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Creatinine clearance 30 - 60 mL/min, lenalidomide dose determined in phase I, dexamethasone 40 mg orally days 1, 8, 15 and 22 of a 28 day cycle, and anticoagulants.

Creatinine clearance \< 30 mL/min, not on dialysis, lenalidomide dose determined in phase I, dexamethasone 40 mg orally days 1, 8, 15 and 22 of a 28 day cycle, and anticoagulants.

Creatinine clearance \< 30 mL/min and on dialysis, lenalidomide dose determined in phase I, dexamethasone 40 mg orally days 1, 8, 15 and 22 of a 28 day cycle, and anticoagulants.

Given by mouth days 1-21 of a 28-day cycle. There is a 7 day rest (days 22-28). Continue until disease progression or unacceptable toxicity.

40 mg given by mouth days 1, 8, 15 and 22 of a 28-day cycle. Continue until disease progression or unacceptable toxicity.

Anticoagulation consisted of aspirin at either 81 mg/day or 325 mg/day at the physician's discretion. Heparin, low molecular weight heparin, or coumadin could be used if the patient was intolerant to aspirin.

Joseph R. Mikhael, MD

Patients with previously treated multiple myeloma and kidney dysfunction will be treated with lenalidomide and low-dose dexamethasone. Phase I will study the side effects and best dose of lenalidomide when given together with low-dose dexamethasone therapy. After the maximum safe and tolerated dose is found in Phase I, the study will proceed to Phase II. Phase II will study how well the the treatment works in patients with previously treated (relapsed or refractory) multiple myeloma and kidney dysfunction.

Biological therapies, such as lenalidomide, may stimulate the immune system in different ways and stop cancer cells from growing. Drugs used in chemotherapy, such as dexamethasone, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving lenalidomide together with dexamethasone may kill more cancer cells. Lenalidomide and dexamethasone may have different effects in patients who have changes in their kidney function.

Multiple Myeloma (MM) affects approximately 20,000 Americans annually and remains an incurable hematologic malignancy characterized by frequent early response followed by universal treatment relapse necessitating multiple sequential therapeutic regimens. Until recently, few effective therapies existed. Several novel agents for MM have now become available including the immunomodulatory drugs thalidomide, lenalidomide, as well as the proteasome inhibitor, bortezomib. Each of these agents is undergoing extensive clinical evaluation in combination with other therapies to produce unprecedented response rates in newly diagnosed and relapsed MM. Lenalidomide has proven to be a highly effective treatment agent, particularly when used in combination with dexamethasone but is renally excreted and little information is available about its use in myeloma patients with impaired kidney function (20% have renal failure at some time after diagnosis). Defining a safe and effective dose of lenalidomide to use is a critical step in MM treatment.

OUTLINE: This is a Phase I, dose-escalation study of lenalidomide followed by a Phase II study. Patients are stratified according to degree of renal dysfunction (moderate \[creatinine clearance 30-60 mL/min\] vs severe \[creatinine clearance \<30 mL/min and does not require dialysis\] vs end-stage renal disease \[creatinine clearance \<30 mL/min and requires dialysis\]).

Patients receive oral lenalidomide on days 1-21 and low-dose oral dexamethasone 40 mg on days 1, 8, 15, and 22. There is a 7 day rest (days 22-28) from lenalidomide. Each cycle is 28 days and repeated in the absence of disease progression or unacceptable toxicity.

Patients enrolled in the phase II portion of the study will undergo blood sample collection periodically for pharmacokinetic analysis of lenalidomide (Mayo Clinic sites only).

After completion of study treatment, patients are followed every 6 months for up to 3 years.

