Multiple Myeloma and Plasma Cell Neoplasm
Conditions
Keywords
stage I multiple myeloma, stage II multiple myeloma, stage III multiple myeloma
Brief summary
RATIONALE: Lenalidomide and dexamethasone may stop the growth of multiple myeloma by blocking blood flow to the tumor. PURPOSE: This phase II trial is studying how well lenalidomide works with or without dexamethasone in treating patients with newly diagnosed multiple myeloma.
Detailed description
OBJECTIVES: Primary * To assess the progression-free survival at 1 year in patients with newly diagnosed symptomatic multiple myeloma treated with lenalidomide alone or in combination with dexamethasone added for disease progression or lack or partial response. Secondary * To assess the response rate of this regimen in these patients. * To assess the toxicity of this regimen in these patients. Tertiary * To examine the effect of lenalidomide alone on tumor specific immunity and global parameters of immune function. * To examine the effect of dexamethasone addition in patients requiring steroids. * To correlate changes in parameters of immune response and measures of disease response. * To examine the antiangiogenic activity of lenalidomide alone and in combination with dexamethasone. * To examine the effect of lenalidomide alone on tumor cell survival and proliferation. OUTLINE: Patients receive oral lenalidomide once daily on days 1-21. Treatment repeats every 28 days for up to 18 courses in the absence of second disease progression or unacceptable toxicity. Beginning in course 4, patients experiencing stable or progressive disease also receive concurrent oral dexamethasone once daily on days 1, 8, 15, and 22 and for all subsequent courses. Blood and bone marrow samples are collected periodically for pharmacological and correlative studies. Samples are analyzed for parameters of immune activation, cell proliferation and apoptosis, and circulating tumor cells and endothelial cells via flow cytometry; global impact of therapy on immune cell subsets via immunophenotype analysis; and angiogenesis via CD34 staining. After completion of study therapy, patients are followed periodically for up to 2 years.
Interventions
DRUGdexamethasone
Dose: -40 mg once weekly (days 1, 8, 15, & 22) orally with food until progression. If after 3 cycles, a partial response is not achieved on lenalidomide alone, dexamethasone 10 mg weekly will be added, and the weekly dexamethasone dose will be increased by 10 mg each cycle to a maximum of 40 mg weekly, as long as a partial response is not achieved. If a partial response is achieved at a dose of dexamethasone less than 40 mg weekly, patients will continue on that dose. If progression at any time, increase dexamethasone to 40 mg weekly. Patient will go off study only when progression is documented while receiving 40 mg/week of dexamethasone or the maximum tolerated dose of dexamethasone (if prior dose reductions have been implemented for toxicity). Increases in dexamethasone dose are to be made only at the initiation of a cycle. If progression at any time while on lenalidomide alone (first 3 cycles), add dexamethasone 40 mg weekly.
DRUGlenalidomide
25mg once daily orally with food on days 1-21 of 28 day cycle until progression or to a maximum of 18 cycles. Lenalidomide alone will be administered for the first 3 cycles, then in combination with dexamethasone as needed (described).
Sponsors
National Cancer Institute (NCI)
Mayo Clinic
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 120 Years
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: * Newly diagnosed multiple myeloma, meeting the following criteria: * Symptomatic disease * Previously untreated disease * Measurable or evaluable disease, defined by ≥ 1 of the following: * Serum monoclonal protein ≥ 1.0 g/dL * Monoclonal protein \> 200 mg by 24-hour urine electrophoresis * Serum immunoglobulin free light chain ≥ 10 mg/dL AND abnormal serum immunoglobulin kappa:lambda free light chain ratio * Monoclonal bone marrow plasmacytosis ≥ 30% (evaluable disease) * Measurable soft tissue plasmacytoma, not previously radiated * No monoclonal gammopathy of unknown significance or asymptomatic myeloma PATIENT CHARACTERISTICS: * ECOG performance status (PS) 0-2 (PS 3 allowed if secondary to pain) * ANC ≥ 1,500/μL * Platelet count ≥ 75,000/μL * Creatinine ≤ 2.0 mg/dL * Total bilirubin ≤ 1.5 mg/dL * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use 2 effective forms of contraception 28 days prior to, during and 28 days after study treatment * Registered into the RevAssist® program and willing to comply with program requirements * Able to take prophylactic aspirin (325 mg/day) or warfarin or