Carfilzomib, Lenalidomide, and Dexamethasone in New Multiple Myeloma Patients

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT01402284
• Collaborator: Celgene (Industry), Onyx Therapeutics, Inc. (Industry)
• Enrollment: 45
• Location: 1
• Arm: 1
• Actual Duration (Months): 110.2
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

Background:

• Carfilzomib is an experimental anti-cancer drug that has not yet been approved for treating multiple myeloma. Lenalidomide is a drug that may stop tumor growth and help the immune system kill cancer cells. Dexamethasone is a drug that helps stop inflammation. It is sometimes used to treat (alone or with other drugs) certain types of cancer, especially multiple myeloma. This combination of drugs has not been tested in people with multiple myeloma. Researchers want to see whether it is safe and effective for this group.

Objectives:

• To test the effectiveness of combined carfilzomib, lenalidomide, and dexamethasone in treating multiple myeloma.

Eligibility:

• People at least 18 years of age who have multiple myeloma that has not been treated.

Design:

• Participants will be screened with a medical history and physical exam. They will also have blood and urine tests, a bone marrow sample, and molecular imaging studies.

• Participants will have eight 28-day cycles of treatment. The combined study drugs will be given as tablets and injections. Those in the study will be monitored with frequent blood tests, bone marrow samples, and molecular imaging studies. In addition to current standard measures to determine clinical responses, molecular tests will be conducted to define evidence of minimal residual disease.

• After the first four cycles of therapy, those who are eligible for a stem cell transplant will have stem cells collected and stored for use if the cancer returns.

• After stem cell collection, participants will have the second four treatment cycles.

-, If the disease has improved or is stable at the end of eight cycles, those in the study may have another 12 cycles of low-dose (maintenance) lenalidomide alone.

• Participants will have regular follow-up visits after the end of the study chemotherapy.

Condition or Disease	Intervention/Treatment	Phase
Multiple Myeloma	Drug: Carfilzomib; Drug: Lenalidomide; Drug: Dexamethasone; Drug: Lenalidomide; Drug: Lenalidomide	Phase 2

Detailed Description

Background:

• Multiple myeloma (MM) is an incurable plasma cell neoplasm with a median survival of 3-4 years.

• Novel agent combinations with proteasome inhibitors demonstrate improved response rates while increasing survival in MM patients.

• A common debilitating side effect of the proteasome inhibitor bortezomib is neuropathy.

• Carfilzomib is a new proteasome inhibitor with potent anti-MM effects and decreased peripheral neuropathy

Objectives:

-Evaluate toxicity, including peripheral neuropathy, of carfilzomib, lenalidomide, and dexamethasone (CRd) in untreated MM patients

Eligibility:

• Newly diagnosed patients with histologically confirmed multiple myeloma

• Age greater than or equal to 18 years

• Creatinine Clearance (CrCl) greater than or equal to 60 ml/min. CrCl will be calculated using the Cockcroft- Gault method. If the calculated CrCl based on Cockcroft-Gault method is <60 mL/min, patient will have a 24 hr urine collection to measure CrCl. The measured CrCl must also be greater than or equal to 60 ml/min.

• Without serious co-morbidity that would interfere with receipt of CRd

• Absolute neutrophil count (ANC) greater than or equal to 1.0 K/uL, hemoglobin greater than or equal to 8 g/dL, and platelet count greater than or equal to 75 K/uL

• Adequate hepatic function, with bilirubin less than 1.5 x the upper limit of normal (ULN), and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than 3.0 x ULN

Design:

• Single arm, single stage phase II trial of combination therapy (carfilzomib, lenalidomide, and dexamethasone) for untreated multiple myeloma patients with an early stopping rule for toxicity

• Patients will receive 8 cycles of induction combination therapy of CRd

• Each cycle consists of 28-days

• After 4 cycles of therapy, transplant eligible patients will undergo stem cell collection

• Patients achieving stable disease or better after 8 cycles of CRd will receive lenalidomide extended dosing (phase I) for 12 cycles. After 12 cycles, patients will have the option to continue extended dosing (phase II) for one additional year.

• Patients will have routine blood work with serum protein electrophoresis (SPEP) and free light chains monthly

• Pre- and post-treatment bone marrow biopsies will be obtained for confirmation of diagnosis and correlative studies

• Patients will also undergo evaluation for minimal residual disease at regular interval time points, using multi-parametric flow cytometry and fludeoxyglucose 18F-positron emission tomography - computed tomography (FDG PET-CT)

• A single stage phase II design will be employed, with an early stopping rule. Unless 4 or more patients in the first 20 have Grade 3 or higher neurologic toxicity in the first 2 completed cycles, a total of 45 evaluable patients will be enrolled in this study.

Study Design

• Study Type: Interventional
• Actual Enrollment: 45 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Carfilzomib, Lenalidomide, and Dexamethasone in Newly Diagnosed Multiple Myeloma: Clinical and Correlative Phase II Study
• Actual Study Start Date: Jul 21, 2011
• Actual Primary Completion Date: Jul 10, 2016
• Actual Study Completion Date: Sep 24, 2020

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Carfilzomib, Lenalidomide, Dexamethasone Patients will receive 8 cycles of induction combination therapy of carfilzomib, lenalidomide, and dexamethasone (CRd). Patients achieving stable disease or better after 8 cycles of CRd will receive lenalidomide extended dosing (phase I) for 12 cycles. After 12 cycles, patients will have the option to continue extended dosing (phase II) for one additional year

Drug: Carfilzomib; Cycle 1: 20 mg/m(2) intravenous (IV) infusion over 30 minutes on days 1 and 2, then 36 mg/m(2) IV on days 8, 9, 15, and 16 Cycle 2-8: 36mg/ m(2) IV infusion over 30 minutes on days 1, 2, 8, 9, 15, and 16; Other Names: Kyprolis ; Drug: Lenalidomide; Cycle 1: 25 mg oral days 2-21 of 28-day cycle; Cycle 2 - 8: 25 mg oral days 1-21 of 28-day cycle; After 8 cycles of combination carfilzomib, lenalidomide, and dexamethasone (CRd), patients may continue Lenalidomide for 12 cycles; After 12 cycles of extended dosing of Lenalidomide, patients may continue Lenalidomide for one year; Other Names: Revlimid ; Drug: Dexamethasone; Cycle 1: 20 mg oral or IV on days 2, 8, 9, 15, 16, 22, and 23 Cycle 2-4: 20 mg oral or IV on days 1, 2, 8, 9, 15, 16, 22, and 23 Cycle 5-8: 10 mg oral or IV on days 1, 2, 8, 9, 15, 16, 22, and 23; Other Names: Ozurdex ; Drug: Lenalidomide; After 8 cycles of combination carfilzomib, lenalidomide, and dexamethasone (CRd), patients may continue Lenalidomide for 12 cycles; Other Names: Revlimid ; Drug: Lenalidomide; After 12 cycles of extended dosing of Lenalidomide, patients may continue Lenalidomide for one year; Other Names: Revlimid

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Serious and Non-serious Adverse Events [4 years and 9 months and 2 days]

   Here is the number of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

Secondary Outcome Measures

1. Overall Response Rate [48.3 months]

   Response is assessed by the International Myeloma Working Group Criteria. Patients who attained a partial response or better (BoR) response by the end of induction. Partial response is ≥50% reduction of serum M-protein and reduction in 24h urinary M-protein.

