Multiple Myeloma and Plasma Cell Neoplasm
Conditions
Keywords
stage II multiple myeloma, stage III multiple myeloma
Brief summary
RATIONALE: Drugs used in chemotherapy such as cyclophosphamide and dexamethasone work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving cyclophosphamide and dexamethasone together with bortezomib may kill more cancer cells. PURPOSE: This phase II trial is studying giving cyclophosphamide and dexamethasone together with bortezomib to see how well it works in treating patients with newly diagnosed multiple myeloma.
Detailed description
OBJECTIVES: Primary \* To evaluate the response rate (complete response \[CR\], near CR \[nCR\], and very good partial response) in patients with newly diagnosed multiple myeloma treated with bortezomib in combination with cyclophosphamide and dexamethasone . Secondary * Determine the overall response rate (partial response, PR, or better) in these patients after 4, 8, and 12 courses of this regimen. * Determine the duration of progression-free and overall survival of patients treated with this regimen. * To evaluate the toxicity of this regimen in these patients. * To evaluate the ability to successfully collect peripheral blood stem cells from these patients after 4 months of this regimen. * To evaluate the CR or nCR rate in these patients after 8 and 12 courses of this regimen. OUTLINE: This is a multicenter study. Patients receive oral cyclophosphamide on days 1, 8, 15, and 22; bortezomib IV on days 1, 4, 8 , and 11 OR days 1, 8, 15 and 22; and dexamethasone on days 1-4, 9-12, and 17-20 in courses 1 and 2 and days 1, 18, 15, and 22 in all subsequent courses. Courses repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.
Interventions
DRUGbortezomib
First 33 patients: 1.3 mg/m\^2 IV Days 1, 4, 8 & 11 Remaining 30 patients: 1.5 mg/m\^2 IV Days 1, 8, 15 & 22
DRUGcyclophosphamide
300mg/m\^2 PO days 1, 8, 15 & 22
DRUGdexamethasone
First 33 patients: 40 mg PO Days 1-4, 9-12, 17-20 Remaining 30 patients: 40 mg PO Days 1-4, 9-12, 17-20 for cycles 1-2; Days 1, 8, 15, 22 for cycle 3+2 for cycle 3 and beyond
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: * Confirmed diagnosis of symptomatic multiple myeloma * Durie Salmon stage 2 or higher * Previously untreated multiple myeloma (including immunomodulatory drugs such as thalidomide) with the exception of bisphosphonates * Evaluable or measurable disease, as defined by at least one of the following: * Serum monoclonal protein ≥ 1 g/dL (measurable disease) * Urine monoclonal protein ≥ 200 mg/24 hours by protein electrophoresis (measurable disease) * Serum-free light chains (FLC) ≥ 10 mg/dL, kappa or lambda, accompanied by an abnormal kappa/lambda ratio Serum FLC's should only be used for patients without measurable serum or urine m-spike \- Monoclonal bone marrow plasmacytosis ≥ 30% (evaluable disease) \* Patients diagnosed with smoldering myeloma or monoclonal gammopathy of undetermined significance are not eligible PATIENT CHARACTERISTICS: Inclusion criteria: * Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0, 1, or 2 \- ECOG PS of 3 will be allowed if secondary to pain in the opinion of the Investigator * Total bilirubin normal OR direct bilirubin ≤ 2.0 mg/dL * Alkaline phosphatase ≤ 3 times upper limit of normal (ULN) * AST ≤ 3 times ULN * Creatinine ≤ 3.5 mg/dL * Absolute neutrophil count ≥ 1,000/mm³ without transfusion or growth factor * Platelet count ≥ 100,000/mm³ without transfusion or growth factor * Willingness and the physical and mental capability to provide written informed consent * Willingness to return to Mayo Clinic Arizona/Princess Margaret Hospital for follow-up * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception
Exclusion criteria
