (100%)	8	19/35 (54.3%)	52
Respiratory, thoracic and mediastinal disorders
Dyspnea	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/2 (0%)	0	1/35 (2.9%)	1
Pulmonary edema	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/2 (0%)	0	1/35 (2.9%)	1
Sleep apnea	0/6 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/2 (0%)	0	0/35 (0%)	0
Skin and subcutaneous tissue disorders
Alopecia	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/2 (0%)	0	16/35 (45.7%)	18
Urticaria	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/2 (0%)	0	1/35 (2.9%)	1
Vascular disorders
Hypertension	1/6 (16.7%)	1	0/3 (0%)	0	0/3 (0%)	0	0/2 (0%)	0	3/35 (8.6%)	3
Hypotension	3/6 (50%)	3	3/3 (100%)	3	1/3 (33.3%)	1	0/2 (0%)	0	17/35 (48.6%)	19

Limitations/Caveats

[Not Specified]

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Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.