2. Progression Free Survival (PFS) at 48 Months [48 months]

   PFS is defined as time of start of treatment to time of progression or death, whichever occurs first. Response is assessed by the International Myeloma Working Group Criteria. Progressive disease requires any one or more of the following: increase of ≥25% from lowest response value in the following on 2 consecutive measurements: serum M-component and/or (the absolute increase must be ≥0.5g/dl). Urine M-component and/or (the absolute increase must be ≥200mg/24h. Only in patients without measurable serum and urine M-protein levels: the difference between involved and uninvolved free light chain (FLC) levels. The absolute increase must be >10mg/dl. Bone marrow plasma cell percentage: the absolute % must be ≥10%. Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in size of existing bone lesions or soft tissue plasmacytomas. Development of hypercalcemia that can be attributed solely to the plasma cell proliferative disorder.

3. Percentage of Responders With Duration of Response (DOR) at 48 Months [48 months]

   Response is assessed by the International Myeloma Working Group Criteria. DOR is measured from the time measurement criteria are met for a partial response or better until first date that recurrent or progressive disease is objectively documented. Partial response is ≥50% reduction of serum M-protein and reduction in 24-h urinary M-protein by ≥90% or to <200mg per 24h. Progressive disease requires any one or more of the following: increase of ≥25% from lowest response value in the following on 2 consecutive measurements: serum M-component and/or (the absolute increase must be ≥0.5g/dl). Urine M-component and/or (the absolute increase must be ≥200mg/24h. Only in patients without measurable serum and urine M-protein levels: the difference between involved and uninvolved free light chain (FLC) levels. The absolute increase must be >10mg/dl. Bone marrow plasma cell percentage: the absolute % must be ≥10%.

4. Overall Survival (OS) Rate [up to 6 months]

   OS is defined as the time of start of treatment to death from any cause.

5. Cluster of Differentiation 138 (CD138) + Plasma Cells Gene Expression Profiling on Pre and Post Carfilzomib Exposure Bone Marrow Samples [Cycle 1 Day 1, an average of 28 days ± 2 days]

   Cluster of differentiation 138+ (CD138)+ plasma cells purified from bone marrow aspirates to identify potential markers of early progression. Changes in selected genes were confirmed by quantitative polymerase chain reaction (PCR) if suggested to be related to risk of progression to multiple myeloma.

6. Rate of Minimal Residual Disease (MRD) by Flow Cytometry [Day 100]

   Response is assessed by the International Myeloma Working Group Criteria. Complete response is negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and ≤ 5% plasma cells in bone marrow. MRD is defined by M-spike, plasma cell burden, and abnormal free light chains. Immunophenotyping is performed by multi-parametric flow cytometry.

7. Complete Response (CR) and Minimal Residual Disease Neg (MRDneg) CR Rates at Treatment Intervals With Carfilzomib, Lenalidomide & Dexamethasone (CRd) in New Multiple Myeloma Patients After 8 Cycles of Induction, 1 Year Maintenance, and 2 Years Maintenance [up to 2 years]

   Response is assessed by the International Myeloma Working Group Criteria. MRD is defined by M-spike, plasma cell burden, and abnormal free light chains (FLC). Complete response is negative immunofixation on serum, and urine and disappearance of any soft tissue plasmacytomas and ≤ 5% plasma cells in bone marrow. Stringent complete response (sCR) is normal FLC ratio and absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescence. Near complete response (nCR) is the absence of myeloma protein on electrophoresis, independent of immunofixation status. Very good partial response (VGPR) is serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein plus urine M-protein level <100mg per 24h. Overall response rate (ORR) is patients who attained a partial response (PR) (≥50% reduction of serum M-protein and reduction in 24h urinary M-protein) or better (BoR) response.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 99 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

• INCLUSION CRITERIA:

• Newly diagnosed patients with histologically confirmed multiple myeloma (MM) based on the following criteria:

1. Clonal plasma cells in the bone marrow

2. Measurable disease within the past 4 weeks defined by any one of the following:

3. Serum monoclonal protein greater than or equal to 1.0 g/dL

4. Urine monoclonal protein greater than 200 mg/24 hour

5. Serum immunoglobulin free light chain greater than 10 mg/dL AND abnormal kappa/lambda ratio

6. Evidence of underlying end organ damage attributed to underlying plasma cell proliferative disorder meeting at least one of the following:

7. Hypercalcemia: serum calcium greater than or equal to 2.65 mmol/L

8. Renal Insufficiency: serum creatinine greater than 2.0 mg/dL

9. Anemia: hemoglobin value less than10 g/dL or 2 g/dL less than normal reference

10. Bone disease: lytic lesions, severe osteopenia or pathological fractures

• Creatinine Clearance (CrCl) greater than or equal to 60 ml/min. CrCl will be calculated by Cockcroft-Gault method. CrCl (calculated) = (140 Age) x Mass (in kilograms) x [0.85 if Female] 72 times Serum Creatinine (in mg/dL). If calculated CrCl based on Cockcroft-Gault method is <60 mL/min, patient will have a 24 hr urine collection to measure CrCl. The measured CrCl must be also greater than or equal to 60 ml/min.

• Age greater than or equal to 18 years. Because no dosing or adverse event data are currently available on the use of carfilzomib in combination with lenalidomide in patients less than18 years of age, children are excluded from this study, but will be eligible for future pediatric trials.