* Peripheral sensory neuropathy ≥ grade 2 as defined by National Cancer Institute (NCI) Common Terminology for Common Adverse Events (CTCAE) version 3.0 * Known hypersensitivity to compounds containing boron or mannitol * Active uncontrolled infection * Severe cardiac comorbidity including but not limited to: * New York Heart Association class III or IV heart failure * History of myocardial infarction within the past 6 months * Uncontrolled angina or electrocardiographic (ECG) evidence of acute ischemia * Severe uncontrolled ventricular arrhythmias or ECG evidence of active conduction system abnormalities * Cardiac amyloidosis with hypotension (i.e., systolic blood pressure \< 100 mm Hg) * Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent study compliance or completion of study treatment PRIOR CONCURRENT THERAPY: * See Disease Characteristics * Prior high-dose corticosteroid therapy for 12 days or less is permitted for emergent complications from newly diagnosed multiple myeloma * More than 14 days since prior investigational agents * No concurrent steroids or any other anticancer agents or treatments \- Patients may receive the equivalent of up to 20 mg prednisone per day for concurrent illness or adrenal replacement therapy * Concurrent palliative radiotherapy for bony pain or fracture is allowed
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Achieved a Confirmed Responses Defined as a Complete Response (CR), Near CR or Very Good Partial Response (VGPR) After the First 4 Months of Treatment | After 4 months of treatment | Response that was confirmed on 2 consecutive evaluations during the first 4 months of 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. near Complete Response (nCR): Patients who meet all criteria for CR except a positive immunofixation will be classified as nCR. Very Good Partial Response(VGPR): \>=90% reduction in serum M-component; Urine M-Component \<100mg per 24hours; \<=5% plasma cells in bone marrow. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | From date of registration until death (up to 5 years) | OS was defined as the time from registration to death of any cause. |
| Number of Participants Who Responded to Treatment (Complete Response,CR; Near Complete Response, nCR; Very Good Partial Response, VGPR; or Partial Response, PR) After 4 Cycles | 4 cycles | Response that was confirmed on 2 consecutive evaluations after 8 months of treatment. CR, nCR and VGPR as defined in the primary outcome. 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. |
| Duration of Response | Duration of study (up to 12 cycles) | Duration of response was calculated from the documentation (date) of first response (CR, nCR, VGPR, or PR) until the date of progression or last follow-up in the subset of patients who responded. |
| Progression Free Survival (PFS) | up to 5 years | PFS was defined as the time from registration to progression or death due to any cause. 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%) * Definite development of new bone lesion or soft tissue plasmacytomas |
| Number of Participants Who Responded to Treatment (CR, nCR, VGPR or PR) After 12 Cycles | After 12 cycles of treatment | Response that was confirmed on 2 consecutive evaluations after 12 cycles of treatment. Criteria for CR, nCR, VGPR and PR are defined in prior outcomes. |
| Number of Participants With Severe Adverse Events | Every cycle during treatment (up to 12 cycles) | Severe adverse events were defined as grade 3 or higher, regardless of attribution to study drugs. Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3. |
| Participants Who Successfully Completed Collection of Peripheral Blood Stem Cells for Transplant | After 4 cycles of treatment | Evaluation of the ability to successfully collect peripheral blood stem cells following four months (cycles) of combination therapy. |
| Number of Participants Who Responded to Treatment (CR, nCR, VGPR or PR) After 8 Cycles | After 8 cycles of treatment | Response that was confirmed on 2 consecutive evaluations after 8 cycles of treatment. Criteria for CR, nCR, VGPR and PR are defined in prior outcomes. |
Countries
Canada, United States
Participant flow
Recruitment details
Sixty-three(63) participants were recruited between December 2006 and October 2008 at either Mayo Clinic Arizona or Princess Margaret Hospital.
