Multiple Myeloma
Conditions
Keywords
relapsed multiple myeloma, refractory multiple myeloma
Brief summary
The purpose of this study is to evaluate the effectiveness and side effects of the bortezomib, lenalidomide and dexamethasone combination in relapsed or relapsed and refractory multiple myeloma. Each of these drugs are approved by the U.S Food and Drug Administration, but have not been approved in the combination for treating patients in this setting.
Detailed description
* Participants took the study medication in the clinic on Cycle 1 day 1. Each treatment cycle lasted three weeks. They took the lenalidomide (capsules) every day for the first two weeks only (days 1-14). They took dexamethasone (tablets) on Day 1, 2, 4, 5, 8, 9, 11 and 12 and came to the outpatient treatment center for intravenous bortezomib on Day 1, 4, 8 and 11. The third week of the cycle was a rest period and the participant did not take any study medication. * Certain tests and procedures were performed throughout each treatment cycle at definitive time periods. These tests included: medical history update, physical/neurological examination, skeletal survey (x-rays or scan), blood samples, urine samples, optional bone marrow aspiration/tissue biopsy, 12-lead ECG, and MRI/CT (if needed). * It was expected that participants were going to complete at least 8 cycles of the study, which adds up to 168 days. If the participant completed the first 8 cycles, had stable or responding disease and had not experienced bad side effects, they were allowed to continue treatment on a maintenance schedule, detailed in the protocol, at the study doctor's discretion.
Interventions
DRUGBortezomib
Given intravenously on days 1,4,8 and 11 of a 21-day cycle for a minimum of 8 cycles.
DRUGLenalidomide
Taken orally once a day for 2 weeks (days 1-14) of a 21-day cycle for a minimum of 8 cycles
DRUGDexamethasone
Taken orally on days 1,2,4,5,8,9,11,and 12 of a 21-day cycle for a minimum of 8 cycles
Sponsors
Brigham and Women's Hospital
Massachusetts General Hospital
Celgene Corporation
Millennium Pharmaceuticals, Inc.
Dana-Farber Cancer Institute
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Diagnosis of multiple myeloma based on standard diagnostic criteria or by the new International Myeloma Foundation 2003 Diagnostic Criteria * Relapsed or relapsed and refractory disease after receiving between 1 and 3 prior regimens * Negative serum or urine pregnancy test * Age 18 years or older * Karnofsky performance status of 60 or greater
Exclusion criteria
* Grade 2 or greater peripheral neuropathy within 14 days before enrollment * Renal insufficiency (serum creatinine \> 2.5 mg/dL) * Evidence of mucosal or internal bleeding and/or platelet refractory * ANC \< 1000 cells/mm3 * Hemoglobin \< 8.0 g/dL * AST or ALT greater than or equal to 2 x ULN * Concomitant therapy medications that include corticosteroids * Myocardial infarction within 6 months prior to enrollment or has NYHA Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities * Clinically relevant active infection or serious co-morbid medical conditions * Prior malignancy (within last 3 years) except for adequately treated basal cell or squamous cell skin cancer, in situ cervical or breast cancer, in situ prostate cancer * Pregnant or breast-feeding * Serious medical or psychiatric illness likely to interfere with participation in this clinical study. * Uncontrolled diabetes mellitus * Hypersensitivity to acyclovir or similar anti-viral drug * POEMS syndrome * Known HIV infection * Known active hepatitis B or C viral infection * Known intolerance to steroid therapy * Subjects with primary refractory disease, defined as progression during initial treatment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Proportion of Patients Alive and Without Progressive Disease (PD) for ≥6 Months | 6 months after therapy | Response assessed by the European Group for Blood and Marrow Transplant (EBMT) criteria, modified to include nCR and VGPR from the international uniform response criteria (IMWG). Progressive disease (PD) required one or more of the following: \>25% increased in serum monoclonal paraprotein (must also be an absolute increase of at least 5 g/L and confirmed on a repeat investigation) \>25% increased in 24-hour urinary light chain excretion (must also be an absolute increase of at least 200 mg/24 h and confirmed on a repeat investigation) \>25% increased in plasma cells in a bone marrow aspirate or on trephine biopsy (must also be an absolute increase of at least 10%) Definite increase in the size of existing lytic bone lesions or soft tissue plasmacytomas. Development of new bone lesions or soft tissue plasmacytomas (not including compression fracture). Development of hypercalcemia (corrected serum calcium \>11.5 mg/dL or 2.8 mmol/L not attributable to any other cause). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate | Assessed every cycle for up to 8 cycles and best response was reported | Response assessed by the European Group for Blood and Marrow Transplant (EBMT) criteria, modified to include nCR and VGPR from the international uniform response criteria (IMWG). Objective response was defined by the achievement of at least Partial Response (PR) or better (CR-complete response, nCR-near complete response, and VGPR-very good partial response). |
| Duration of Response | Assessed at a median follow-up of 44 months | Duration of response will be measured as the time from initiation of a response to first documentation of disease progression or death, or date last known progression-free and alive for those who have not progressed or died. |
| Progression Free Survival | aassesed at a median follow-up of 44 months | Progression-free survival is defined as the time from registration to the disease progression or death from any cause, censored at date last known progression-free for those who have not progressed or died. |
| Overall Survival | assesed at a median follow-up of 44 months | defined as time from treatment initiation to death, or last known to be alive for those who had not died |
Countries
United States
Participant flow
Recruitment details
65 eligible participants were enrolled from the 6 institutions in the United States between September 2006 and April 2008 and 64 out of 65 received protocol treatment.
