Multiple Myeloma and Plasma Cell Neoplasm
Conditions
Keywords
stage II multiple myeloma, stage III multiple myeloma, refractory multiple myeloma
Brief summary
RATIONALE: Biological therapies, such as CC-4047, may stimulate the immune system in different ways and stop cancer cells from growing. Dexamethasone and CC-4047 may stop the growth of cancer cells by blocking blood flow to the cancer. Giving CC-4047 together with dexamethasone may kill more cancer cells. PURPOSE: This phase II trial is studying how well giving CC-4047 together with dexamethasone works in treating patients with relapsed or refractory multiple myeloma or amyloidosis.
Detailed description
OBJECTIVES: * To assess the response rate and duration of remission with low-dose CC-4047 plus dexamethasone in patients with relapsed or refractory multiple myeloma or amyloidosis. * To assess the toxicity of CC-4047 plus dexamethasone in this patient population. * To assess in an expansion cohort the response rate with an increase in CC-4047 dose among patients who fail to respond adequately to the initial starting dose following the first 2 courses of treatment. * To assess the response rate and duration of remission with CC-4047 plus dexamethasone in patients with lenalidomide resistant or refractory multiple myeloma. * To assess the response rate and duration of remission with CC-4047 plus dexamethasone in patients with previously treated light chain amyloidosis. * To assess the response rate and duration of remission with low- and high-dose CC-4047 plus dexamethasone in patients with lenalidomide and bortezomib refractory multiple myeloma. * To assess the response rate and duration of remission with high-dose CC-4047 plus dexamethasone in patients with relapsed or refractory myeloma who received ≤ 3 treatment regimens. OUTLINE: Patients are grouped according to disease status (relapsed/refractory myeloma \[closed to accrual as of 8/5/2008\] vs lenalidomide resistant/refractory myeloma \[closed to accrual as of 4/2/2009\] vs previously treated light chain amyloidosis vs lenalidomide and bortezomib resistant/refractory myeloma {low-dose/day}\[closed to accrual as of 11/20/09\] vs lenalidomide and bortezomib resistant/refractory myeloma (high-dose/day) vs relapsed/refractory myeloma {high-dose/day}). Patients receive oral CC-4047 on days 1-28 and oral dexamethasone on days 1, 8, 15, and 22. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed for 4 weeks and then at 6 months.
Interventions
DRUGdexamethasone
40 mg/day administered through PO (with food) at Days 1, 8, 15, 22 per cycle.
DRUGpomalidomide
2 or 4 mg/day administered through PO at days 1 - 28 or days 1-21 (see Arm description for specific dosing).
Sponsors
National Cancer Institute (NCI)
Mayo Clinic
Study design
Allocation
NON_RANDOMIZED
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: * Symptomatic multiple myeloma * Previously treated disease meeting one of the following criteria: * Have light-chain amyloidosis that has been treated with at least one prior regimen * Symptomatic (relapsed or refractory) multiple myeloma * Patients must have received 1-3 treatment regimens * Induction therapy followed by autologous stem cell transplantation and consolidation considered one regimen * Measurable disease, as defined by 1 of the following: * Serum monoclonal protein ≥ 1.0 g by protein electrophoresis * More than 200 mg of monoclonal protein in the urine on 24-hour electrophoresis * Serum immunoglobulin free light chain (FLC) \> 10 mg/dL and an abnormal FLC ratio * Measurable soft tissue plasmacytoma, not previously irradiated * More than 30% plasma cells in bone marrow * At least 10% plasma cells as measured by bone marrow aspirate, bone marrow biopsy, or labeling index * No monoclonal gammopathy of undetermined significance (not applicable for patients with amyloid) * No smoldering myeloma (not applicable for patients with amyloid) PATIENT CHARACTERISTICS: * ECOG performance status 0, 1, or 2 * ANC ≥ 1,000/μL * Platelet count ≥ 75,000/μL * Creatinine ≤ 2.5 mg/dL * Not pregnant or nursing * Women must refrain from breastfeeding during study participation and for at least 28 days after discontinuation of study drug * Negative pregnancy test * Fertile