Multiple Myeloma
Conditions
Brief summary
BEAM regimen (BCNU, etoposide, cytarabine, and melphalan) is the most commonly used conditioning regimen for relapsed/refractory lymphoma patients needing autologous stem cell transplantation. Since these components are all effective in myeloma and bortezomib has shown promising results in the transplant setting, here the investigators propose a phase II study to investigate the combination of bortezomib and BEAM as a new conditioning regimen for patients who relapse or progress after the first autologous transplantation and for whom a second autologous transplant is considered.
Interventions
PROCEDUREStem cell infusion
DRUGBortezomib
DRUGCarmustine
DRUGEtoposide
DRUGCytarabine
DRUGMelphalan
Sponsors
Washington University School of Medicine
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
* Patient must have a histologically confirmed diagnosis of multiple myeloma. * Patient must have received a prior autologous stem cell transplantation with melphalan conditioning for multiple myeloma with subsequent disease progression and repeat autologous stem cell transplantation is deemed appropriate by the treating physicians. * Patient must receive induction chemotherapy including 2 to 4 cycles of anti-myeloma therapy including bortezomib, with or without immune modulating agents and/or corticosteroids, Completion of induction therapy will occur within 30 days of first study drug dose. * Patient must have ≥ 2x106/kg CD34+ autologous stem cells available for transplantation. * Patient must be ≥ 18 years of age. * Patient must have life expectancy of greater than 6 months. * Patient must have an ECOG performance status ≤ 2 or Karnofsky performance status ≥ 60% (see Appendices A and B) * Patient must have normal bone marrow and organ function as defined below within 14 days prior to first study drug dose (conditioning regimen): * Absolute neutrophil count ≥500/mm3 * Platelets ≥ 50,000/mm3 * Hemoglobin ≥ 8 g/dl * Total bilirubin ≤ 1.5 x IULN * AST(SGOT)/ALT(SGPT) ≤ 3.0 x IULN * Creatinine clearance (Appendix C) ≥30 mL/min/1.73m2 * Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry through Day +100 visit. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately. * Patient must be able to understand and willing to sign an IRB approved written informed consent document.
Exclusion criteria
* Patient must not be refractory to induction therapy. Refractory is defined as disease progression while on therapy or within 30 days following completion of therapy. * Patient must not have had disease progression requiring active treatment within 12 months of previous autologous stem cell transplant. Maintenance therapy is not considered active treatment. * Patient must not have peripheral neuropathy ≥ grade 3 based on NCI CTCAE v 4.0 (Appendix D). * Patient must not be receiving renal replacement therapy, hemodialysis, or peritoneal dialysis. * Patient must not have another concurrent malignancy requiring treatment. * Patient must not be receiving any other investigational agents within 14 days prior to the first dose of study drug. * Patient must not have known brain metastases. Patients with known brain metastases must be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. * Patient must not have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to bortezomib, carmustine, etoposide, cytarabine, and melphalan, or other agents used in the study. * Patient must not have an uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. * Patient must not be pregnant and/or breastfeeding. Inclusion of Women and Minorities -Both men and women and members of all races and ethnic groups are eligible for this trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Complete Response Rate (Complete Response + Stringent Complete Response) | Day +100 | Defined by the International Myeloma Working Group (IMWG) criteria |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) | 3 months following Day +100 visit | ORR includes Partial Response (PR) + Very Good Partial Response (VGPR) + Complete Response (CR) Response will be assessed per the International Myeloma Working Group (IMWG) Response Criteria. |
| Very Good Partial Response Rate (VGPR+nCR+sCR+CR) | Day +100 | Response will be assessed per the International Myeloma Working Group (IMWG) Response Criteria. |
| Toxicity of V-BEAM | 30 days after end of treatment / Day +100 | Graded per the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Patients are evaluated from first receiving study treatment until a 30-day follow-up after the conclusion of treatment for adverse events not resulting in death. Adverse events resulting in death will be evaluated through Day +100. This outcomes measures the common toxicities observed. Please refer to the Serious Adverse Event and Other Adverse Event sections of the results for further details. |
| Number of Participants With Progression-free Survival (PFS) | Median follow-up of 6 months (range: 6.0-12.0 months) | PFS is defined as the duration from transplant to time of first progression, death, relapse after CR, or the date the patient was last known to be in remission. Response will be assessed per the International Myeloma Working Group (IMWG) Response Criteria. |
| Number of Participants With Overall Survival (OS) | Median follow-up of 6 months (range: 6-12 months) | OS is defined as the duration from the time of transplant to death or last follow-up. |
| Treatment Related Mortality (TRM) of V-BEAM | Day +100 | — |
| Time to Platelet Engraftment After V-BEAM. | Day +100 | Time to platelet engraftment is defined as the duration between Day 0 to the first day of platelet count sustained at \> 20x109/L without transfusion. The median time to neutrophil and platelet engraftment will be reported. |
| Time to Neutrophil Engraftment After V-BEAM. | Day +100 | Time to neutrophil engraftment is defined as duration between Day 0 to the first day of ANC \> 0.5x109/L post transplant when it is sustained for more than three consecutive days. |
Countries
United States
Participant flow
Recruitment details
The study opened to participant enrollment on 09/20/2012 and closed to participant enrollment on 06/18/2013.