Pre-assignment details
Participants screened over a 3 week period.
Participants by arm
| Arm | Count |
|---|---|
| Lenalidomide, Dexamethasone, Bortezomib Combination Patients were treated for up to 8 21-day cycles with the combination of bortezomib 1.0 mg/m2 IV, days 1, 4, 8, and 11, and oral lenalidomide 15 mg/day, days 1 through 14, with oral dexamethasone 40 mg/day (cycles 1-4) and 20 mg/day (cycles 5-8) on the days of and days after bortezomib dosing (days 1, 2, 4, 5, 8, 9, 11, and 12).Following a protocol amendment , dexamethasone dosing was reduced to 20 mg/day in cycles 1 through 4 and 10 mg/day in cycles 5 through 8.
Beyond cycle 8, responding patients and those with stable disease (SD) could receive maintenance therapy until disease progression or unacceptable toxicity. Maintenance therapy comprised bortezomib and lenalidomide at the doses tolerated on completion of cycle 8, with lenalidomide on days 1 through 14 and using an amended schedule of weekly bortezomib (days 1 and 8) and dexamethasone 10 mg on days 1, 2, 8, and 9. | 64 |
| Total | 64 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 3 |
| Overall Study | Death | 1 |
| Overall Study | Initiation of non-protocol therapy | 3 |
| Overall Study | Physician Decision | 3 |
| Overall Study | Progressive disease | 11 |
| Overall Study | Treatment delay | 1 |
Baseline characteristics
| Characteristic | Lenalidomide, Dexamethasone, Bortezomib Combination |
|---|---|
| Age, Continuous | 65 years |
| Sex: Female, Male Female | 22 Participants |
| Sex: Female, Male Male | 42 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 34 / 64 |
| serious Total, serious adverse events | 47 / 64 |
Outcome results
Primary
The Proportion of Patients Alive and Without Progressive Disease (PD) for ≥6 Months
Response assessed by the European Group for Blood and Marrow Transplant (EBMT) criteria, modified to include nCR and VGPR from the international uniform response criteria (IMWG). Progressive disease (PD) required one or more of the following: \>25% increased in serum monoclonal paraprotein (must also be an absolute increase of at least 5 g/L and confirmed on a repeat investigation) \>25% increased in 24-hour urinary light chain excretion (must also be an absolute increase of at least 200 mg/24 h and confirmed on a repeat investigation) \>25% increased in plasma cells in a bone marrow aspirate or on trephine biopsy (must also be an absolute increase of at least 10%) Definite increase in the size of existing lytic bone lesions or soft tissue plasmacytomas. Development of new bone lesions or soft tissue plasmacytomas (not including compression fracture). Development of hypercalcemia (corrected serum calcium \>11.5 mg/dL or 2.8 mmol/L not attributable to any other cause).
Time frame: 6 months after therapy
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lenalidomide, Dexamethasone, Bortezomib Combination | The Proportion of Patients Alive and Without Progressive Disease (PD) for ≥6 Months | 75 percentage of treated patients |
Secondary
Duration of Response
Duration of response will be measured as the time from initiation of a response to first documentation of disease progression or death, or date last known progression-free and alive for those who have not progressed or died.
Time frame: Assessed at a median follow-up of 44 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lenalidomide, Dexamethasone, Bortezomib Combination | Duration of Response | 8.7 months |
Secondary
Objective Response Rate
Response assessed by the European Group for Blood and Marrow Transplant (EBMT) criteria, modified to include nCR and VGPR from the international uniform response criteria (IMWG). Objective response was defined by the achievement of at least Partial Response (PR) or better (CR-complete response, nCR-near complete response, and VGPR-very good partial response).
Time frame: Assessed every cycle for up to 8 cycles and best response was reported
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lenalidomide, Dexamethasone, Bortezomib Combination | Objective Response Rate | 64 percentage of treated patients |
Secondary
Overall Survival
defined as time from treatment initiation to death, or last known to be alive for those who had not died
Time frame: assesed at a median follow-up of 44 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lenalidomide, Dexamethasone, Bortezomib Combination | Overall Survival | 30 month |
Secondary
Progression Free Survival
Progression-free survival is defined as the time from registration to the disease progression or death from any cause, censored at date last known progression-free for those who have not progressed or died.
Time frame: aassesed at a median follow-up of 44 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lenalidomide, Dexamethasone, Bortezomib Combination | Progression Free Survival | 9.5 months |