female patients must use two reliable forms of contraception simultaneously at least 28 days before beginning, during, and at least 28 days after completion of study drug * The two methods of reliable contraception must include one highly effective method (i.e., intrauterine device \[IUD\], hormonal \[birth control pills, injections, or implants\], tubal ligation, or partner's vasectomy) and one additional effective (barrier) method (i.e., latex condom, diaphragm, or cervical cap) * Fertile male patients must use a latex 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 * Men must agree to abstain from donating semen or sperm during study participation and for 28 days after discontinuation of study drug * Willing to abstain from donating blood during study participation and for 28 days after discontinuation of study drug * No uncontrolled infection * No other active malignancy * No New York Heart Association class III or IV cardiac disease (all patients) * Serum troponin T \> 0.10 ng/mL (amyloid patients only) * No known positivity for HIV or active hepatitis infection * No active deep vein thrombosis or pulmonary embolism that has not been therapeutically anticoagulated * No condition, including the presence of laboratory abnormalities, that places the patient at unacceptable risk for participating in the study or confounds the ability to interpret data from the study * No known hypersensitivity to thalidomide or lenalidomide including development of erythema nodosum if characterized by a desquamating rash * No peripheral neuropathy \> grade 2 PRIOR CONCURRENT THERAPY: * All previous cancer therapy, including chemotherapy and investigational agents, must have been discontinued ≥ 2 weeks prior to study registration * No radiotherapy ≤ 14 days prior to study registration * No other concurrent anti-myeloma therapy * No concurrent radiotherapy, except for palliation of a single painful bone lesion or fracture * Routine concurrent bisphosphonate therapy allowed for patients with myeloma bone disease * Willing and able to take aspirin or alternate prophylactic anticoagulation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Number of Confirmed Hematologic Responses (Complete, Partial, or Very Good Partial Response) | Duration of study (up to 3 years) | Response that was confirmed on 2 consecutive evaluations * Complete Response(CR): Complete disappearance of M-protein from serum and urine on immunofixation, normalization of Free Light Chain (FLC) ratio and \<5% plasma cells in bone marrow. * Very Good Partial Response(VGPR): \>=90% reduction in serum M-component; Urine M-Component \<100mg per 24hours; \<=5% plasma cells in bone marrow. * Partial Response(PR): \>=50% reduction in serum M-component and/or Urine M-Component \>=90% reduction or \<200mg per 24hours; or \>=50% decrease in difference between involved and uninvolved FLC levels. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) | Duration of study (up to 5 years) | PFS was defined as the time from registration to progression or death due to any cause. PFS was analyzed using Kaplan Meier method. Progression was defined as any one or more of the following: * 25% increase in serum M-component (absolute increase \>= 0.5g/dl) * 25% increase in urine M-component (absolute increase \>= 200mg/24hour * 25% increase in the difference between involved and uninvolved Free Light Chain levels (absolute increase \>= 10mg/dl) * 25% increase in bone marrow plasma cell percentage (absolute increase of \>=10%) * Definite development of new bone lesion or soft tissue plasmacytomas |
| Duration of Response | Duration of study (up to 5 years) | Duration of response was calculated from the documentation (date) of first response (CR, VGPR, or PR) until the date of progression or last follow-up in the subset of patients who responded. Kaplan Meier method was used to compute this outcome. |
Countries
United States
Participant flow
Recruitment details
Between November 2007 and March 2012, 7 sequential phase 2 trials (reported as separate arms) were conducted. A total of 378 participants were recruited at Mayo Clinic (Arizona, Florida or Arizona).
Pre-assignment details
One patient was deemed ineligible and excluded from all analyses.
