Multiple Myeloma
Conditions
Keywords
Multiple Myeloma, Autologous Stem Cell Transplantation, Ixazomib, Lenalidomide, Dexamethasone
Brief summary
The purpose of this research study is to evaluate a treatment regimen called IRD which will be given to participants after their stem cell transplant in an effort to help prolong the amount of time the participants are disease-free after transplant. IRD is a three-drug regimen consisting of ixazomib, lenalidomide (also called Revlimid), and dexamethasone. After 4 cycles of IRD, the participants will be randomized to receive maintenance therapy either with ixazomib or lenalidomide.
Detailed description
Based on the further need to improve progression-free survival and overall survival post-autologous stem cell transplantation (ASCT) for multiple myeloma and the benefits seen of consolidation/maintenance treatment with immunomodulatory drugs thalidomide and lenalidomide and the proteasome inhibitor bortezomib, the natural next step is to evaluate combination regimens of immunomodulatory drugs and proteasome inhibitors as consolidation/maintenance post-ASCT. The regimen consisting of ixazomib, lenalidomide, and dexamethasone (IRD) has been shown to have low toxicity, and the availability of an oral formulation of ixazomib allows for easier administration when compared to bortezomib. In this study, following consolidation with IRD, patients will be randomized to maintenance therapy with lenalidomide or ixazomib in order to collect pilot data comparing the toxicity and efficacy of maintenance therapy with immunomodulatory drugs and proteasome inhibitors. 09/23/2019: Upon review of the interim analysis, there will be no further randomizations into the maintenance portion of the trial. All patients will be enrolled into the lenalidomide arm with the exception of those who discontinue lenalidomide during the consolidation phase due to toxicity. Patients who discontinue lenalidomide may be enrolled into the ixazomib arm following approval from the principal investigator. 09/30/2021: Following analysis 4 in 2021, analysis of the primary endpoint, all patients receiving lenalidomide maintenance will be transitioned off-study. Patients receiving ixazomib may remain on trial until disease progression or unacceptable toxicity at the discretion of the treating physician and the site principal investigator.
Interventions
BIOLOGICALIxazomib
DRUGLenalidomide
DRUGDexamethasone
Sponsors
Millennium Pharmaceuticals, Inc.
Multiple Myeloma Research Consortium
Washington University School of Medicine
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
Each patient must meet all of the following inclusion criteria to begin IRD Consolidation: * Between the ages of 18 and 70 years of age (inclusive) at time of enrollment * Voluntary written consent must be given before performance of any study-related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care * Confirmed diagnosis of symptomatic multiple myeloma. (Patients with multiple myeloma with secondary amyloidosis are eligible.) * Received at least two cycles of any regimen as initial systemic therapy for multiple myeloma and are within 2-16 months of the first dose of initial therapy * Eastern Cooperative Oncology Group (ECOG) performance status and/or other performance status 0, 1, or 2 * Adequate organ function as defined below: Absolute neutrophil count (ANC) \>= 1,000 mm\^3 Platelet count \>= 75,000/mm\^3; platelet transfusions to help patient meet eligibility criteria are not allowed within 7 days before study enrollment Total bilirubin \<= 1.5 x upper limit of normal range (ULN) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) \<=3 x ULN Calculated creatinine clearance \>= 30 mL/min * Women of childbearing potential must follow pregnancy testing requirements as outlined in the Revlimid REMS program material. This is defined as either committing to continued abstinence from heterosexual intercourse or beginning TWO acceptable methods of contraception (one highly effective method and one additional effective method AT THE SAME TIME) at least 28 days prior to the start of lenalidomide, for the duration of study participation, and for 28 days following the last dose of lenalidomide. Women of childbearing potential must also agree to ongoing pregnancy testing. * Men must agree to use a latex condom during sexual contact with a woman of childbearing potential even if they have had a successful vasectomy. All patients must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately. * All study participants must be registered into the mandatory Revlimind REMS program and be willing to comply with its requirements. Per standard Revlimid REMS program requirements, all physicians who prescribe lenalidomide for research subjects enrolled into this trial, must be registered in, and must comply with, all requirements of the Revlimid REMS program.