Participants by arm
| Arm | Count |
|---|---|
| V-BEAM + Stem Cell Infusion Bortezomib IV or SC (1.3mg/m2) on Days -6, -3, +1 and +4 Carmustine IV (300mg/m2) on Day -7 Etoposide IV twice daily (100 mg/m2) on Days -6, -5, -4, and -3 Cytarabine IV twice daily (100 mg/m2) on Days -6, -5, -4, and -3 Melphalan IV (140 mg/m2) on Day-2 Stem cell infusion on Day 0 | 10 |
| Total | 10 |
Baseline characteristics
| Characteristic | V-BEAM + Stem Cell Infusion |
|---|---|
| Age, Continuous | 64.5 years |
| Durie-Salmon Stage of Myeloma on Diagnosis Stage I | 0 participants |
| Durie-Salmon Stage of Myeloma on Diagnosis Stage IIA | 3 participants |
| Durie-Salmon Stage of Myeloma on Diagnosis Stage IIIA | 7 participants |
| International Staging System (ISS) Stage of Myeloma on Diagnosis Stage I | 2 participants |
| International Staging System (ISS) Stage of Myeloma on Diagnosis Stage II | 5 participants |
| International Staging System (ISS) Stage of Myeloma on Diagnosis Stage III | 2 participants |
| International Staging System (ISS) Stage of Myeloma on Diagnosis Unknown | 1 participants |
| Monoclonal Protein Type IgA | 5 participants |
| Monoclonal Protein Type IgG | 3 participants |
| Monoclonal Protein Type Light chain only | 2 participants |
| Number of Prior Therapies (including prior transplant) | 4 prior therapies |
| Region of Enrollment United States | 10 participants |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 5 Participants |
| Time from Diagnosis to V-BEAM transplant | 42 months |
| Time to Progression from First Transplant | 29 months |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 10 / 10 |
| serious Total, serious adverse events | 4 / 10 |
Outcome results
Primary
Complete Response Rate (Complete Response + Stringent Complete Response)
Defined by the International Myeloma Working Group (IMWG) criteria
Time frame: Day +100
Population: Two participants without evaluable responses due to early mortality were not included in this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| V-BEAM + Stem Cell Infusion | Complete Response Rate (Complete Response + Stringent Complete Response) | 6 participants |
Secondary
Number of Participants With Overall Survival (OS)
OS is defined as the duration from the time of transplant to death or last follow-up.
Time frame: Median follow-up of 6 months (range: 6-12 months)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| V-BEAM + Stem Cell Infusion | Number of Participants With Overall Survival (OS) | Expired Day +3 | 1 participants |
| V-BEAM + Stem Cell Infusion | Number of Participants With Overall Survival (OS) | Expired Day +18 | 1 participants |
| V-BEAM + Stem Cell Infusion | Number of Participants With Overall Survival (OS) | Alive | 8 participants |
Secondary
Number of Participants With Progression-free Survival (PFS)
PFS is defined as the duration from transplant to time of first progression, death, relapse after CR, or the date the patient was last known to be in remission. Response will be assessed per the International Myeloma Working Group (IMWG) Response Criteria.