• Eastern Cooperative Oncology Group (ECOG) performance status 0-2

• Absolute neutrophil count (ANC) greater than or equal to 1.0 K/uL, hemoglobin greater than or equal to 8 g/dL (transfusions are permissible), and platelet count greater than or equal to 75 K/uL

• Adequate hepatic function, with bilirubin less than 1.5 times the upper limit of normal (ULN), and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than 3.0 times ULN.

• All study participants must be able to tolerate one of the following thromboprophylactic strategies: aspirin, low molecular weight heparin or warfarin (coumadin).

• All study participants must be registered into the mandatory RevAssist program, and be willing and able to comply with the requirements of RevAssist .

• Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test within 10-14 days and again within 24 hours prior to prescribing lenalidomide for Cycle 1 (prescriptions must be filled within 7 days) 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 lenalidomide. Females of child bearing potential (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 successful vasectomy.

• Subjects must be able to give informed consent

EXCLUSION CRITERIA:

• Prior or concurrent systemic treatment for MM.

• Treatment of hypercalcemia or spinal cord compression or aggressively progressing myeloma with corticosteroids is permitted.

• Bisphosphonates are permitted.

• Treatment with corticosteroids for indications other than MM is permitted.

• Radiotherapy is permitted.

• Treatment for smoldering myeloma is permitted.

• Plasma cell leukemia

• Pregnant or lactating females. Because there is a potential risk for adverse events in nursing infants secondary to treatment of the mother with carfilzomib in combination with lenalidomide, breastfeeding should be discontinued if the mother is treated with carfilzomib and lenalidomide. These potential risks may also apply to other agents used in this study.

• Uncontrolled hypertension or diabetes

• Active hepatitis B or C infection

• Has significant cardiovascular disease with New York Heart Association (NYHA) Class III or IV symptoms, or hypertrophic cardiomyopathy, or restrictive cardiomyopathy, or myocardial infarction within 3 months prior to enrollment, or unstable angina, or unstable arrhythmia as determined by history and physical examination. Echocardiogram will be performed if clinically warranted.

• Has refractory gastrointestinal (GI) disease with refractory nausea/vomiting, inflammatory bowel disease, or bowel resection that would prevent absorption

• Uncontrolled intercurrent illness including but not limited to active infection or psychiatric illness/social situations that would compromise compliance with study requirements

• Significant neuropathy greater than or equal to Grade 3 at baseline

• Contraindication to any concomitant medication, including antivirals, anticoagulation prophylaxis, tumor lysis prophylaxis, or hydration given prior to therapy

• Major surgery within 1 month prior to enrollment

• Recruitment Strategies:

• Patients that progress from the smoldering multiple myeloma (SMM) and monoclonal gammopathy of undetermined significance (MGUS) Natural History Study (NCI Protocol: 10-C-0096) will be potential candidates.

• Other participant sources will be from outside physician referrals.

• Our ongoing natural history study and outside physician referral network has a high representation of minorities.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	National Institutes of Health Clinical Center, 9000 Rockville Pike	Bethesda	Maryland	United States	20892

Sponsors and Collaborators

• National Cancer Institute (NCI)
• Celgene
• Onyx Therapeutics, Inc.

Investigators

• Principal Investigator: Dickran Kazandjian, M.D., National Cancer Institute (NCI)

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Mar 27, 2020
• Informed Consent Form - Apr 20, 2020

More Information

Additional Information:

• NIH Clinical Center Detailed Web Page

Publications

• International Myeloma Working Group. Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group. Br J Haematol. 2003 Jun;121(5):749-57.
• Kristinsson SY, Landgren O, Dickman PW, Derolf AR, Björkholm M. Patterns of survival in multiple myeloma: a population-based study of patients diagnosed in Sweden from 1973 to 2003. J Clin Oncol. 2007 May 20;25(15):1993-9. Epub 2007 Apr 9.
• Kumar SK, Rajkumar SV, Dispenzieri A, Lacy MQ, Hayman SR, Buadi FK, Zeldenrust SR, Dingli D, Russell SJ, Lust JA, Greipp PR, Kyle RA, Gertz MA. Improved survival in multiple myeloma and the impact of novel therapies. Blood. 2008 Mar 1;111(5):2516-20. Epub 2007 Nov 1.

• Responsible Party: Dickran Kazandjian, M.D., Principal Investigator, National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT01402284
• Other Study ID Numbers: 110221; 11-C-0221
• First Posted: Jul 26, 2011
• Last Update Posted: Mar 2, 2021
• Last Verified: Feb 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Dickran Kazandjian, M.D., Principal Investigator, National Cancer Institute (NCI): Novel Drug Combinations; Protease Inhibitors; Decreased Peripheral Neuropathy; Auto Stem Cell Transplant; Multiple Myeloma
• Additional relevant MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell; Dexamethasone; Lenalidomide

Study Results

Participant Flow

Arm/Group Title	Carfilzomib, Lenalidomide, and Dexamethasone Therapy
Arm/Group Description	Patients will receive 8 cycles of induction combination therapy of carfilzomib, lenalidomide, and dexamethasone (CRd). Patients achieving stable disease or better after 8 cycles of CRd will receive lenalidomide extended dosing (phase I) for 12 cycles. After 12 cycles, patients will have the option to continue extended dosing (phase II) for one additional year Carfilzomib: Cycle 1: 20 mg/m(2) intravenous (IV) infusion over 30 minutes on days 1 and 2, then 36 mg/m(2) IV on days 8, 9, 15, and 16 Cycle 2-8: 36mg/ m(2) IV infusion over 30 minutes on days 1, 2, 8, 9, 15, and 16 Lenalidomide: Cycle 1: 25 mg oral days 2-21 of 28-day cycle; Cycle 2 - 8: 25 mg oral days 1-21 of 28-day cycle; After 8 cycles of combination carfilzomib, lenalidomide, and dexamethasone (CRd), patients may continue Lenalidomide for 12 cycles; After 12 cycles of extended dosing of Lenalidomide, patients may continue Lenalidomide for one year Dexamethasone: Cycle 1: 20 mg oral or IV on days 2, 8, 9, 15, 16, 22,
Period Title: Overall Study
STARTED	45
COMPLETED	31
NOT COMPLETED	14