Exclusion criteria
Patients meeting any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Improvement in Minimal Residual Disease (MRD) | After 4 cycles of IRD consolidation treatment (approximately Day 112 of consolidation treatment) | For the purposes of this study, a patient will be considered as having minimal residual disease if a positive result (1x10E06) is obtained using the Adaptive Clonoseq MRD testing. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Toxicity of IRD Consolidation | After 4 cycles of IRD consolidation treatment (approximately Day 112 of consolidation treatment) | For the purposes of this study, toxicity will be defined as inability to receive 4 cycles of IRD consolidation due to toxicity. |
| Response Rate of IRD Consolidation | After 4 cycles of IRD consolidation treatment (approximately Day 112 of consolidation treatment) | For the purposes of this study, response rate is defined as the improvement in complete response rate. Response will be determined by the International Myeloma Working Group (IMWG) Uniform Response Criteria. |
| Progression-free Survival of IRD Consolidation | Up to 18 months after completion of maintenance therapy (Up to 5 years after starting the study) | Progression-free survival (PFS) will be defined as time from ASCT to progression, relapse, or death, whichever occurs first, and those event-free survivors will be censored at withdrawal or study closeout. |
| Overall Survival of IRD Consolidation | Up to 18 months after completion of maintenance therapy (Up to 5 years after starting the study) | Overall survival (OS) will be defined as time from ASCT to death due to any causes, and survivors will be censored at withdrawal or study closeout. |
| Compare Toxicity Between the Two Maintenance Arms | 30 days after the completion of maintenance treatment (estimated to be Day 1125 of maintenance treatment) | The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for all toxicity reporting. |
| Compare Response Rate Between the Two Maintenance Arms | Through completion of maintenance treatment (estimated to be day 1095 of maintenance treatment) | * Response will be determined by the International Myeloma Working Group (IMWG) Uniform Response Criteria. Response includes stringent complete response (sCR) and complete response (CR). * sCR requires all of the following: * CR as defined below * Normal free light chain ratio (0.26-1.65) * Absence of clonal cells in the bone marrow by immunohistochemistry or immunofluorescence * CR requires all of the following: * Disappearance of monoclonal protein by both protein electrophoresis and immunofixation studies from the blood and urine * If serum and urine monoclonal protein are unmeasurable, Normal free light chain ratio (0.26-1.65) * \<5% plasma cells in the bone marrow * Disappearance of soft tissue plasmacytoma |
| MRD-negative Rate After ASCT | Prior to beginning consolidation treatment (Day -28 to Day 0) | For the purposes of this study, a patient will be considered as having minimal residual disease if a positive result (1x10E06) is obtained using the Adaptive Clonoseq MRD testing |
| Compare Overall Survival Between the Two Maintenance Arms | Up to 18 months after completion of maintenance therapy (Up to 5 years after starting the study) | Overall survival (OS) will be defined as time from ASCT to death due to any causes, and survivors will be censored at withdrawal or study closeout. |
| Rate of MRD-positive to MRD-negative Conversion Between the Two Maintenance Arms | Cycle 13 Day 1 of maintenance treatment (Approximately Day 364 of maintenance treatment) | — |
| Association of Progression-free Survival With MRD-negativity | Up to 18 months after completion of maintenance therapy (Up to 5 years after starting the study) | Progression-free survival (PFS) will be defined as time from ASCT to progression, relapse, or death, whichever occurs first, and those event-free survivors will be censored at withdrawal or study closeout. |
| Association of Progression-free Survival With MRD-positivity | Up to 18 months after completion of maintenance therapy (Up to 5 years after starting the study) | Progression-free survival (PFS) will be defined as time from ASCT to progression, relapse, or death, whichever occurs first, and those event-free survivors will be censored at withdrawal or study closeout. |