Lenalidomide and Low-Dose Dexamethasone in Patients With Previously Treated Multiple Myeloma and Kidney Dysfunction

A Phase I/II Study of the Tolerability of Lenalidomide and Low Dose Dexamethasone in Previously Treated Multiple Myeloma Patients With Impaired Renal Function

Dose Limiting Toxicity (DLT) was defined as any of the following events determined by the investigator to be possibly, probably, or definitely related to lenalidomide within the first cycle of therapy irrespective of whether the adverse events resolved:

* Grade 3 or higher neutropenia with fever ≥38.5 degrees C
* Grade 4 neutropenia ≥7 days
* Grade 4 or higher thrombocytopenia
* Other non-hematologic Grade 4 or higher adverse event not present prior to starting therapy or not due to underlying cause

Per International Myeloma Working Group criteria, complete response (CR): negative immunofixation of serum and urine, normalization of free light chain (FLC) ratio if at study entry FLC was only measurable non-bone parameter, \<5% plasma cells in bone marrow, disappearance of any soft tissue plasma cytomas; stringent complete response (sCR): all of above, + normal serum FLC ratio in all patients and absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescence; partial response (PR): \>=50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by \>=90% or to \< 200 mg per 24 hours, \>=50% decrease in difference between involved and uninvolved FLC levels or a 50% decrease in level of involved FLC with 50% decrease in ratio, \>=50% reduction in bone marrow plasma cells, if baseline percentage was \>=30%, \>=50% reduction in size of soft tissue plasmacytoma; very good partial response (VGPR): PR + improvements in serum and urine M-components

Overall survival is the time from registration to death from any cause. Patients alive at the time of analysis were censored at the date last known alive.

Duration of response was defined as time between the onset of response and disease progression in months, among patients treated at the recommended phase II dose who experienced a response to treatment. Per criteria of the International Myeloma Working Group, progressive disease was defined as one of the following: increase of 25% from best confirmed response in serum M-component, urine M-component, free light chain (FLC), bone marrow plasma cell percentage, or development of new or increase in size of bone lesions or soft tissue plasma cytomas. Development of hypercalcemia that can be attributed solely to the myeloma also constituted progression.

The highest degree of any adverse event experienced by each patient, as assessed by NCI CTCAE Version 4, with an attribution of possibly, probably, or definitely related to treatment. Reportable adverse events included those occurring while on treatment or within 30 days of the end of treatment.

To describe renal function over time and to evaluate the safety profile of a onetime increase in lenalidomide dose at least 2 cycles after start of treatment due to improved renal function.

To determine the pharmacokinetics of lenalidomide administration in myeloma patients with impaired renal function (pharmacokinetic analysis will be performed in up to 12 consented Mayo Clinic subjects treated during the Phase II component of the trial (only).

Progression-free survival is the time from registration to disease progression or death. Patients alive without disease progression were censored at the time of the last disease assessment.

Celgene

PrECOG, LLC.

Serious adverse events include any adverse event occurring at least once at grade 3 or higher. The remaining adverse events occurring in at least 5% of patients (3 or more patients) are reported as other adverse events. Events were captured during each clinic visit while on treatment and for 30 days following the end of treatment.

CrCl 30-60 mL/min. Lenalidomide 10 mg/day for days 1-21 and Dexamethasone 40 mg days 1, 8, 15 and 22 every 28 days.

Group A Lenalidomide 10 mg/Day

CrCl 30-60 mL/min. Lenalidomide 15 mg/day for days 1-21 and Dexamethasone 40 mg days 1, 8, 15 and 22 every 28 days.

Group A Lenalidomide 15 mg/Day

CrCl 30-60 mL/min. Lenalidomide 25 mg/day for days 1-21 and Dexamethasone 40 mg days 1, 8, 15 and 22 every 28 days.

Group A Lenalidomide 25 mg/Day

CrCl 30-60 mL/min. Lenalidomide 25 mg/day for days 1-21 and Dexamethasone 40 mg days 1, 8, 15 and 22 every 28 days. Enrolled after determination of recommended phase 2 dose.