Baseline Characteristics

Arm/Group Title	Carfilzomib, Lenalidomide, and Dexamethasone
Arm/Group Description	Patients will receive 8 cycles of induction combination therapy of carfilzomib, lenalidomide, and dexamethasone (CRd). Patients achieving stable disease or better after 8 cycles of CRd will receive lenalidomide extended dosing (phase I) for 12 cycles. After 12 cycles, patients will have the option to continue extended dosing (phase II) for one additional year Carfilzomib: Cycle 1: 20 mg/m(2) intravenous (IV) infusion over 30 minutes on days 1 and 2, then 36 mg/m(2) IV on days 8, 9, 15, and 16 Cycle 2-8: 36mg/ m(2) IV infusion over 30 minutes on days 1, 2, 8, 9, 15, and 16 Lenalidomide: Cycle 1: 25 mg oral days 2-21 of 28-day cycle; Cycle 2 - 8: 25 mg oral days 1-21 of 28-day cycle; After 8 cycles of combination carfilzomib, lenalidomide, and dexamethasone (CRd), patients may continue Lenalidomide for 12 cycles; After 12 cycles of extended dosing of Lenalidomide, patients may continue Lenalidomide for one year Dexamethasone: Cycle 1: 20 mg oral or IV on days 2, 8, 9, 15, 16, 22,
Overall Participants	45
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	26 57.8%
>=65 years	19 42.2%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	60
Sex: Female, Male (Count of Participants)
Female	18 40%
Male	27 60%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	45 100%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	2 4.4%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	6 13.3%
White	37 82.2%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (Count of Participants)
United States	45 100%
Isotypes (percentage of participants) [Number]
IgG kappa	51 113.3%
IgG lambda	16 35.6%
IgA kappa	9 20%
IgA lambda	9 20%
Free kappa	9 20%
Free lambda	4 8.9%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Serious and Non-serious Adverse Events
Description	Here is the number of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.
Time Frame	4 years and 9 months and 2 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Carfilzomib, Lenalidomide, and Dexamethasone
Arm/Group Description	Patients will receive 8 cycles of induction combination therapy of carfilzomib, lenalidomide, and dexamethasone (CRd). Patients achieving stable disease or better after 8 cycles of CRd will receive lenalidomide extended dosing (phase I) for 12 cycles. After 12 cycles, patients will have the option to continue extended dosing (phase II) for one additional year Carfilzomib: Cycle 1: 20 mg/m(2) intravenous (IV) infusion over 30 minutes on days 1 and 2, then 36 mg/m(2) IV on days 8, 9, 15, and 16 Cycle 2-8: 36mg/ m(2) IV infusion over 30 minutes on days 1, 2, 8, 9, 15, and 16 Lenalidomide: Cycle 1: 25 mg oral days 2-21 of 28-day cycle; Cycle 2 - 8: 25 mg oral days 1-21 of 28-day cycle; After 8 cycles of combination carfilzomib, lenalidomide, and dexamethasone (CRd), patients may continue Lenalidomide for 12 cycles; After 12 cycles of extended dosing of Lenalidomide, patients may continue Lenalidomide for one year Dexamethasone: Cycle 1: 20 mg oral or IV on days 2, 8, 9, 15, 16, 22,
Measure Participants	45
Count of Participants [Participants]	45 100%

2. Secondary Outcome

Title	Overall Response Rate
Description	Response is assessed by the International Myeloma Working Group Criteria. Patients who attained a partial response or better (BoR) response by the end of induction. Partial response is ≥50% reduction of serum M-protein and reduction in 24h urinary M-protein.
Time Frame	48.3 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Carfilzomib, Lenalidomide, and Dexamethasone
Arm/Group Description	Patients will receive 8 cycles of induction combination therapy of carfilzomib, lenalidomide, and dexamethasone (CRd). Patients achieving stable disease or better after 8 cycles of CRd will receive lenalidomide extended dosing (phase I) for 12 cycles. After 12 cycles, patients will have the option to continue extended dosing (phase II) for one additional year Carfilzomib: Cycle 1: 20 mg/m(2) intravenous (IV) infusion over 30 minutes on days 1 and 2, then 36 mg/m(2) IV on days 8, 9, 15, and 16 Cycle 2-8: 36mg/ m(2) IV infusion over 30 minutes on days 1, 2, 8, 9, 15, and 16 Lenalidomide: Cycle 1: 25 mg oral days 2-21 of 28-day cycle; Cycle 2 - 8: 25 mg oral days 1-21 of 28-day cycle; After 8 cycles of combination carfilzomib, lenalidomide, and dexamethasone (CRd), patients may continue Lenalidomide for 12 cycles; After 12 cycles of extended dosing of Lenalidomide, patients may continue Lenalidomide for one year Dexamethasone: Cycle 1: 20 mg oral or IV on days 2, 8, 9, 15, 16, 22,
Measure Participants	45
Number (95% Confidence Interval) [percentage of participants]	97.8 217.3%

3. Secondary Outcome

Title	Progression Free Survival (PFS) at 48 Months
Description	PFS is defined as time of start of treatment to time of progression or death, whichever occurs first. Response is assessed by the International Myeloma Working Group Criteria. Progressive disease requires any one or more of the following: increase of ≥25% from lowest response value in the following on 2 consecutive measurements: serum M-component and/or (the absolute increase must be ≥0.5g/dl). Urine M-component and/or (the absolute increase must be ≥200mg/24h. Only in patients without measurable serum and urine M-protein levels: the difference between involved and uninvolved free light chain (FLC) levels. The absolute increase must be >10mg/dl. Bone marrow plasma cell percentage: the absolute % must be ≥10%. Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in size of existing bone lesions or soft tissue plasmacytomas. Development of hypercalcemia that can be attributed solely to the plasma cell proliferative disorder.
Time Frame	48 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Carfilzomib, Lenalidomide, and Dexamethasone
Arm/Group Description	Patients will receive 8 cycles of induction combination therapy of carfilzomib, lenalidomide, and dexamethasone (CRd). Patients achieving stable disease or better after 8 cycles of CRd will receive lenalidomide extended dosing (phase I) for 12 cycles. After 12 cycles, patients will have the option to continue extended dosing (phase II) for one additional year Carfilzomib: Cycle 1: 20 mg/m(2) intravenous (IV) infusion over 30 minutes on days 1 and 2, then 36 mg/m(2) IV on days 8, 9, 15, and 16 Cycle 2-8: 36mg/ m(2) IV infusion over 30 minutes on days 1, 2, 8, 9, 15, and 16 Lenalidomide: Cycle 1: 25 mg oral days 2-21 of 28-day cycle; Cycle 2 - 8: 25 mg oral days 1-21 of 28-day cycle; After 8 cycles of combination carfilzomib, lenalidomide, and dexamethasone (CRd), patients may continue Lenalidomide for 12 cycles; After 12 cycles of extended dosing of Lenalidomide, patients may continue Lenalidomide for one year Dexamethasone: Cycle 1: 20 mg oral or IV on days 2, 8, 9, 15, 16, 22,
Measure Participants	45
Number (95% Confidence Interval) [percentage of participants]	79.2 176%

