Multiple Myeloma
Conditions
Keywords
multiple myeloma, POEMS (Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes), amyloidosis, bone marrow transplant, autologous
Brief summary
This study is designed to decrease toxicity associated with prior tandem transplant protocols by reducing the intensity of induction, consolidation and maintenance therapy, while increasing event-free survival by adding bortezomib (Velcade®), thalidomide, gemcitabine and carmustine to the transplant regimens to down-regulate the rescue of myeloma cells by the micro-environment and to prevent DNA repair post high-dose alkylating agent therapy. By reducing drug resistance, it is hoped that 3-year event-free survival will be increased significantly when compared to Total Therapy II. Additionally, participants will have the option of providing biospecimens for a sub-study evaluating gene expression profiling at specific timepoints to better understand drug-resistance in myeloma, and to determine whether there are genes or gene products in the resistant population that can be targeted by novel therapies.
Detailed description
This study is targeted towards patients who have been diagnosed with Multiple Myeloma, POEMS(Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes), or myeloma plus amyloidosis and have had no more than 12 months of prior treatment. Furthermore, participants cannot have had a prior autologous or allogeneic transplant. The study schema consists of one round of induction chemotherapy, two transplants, one round of consolidation chemotherapy, and two years of maintenance treatment. This study design differs from its historical predecessors in the following manner: * In contrast to Total Therapy II and III, which only allow enrollment of patients with one cycle or one month of treatment prior to enrollment, the proposed study allows enrollment of participants with up to 12 months of prior treatment. * Induction therapy has been reduced to a single cycle. * Bortezomib and thalidomide have been added to the transplant regimen. * Carmustine is added to the second transplant. * Gemcitabine is added to the second transplant regimen. * Consolidation treatment has been reduced to a single cycle. * The first year of maintenance consists of 12 28-day cycles of bortezomib,dexamethasone, and either thalidomide, lenalidomide, or cyclophoshamide. The second year of maintenance therapy consists of lenalidomide and dexamethasone. * The novel agents thalidomide and bortezomib are not introduced upfront, but only with transplantation, consolidation, and maintenance.
Interventions
DRUGDexamethasone
Given PO
PROCEDURETandem autologous stem cell transplant
DRUGCisplatin
Given IV
DRUGDoxorubicin
Given IV
DRUGCyclophosphamide
Given IV or PO
DRUGEtoposide
Given IV
DRUGBortezomib
Given IV
DRUGThalidomide
Given PO
DRUGMelphalan
Given IV
Sponsors
National Cancer Institute (NCI)
University of Iowa
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
1. Participants must have had a diagnosis of symptomatic MM, MM + amyloidosis, or POEMS (osteosclerotic myeloma: Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal protein, Skin changes) requiring treatment. Participants with a previous history of smoldering myeloma will be eligible if there is evidence of progressive disease requiring chemotherapy. Note that study participants do not need to have active disease at the time of study entry, as participants may have received up to 12 months of prior chemotherapy, which might have induced a response. 2. Protein criteria must be present (quantifiable M-component of IgG, IgA, IgD, or IgE and/or urinary kappa or lambda light chain, Bence-Jones protein, or Free Kappa Light Chain or Free Lambda Light Chain) in order to evaluate response. Non-secretory participants are eligible provided the participant has \> 20% plasmacytosis OR multiple (\>3) focal plasmacytomas or focal lesions on MRI. 3. Participants must have received no more than 12 months of prior chemotherapy for this disease. Participants may have received prior radiotherapy provided approval has been obtained from the PI. 4. Participants must not have had a prior transplant. 5. Participants must be 18-80 years of age at the time of study entry. 6. Ejection fraction by ECHO or MUGA of ≥ 40% performed. 7. Participants must have adequate pulmonary function studies, \> 50% of predicted on mechanical aspects (FEV1, FVC) and diffusion capacity (DLCO) \> 50% of predicted (adjusted for hemoglobin). If the participant is unable to complete pulmonary function tests due to disease related pain or condition, a participant may still be enrolled provided that the PI or enrolling investigator documents that the participant is a transplant candidate. 8. Participants must have a creatinine \< 3 mg/dl and a calculated creatinine clearance \>30mL/min. The Cockroft-Gault equation may be used to obtain calculated creatinine clearance. 9. Participants must have a performance status of 0-2 based on ECOG criteria. Participants with a poor performance status (3-4)based solely on bone pain will be eligible, provided there is documentation to verify this. 10. Participants must sign the most current IRB-approved study ICF (Informed Consent Form).