Participants by arm
| Arm | Count |
|---|---|
| Relapsed Myeloma (<4 Prior Regimens): Low Dose Pomalidomide: 2 mg orally once daily, days 1-28 of 28 day cycle
Dexamethasone: 40 mg on days 1, 8, 15 ad 22 of 28 day cycle | 60 |
| Lenalidomide Refractory Myeloma: Low Dose Pomalidomide: 2 mg orally once daily, days 1-28 of 28 day cycle
Dexamethasone: 40 mg on days 1, 8, 15 ad 22 of 28 day cycle | 34 |
| Bortezomib/Lenalidomide Refractory/Relapsed Myeloma: Low Dose Pomalidomide: 2 mg orally once daily, days 1-28 of 28 day cycle
Dexamethasone: 40 mg on days 1, 8, 15 ad 22 of 28 day cycle | 35 |
| Bortezomib/Lenalidomide Relapsed/Refractory Myeloma: High Dose Pomalidomide: 4 mg orally once daily, days 1-28 of 28 day cycle
Dexamethasone: 40 mg on days 1, 8, 15 ad 22 of 28 day cycle | 35 |
| Relapsed Myeloma (< 4 Prior Regimens): High Dose Pomalidomide: 4 mg orally once daily, days 1-28 of 28 day cycle
Dexamethasone: 40 mg on days 1, 8, 15 ad 22 of 28 day cycle | 60 |
| Relapsed/Refractory Myeloma: High Dose Pomalidomide: 4 mg orally once daily, days 1-21 of 28 day cycle
Dexamethasone: 40 mg on days 1, 8, 15 ad 22 of 28 day cycle | 120 |
| Relapsed Amyloidosis: Low Dose Pomalidomide: 2 mg orally once daily, days 1-28 of 28 day cycle
Dexamethasone: 40 mg on days 1, 8, 15 ad 22 of 28 day cycle | 33 |
| Total | 377 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 | 1 | 3 | 4 | 10 | 3 |
| Overall Study | Alternative Treatment | 2 | 2 | 0 | 2 | 6 | 7 | 1 |
| Overall Study | Continues on treatment | 10 | 1 | 0 | 1 | 9 | 25 | 6 |
| Overall Study | Death | 3 | 0 | 2 | 3 | 2 | 2 | 6 |
| Overall Study | Physician discretion | 3 | 2 | 1 | 2 | 1 | 3 | 3 |
| Overall Study | Withdrawal by Subject | 2 | 1 | 1 | 1 | 1 | 5 | 5 |
Baseline characteristics
| Characteristic | Relapsed Myeloma (<4 Prior Regimens): Low Dose | Lenalidomide Refractory Myeloma: Low Dose | Bortezomib/Lenalidomide Refractory/Relapsed Myeloma: Low Dose | Bortezomib/Lenalidomide Relapsed/Refractory Myeloma: High Dose | Relapsed Myeloma (< 4 Prior Regimens): High Dose | Relapsed/Refractory Myeloma: High Dose | Relapsed Amyloidosis: Low Dose | Total |
|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 65.5 years | 61.5 years | 62 years | 61 years | 65.5 years | 65 years | 66 years | 64 years |
| Region of Enrollment United States | 60 participants | 34 participants | 35 participants | 35 participants | 60 participants | 120 participants | 33 participants | 377 participants |
| Sex: Female, Male Female | 24 Participants | 11 Participants | 8 Participants | 14 Participants | 20 Participants | 47 Participants | 14 Participants | 138 Participants |
| Sex: Female, Male Male | 36 Participants | 23 Participants | 27 Participants | 21 Participants | 40 Participants | 73 Participants | 19 Participants | 239 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 60 / 60 | 34 / 34 | 34 / 35 | 35 / 35 | 60 / 60 | 119 / 119 | 32 / 33 |
| serious Total, serious adverse events | 22 / 60 | 11 / 34 | 15 / 35 | 11 / 35 | 21 / 60 | 32 / 119 | 18 / 33 |
Outcome results
Primary
The Number of Confirmed Hematologic Responses (Complete, Partial, or Very Good Partial Response)
Response that was confirmed on 2 consecutive evaluations * Complete Response(CR): Complete disappearance of M-protein from serum and urine on immunofixation, normalization of Free Light Chain (FLC) ratio and \<5% plasma cells in bone marrow. * Very Good Partial Response(VGPR): \>=90% reduction in serum M-component; Urine M-Component \<100mg per 24hours; \<=5% plasma cells in bone marrow. * Partial Response(PR): \>=50% reduction in serum M-component and/or Urine M-Component \>=90% reduction or \<200mg per 24hours; or \>=50% decrease in difference between involved and uninvolved FLC levels.