Participants by arm
| Arm | Count |
|---|---|
| CyBorD (Bortezomib 1.3mg/m^2) Bortezomib 1.3mg/m\^2 by IV days 1, 4, 8 & 11
Cyclophosphamide 300mg/m\^2 PO days 1, 8, 15 & 22
Dexamethasone 40mg PO days 1-4, 9-12, 17-20 | 33 |
| CyBorD (Bortezomib 1.5mg/m^2) Bortezomib 1.5mg/m\^2 by IV days 1, 8, 15 & 22
Cyclophosphamide 300mg/m\^2 PO days 1, 8, 15 & 22
Dexamethasone 40mg PO cycle 1-2 days 1-4, 9-12, 17-20, cycle 3 and beyond days 1, 8, 15 & 22 | 30 |
| Total | 63 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 5 | 1 |
| Overall Study | Disease Progression | 1 | 0 |
| Overall Study | Lack of Efficacy | 1 | 0 |
| Overall Study | Stem Cell Transplant | 0 | 6 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | CyBorD (Bortezomib 1.3mg/m^2) | CyBorD (Bortezomib 1.5mg/m^2) | Total |
|---|---|---|---|
| Age Continuous | 60 years | 61 years | 61 years |
| Parameter of Hematologic Response - Bone Marrow Plasma Cells > 30% No | 10 participants | 8 participants | 18 participants |
| Parameter of Hematologic Response - Bone Marrow Plasma Cells > 30% Yes | 23 participants | 22 participants | 45 participants |
| Parameter of Hematologic Response - Serum Immunoglobulin Free Light Chain >=10mg/dL No | 9 participants | 4 participants | 13 participants |
| Parameter of Hematologic Response - Serum Immunoglobulin Free Light Chain >=10mg/dL Yes | 24 participants | 26 participants | 50 participants |
| Parameter of Hematologic Response - Urine M-Spike >= 200mg/24 hours No | 17 participants | 19 participants | 36 participants |
| Parameter of Hematologic Response - Urine M-Spike >= 200mg/24 hours Yes | 16 participants | 11 participants | 27 participants |
| Parameters of Hematologic Response - Serum M-spike >=1g/dL No | 8 participants | 12 participants | 20 participants |
| Parameters of Hematologic Response - Serum M-spike >=1g/dL Yes | 25 participants | 18 participants | 43 participants |
| Region of Enrollment Canada | 21 participants | 18 participants | 39 participants |
| Region of Enrollment United States | 12 participants | 12 participants | 24 participants |
| Sex: Female, Male Female | 16 Participants | 14 Participants | 30 Participants |
| Sex: Female, Male Male | 17 Participants | 16 Participants | 33 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 33 / 33 | 27 / 30 |
| serious Total, serious adverse events | 4 / 33 | 3 / 30 |
Outcome results
Primary
Number of Participants Who Achieved a Confirmed Responses Defined as a Complete Response (CR), Near CR or Very Good Partial Response (VGPR) After the First 4 Months of Treatment
Response that was confirmed on 2 consecutive evaluations during the first 4 months of 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. near Complete Response (nCR): Patients who meet all criteria for CR except a positive immunofixation will be classified as nCR. Very Good Partial Response(VGPR): \>=90% reduction in serum M-component; Urine M-Component \<100mg per 24hours; \<=5% plasma cells in bone marrow.
Time frame: After 4 months of treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CyBorD (Bortezomib 1.3mg/m^2) | Number of Participants Who Achieved a Confirmed Responses Defined as a Complete Response (CR), Near CR or Very Good Partial Response (VGPR) After the First 4 Months of Treatment | 20 participants |
| CyBorD (Bortezomib 1.5mg/m^2) | Number of Participants Who Achieved a Confirmed Responses Defined as a Complete Response (CR), Near CR or Very Good Partial Response (VGPR) After the First 4 Months of Treatment | 18 participants |
Secondary
Duration of Response
Duration of response was calculated from the documentation (date) of first response (CR, nCR, VGPR, or PR) until the date of progression or last follow-up in the subset of patients who responded.