| Association of Overall Survival With MRD-negativity | Up to 18 months after completion of maintenance therapy (Up to 5 years after starting the study) | Overall survival (OS) will be defined as time from ASCT to death due to any causes, and survivors will be censored at withdrawal or study closeout. |
| Association of Overall Survival With MRD-positivity | Up to 18 months after completion of maintenance therapy (Up to 5 years after starting the study) | Overall survival (OS) will be defined as time from ASCT to death due to any causes, and survivors will be censored at withdrawal or study closeout. |
| Compare Progression-free Survival Between the Two Maintenance Arms | Up to 18 months after completion of maintenance therapy (Up to 5 years after starting the study) | Progression-free survival (PFS) will be defined as time from ASCT to progression, relapse, or death, whichever occurs first, and those event-free survivors will be censored at withdrawal or study closeout. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Consolidation: Ixazomib, Lenalidomide, & Dexamethasone Consolidation therapy will begin between Day 80 and Day 120 following ASCT and will consist of four 28-day cycles of IRD (ixazomib, lenalidomide, & dexamethasone). Barring dose modifications for toxicity, 4 mg of ixazomib and 40 mg of dexamethasone will be administered on Days 1, 8, and 15, and 15 mg of lenalidomide will be administered on daily on Days 1-21. | 236 |
| Total | 236 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Consolidation | Adverse Event | 7 | 0 | 0 |
| Consolidation | Non-Compliance | 1 | 0 | 0 |
| Consolidation | Patient Withdrew Logistical Concerns | 2 | 0 | 0 |
| Consolidation | Progression | 4 | 0 | 0 |
| Consolidation | Secondary Malignancy | 2 | 0 | 0 |
| Maintenance | Adverse Event | 0 | 8 | 12 |
| Maintenance | Non-Compliance | 0 | 1 | 1 |
| Maintenance | Patient Withdrew Logistical Concerns | 0 | 7 | 7 |
| Maintenance | Physician Decision | 0 | 7 | 16 |
| Maintenance | Secondary Malignancy | 0 | 2 | 6 |
| Maintenance | Still receiving active treatment | 0 | 4 | 0 |
Baseline characteristics
| Characteristic | Consolidation: Ixazomib, Lenalidomide, & Dexamethasone |
|---|---|
| Age, Continuous | 58 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 15 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 217 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 4 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 8 Participants |
| Race (NIH/OMB) Black or African American | 30 Participants |
| Race (NIH/OMB) More than one race | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 11 Participants |
| Race (NIH/OMB) White | 185 Participants |
| Region of Enrollment United States | 236 participants |
| Sex: Female, Male Female | 91 Participants |
| Sex: Female, Male Male | 145 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 236 | 0 / 99 | 1 / 116 |
| other Total, other adverse events | 236 / 236 | 99 / 99 | 116 / 116 |
| serious Total, serious adverse events | 44 / 236 | 24 / 99 | 48 / 116 |
Outcome results
Primary
Number of Participants With Improvement in Minimal Residual Disease (MRD)
For the purposes of this study, a patient will be considered as having minimal residual disease if a positive result (1x10E06) is obtained using the Adaptive Clonoseq MRD testing.
Time frame: After 4 cycles of IRD consolidation treatment (approximately Day 112 of consolidation treatment)
Population: Only participants in the consolidation portion of the trial are evaluable for this outcome measure. 52 patients in consolidation were not evaluable for the outcome because 26 did not have appropriate VDJ rearrangements on clonoSEQ assessment, 10 did not have sample available from one or both time points, and 16 were removed prior to completion of 4 cycles of IRD.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Consolidation: Ixazomib, Lenalidomide, & Dexamethasone | Number of Participants With Improvement in Minimal Residual Disease (MRD) | 19 Participants |
Secondary
Association of Overall Survival With MRD-negativity
Overall survival (OS) will be defined as time from ASCT to death due to any causes, and survivors will be censored at withdrawal or study closeout.
Time frame: Up to 18 months after completion of maintenance therapy (Up to 5 years after starting the study)
Secondary
Association of Overall Survival With MRD-positivity
Overall survival (OS) will be defined as time from ASCT to death due to any causes, and survivors will be censored at withdrawal or study closeout.
