Multiple Myeloma and Plasma Cell Neoplasm
Conditions
Keywords
stage I multiple myeloma, stage II multiple myeloma, stage III multiple myeloma
Brief summary
RATIONALE: Drugs used in chemotherapy, such as melphalan, prednisone, and lenalidomide, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more cancer cells. PURPOSE: This phase I/II trial is studying the side effects and best dose of melphalan and lenalidomide when given together with prednisone and to see how well they work in treating patients with newly diagnosed multiple myeloma.
Detailed description
OBJECTIVES: Primary * Determine the maximum tolerated dose of melphalan and lenalidomide in combination with prednisone in patients with newly diagnosed multiple myeloma. * Determine the response rate in patients treated with this regimen. Secondary * Determine the toxicity of this regimen in these patients. OUTLINE: This is a dose-escalation study of melphalan and lenalidomide followed by a phase II study. * Phase I: Patients receive oral melphalan and oral prednisone daily on days 1-4. Patients also receive oral lenalidomide daily on days 1-21. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of melphalan and lenalidomide until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. \* Phase II: Patients receive oral melphalan and oral lenalidomide as in phase I at the MTD. Patients also receive oral prednisone as in phase I. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed every 3 months for 3 years.
Interventions
DRUGlenalidomide
Phase I - dose escalating: 5mg level -1, 10mg level 0, 10mg level 1, 15mg level 2, 20mg level 3, 25mg level 4, orally days 1-21 every 28 days until progression Phase II - 10 mg orally days 1-21 every 28 days until progression
DRUGmelphalan
Phase I - dose escalating: 5mg/m\^2 dose level -1, 5 mg/m\^2 dose level 0, 8 mg/m\^2 dose level 1 - 4, daily x 4 orally days every 28 days until progression Phase II - 5mg/m\^2 orally days 1-4 every 28 days until progression
DRUGprednisone
60mg/m\^2, orally days 1-4 every 28 days until progression
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 No maximum
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: * Diagnosis of multiple myeloma * Newly diagnosed disease * Requires treatment, in the judgment of the treating physician * Not a candidate for (or patient declines) autologous stem cell transplantation * Meets 1 of the following criteria: * Measurable disease, defined by any of the following: * Serum monoclonal protein ≥ 1 g/dL * Urine protein monoclonal light chain ≥ 200 mg/24 hours by electrophoresis * Measurable serum free light chains ≥ 10 mg/dL, kappa or lambda, AND κ/λ ratio is abnormal (if serum and urine are not measurable as defined above) * Evaluable disease, defined as monoclonal bone marrow plasmacytosis ≥ 30% PATIENT CHARACTERISTICS: * ECOG performance status 0-3 * Life expectancy \> 3 months * ANC ≥ 1,500/mm³ * Bilirubin ≤ 2.0 mg/dL * Alkaline phosphatase ≤ 3 times upper limit of normal (ULN) * AST ≤ 3 times ULN * Creatinine ≤ 3.0 mg/dL * Platelet count ≥ 100,000/mm³ * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use 2 effective methods of contraception, including ≥ 1 highly effective method, ≥ 4 weeks before and during study treatment * No uncontrolled infection * No peripheral neuropathy ≥ grade 2 * No serious medical condition, laboratory abnormality, or psychiatric illness that would preclude study compliance * No other active malignancy except for nonmelanoma skin cancer or carcinoma in situ \- Prior malignancy allowed if treated with curative intent and is free of disease for a period appropriate for that cancer * No known hypersensitivity to thalidomide * No known HIV positivity * No infectious hepatitis A, B or C * No history of deep vein thrombosis or other medical condition requiring the use of warfarin * Able to take daily prophylactic acetylsalicylic acid (81 or 325 mg) PRIOR CONCURRENT THERAPY: * See Disease Characteristics * More than 4 weeks since prior radiotherapy for treatment of multiple myeloma * No prior lenalidomide * No other concurrent anticancer agents or treatments * No concurrent steroids except prednisone ≤ 20 mg/day (or the equivalent) for concurrent illness or adrenal replacement therapy * No other concurrent investigational therapy or agent for treatment of multiple myeloma * No concurrent warfarin
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Patients With Overall Confirmed Response | Every cycle during treatment | Response that was confirmed on 2 consecutive evaluations.\> * Complete Response (CR): Complete disappearance of M-protein from serum and urine on immunofixations, normalization of Free Light Chain (FLC) ratio and \<=5% plasma cells in bone marrow\> * Very Good Partial Response (VGPR): \>=90% reduction in serum M-spike, Urine M-spike \<100mg per 24 hours\> * Partial Response (PR): \>=50% reduction in serum M-spike, Urine M-spike \>=90% reduction or \< 200mg per 24 hours, or \>=50% decrease in difference between involved and uninvolved FLC levels or 50% decrease in bone marrow plasma cells |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) at 3 Years | registration to death (up to 3 years) | OS was defined as the time from registration to death due to any cause. Patients who were alive were censored at date of last follow-up. The overall survival at 3 years (a percentage) is reported below. |
| Progression-free Survival | registration to progressive disease (up to 3 years) | Progression free survival (PFS) is defined as the time from the date of randomization to the date of disease progression or death resulting from any cause, whichever comes first. 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%) |
| Duration of Response (DOR) | from first response to progression or death (up to 3 years) | Duration of response was calculated from documentation of first response to date of progression in the subset of patients who responded. Patients without progression were censored at the date of last tumor evaluation. |
| Percentage of Participants With Toxicity, Assessed Using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 (v3) | Every cycle during treatment up to 3 years | The overall toxicity rates (percentages) for grade 3 or higher adverse events considered at least possibly related to treatment are reported below. |
Countries
United States
Participant flow
Pre-assignment details
This was as Phase I/II trial. There were 7 patients recruited to the Phase I portion; no patients qualified for the Phase II portion. Twenty-six (26) patients were recruited for the Phase II portion. Results presented here are on the 26 Phase II patients.