low molecular weight heparin * Willing to provide mandatory blood and bone marrow samples * Willing to return for follow up * No uncontrolled infection * No NYHA class III or IV heart failure * No active deep vein thrombosis that has not been therapeutically anticoagulated * No known hypersensitivity to thalidomide * No known HIV positivity * No known hepatitis type A, B, or C infection * No other prior active malignancy within the past 2 years, except currently treated basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix or breast * No development of erythema nodosum if characterized by a desquamating rash while taking thalidomide or similar drugs PRIOR CONCURRENT THERAPY: * At least 3 weeks since prior radiotherapy for solitary plasmacytoma * More than 28 days since other prior experimental drug or therapy * Prior clarithromycin, DHEA, anakinra, pamidronate, or zoledronic acid allowed * No prior lenalidomide * No prior cytotoxic chemotherapy * No prior corticosteroids (≥ 160 mg of dexamethasone or equivalent) for this disease * Prior corticosteroid for nonmalignant disease allowed * Concurrent corticosteroids allowed (≤ 20 mg/day of prednisone or equivalent) * Concurrent palliative radiotherapy for bone pain or fracture allowed * No other concurrent anticancer agents or treatments
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) Rate at 12 Months | 12 months from registration | PFS rate at 12 months is defined as the percentage of participants who are alive and progression-free at 12 months. Progression is exclusively defined as a patient with progressive disease while receiving treatment with lenalidomide in combination with dexamethasone. Progression was defined as any one or more of the following: An increase of 25% from lowest confirmed response in: * Serum M-component (absolute increase \>= 0.5g/dl) * Urine M-component (absolute increase \>= 200mg/24hour * Difference between involved and uninvolved Free Light Chain levels (absolute increase \>= 10mg/dl * Bone marrow plasma cell percentage (absolute increase of \>=10%) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Confirmed Response Rate | Up to 18 cycles from registration | Confirmed response rate is defined as the percentage of participants who achieved a response that was confirmed on 2 consecutive evaluations during treatment * Complete Response(CR): Complete disappearance of M-protein from serum & urine on immunofixation, normalization of Free Light Chain (FLC) ratio & \<5% plasma cells in bone marrow (BM) * Very Good Partial Response(VGPR): \>=90% reduction in serum M-component; Urine M-Component \<100 mg per 24 hours; \<=5% plasma cells in BM * Partial Response PR): \>= 50% reduction in serum M-Component and/or Urine M-Component \>= 90% reduction or \<200 mg per 24 hours; or \>= 50% decrease in difference between involved and uninvolved FLC levels |
| Overall Survival (OS) | Time from registration to death (up to 3 years) | OS was defined as the time from registration to death of any cause. Participants were followed for a maximum of 3 years from randomization. The median OS with 95% CI was estimated using the Kaplan Meier method |
| Progression-free Survival (PFS) | Time from registration to progression or death (up to 3 years) | PFS was defined as the time from registration to progression or death due to any cause. The median PFS with 95%CI was estimated using the Kaplan Meier method. Progression was defined as any one or more of the following:An increase of 25% from lowest confirmed response in: * Serum M-component (absolute increase \>= 0.5g/dl) * Urine M-component (absolute increase \>= 200mg/24hour * Difference between involved and uninvolved Free Light Chain levels (absolute increase \>= 10mg/dl * Bone marrow plasma cell percentage (absolute increase of \>=10%) |
| Number of Participants Who Experienced at Least One Grade 3 or Higher Adverse Event at Least Possibly Related to Treatment (Toxicity) | Duration on treatment (up to 18 cycles from registration) | The number of participants who experienced toxicity (defined as at least one grade 3 or higher adverse event at least possibly related to treatment) is reported below. |
Countries
United States
Participant flow
Recruitment details
Thirty-nine (39) participants were recruited at Mayo Clinic (Rochester) between December 2008 and April 2010.
Pre-assignment details
One participant canceled prior to starting treatment; this participant has been removed from all analyses.
Participants by arm
| Arm | Count |
|---|---|
| Lenalidomide With On-Demand Dexamethasone Lenalidomide: 25mg once daily orally with food on days 1-21 of 28 day cycle until progression or to a maximum of 18 cycles.