Group A Expansion Cohort

CrCl \<30 mL/min, not on dialysis. Lenalidomide 15 mg every 2 days for days 1-21 and Dexamethasone 40 mg days 1, 8, 15 and 22 every 28 days.

Group B Lenalidomide 15 mg/2 Days

CrCl \<30 mL/min, not on dialysis. Lenalidomide 25 mg every 2 days for days 1-21 and Dexamethasone 40 mg days 1, 8, 15 and 22 every 28 days.

Group B Lenalidomide 25 mg/2 Days

CrCl \<30 mL/min, not on dialysis. Lenalidomide 15 mg/day for days 1-21 and Dexamethasone 40 mg days 1, 8, 15 and 22 every 28 days.

Group B Lenalidomide 15 mg/Day

CrCl \<30 mL/min, not on dialysis. Lenalidomide 25 mg/day for days 1-21 and Dexamethasone 40 mg days 1, 8, 15 and 22 every 28 days.

Group B Lenalidomide 25 mg/Day

CrCl \<30 mL/min, not on dialysis. Lenalidomide 25 mg/day for days 1-21 and Dexamethasone 40 mg days 1, 8, 15 and 22 every 28 days. Enrolled after determination of recommended phase 2 dose.

Group B Expansion Cohort

CrCl \< 30 mL/min, on dialysis. Lenalidomide 15 mg three times weekly for days 1-21 and Dexamethasone 40 mg days 1, 8, 15 and 22 every 28 days.

Group C Lenalidomide 15 mg 3x/wk

CrCl \< 30 mL/min, on dialysis. Lenalidomide 10 mg/day for days 1-21 and Dexamethasone 40 mg days 1, 8, 15 and 22 every 28 days.

Group C Lenalidomide 10 mg/Day

CrCl \< 30 mL/min, on dialysis. Lenalidomide 15 mg/day for days 1-21 and Dexamethasone 40 mg days 1, 8, 15 and 22 every 28 days.

Group C Lenalidomide 15 mg/Day

CrCl \< 30 mL/min, on dialysis. Lenalidomide 25 mg/day for days 1-21 and Dexamethasone 40 mg days 1, 8, 15 and 22 every 28 days.

Group C Lenalidomide 25 mg/Day

Lenalidomide days 1-21 and Dexamethasone 40 mg days 1, 8, 15 and 22 every 28 days. Phase I will determine the dose of lenalidomide to be used in Phase II.

Group A=30-60 CrCl (mL/min): Each Cycle=28 days. Lenalidomide by mouth days 1-21 and Dexamethasone 40 mg by mouth days 1, 8, 15 and 22. There is a 7 day rest (days 22-28) from lenalidomide. Continue until disease progression or unacceptable toxicity. Phase I will determine the dose of lenalidomide to be used in Phase II.

Group A=30-60 CrCl (mL/Min)

Lenalidomide days 1-21 and Dexamethasone 40 mg days 1, 8, 15 and 22 every 28 days. Phase I will determine the dose of lenalidomide to be used in Phase II.

Group B=CrCL\<30 mL/min not on dialysis: Each Cycle=28 days. Lenalidomide by mouth days 1-21 and Dexamethasone 40 mg by mouth days 1, 8, 15 and 22. There is a 7 day rest (days 22-28) from lenalidomide. Continue until disease progression or unacceptable toxicity. Phase I will determine the dose of lenalidomide to be used in Phase II.

Group B=CrCL<30 mL/Min Not on Dialysis

Lenalidomide days 1-21 and Dexamethasone 40 mg days 1, 8, 15 and 22 every 28 days. Phase I will determine the dose of lenalidomide to be used in Phase II.

Group C=CrCL\<30 mL/min and on dialysis: Each Cycle=28 days. Lenalidomide by mouth days 1-21 and Dexamethasone 40 mg by mouth days 1, 8, 15 and 22. There is a 7 day rest (days 22-28) from lenalidomide. Continue until disease progression or unacceptable toxicity. Phase I will determine the dose of lenalidomide to be used in Phase II.