Participants by arm
| Arm | Count |
|---|---|
| Treatment (Lenalidomide, Melphalan, Prednisone) Intervention: Drug: lenalidomide 10 mg orally days 1-21 every 28 days until progression
Intervention: Drug: melphalan 5mg/m\^2 orally days 1-4 every 28 days until progression
Intervention: Drug: prednisone 60mg/m\^2, orally days 1-4 every 28 days until progression | 26 |
| Total | 26 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Currently Receiving Treatment | 11 |
Baseline characteristics
| Characteristic | Treatment (Lenalidomide, Melphalan, Prednisone) |
|---|---|
| Age, Continuous | 73.5 years |
| Durie-Salmon Stage at Diagnosis III - High Cell Mass | 11 participants |
| Durie-Salmon Stage at Diagnosis II - Intermediate Cell Mass | 11 participants |
| Durie-Salmon Stage at Diagnosis I - Low Cell Mass | 1 participants |
| Durie-Salmon Stage at Diagnosis unknown | 3 participants |
| Parameter of Hematologic Response - None (non-secretory myeloma, bone marrow only) No | 26 participants |
| Parameter of Hematologic Response - None (non-secretory myeloma, bone marrow only) Yes | 0 participants |
| Parameter of Hematologic Response - Serum Immunoglobulin Free Light Chain >= 10mg/dL No | 14 participants |
| Parameter of Hematologic Response - Serum Immunoglobulin Free Light Chain >= 10mg/dL Yes | 12 participants |
| Parameter of Hematologic Response - Serum M-spike >= 1g/dL No | 6 participants |
| Parameter of Hematologic Response - Serum M-spike >= 1g/dL Yes | 20 participants |
| Parameter of Hematologic Response - Urine M-spike >= 200 mg/24 hours No | 20 participants |
| Parameter of Hematologic Response - Urine M-spike >= 200 mg/24 hours Yes | 6 participants |
| Region of Enrollment United States | 26 participants |
| Sex: Female, Male Female | 9 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 | 26 / 26 |
| serious Total, serious adverse events | 7 / 26 |
Outcome results
Primary
Patients With Overall Confirmed Response
Response that was confirmed on 2 consecutive evaluations.\> * Complete Response (CR): Complete disappearance of M-protein from serum and urine on immunofixations, normalization of Free Light Chain (FLC) ratio and \<=5% plasma cells in bone marrow\> * Very Good Partial Response (VGPR): \>=90% reduction in serum M-spike, Urine M-spike \<100mg per 24 hours\> * Partial Response (PR): \>=50% reduction in serum M-spike, Urine M-spike \>=90% reduction or \< 200mg per 24 hours, or \>=50% decrease in difference between involved and uninvolved FLC levels or 50% decrease in bone marrow plasma cells
Time frame: Every cycle during treatment
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment (Lenalidomide, Melphalan, Prednisone) | Patients With Overall Confirmed Response | CR | 3 participants |
| Treatment (Lenalidomide, Melphalan, Prednisone) | Patients With Overall Confirmed Response | VGPR | 5 participants |
| Treatment (Lenalidomide, Melphalan, Prednisone) | Patients With Overall Confirmed Response | PR | 10 participants |
Secondary
Duration of Response (DOR)
Duration of response was calculated from documentation of first response to date of progression in the subset of patients who responded. Patients without progression were censored at the date of last tumor evaluation.
Time frame: from first response to progression or death (up to 3 years)
Population: Phase 2 Patients who had a response of PR or better are included in this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Lenalidomide, Melphalan, Prednisone) | Duration of Response (DOR) | 16.3 months |
Secondary
Overall Survival (OS) at 3 Years
OS was defined as the time from registration to death due to any cause. Patients who were alive were censored at date of last follow-up. The overall survival at 3 years (a percentage) is reported below.
Time frame: registration to death (up to 3 years)
Population: Phase 2 patients.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (Lenalidomide, Melphalan, Prednisone) | Overall Survival (OS) at 3 Years | 58 percentage of patients |
Secondary
Percentage of Participants With Toxicity, Assessed Using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 (v3)
The overall toxicity rates (percentages) for grade 3 or higher adverse events considered at least possibly related to treatment are reported below.
Time frame: Every cycle during treatment up to 3 years
Population: Patients who experienced an adverse event that is at least possibly related are included in this analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment (Lenalidomide, Melphalan, Prednisone) | Percentage of Participants With Toxicity, Assessed Using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 (v3) | Grade 3 | 33 percentage of patients |
| Treatment (Lenalidomide, Melphalan, Prednisone) | Percentage of Participants With Toxicity, Assessed Using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 (v3) | Grade 4 | 67 percentage of patients |
| Treatment (Lenalidomide, Melphalan, Prednisone) | Percentage of Participants With Toxicity, Assessed Using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 (v3) | Grade 5 | 0 percentage of patients |
Secondary
Progression-free Survival
Progression free survival (PFS) is defined as the time from the date of randomization to the date of disease progression or death resulting from any cause, whichever comes first. 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: registration to progressive disease (up to 3 years)
Population: Phase 2 patients
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Lenalidomide, Melphalan, Prednisone) | Progression-free Survival | 21.4 months |