4. Secondary Outcome

Title	Percentage of Responders With Duration of Response (DOR) at 48 Months
Description	Response is assessed by the International Myeloma Working Group Criteria. DOR is measured from the time measurement criteria are met for a partial response or better until first date that recurrent or progressive disease is objectively documented. Partial response is ≥50% reduction of serum M-protein and reduction in 24-h urinary M-protein by ≥90% or to <200mg per 24h. Progressive disease requires any one or more of the following: increase of ≥25% from lowest response value in the following on 2 consecutive measurements: serum M-component and/or (the absolute increase must be ≥0.5g/dl). Urine M-component and/or (the absolute increase must be ≥200mg/24h. Only in patients without measurable serum and urine M-protein levels: the difference between involved and uninvolved free light chain (FLC) levels. The absolute increase must be >10mg/dl. Bone marrow plasma cell percentage: the absolute % must be ≥10%.
Time Frame	48 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Carfilzomib, Lenalidomide, and Dexamethasone
Arm/Group Description	Patients will receive 8 cycles of induction combination therapy of carfilzomib, lenalidomide, and dexamethasone (CRd). Patients achieving stable disease or better after 8 cycles of CRd will receive lenalidomide extended dosing (phase I) for 12 cycles. After 12 cycles, patients will have the option to continue extended dosing (phase II) for one additional year Carfilzomib: Cycle 1: 20 mg/m(2) intravenous (IV) infusion over 30 minutes on days 1 and 2, then 36 mg/m(2) IV on days 8, 9, 15, and 16 Cycle 2-8: 36mg/ m(2) IV infusion over 30 minutes on days 1, 2, 8, 9, 15, and 16 Lenalidomide: Cycle 1: 25 mg oral days 2-21 of 28-day cycle; Cycle 2 - 8: 25 mg oral days 1-21 of 28-day cycle; After 8 cycles of combination carfilzomib, lenalidomide, and dexamethasone (CRd), patients may continue Lenalidomide for 12 cycles; After 12 cycles of extended dosing of Lenalidomide, patients may continue Lenalidomide for one year Dexamethasone: Cycle 1: 20 mg oral or IV on days 2, 8, 9, 15, 16, 22,
Measure Participants	45
Number (95% Confidence Interval) [percentage of participants]	81.1 180.2%

5. Secondary Outcome

Title	Overall Survival (OS) Rate
Description	OS is defined as the time of start of treatment to death from any cause.
Time Frame	up to 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Carfilzomib, Lenalidomide, and Dexamethasone
Arm/Group Description	Patients will receive 8 cycles of induction combination therapy of carfilzomib, lenalidomide, and dexamethasone (CRd). Patients achieving stable disease or better after 8 cycles of CRd will receive lenalidomide extended dosing (phase I) for 12 cycles. After 12 cycles, patients will have the option to continue extended dosing (phase II) for one additional year Carfilzomib: Cycle 1: 20 mg/m(2) intravenous (IV) infusion over 30 minutes on days 1 and 2, then 36 mg/m(2) IV on days 8, 9, 15, and 16 Cycle 2-8: 36mg/ m(2) IV infusion over 30 minutes on days 1, 2, 8, 9, 15, and 16 Lenalidomide: Cycle 1: 25 mg oral days 2-21 of 28-day cycle; Cycle 2 - 8: 25 mg oral days 1-21 of 28-day cycle; After 8 cycles of combination carfilzomib, lenalidomide, and dexamethasone (CRd), patients may continue Lenalidomide for 12 cycles; After 12 cycles of extended dosing of Lenalidomide, patients may continue Lenalidomide for one year Dexamethasone: Cycle 1: 20 mg oral or IV on days 2, 8, 9, 15, 16, 22,
Measure Participants	45
Number (95% Confidence Interval) [percentage of participants]	89.5 198.9%

6. Secondary Outcome

Title	Cluster of Differentiation 138 (CD138) + Plasma Cells Gene Expression Profiling on Pre and Post Carfilzomib Exposure Bone Marrow Samples
Description	Cluster of differentiation 138+ (CD138)+ plasma cells purified from bone marrow aspirates to identify potential markers of early progression. Changes in selected genes were confirmed by quantitative polymerase chain reaction (PCR) if suggested to be related to risk of progression to multiple myeloma.
Time Frame	Cycle 1 Day 1, an average of 28 days ± 2 days

Outcome Measure Data

Analysis Population Description

Data were not collected due to lack of financial resources.

Arm/Group Title	Carfilzomib, Lenalidomide, and Dexamethasone
Arm/Group Description	Patients will receive 8 cycles of induction combination therapy of carfilzomib, lenalidomide, and dexamethasone (CRd). Patients achieving stable disease or better after 8 cycles of CRd will receive lenalidomide extended dosing (phase I) for 12 cycles. After 12 cycles, patients will have the option to continue extended dosing (phase II) for one additional year Carfilzomib: Cycle 1: 20 mg/m(2) intravenous (IV) infusion over 30 minutes on days 1 and 2, then 36 mg/m(2) IV on days 8, 9, 15, and 16 Cycle 2-8: 36mg/ m(2) IV infusion over 30 minutes on days 1, 2, 8, 9, 15, and 16 Lenalidomide: Cycle 1: 25 mg oral days 2-21 of 28-day cycle; Cycle 2 - 8: 25 mg oral days 1-21 of 28-day cycle; After 8 cycles of combination carfilzomib, lenalidomide, and dexamethasone (CRd), patients may continue Lenalidomide for 12 cycles; After 12 cycles of extended dosing of Lenalidomide, patients may continue Lenalidomide for one year Dexamethasone: Cycle 1: 20 mg oral or IV on days 2, 8, 9, 15, 16, 22,
Measure Participants	0

7. Secondary Outcome

Title	Rate of Minimal Residual Disease (MRD) by Flow Cytometry
Description	Response is assessed by the International Myeloma Working Group Criteria. Complete response is negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and ≤ 5% plasma cells in bone marrow. MRD is defined by M-spike, plasma cell burden, and abnormal free light chains. Immunophenotyping is performed by multi-parametric flow cytometry.
Time Frame	Day 100