Dialysis includes hemodialysis or peritoneal dialysis. When lenalidomide and/or dexamethasone treatment occurs on a dialysis day, lenalidomide and/or dexamethasone must be taken after dialysis.

Group C=CrCL<30 mL/Min and on Dialysis

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Creatinine Clearance

PrECOG Statistician

Recommended phase 2 dose for patients in Group B

CrCl 30-60 mL/min, Lenalidomide at 10 mg/day for days 1-21 and Dexamethasone 40 mg days 1, 8, 15 and 22 every 28 days along with anticoagulants.

CrCl 30-60 mL/min, Lenalidomide at 15 mg/day for days 1-21 and Dexamethasone 40 mg days 1, 8, 15 and 22 every 28 days, along with anticoagulants.

CrCL 30-60 mL/min, Lenalidomide at 25 mg/day for days 1-21 and Dexamethasone 40 mg days 1, 8, 15 and 22 every 28 days, along with anticoagulants.

CrCl\<30 mL/min, not on dialysis, Lenalidomide at 15 mg/every 2 days for days 1-21 and Dexamethasone 40 mg days 1, 8, 15 and 22 every 28 days, along with anticoagulants.

CrCl \< 30 mL/min, not on dialysis, Lenalidomide at 25 mg every 2 days for days 1-21 and Dexamethasone 40 mg days 1, 8, 15 and 22 every 28 days, along with anticoagulants.

CrCl \< 30 mL/min, not on dialysis, Lenalidomide at 15 mg/day for days 1-21 and Dexamethasone 40 mg days 1, 8, 15 and 22 every 28 days, along with anticoagulants.

CrCl \< 30 mL/min, not on dialysis, Lenalidomide at 25 mg/day for days 1-21 and Dexamethasone 40 mg days 1, 8, 15 and 22 every 28 days, along with anticoagulants.

CrCl \< 30 mL/min, on dialysis, Lenalidomide at 15 mg 3 times per week for days 1-21 and Dexamethasone 40 mg days 1, 8, 15 and 22 every 28 days, along with anticoagulants.

Group C Lenalidomide 15 mg 3x/Week

CrCl \< 30 mL/min, on dialysis, Lenalidomide at 10 mg/day for days 1-21 and Dexamethasone 40 mg days 1, 8, 15 and 22 every 28 days, along with anticoagulants.

CrCl \< 30 mL/min, on dialysis, Lenalidomide at 15 mg/day for days 1-21 and Dexamethasone 40 mg days 1, 8, 15 and 22 every 28 days, along with anticoagulants.

CrCl \< 30 ml/min, on dialysis, Lenalidomide at 25 mg/day for days 1-21 and Dexamethasone 40 mg days 1, 8, 15 and 22 every 28 days, along with anticoagulants.

Patients treated during the dose finding phase of the study

Number of Participants in Phase I Component With Dose Limiting Toxicities During the First Cycle of Therapy

Lenalidomide at 25 mg/day days 1-21 and Dexamethasone 40 mg days 1, 8, 15 and 22 every 28 days.

Group A CrCl 30-60 mL/Min

Group B CrCL<30 mL/Min, Not on Dialysis

Lenalidomide at 25 mg/day for days 1-21 and Dexamethasone 40 mg days 1, 8, 15 and 22 every 28 days.

Group C CrCL<30 mL/Min and on Dialysis

Patients treated at the recommended phase II dose

Percentage of Participants Who Experience a Response [sCR, CR, VGPR, PR]

Overall Survival Time

Lenalidomide 25 mg/day days 1-21 and Dexamethasone 40 mg days 1, 8, 15 and 22 every 28 days.

Lenalidomide 25 mg/day days 1-21 and Dexamethasone 40 mg days 1, 8, 15 and 22 every 28 days. Dialysis includes hemodialysis or peritoneal dialysis. When lenalidomide and/or dexamethasone treatment occurs on a dialysis day, lenalidomide and/or dexamethasone must be taken after dialysis.