Time frame: Duration of study (up to 3 years)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Relapsed Myeloma (<4 Prior Regimens): Low Dose | The Number of Confirmed Hematologic Responses (Complete, Partial, or Very Good Partial Response) | 39 participants |
| Lenalidomide Refractory Myeloma: Low Dose | The Number of Confirmed Hematologic Responses (Complete, Partial, or Very Good Partial Response) | 11 participants |
| Bortezomib/Lenalidomide Refractory/Relapsed Myeloma: Low Dose | The Number of Confirmed Hematologic Responses (Complete, Partial, or Very Good Partial Response) | 9 participants |
| Bortezomib/Lenalidomide Relapsed/Refractory Myeloma: High Dose | The Number of Confirmed Hematologic Responses (Complete, Partial, or Very Good Partial Response) | 10 participants |
| Relapsed Myeloma (< 4 Prior Regimens): High Dose | The Number of Confirmed Hematologic Responses (Complete, Partial, or Very Good Partial Response) | 23 participants |
| Relapsed/Refractory Myeloma: High Dose | The Number of Confirmed Hematologic Responses (Complete, Partial, or Very Good Partial Response) | 25 participants |
| Relapsed Amyloidosis: Low Dose | The Number of Confirmed Hematologic Responses (Complete, Partial, or Very Good Partial Response) | 16 participants |
Secondary
Duration of Response
Duration of response was calculated from the documentation (date) of first response (CR, VGPR, or PR) until the date of progression or last follow-up in the subset of patients who responded. Kaplan Meier method was used to compute this outcome.
Time frame: Duration of study (up to 5 years)
Population: Participants who achieved a partial response(PR) or better were evaluable for this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Relapsed Myeloma (<4 Prior Regimens): Low Dose | Duration of Response | 21.3 months |
| Lenalidomide Refractory Myeloma: Low Dose | Duration of Response | 8.2 months |
| Bortezomib/Lenalidomide Refractory/Relapsed Myeloma: Low Dose | Duration of Response | 15.6 months |
| Bortezomib/Lenalidomide Relapsed/Refractory Myeloma: High Dose | Duration of Response | 3.1 months |
| Relapsed Myeloma (< 4 Prior Regimens): High Dose | Duration of Response | NA months |
| Relapsed/Refractory Myeloma: High Dose | Duration of Response | 8.3 months |
| Relapsed Amyloidosis: Low Dose | Duration of Response | 19 months |
Secondary
Progression Free Survival (PFS)
PFS was defined as the time from registration to progression or death due to any cause. PFS was analyzed using Kaplan Meier method. Progression was defined as any one or more of the following: * 25% increase in serum M-component (absolute increase \>= 0.5g/dl) * 25% increase in urine M-component (absolute increase \>= 200mg/24hour * 25% increase in the difference between involved and uninvolved Free Light Chain levels (absolute increase \>= 10mg/dl) * 25% increase in bone marrow plasma cell percentage (absolute increase of \>=10%) * Definite development of new bone lesion or soft tissue plasmacytomas
Time frame: Duration of study (up to 5 years)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Relapsed Myeloma (<4 Prior Regimens): Low Dose | Progression Free Survival (PFS) | 13 months |
| Lenalidomide Refractory Myeloma: Low Dose | Progression Free Survival (PFS) | 5 months |
| Bortezomib/Lenalidomide Refractory/Relapsed Myeloma: Low Dose | Progression Free Survival (PFS) | 6.4 months |
| Bortezomib/Lenalidomide Relapsed/Refractory Myeloma: High Dose | Progression Free Survival (PFS) | 3.3 months |
| Relapsed Myeloma (< 4 Prior Regimens): High Dose | Progression Free Survival (PFS) | 7.7 months |
| Relapsed/Refractory Myeloma: High Dose | Progression Free Survival (PFS) | 4.3 months |
| Relapsed Amyloidosis: Low Dose | Progression Free Survival (PFS) | 14.1 months |