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Carfilzomib, Lenalidomide, and Dexamethasone
Arm/Group Description	Patients will receive 8 cycles of induction combination therapy of carfilzomib, lenalidomide, and dexamethasone (CRd). Patients achieving stable disease or better after 8 cycles of CRd will receive lenalidomide extended dosing (phase I) for 12 cycles. After 12 cycles, patients will have the option to continue extended dosing (phase II) for one additional year Carfilzomib: Cycle 1: 20 mg/m(2) intravenous (IV) infusion over 30 minutes on days 1 and 2, then 36 mg/m(2) IV on days 8, 9, 15, and 16 Cycle 2-8: 36mg/ m(2) IV infusion over 30 minutes on days 1, 2, 8, 9, 15, and 16 Lenalidomide: Cycle 1: 25 mg oral days 2-21 of 28-day cycle; Cycle 2 - 8: 25 mg oral days 1-21 of 28-day cycle; After 8 cycles of combination carfilzomib, lenalidomide, and dexamethasone (CRd), patients may continue Lenalidomide for 12 cycles; After 12 cycles of extended dosing of Lenalidomide, patients may continue Lenalidomide for one year Dexamethasone: Cycle 1: 20 mg oral or IV on days 2, 8, 9, 15, 16, 22,
Measure Participants	45
Number (95% Confidence Interval) [percentage of participants]	44.4 98.7%

8. Secondary Outcome

Title	Complete Response (CR) and Minimal Residual Disease Neg (MRDneg) CR Rates at Treatment Intervals With Carfilzomib, Lenalidomide & Dexamethasone (CRd) in New Multiple Myeloma Patients After 8 Cycles of Induction, 1 Year Maintenance, and 2 Years Maintenance
Description	Response is assessed by the International Myeloma Working Group Criteria. MRD is defined by M-spike, plasma cell burden, and abnormal free light chains (FLC). Complete response is negative immunofixation on serum, and urine and disappearance of any soft tissue plasmacytomas and ≤ 5% plasma cells in bone marrow. Stringent complete response (sCR) is normal FLC ratio and absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescence. Near complete response (nCR) is the absence of myeloma protein on electrophoresis, independent of immunofixation status. Very good partial response (VGPR) is serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein plus urine M-protein level <100mg per 24h. Overall response rate (ORR) is patients who attained a partial response (PR) (≥50% reduction of serum M-protein and reduction in 24h urinary M-protein) or better (BoR) response.
Time Frame	up to 2 years

Outcome Measure Data

Analysis Population Description

*Six patients withdrew from the study, four due to non-compliance and two to continue treatment at another institution. 'One patient refused to have a bone marrow biopsy procedure and one patient withdrew due to non-compliance. CR (n=0) after 8 cycles.

Arm/Group Title	Carfilzomib, Lenalidomide, and Dexamethasone
Arm/Group Description	Patients will receive 8 cycles of induction combination therapy of carfilzomib, lenalidomide, and dexamethasone (CRd). Patients achieving stable disease or better after 8 cycles of CRd will receive lenalidomide extended dosing (phase I) for 12 cycles. After 12 cycles, patients will have the option to continue extended dosing (phase II) for one additional year Carfilzomib: Cycle 1: 20 mg/m(2) intravenous (IV) infusion over 30 minutes on days 1 and 2, then 36 mg/m(2) IV on days 8, 9, 15, and 16 Cycle 2-8: 36mg/ m(2) IV infusion over 30 minutes on days 1, 2, 8, 9, 15, and 16 Lenalidomide: Cycle 1: 25 mg oral days 2-21 of 28-day cycle; Cycle 2 - 8: 25 mg oral days 1-21 of 28-day cycle; After 8 cycles of combination carfilzomib, lenalidomide, and dexamethasone (CRd), patients may continue Lenalidomide for 12 cycles; After 12 cycles of extended dosing of Lenalidomide, patients may continue Lenalidomide for one year Dexamethasone: Cycle 1: 20 mg oral or IV on days 2, 8, 9, 15, 16, 22,
Measure Participants	45
sCR/CR after 8 cycles	46.7 103.8%
MRDnegCR after 8 cycles	44.4 98.7%
nCR after 8 cycles	20 44.4%
≥VGPR after 8 cycles	89 197.8%
ORR after 8 cycles	97.8 217.3%
sCR after 8 cycles	46.7 103.8%
sCR/CR after 1 year	62.2 138.2%
sCR after 1 year	60.0 133.3%
CR after 1 year	2.2 4.9%
MRDnegCR after 1 year'	53.5 118.9%
nCR after 1 year	11.1 24.7%
≥VGPR after 1 year	89 197.8%
ORR after 1 year	97.8 217.3%
sCR/CR after 2 years	64.4 143.1%
sCR after 2 years	62.2 138.2%
CR after 2 years	2.2 4.9%
MRDnegCR after 2 years*	46.2 102.7%
nCR after 2 years	11.1 24.7%
≥VGPR after 2 years	91.1 202.4%
ORR after 2 years	97.8 217.3%