Time frame: Duration of study (up to 12 cycles)
Population: Participants who achieved a partial response(PR) or better were evaluable for this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| CyBorD (Bortezomib 1.3mg/m^2) | Duration of Response | NA months |
| CyBorD (Bortezomib 1.5mg/m^2) | Duration of Response | NA months |
Secondary
Number of Participants Who Responded to Treatment (Complete Response,CR; Near Complete Response, nCR; Very Good Partial Response, VGPR; or Partial Response, PR) After 4 Cycles
Response that was confirmed on 2 consecutive evaluations after 8 months of treatment. CR, nCR and VGPR as defined in the primary outcome. 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: 4 cycles
Population: Participants who received 4 cycles of treatment were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CyBorD (Bortezomib 1.3mg/m^2) | Number of Participants Who Responded to Treatment (Complete Response,CR; Near Complete Response, nCR; Very Good Partial Response, VGPR; or Partial Response, PR) After 4 Cycles | 29 participants |
| CyBorD (Bortezomib 1.5mg/m^2) | Number of Participants Who Responded to Treatment (Complete Response,CR; Near Complete Response, nCR; Very Good Partial Response, VGPR; or Partial Response, PR) After 4 Cycles | 28 participants |
Secondary
Number of Participants Who Responded to Treatment (CR, nCR, VGPR or PR) After 12 Cycles
Response that was confirmed on 2 consecutive evaluations after 12 cycles of treatment. Criteria for CR, nCR, VGPR and PR are defined in prior outcomes.
Time frame: After 12 cycles of treatment
Population: No participants received 12 cycles of treatment; therefore, all participants are non-evalualble.
Secondary
Number of Participants Who Responded to Treatment (CR, nCR, VGPR or PR) After 8 Cycles
Response that was confirmed on 2 consecutive evaluations after 8 cycles of treatment. Criteria for CR, nCR, VGPR and PR are defined in prior outcomes.
Time frame: After 8 cycles of treatment
Population: Participants who received 8 cycles of treatment were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CyBorD (Bortezomib 1.5mg/m^2) | Number of Participants Who Responded to Treatment (CR, nCR, VGPR or PR) After 8 Cycles | 1 participants |
Secondary
Number of Participants With Severe Adverse Events
Severe adverse events were defined as grade 3 or higher, regardless of attribution 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: Every cycle during treatment (up to 12 cycles)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CyBorD (Bortezomib 1.3mg/m^2) | Number of Participants With Severe Adverse Events | 16 participants |
| CyBorD (Bortezomib 1.5mg/m^2) | Number of Participants With Severe Adverse Events | 11 participants |
Secondary
Overall Survival (OS)
OS was defined as the time from registration to death of any cause.
Time frame: From date of registration until death (up to 5 years)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| CyBorD (Bortezomib 1.3mg/m^2) | Overall Survival (OS) | NA months |
| CyBorD (Bortezomib 1.5mg/m^2) | Overall Survival (OS) | NA months |
Secondary
Participants Who Successfully Completed Collection of Peripheral Blood Stem Cells for Transplant
Evaluation of the ability to successfully collect peripheral blood stem cells following four months (cycles) of combination therapy.
Time frame: After 4 cycles of treatment
Population: At the time of publication, data was available on 18 patients for group 2.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CyBorD (Bortezomib 1.3mg/m^2) | Participants Who Successfully Completed Collection of Peripheral Blood Stem Cells for Transplant | 33 participants |
| CyBorD (Bortezomib 1.5mg/m^2) | Participants Who Successfully Completed Collection of Peripheral Blood Stem Cells for Transplant | 17 participants |
Secondary
Progression Free Survival (PFS)
PFS was defined as the time from registration to progression or death due to any cause. 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%) * Definite development of new bone lesion or soft tissue plasmacytomas
Time frame: up to 5 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| CyBorD (Bortezomib 1.3mg/m^2) | Progression Free Survival (PFS) | NA months |
| CyBorD (Bortezomib 1.5mg/m^2) | Progression Free Survival (PFS) | NA months |