Patients treated at the recommended phase II dose who experienced a response to treatment

Duration of Response

None

Grade 1

Grade 2

Grade 3

Grade 4

Grade 5

CrCl 30-60 mL/min, Lenalidomide 10 mg/day on days 1-21 and Dexamethasone 40 mg days 1, 8, 15 and 22 every 28 days.

CrCl 30-60 mL/min, Lenalidomide 15 mg/day on days 1-21 and Dexamethasone 40 mg days 1, 8, 15 and 22 every 28 days.

CrCl 30-60 mL/min, Lenalidomide 25 mg/day on days 1-21 and Dexamethasone 40 mg days 1, 8, 15 and 22 every 28 days.

CrCl 30-60 mL/min, Lenalidomide 25 mg/day on days 1-21 and Dexamethasone 40 mg days 1, 8, 15 and 22 every 28 days. Enrolled after determination of recommended phase 2 dose.

CrCl \< 30 mL/min, not on dialysis. Lenalidomide days 15 mg every 2 days from days 1-21 and Dexamethasone 40 mg days 1, 8, 15 and 22 every 28 days.

CrCl \< 30 mL/min, not on dialysis. Lenalidomide 25 mg every 2 days from days 1-21 and Dexamethasone 40 mg days 1, 8, 15 and 22 every 28 days.

CrCl \< 30 mL/min, not on dialysis. Lenalidomide 15 mg/day on days 1-21 and Dexamethasone 40 mg days 1, 8, 15 and 22 every 28 days.

CrCl \< 30 mL/min, not on dialysis. Lenalidomide 25 mg/day on days 1-21 and Dexamethasone 40 mg days 1, 8, 15 and 22 every 28 days.

CrCl \< 30 mL/min, not on dialysis. Lenalidomide 25 mg/day on days 1-21 and Dexamethasone 40 mg days 1, 8, 15 and 22 every 28 days. Enrolled after determination of recommended phase 2 dose.

CrCl \< 30 mL/min, on dialysis, Lenalidomide 15 mg 3 times a week from days 1-21 and Dexamethasone 40 mg days 1, 8, 15 and 22 every 28 days.

CrCl \< 30 mL/min, on dialysis, Lenalidomide 10 mg/day on days 1-21 and Dexamethasone 40 mg days 1, 8, 15 and 22 every 28 days.

CrCl \< 30 mL/min, on dialysis, Lenalidomide 15 mg/day on days 1-21 and Dexamethasone 40 mg days 1, 8, 15 and 22 every 28 days.

CrCl \< 30 mL/min, on dialysis, Lenalidomide 25 mg/day on days 1-21 and Dexamethasone 40 mg days 1, 8, 15 and 22 every 28 days.

Worst Degree Treatment-Related Adverse Events Across All Event Types Per Patient

This outcome was not analyzed because the dose increase was not implemented.

Renal Function Over Time

As only 1 patient was enrolled from Mayo Clinic during the Phase II component of the study, samples were neither collected nor analyzed for this endpoint.

Pharmacokinetics of Lenalidomide in Impaired Renal Function

Progression-free Survival

Creatinine clearance (CrCl) of 30 - 60 mL/min. Lenalidomide 10 mg/day on days 1-21 and dexamethasone 40 mg/day on days 1, 8, 15 and 22 of a 28-day cycle. Anticoagulation consisting of aspirin at 81 or 325 mg/day at physician's discretion. Heparin, low molecular weight heparin, or coumadin could be used if the patient was intolerant to aspirin.

Creatinine clearance of 30 - 60 mL/min. Treated with lenalidomide 15 mg/day on days 1-21 and dexamethasone 40 mg/day on days 1, 8, 15 and 22 of a 28-day cycle. Anticoagulation consisting of aspirin at 81 or 325 mg/day at physician's discretion. Heparin, low molecular weight heparin, or coumadin could be used if the patient was intolerant to aspirin.