Adverse Events

Time Frame	4 years and 9 months and 2 days
Arm/Group Title	Carfilzomib, Lenalidomide, and Dexamethasone
Arm/Group Description	Patients will receive 8 cycles of induction combination therapy of carfilzomib, lenalidomide, and dexamethasone (CRd). Patients achieving stable disease or better after 8 cycles of CRd will receive lenalidomide extended dosing (phase I) for 12 cycles. After 12 cycles, patients will have the option to continue extended dosing (phase II) for one additional year Carfilzomib: Cycle 1: 20 mg/m(2) intravenous (IV) infusion over 30 minutes on days 1 and 2, then 36 mg/m(2) IV on days 8, 9, 15, and 16 Cycle 2-8: 36mg/ m(2) IV infusion over 30 minutes on days 1, 2, 8, 9, 15, and 16 Lenalidomide: Cycle 1: 25 mg oral days 2-21 of 28-day cycle; Cycle 2 - 8: 25 mg oral days 1-21 of 28-day cycle; After 8 cycles of combination carfilzomib, lenalidomide, and dexamethasone (CRd), patients may continue Lenalidomide for 12 cycles; After 12 cycles of extended dosing of Lenalidomide, patients may continue Lenalidomide for one year Dexamethasone: Cycle 1: 20 mg oral or IV on days 2, 8, 9, 15, 16, 22,
All Cause Mortality
	Carfilzomib, Lenalidomide, and Dexamethasone
	Affected / at Risk (%)	# Events
Total	3/45 (6.7%)
Serious Adverse Events
	Carfilzomib, Lenalidomide, and Dexamethasone
	Affected / at Risk (%)	# Events
Total	19/45 (42.2%)
Blood and lymphatic system disorders
Anemia	4/45 (8.9%)	8
Cardiac disorders
Supraventricular tachycardia	1/45 (2.2%)	1
Endocrine disorders
Adrenal insufficiency	1/45 (2.2%)	2
Gastrointestinal disorders
Diarrhea	1/45 (2.2%)	1
Enterocolitis infectious	2/45 (4.4%)	2
General disorders
Edema limbs	2/45 (4.4%)	2
Fatigue	1/45 (2.2%)	3
Fever	3/45 (6.7%)	3
General disorders and administration site conditions - Other, night sweats/tremors	1/45 (2.2%)	1
Death	2/45 (4.4%)	45
Hepatobiliary disorders
Cholecystitis	1/45 (2.2%)	1
Immune system disorders
Cytokine release syndrome	1/45 (2.2%)	1
Infections and infestations
Infections and infestations - Other, specify	1/45 (2.2%)	1
Lung infection	3/45 (6.7%)	3
Investigations
Alanine aminotransferase increased	1/45 (2.2%)	1
CD4 lymphocytes decreased	1/45 (2.2%)	1
Creatinine increased	2/45 (4.4%)	3
Lymphocyte count decreased	3/45 (6.7%)	4
Neutrophil count decreased	1/45 (2.2%)	1
Platelet count decreased	2/45 (4.4%)	4
White blood cell decreased	1/45 (2.2%)	1
Metabolism and nutrition disorders
Dehydration	2/45 (4.4%)	3
Hypercalcemia	1/45 (2.2%)	1
Hyponatremia	2/45 (4.4%)	2
Musculoskeletal and connective tissue disorders
Myalgia	1/45 (2.2%)	1
Nervous system disorders
Presyncope	1/45 (2.2%)	1
Psychiatric disorders
Confusion	1/45 (2.2%)	1
Respiratory, thoracic and mediastinal disorders
Bronchospasm	1/45 (2.2%)	1
Dyspnea	5/45 (11.1%)	10
Hiccups	1/45 (2.2%)	1
Hypoxia	1/45 (2.2%)	1
Pleural effusion	2/45 (4.4%)	2
Respiratory failure	1/45 (2.2%)	1
Vascular disorders
Hypertension	1/45 (2.2%)	1
Hypotension	2/45 (4.4%)	3
Thromboembolic event	6/45 (13.3%)	6
Other (Not Including Serious) Adverse Events
	Carfilzomib, Lenalidomide, and Dexamethasone
	Affected / at Risk (%)	# Events
Total	45/45 (100%)
Blood and lymphatic system disorders
Anemia	34/45 (75.6%)	148
Febrile neutropenia	1/45 (2.2%)	1
Cardiac disorders
Atrioventricular block first degree	1/45 (2.2%)	1
Cardiac disorders - Other, cardiac NOS	1/45 (2.2%)	1
Electrocardiogram QT corrected interval prolonged	1/45 (2.2%)	1
Heart failure	2/45 (4.4%)	2
Palpitations	3/45 (6.7%)	3
Sinus bradycardia	4/45 (8.9%)	5
Sinus tachycardia	2/45 (4.4%)	3
Ventricular arrhythmia	1/45 (2.2%)	1
Ear and labyrinth disorders
Otitis media	1/45 (2.2%)	1
Tinnitus	1/45 (2.2%)	1
Vertigo	1/45 (2.2%)	1
Vestibular disorder	1/45 (2.2%)	1
Endocrine disorders
Hypothyroidism	2/45 (4.4%)	2
Eye disorders
Blurred vision	6/45 (13.3%)	6
Cataract	1/45 (2.2%)	1
Conjunctivitis	1/45 (2.2%)	1
Dry eye	1/45 (2.2%)	1
Eye disorders - Other, specify	8/45 (17.8%)	9
Glaucoma	2/45 (4.4%)	2
Papilledema	1/45 (2.2%)	2
Gastrointestinal disorders
Abdominal pain	3/45 (6.7%)	4
Anal hemorrhage	1/45 (2.2%)	1
Bloating	2/45 (4.4%)	2
Constipation	25/45 (55.6%)	34
Dental caries	1/45 (2.2%)	1
Diarrhea	30/45 (66.7%)	51
Dry mouth	6/45 (13.3%)	6
Dyspepsia	6/45 (13.3%)	6
Enterocolitis infectious	1/45 (2.2%)	1
Gastric ulcer	1/45 (2.2%)	1
Gastritis	3/45 (6.7%)	3
Gastroesophageal reflux disease	8/45 (17.8%)	8
Gastrointestinal disorders - Other, specify	1/45 (2.2%)	1
Gingival pain	1/45 (2.2%)	1
Lower gastrointestinal hemorrhage	1/45 (2.2%)	1
Mucositis oral	1/45 (2.2%)	1
Nausea	8/45 (17.8%)	10
Rectal hemorrhage	1/45 (2.2%)	1
Rectal pain	1/45 (2.2%)	1
Toothache	2/45 (4.4%)	2
Vomiting	4/45 (8.9%)	7
General disorders
Chills	5/45 (11.1%)	6
Edema face	4/45 (8.9%)	5
Edema limbs	17/45 (37.8%)	30
Fatigue	28/45 (62.2%)	43
Fever	12/45 (26.7%)	18
Flu like symptoms	5/45 (11.1%)	5
Gait disturbance	1/45 (2.2%)	1
General disorders and administration site conditions - Other, Gastrointeritis	1/45 (2.2%)	1
