Multiple Myeloma and Plasma Cell Neoplasm
Conditions
Keywords
primary systemic amyloidosis
Brief summary
RATIONALE: Biological therapies, such as lenalidomide, may stimulate the immune system in different ways and stop plasma cells from growing. Drugs used in chemotherapy, such as cyclophosphamide and dexamethasone, work in different ways to stop the growth of plasma cells, either by killing the cells or by stopping them from dividing. Giving lenalidomide together with cyclophosphamide and dexamethasone may be an effective treatment for primary systemic amyloidosis. PURPOSE: This phase II trial is studying how well giving lenalidomide together with cyclophosphamide and dexamethasone works in treating patients with primary systemic amyloidosis.
Detailed description
OBJECTIVES: Primary \* Assess the hematologic response rate in patients with primary systemic amyloidosis treated with lenalidomide, cyclophosphamide, and dexamethasone. Secondary * Determine the organ response rate in patients treated with this regimen. * Determine the toxicity of this regimen in these patients. * Determine the time to progression in patients treated with this regimen. * Determine the survival of patients treated with this regimen. OUTLINE: Patients receive oral lenalidomide on days 1-21, oral cyclophosphamide\* on days 1, 8, and 15, and oral dexamethasone on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. NOTE: \*Patients may receive cyclophosphamide for up to 1 year. After completion of study treatment, patients are followed every 6 months for up to 3 years.
Interventions
DRUGdexamethasone
40 mg weekly taken orally
DRUGlenalidomide
15 mg daily days 1-21 of a 28 day cycle taken orally with food
DRUGcyclophosphamide
300 mg/m\^2 days 1, 8 & 15 of a 28 day cycle taken orally with food
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: * Histochemical diagnosis of AL amyloidosis based on detection of green birefringent material in Congo red-stained tissue specimens by polarizing microscopy * Measurable disease, as defined by one of the following: * Serum monoclonal protein ≥ 1.0 g by serum electrophoresis * Urine monoclonal protein \> 200 mg by 24-hour urine electrophoresis * Serum immunoglobulin free light chain ≥ 10 mg/dL AND abnormal serum immunoglobulin kappa to lambda free light chain ratio * Symptomatic organ involvement with amyloid to justify therapy * May include liver involvement, cardiac involvement, renal involvement, grade 1 peripheral neuropathy, or soft tissue involvement * Must have more than skin purpura or carpal tunnel syndrome * No amyloid-specific syndrome, such as carpal tunnel syndrome or skin purpura, as only evidence of disease \- Vascular amyloid only in a bone marrow biopsy specimen or in a plasmacytoma is not indicative of systemic amyloidosis * No clinically overt multiple myeloma (i.e., monoclonal BMPC \> 30%, bone lesions, or hypercalcemia) PATIENT CHARACTERISTICS: * ECOG performance status 0-2 * ANC ≥ 1,000/μL * Platelet count ≥ 75,000/μL * Creatinine \< 3.0 mg/dL * Not pregnant * Negative pregnancy test * Fertile patients must use two acceptable methods of contraception for ≥ 28 days prior to, during, and for ≥ 28 days after completion of study treatment * No nursing during and for ≥ 28 days after completion of study treatment * No blood, semen, or sperm donation during and for ≥ 28 days after completion of study treatment * No malignancies within the past 5 years except treated basal cell or squamous cell carcinoma of the skin, or carcinoma in situ of the cervix or breast * No neuropathy ≥ grade 2, defined as motor neuropathy (symptomatic weakness interfering with function, but not interfering with activities of daily living \[ADL\]) or sensory neuropathy (sensory alteration or paresthesia \[including tingling\], interfering with function, but not interfering with ADL) * No uncontrolled infection * No syncope within the past 30 days * No known hypersensitivity to thalidomide, including desquamating rash with thalidomide in the past * No known seropositivity for HIV * No active hepatitis A, B, or C * No New York Heart Association class III or IV heart disease * No venous thromboembolic event within the past 42 days * Able to take aspirin (81 or 325 mg) daily as prophylactic anticoagulation - Patients intolerant to aspirin may use low molecular weight heparin PRIOR CONCURRENT THERAPY: * No prior lenalidomide * More than 2 weeks since prior and no other concurrent anticancer agents or treatments * More than 4 weeks since prior experimental agents * No other concurrent corticosteroids except chronic steroids (maximum dose 20 mg/day of prednisone equivalent) for disorders other than amyloidosis (e.g., adrenal insufficiency or rheumatoid arthritis)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Achieved a Confirmed Response Defined as a Complete Response (CR), Very Good Partial Response (VGPR) or Partial Response (PR) | Duration on study (up to 3 years) | Response that was confirmed on 2 consecutive evaluations during treatment. 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 \<=100 mg per 24 hours. 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Organ Response | Duration of study (up to 3 years) | Organ response was evaluated on the basis of improvement of one or more affected organ; only one parameter was required to satisfy the criteria. Response needed to be maintained for a minimum of 3 months to be considered valid. Renal response required a 50% reduction in 24-hour urine protein excretion (at least 0.5 g/d) with stable creatinine. Cardiac response required one of \>= 2-mm reduction in the interventricular septal (IVS) thickness by echocardiogram, or improvement of ejection fraction by \>= 20%, or improvement by 2 NYHA classes without an increase in diuretic use. Hepatic response required either \>= 50% decrease in (or normalization of) an initially elevated alkaline phosphatase level or reduction in the size of the liver by at least 2 cm by radiographic determination. Gastrointestinal tract improvement was defined as normalization of a low serum carotene level, or reduction of diarrhea to \< 50% of previous movements/day, or decrease in fecal fat excretion by 50%. |
| Number of Participants With Severe Adverse Events | Duration of study (up to 3 years) | Severe adverse events were defined as grade 3 or higher, at least possibly related to study drugs. Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3. |
| Progression Free Survival (PFS) | Duration of study (up to 3 years) | Progression free survival (PFS) was defined as the time from registration to hematologic progression or death of any cause. Progression free and alive patients were censored at the date of last follow-up. The median PFS with 95% CI was estimated using the Kaplan Meier method. |
| Overall Survival (OS) | Duration of study (up to 3 years) | Overall survival (OS) was defined as the time from registration to death of any cause. Surviving patients were censored at the date of last follow-up. The median OS with 95% CI was estimated using the Kaplan Meier method. |
Countries
United States
Participant flow
Recruitment details
Thirty-five(35) participants were recruited between December 2007 and November 2008 at Mayo Clinic.