Creatinine clearance of 30 - 60 mL/min. Treated with lenalidomide 25 mg/day on days 1-21 and dexamethasone 40 mg/day on days 1, 8, 15 and 22 of a 28-day cycle. Anticoagulation consisting of aspirin at 81 or 325 mg/day at physician's discretion. Heparin, low molecular weight heparin, or coumadin could be used if the patient was intolerant to aspirin.

Creatinine clearance \< 30 mL/min, not on dialysis. Treated with lenalidomide 15 mg/every other day on days 1-21 and dexamethasone 40 mg/day on days 1, 8, 15 and 22 of a 28-day cycle. Anticoagulation consisting of aspirin at 81 or 325 mg/day at physician's discretion. Heparin, low molecular weight heparin, or coumadin could be used if the patient was intolerant to aspirin.

Creatinine clearance of \<30 mL/min, not on dialysis. Treated with lenalidomide 25 mg every other day for days 1-21 and dexamethasone 40 mg/day on days 1, 8, 15 and 22 of a 28-day cycle. Anticoagulation consisting of aspirin at 81 or 325 mg/day at physician's discretion. Heparin, low molecular weight heparin, or coumadin could be used if the patient was intolerant to aspirin.

Creatinine clearance \< 30 mL/min, not on dialysis. Treated with lenalidomide at 15 mg/day for days 1-21 and dexamethasone 40 mg/day on days 1, 8, 15 and 22 of a 28-day cycle. Anticoagulation consisting of aspirin at 81 or 325 mg/day at physician's discretion. Heparin, low molecular weight heparin, or coumadin could be used if the patient was intolerant to aspirin.

Creatinine clearance \< 30 mL/min, not on dialysis. Treated with lenalidomide at 25 mg/day for days 1-21 and dexamethasone 40 mg/day on days 1, 8, 15 and 22 of a 28-day cycle. Anticoagulation consisting of aspirin at 81 or 325 mg/day at physician's discretion. Heparin, low molecular weight heparin, or coumadin could be used if the patient was intolerant to aspirin.

Creatinine clearance of 30 - 60 mL/min and on dialysis. Treated with lenalidomide 15 mg 3 days/week for days 1-21 and dexamethasone 40 mg/day on days 1, 8, 15 and 22 of a 28-day cycle. Anticoagulation consisting of aspirin at 81 or 325 mg/day at physician's discretion. Heparin, low molecular weight heparin, or coumadin could be used if the patient was intolerant to aspirin.

Dialysis includes hemodialysis or peritoneal dialysis. When lenalidomide and/or dexamethasone treatment occurs on a dialysis day, lenalidomide and/or dexamethasone must be taken after dialysis.

Creatinine Clearance \< 30 mL/min and on dialysis, treated with lenalidomide 15 mg 3 times per week, dexamethasone and anticoagulant

Creatinine Clearance \< 30 mL/min and on dialysis, treated with lenalidomide 10 mg/day, dexamethasone, and anticoagulants

Creatinine clearance \< 30 mL/min and on dialysis, treated with lenalidomide at 25 mg/day, dexamethasone, and anticoagulants

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Lenalidomide and Low-Dose Dexamethasone in Patients With Previously Treated Multiple Myeloma and Kidney Dysfunction	NCT00790842	Multiple Myelom... Plasma Cell Neo...	Lenalidomide Dexamethasone Anticoagulants	18 Years -	PrECOG, LLC.
Lenalidomide and Low-Dose Dexamethasone in Patients With Previously Treated Multiple Myeloma and Kidney Dysfunction	NCT00790842	Multiple Myelom... Plasma Cell Neo...	Lenalidomide Dexamethasone Anticoagulants	18 Years -	PrECOG, LLC.

Spots Global Cancer Trial Database for multiple myeloma with renal dysfunction