Generalized muscle weakness	1/45 (2.2%)	1
Infusion related reaction	3/45 (6.7%)	5
Injection site reaction	32/45 (71.1%)	51
Irritability	4/45 (8.9%)	4
Pain	19/45 (42.2%)	25
Hepatobiliary disorders
Gallbladder obstruction	1/45 (2.2%)	1
Immune system disorders
Allergic reaction	1/45 (2.2%)	1
Infections and infestations
Appendicitis	1/45 (2.2%)	1
Bronchial infection	1/45 (2.2%)	1
Infections and infestations - Other, specify	4/45 (8.9%)	4
Laryngitis	1/45 (2.2%)	1
Lung infection	2/45 (4.4%)	4
Peripheral nerve infection	1/45 (2.2%)	1
Rhinitis infective	1/45 (2.2%)	1
Sinusitis	5/45 (11.1%)	6
Skin infection	4/45 (8.9%)	4
Tooth infection	1/45 (2.2%)	1
Urinary tract infection	2/45 (4.4%)	3
Vaginal infection	1/45 (2.2%)	1
Injury, poisoning and procedural complications
Bruising	2/45 (4.4%)	2
Fall	2/45 (4.4%)	2
Fracture	1/45 (2.2%)	1
Radiation recall reaction (dermatologic)	1/45 (2.2%)	1
Vascular access complication	1/45 (2.2%)	1
Investigations
Activated partial thromboplastin time prolonged	7/45 (15.6%)	9
Alanine aminotransferase increased	36/45 (80%)	166
Alkaline phosphatase increased	29/45 (64.4%)	67
Aspartate aminotransferase increased	25/45 (55.6%)	71
Blood bilirubin increased	23/45 (51.1%)	72
CPK increased	10/45 (22.2%)	19
Creatinine increased	18/45 (40%)	51
Lipase increased	1/45 (2.2%)	2
Lymphocyte count decreased	45/45 (100%)	438
Lymphocyte count increased	1/45 (2.2%)	1
Neutrophil count decreased	35/45 (77.8%)	207
Platelet count decreased	42/45 (93.3%)	214
Serum amylase increased	1/45 (2.2%)	1
Weight loss	1/45 (2.2%)	1
White blood cell decreased	38/45 (84.4%)	284
Metabolism and nutrition disorders
Anorexia	5/45 (11.1%)	7
Dehydration	4/45 (8.9%)	5
Hypercalcemia	10/45 (22.2%)	18
Hyperglycemia	3/45 (6.7%)	3
Hyperkalemia	9/45 (20%)	12
Hypermagnesemia	23/45 (51.1%)	35
Hypernatremia	26/45 (57.8%)	52
Hyperuricemia	12/45 (26.7%)	25
Hypoalbuminemia	42/45 (93.3%)	136
Hypocalcemia	20/45 (44.4%)	36
Hypokalemia	10/45 (22.2%)	19
Hypomagnesemia	17/45 (37.8%)	40
Hyponatremia	16/45 (35.6%)	33
Hypophosphatemia	29/45 (64.4%)	79
Musculoskeletal and connective tissue disorders
Arthralgia	10/45 (22.2%)	10
Back pain	7/45 (15.6%)	8
Bone pain	2/45 (4.4%)	2
Chest wall pain	11/45 (24.4%)	14
Muscle weakness lower limb	1/45 (2.2%)	1
Muscle weakness trunk	1/45 (2.2%)	1
Musculoskeletal and connective tissue disorder - Other, specify	6/45 (13.3%)	9
Myalgia	14/45 (31.1%)	19
Neck pain	2/45 (4.4%)	2
Non-cardiac chest pain	1/45 (2.2%)	1
Pain in extremity	15/45 (33.3%)	17
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify	2/45 (4.4%)	2
Nervous system disorders
Cognitive disturbance	4/45 (8.9%)	4
Concentration impairment	2/45 (4.4%)	2
Dizziness	4/45 (8.9%)	4
Dysarthria	1/45 (2.2%)	1
Dysesthesia	1/45 (2.2%)	1
Dysgeusia	9/45 (20%)	10
Headache	15/45 (33.3%)	21
Memory impairment	2/45 (4.4%)	2
Nervous system disorders - Other, specify	1/45 (2.2%)	1
Paresthesia	1/45 (2.2%)	1
Peripheral motor neuropathy	1/45 (2.2%)	1
Peripheral sensory neuropathy	22/45 (48.9%)	33
Presyncope	2/45 (4.4%)	2
Somnolence	1/45 (2.2%)	1
Syncope	1/45 (2.2%)	1
Tremor	9/45 (20%)	11
Psychiatric disorders
Agitation	1/45 (2.2%)	1
Anxiety	3/45 (6.7%)	5
Confusion	1/45 (2.2%)	1
Depression	3/45 (6.7%)	3
Insomnia	26/45 (57.8%)	30
Libido decreased	1/45 (2.2%)	2
Personality change	1/45 (2.2%)	1
Psychiatric disorders - Other, Emotional lability	1/45 (2.2%)	1
Suicidal ideation	1/45 (2.2%)	1
Renal and urinary disorders
Cystitis noninfective	1/45 (2.2%)	1
Nocturia	1/45 (2.2%)	1
Urinary frequency	2/45 (4.4%)	2
Urinary incontinence	1/45 (2.2%)	1
Urinary retention	1/45 (2.2%)	1
Reproductive system and breast disorders
Ejaculation disorder	1/45 (2.2%)	1
Erectile dysfunction	1/45 (2.2%)	1
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis	3/45 (6.7%)	3
Bronchospasm	1/45 (2.2%)	1
Cough	9/45 (20%)	12
Dyspnea	20/45 (44.4%)	37
Epistaxis	1/45 (2.2%)	1
Hiccups	2/45 (4.4%)	3
Hoarseness	6/45 (13.3%)	6
Nasal congestion	3/45 (6.7%)	3
Pericardial effusion	1/45 (2.2%)	1
Pleural effusion	4/45 (8.9%)	4
Pleuritic pain	1/45 (2.2%)	1
Postnasal drip	1/45 (2.2%)	1
Respiratory, thoracic and mediastinal disorders - Other, Rhinorrhea; Rt. Pleural density	2/45 (4.4%)	2
Sore throat	3/45 (6.7%)	4
Upper respiratory infection	30/45 (66.7%)	47
Skin and subcutaneous tissue disorders
Dry skin	3/45 (6.7%)	3
Hyperhidrosis	1/45 (2.2%)	1
Nail discoloration	2/45 (4.4%)	2
Pruritus	6/45 (13.3%)	8
Rash acneiform	2/45 (4.4%)	3
Rash maculo-papular	27/45 (60%)	68
Skin and subcutaneous tissue disorders - Other, specify	5/45 (11.1%)	5
Skin hyperpigmentation	1/45 (2.2%)	1
Skin ulceration	2/45 (4.4%)	2
Vascular disorders
Hematoma	2/45 (4.4%)	2
Hot flashes	6/45 (13.3%)	7
Hypertension	5/45 (11.1%)	16
Hypotension	2/45 (4.4%)	3
Phlebitis	2/45 (4.4%)	2
Superficial thrombophlebitis	3/45 (6.7%)	3
Thromboembolic event	5/45 (11.1%)	6
Vascular disorders - Other, Raynaud's disorder	1/45 (2.2%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT 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.