Exclusion criteria
1. Prior autologous or allogeneic transplant. 2. Platelet count \< 30 x 109/L, unless myeloma-related. If MM-related, the enrolling investigator must document this. 3. \> grade 3 neuropathy. 4. Known hypersensitivity to bortezomib, boron, or mannitol. 5. Uncontrolled diabetes. 6. Recent (\< 6 months) myocardial infarction, unstable angina, difficult to control congestive heart failure, uncontrolled hypertension, or difficult to control cardiac arrhythmias. 7. Participants must not have light chain deposition disease-related renal failure or creatinine \>3 mg/dl. 8. Participants must not have a concurrent malignancy unless it can be adequately treated by surgical, non-chemotherapeutic intervention. Participants may have a history of prior malignancy, provided that he/she has not had any treatment within 365 days of study entry AND that life expectancy exceeds 5 years at the time of study entry. 9. Participants must not have life-threatening co-morbidities. 10. Women of child-bearing potential must have a documented negative pregnancy test documented within one week of study entry. Women and men of reproductive potential may not participate unless they have agreed, by signing the study ICF, to use effective contraceptive method(s) as outlined in that form.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Event-Free Survival (EFS) | 8 years | To determine whether, in comparison to Total Therapy II, the median Event-Free Survival (EFS) can be increased from 4.8 years to 7.2 years, which represents an increase in median EFS of approximately 50%, based on an intent-to-treat analysis. |
| Identification of Drug Resistant Genes | 5 years | To determine whether repeated bone marrow samples analyzed for gene expression profiling (GEP) can identify genes related to drug resistance in myeloma. The drug resistant genes or the gene products might then be targeted specifically to eradicate myeloma cells surviving tandem transplantation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Grade 3 Non-hematologic and Grade 4 Hematologic Serious Adverse Events Associated With the Addition of Bortezomib, Thalidomide, and Dexamethasone Into Autologous Transplant Regimens. | 2 years | To determine whether bortezomib, thalidomide and dexamethasone with transplant 1 and velcade/gemcitabine with transplant 2 can be safely incorporated into well-tested pre-transplant regimens of high-dose melphalan and carmustine/melphalan in doses equivalent to the BEAM(BCNU, etoposide, arabinoside, melphalan)regimen. Treatment-related toxicities will be compared to those reported in the literature using similar intensive approaches. |
| Overall Survival | 10 years | To determine the median overall survival based on an intent-to-treat analysis, which should exceed 10 years, based on the projected 10-year survival of Total Therapy III, keeping in mind that participants are included in this protocol with up to 12 months of prior therapy. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Tandem Transplant in MM <12 Mos of Prior Treatment This was a single arm study for myeloma patients with \<12 months of prior treatment to determine whether the incorporation of bortezomib into a tandem transplant regimen followed by 2 years of maintenance therapy would increase event-free survival. | 19 |
| Total | 19 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 3 |
| Overall Study | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | Tandem Transplant in MM <12 Mos of Prior Treatment |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 3 Participants |
| Age, Categorical Between 18 and 65 years | 16 Participants |
| Age, Continuous | 59.4 years |
| Region of Enrollment United States | 19 participants |
| Sex: Female, Male Female | 8 Participants |
| Sex: Female, Male Male | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 3 / 19 |
| other Total, other adverse events | 19 / 19 |
| serious Total, serious adverse events | 13 / 19 |
Outcome results
Primary
Event-Free Survival (EFS)
To determine whether, in comparison to Total Therapy II, the median Event-Free Survival (EFS) can be increased from 4.8 years to 7.2 years, which represents an increase in median EFS of approximately 50%, based on an intent-to-treat analysis.
Time frame: 8 years
Population: Enrollment halted prematurely. Study met stopping rules (3 or more of the first 20 participants died due to treatment-related toxicity).~Data for outcome measure 1 were not collected.
| Arm | Measure | Value |
|---|---|---|
| Tandem Autologous Stem Cell Transplant | Event-Free Survival (EFS) | 0 |
Primary
Identification of Drug Resistant Genes
To determine whether repeated bone marrow samples analyzed for gene expression profiling (GEP) can identify genes related to drug resistance in myeloma. The drug resistant genes or the gene products might then be targeted specifically to eradicate myeloma cells surviving tandem transplantation.
Time frame: 5 years
Population: Enrollment halted prematurely. Study met stopping rules (3 or more of the first 20 participants died due to treatment-related toxicity).~Data for outcome measure 2 were not collected.
| Arm | Measure | Value |
|---|---|---|
| Tandem Autologous Stem Cell Transplant | Identification of Drug Resistant Genes | 0 |
Secondary
Number of Grade 3 Non-hematologic and Grade 4 Hematologic Serious Adverse Events Associated With the Addition of Bortezomib, Thalidomide, and Dexamethasone Into Autologous Transplant Regimens.
To determine whether bortezomib, thalidomide and dexamethasone with transplant 1 and velcade/gemcitabine with transplant 2 can be safely incorporated into well-tested pre-transplant regimens of high-dose melphalan and carmustine/melphalan in doses equivalent to the BEAM(BCNU, etoposide, arabinoside, melphalan)regimen. Treatment-related toxicities will be compared to those reported in the literature using similar intensive approaches.
Time frame: 2 years
Population: Enrollment halted prematurely. Study met stopping rules (3 or more of the first 20 participants died due to treatment-related toxicity).~Data for outcome measure 3 were not collected.
| Arm | Measure | Value |
|---|---|---|
| Tandem Autologous Stem Cell Transplant | Number of Grade 3 Non-hematologic and Grade 4 Hematologic Serious Adverse Events Associated With the Addition of Bortezomib, Thalidomide, and Dexamethasone Into Autologous Transplant Regimens. | 0 |
Secondary
Overall Survival
To determine the median overall survival based on an intent-to-treat analysis, which should exceed 10 years, based on the projected 10-year survival of Total Therapy III, keeping in mind that participants are included in this protocol with up to 12 months of prior therapy.
Time frame: 10 years
Population: Enrollment halted prematurely. Study met stopping rules (3 or more of the first 20 participants died due to treatment-related toxicity).~Data for outcome measure 4 were not collected.
| Arm | Measure | Value |
|---|---|---|
| Tandem Autologous Stem Cell Transplant | Overall Survival | 0 |