Time frame: Median follow-up of 6 months (range: 6.0-12.0 months)
Population: Two participants without evaluable responses due to early mortality were not included in this analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| V-BEAM + Stem Cell Infusion | Number of Participants With Progression-free Survival (PFS) | No relapse/progression | 7 participants |
| V-BEAM + Stem Cell Infusion | Number of Participants With Progression-free Survival (PFS) | Relapse/progression at 12 months | 1 participants |
Secondary
Overall Response Rate (ORR)
ORR includes Partial Response (PR) + Very Good Partial Response (VGPR) + Complete Response (CR) Response will be assessed per the International Myeloma Working Group (IMWG) Response Criteria.
Time frame: 3 months following Day +100 visit
Population: Two participants without evaluable responses due to early mortality were not included in this analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| V-BEAM + Stem Cell Infusion | Overall Response Rate (ORR) | Partial response | 0 participants |
| V-BEAM + Stem Cell Infusion | Overall Response Rate (ORR) | Very good partial response | 2 participants |
| V-BEAM + Stem Cell Infusion | Overall Response Rate (ORR) | Complete response | 6 participants |
Secondary
Time to Neutrophil Engraftment After V-BEAM.
Time to neutrophil engraftment is defined as duration between Day 0 to the first day of ANC \> 0.5x109/L post transplant when it is sustained for more than three consecutive days.
Time frame: Day +100
Population: Two participants without evaluable responses due to early mortality were not included in this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| V-BEAM + Stem Cell Infusion | Time to Neutrophil Engraftment After V-BEAM. | 10 days |
Secondary
Time to Platelet Engraftment After V-BEAM.
Time to platelet engraftment is defined as the duration between Day 0 to the first day of platelet count sustained at \> 20x109/L without transfusion. The median time to neutrophil and platelet engraftment will be reported.
Time frame: Day +100
Population: Two participants without evaluable responses due to early mortality were not included in this analysis.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| V-BEAM + Stem Cell Infusion | Time to Platelet Engraftment After V-BEAM. | More than 20 x 10^9/L | 22.5 days |
| V-BEAM + Stem Cell Infusion | Time to Platelet Engraftment After V-BEAM. | More than 50 x 10^9/L | 23 days |
Secondary
Toxicity of V-BEAM
Graded per the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Patients are evaluated from first receiving study treatment until a 30-day follow-up after the conclusion of treatment for adverse events not resulting in death. Adverse events resulting in death will be evaluated through Day +100. This outcomes measures the common toxicities observed. Please refer to the Serious Adverse Event and Other Adverse Event sections of the results for further details.
Time frame: 30 days after end of treatment / Day +100
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| V-BEAM + Stem Cell Infusion | Toxicity of V-BEAM | Neutropenic fever | 10 participants |
| V-BEAM + Stem Cell Infusion | Toxicity of V-BEAM | Clostridium difficile colitis | 3 participants |
| V-BEAM + Stem Cell Infusion | Toxicity of V-BEAM | Neutropenic colitis without Clostridium difficile | 3 participants |
| V-BEAM + Stem Cell Infusion | Toxicity of V-BEAM | Sepsis | 3 participants |
| V-BEAM + Stem Cell Infusion | Toxicity of V-BEAM | Mucositis (grade 1-2) | 8 participants |
| V-BEAM + Stem Cell Infusion | Toxicity of V-BEAM | Mucositis (grade 3-4) | 2 participants |
| V-BEAM + Stem Cell Infusion | Toxicity of V-BEAM | Diarrhea (grade 3-4) | 10 participants |
| V-BEAM + Stem Cell Infusion | Toxicity of V-BEAM | Hepatic toxicity (grade 3-4) | 1 participants |
| V-BEAM + Stem Cell Infusion | Toxicity of V-BEAM | Peripheral neuropathy (grade 1-2) | 2 participants |
| V-BEAM + Stem Cell Infusion | Toxicity of V-BEAM | Toxic death | 2 participants |
Secondary
Treatment Related Mortality (TRM) of V-BEAM
Time frame: Day +100
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| V-BEAM + Stem Cell Infusion | Treatment Related Mortality (TRM) of V-BEAM | 2 participants |
Secondary
Very Good Partial Response Rate (VGPR+nCR+sCR+CR)
Response will be assessed per the International Myeloma Working Group (IMWG) Response Criteria.
Time frame: Day +100
Population: Two participants without evaluable responses due to early mortality were not included in this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| V-BEAM + Stem Cell Infusion | Very Good Partial Response Rate (VGPR+nCR+sCR+CR) | 8 participants |