Participants by arm
| Arm | Count |
|---|---|
| Len/Cyc/Dex Lenalidomide (Len) 15mg daily (days 1-21); Cyclophosphamide (Cyc) 300 mg/m\^2 (days 1, 8, 15); Dexamethasone (Dex) 40 mg weekly | 35 |
| Total | 35 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 12 |
| Overall Study | Alternative treatment | 3 |
| Overall Study | Death | 7 |
| Overall Study | Disease progression | 3 |
| Overall Study | Other, not specified | 4 |
Baseline characteristics
| Characteristic | Len/Cyc/Dex |
|---|---|
| Age Continuous | 64 years |
| Had a Prior Stem Cell Transplant No | 28 participants |
| Had a Prior Stem Cell Transplant Yes | 7 participants |
| Received Previous Treatment No | 24 participants |
| Received Previous Treatment Yes | 11 participants |
| Region of Enrollment United States | 35 participants |
| Sex: Female, Male Female | 16 Participants |
| Sex: Female, Male Male | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 35 / 35 |
| serious Total, serious adverse events | 24 / 35 |
Outcome results
Primary
Number of Participants Who Achieved a Confirmed Response Defined as a Complete Response (CR), Very Good Partial Response (VGPR) or Partial Response (PR)
Response that was confirmed on 2 consecutive evaluations during treatment. 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 \<=100 mg per 24 hours. 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: Duration on study (up to 3 years)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Len/Cyc/Dex | Number of Participants Who Achieved a Confirmed Response Defined as a Complete Response (CR), Very Good Partial Response (VGPR) or Partial Response (PR) | 21 participants |
Secondary
Number of Participants With Severe Adverse Events
Severe adverse events were defined as grade 3 or higher, at least possibly related to study drugs. Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.
Time frame: Duration of study (up to 3 years)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Len/Cyc/Dex | Number of Participants With Severe Adverse Events | 26 participants |
Secondary
Number of Patients With Organ Response
Organ response was evaluated on the basis of improvement of one or more affected organ; only one parameter was required to satisfy the criteria. Response needed to be maintained for a minimum of 3 months to be considered valid. Renal response required a 50% reduction in 24-hour urine protein excretion (at least 0.5 g/d) with stable creatinine. Cardiac response required one of \>= 2-mm reduction in the interventricular septal (IVS) thickness by echocardiogram, or improvement of ejection fraction by \>= 20%, or improvement by 2 NYHA classes without an increase in diuretic use. Hepatic response required either \>= 50% decrease in (or normalization of) an initially elevated alkaline phosphatase level or reduction in the size of the liver by at least 2 cm by radiographic determination. Gastrointestinal tract improvement was defined as normalization of a low serum carotene level, or reduction of diarrhea to \< 50% of previous movements/day, or decrease in fecal fat excretion by 50%.
Time frame: Duration of study (up to 3 years)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Len/Cyc/Dex | Number of Patients With Organ Response | 11 participants |
Secondary
Overall Survival (OS)
Overall survival (OS) was defined as the time from registration to death of any cause. Surviving patients were censored at the date of last follow-up. The median OS with 95% CI was estimated using the Kaplan Meier method.
Time frame: Duration of study (up to 3 years)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Len/Cyc/Dex | Overall Survival (OS) | 37.8 months |
Secondary
Progression Free Survival (PFS)
Progression free survival (PFS) was defined as the time from registration to hematologic progression or death of any cause. Progression free and alive patients were censored at the date of last follow-up. The median PFS with 95% CI was estimated using the Kaplan Meier method.
Time frame: Duration of study (up to 3 years)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Len/Cyc/Dex | Progression Free Survival (PFS) | 28.3 months |