Dexamethasone: 10-40 mg once weekly (days 1, 8, 15, & 22) orally with food until progression. | 38 |
| Total | 38 |
Baseline characteristics
| Characteristic | Lenalidomide With On-Demand Dexamethasone |
|---|---|
| Age, Continuous | 66 years |
| Durie Salmon Stage at Diagnosis Not Assessed | 3 participants |
| Durie Salmon Stage at Diagnosis Stage III: High Cell Mass | 12 participants |
| Durie Salmon Stage at Diagnosis Stage II: Intermediate Cell Mass | 15 participants |
| Durie Salmon Stage at Diagnosis Stage I: Low Cell Mass | 8 participants |
| Parameter of Hematologic Response: Serum Immunoglobulin Free Light Chain >= 10 mg/dL No | 13 participants |
| Parameter of Hematologic Response: Serum Immunoglobulin Free Light Chain >= 10 mg/dL Yes | 25 participants |
| Parameter of Hematologic Response: Serum M-Spike >= 1 mg/dL No | 12 participants |
| Parameter of Hematologic Response: Serum M-Spike >= 1 mg/dL Yes | 26 participants |
| Parameter of Hematologic Response: Urine M-Spike >= 200 mg/24 hours No | 24 participants |
| Parameter of Hematologic Response: Urine M-Spike >= 200 mg/24 hours Yes | 14 participants |
| Region of Enrollment United States | 38 participants |
| Sex: Female, Male Female | 21 Participants |
| Sex: Female, Male Male | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 38 / 38 |
| serious Total, serious adverse events | 9 / 38 |
Outcome results
Primary
Progression-free Survival (PFS) Rate at 12 Months
PFS rate at 12 months is defined as the percentage of participants who are alive and progression-free at 12 months. Progression is exclusively defined as a patient with progressive disease while receiving treatment with lenalidomide in combination with dexamethasone. Progression was defined as any one or more of the following: An increase of 25% from lowest confirmed response in: * Serum M-component (absolute increase \>= 0.5g/dl) * Urine M-component (absolute increase \>= 200mg/24hour * Difference between involved and uninvolved Free Light Chain levels (absolute increase \>= 10mg/dl * Bone marrow plasma cell percentage (absolute increase of \>=10%)
Time frame: 12 months from registration
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lenalidomide With On-Demand Dexamethasone | Progression-free Survival (PFS) Rate at 12 Months | 79 percentage of participants |
Secondary
Confirmed Response Rate
Confirmed response rate is defined as the percentage of participants who achieved a response that was confirmed on 2 consecutive evaluations during treatment * Complete Response(CR): Complete disappearance of M-protein from serum & urine on immunofixation, normalization of Free Light Chain (FLC) ratio & \<5% plasma cells in bone marrow (BM) * Very Good Partial Response(VGPR): \>=90% reduction in serum M-component; Urine M-Component \<100 mg per 24 hours; \<=5% plasma cells in BM * Partial Response PR): \>= 50% reduction in serum M-Component and/or Urine M-Component \>= 90% reduction or \<200 mg per 24 hours; or \>= 50% decrease in difference between involved and uninvolved FLC levels
Time frame: Up to 18 cycles from registration
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lenalidomide With On-Demand Dexamethasone | Confirmed Response Rate | 61 percentage of participants |
Secondary
Number of Participants Who Experienced at Least One Grade 3 or Higher Adverse Event at Least Possibly Related to Treatment (Toxicity)
The number of participants who experienced toxicity (defined as at least one grade 3 or higher adverse event at least possibly related to treatment) is reported below.
Time frame: Duration on treatment (up to 18 cycles from registration)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Lenalidomide With On-Demand Dexamethasone | Number of Participants Who Experienced at Least One Grade 3 or Higher Adverse Event at Least Possibly Related to Treatment (Toxicity) | 23 Participants |
Secondary
Overall Survival (OS)
OS was defined as the time from registration to death of any cause. Participants were followed for a maximum of 3 years from randomization. The median OS with 95% CI was estimated using the Kaplan Meier method
Time frame: Time from registration to death (up to 3 years)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lenalidomide With On-Demand Dexamethasone | Overall Survival (OS) | 61.1 months |
Secondary
Progression-free Survival (PFS)
PFS was defined as the time from registration to progression or death due to any cause. The median PFS with 95%CI was estimated using the Kaplan Meier method. Progression was defined as any one or more of the following:An increase of 25% from lowest confirmed response in: * Serum M-component (absolute increase \>= 0.5g/dl) * Urine M-component (absolute increase \>= 200mg/24hour * Difference between involved and uninvolved Free Light Chain levels (absolute increase \>= 10mg/dl * Bone marrow plasma cell percentage (absolute increase of \>=10%)
Time frame: Time from registration to progression or death (up to 3 years)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lenalidomide With On-Demand Dexamethasone | Progression-free Survival (PFS) | 27 months |