Time frame: Up to 18 months after completion of maintenance therapy (Up to 5 years after starting the study)
Secondary
Association of Progression-free Survival With MRD-negativity
Progression-free survival (PFS) will be defined as time from ASCT to progression, relapse, or death, whichever occurs first, and those event-free survivors will be censored at withdrawal or study closeout.
Time frame: Up to 18 months after completion of maintenance therapy (Up to 5 years after starting the study)
Secondary
Association of Progression-free Survival With MRD-positivity
Progression-free survival (PFS) will be defined as time from ASCT to progression, relapse, or death, whichever occurs first, and those event-free survivors will be censored at withdrawal or study closeout.
Time frame: Up to 18 months after completion of maintenance therapy (Up to 5 years after starting the study)
Secondary
Compare Overall Survival Between the Two Maintenance Arms
Overall survival (OS) will be defined as time from ASCT to death due to any causes, and survivors will be censored at withdrawal or study closeout.
Time frame: Up to 18 months after completion of maintenance therapy (Up to 5 years after starting the study)
Secondary
Compare Progression-free Survival Between the Two Maintenance Arms
Progression-free survival (PFS) will be defined as time from ASCT to progression, relapse, or death, whichever occurs first, and those event-free survivors will be censored at withdrawal or study closeout.
Time frame: Up to 18 months after completion of maintenance therapy (Up to 5 years after starting the study)
Secondary
Compare Response Rate Between the Two Maintenance Arms
* Response will be determined by the International Myeloma Working Group (IMWG) Uniform Response Criteria. Response includes stringent complete response (sCR) and complete response (CR). * sCR requires all of the following: * CR as defined below * Normal free light chain ratio (0.26-1.65) * Absence of clonal cells in the bone marrow by immunohistochemistry or immunofluorescence * CR requires all of the following: * Disappearance of monoclonal protein by both protein electrophoresis and immunofixation studies from the blood and urine * If serum and urine monoclonal protein are unmeasurable, Normal free light chain ratio (0.26-1.65) * \<5% plasma cells in the bone marrow * Disappearance of soft tissue plasmacytoma
Time frame: Through completion of maintenance treatment (estimated to be day 1095 of maintenance treatment)
Population: This outcome measure is only for participants who went onto the maintenance arms. Participants in the maintenance arms were not evaluable for this outcome measure if they were removed from treatment for reasons other than progressive disease prior to Month 13.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Maintenance Arm 1: Ixazomib | Compare Response Rate Between the Two Maintenance Arms | 50 Participants |
| Maintenance Arm 2: Lenalidomide | Compare Response Rate Between the Two Maintenance Arms | 80 Participants |
Secondary
Compare Toxicity Between the Two Maintenance Arms
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for all toxicity reporting.
Time frame: 30 days after the completion of maintenance treatment (estimated to be Day 1125 of maintenance treatment)
Secondary
MRD-negative Rate After ASCT
For the purposes of this study, a patient will be considered as having minimal residual disease if a positive result (1x10E06) is obtained using the Adaptive Clonoseq MRD testing
Time frame: Prior to beginning consolidation treatment (Day -28 to Day 0)
Population: Only participants in the consolidation portion of the trial are evaluable for this outcome measure. 33 patients from consolidation were not evaluable for this outcome because 26 patients did not have appropriate VDJ rearrangements found on clonSEQ assessment and 7 patients did not have a sample available.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Consolidation: Ixazomib, Lenalidomide, & Dexamethasone | MRD-negative Rate After ASCT | 51 Participants |
Secondary
Overall Survival of IRD Consolidation
Overall survival (OS) will be defined as time from ASCT to death due to any causes, and survivors will be censored at withdrawal or study closeout.
Time frame: Up to 18 months after completion of maintenance therapy (Up to 5 years after starting the study)
Secondary
Progression-free Survival of IRD Consolidation
Progression-free survival (PFS) will be defined as time from ASCT to progression, relapse, or death, whichever occurs first, and those event-free survivors will be censored at withdrawal or study closeout.
Time frame: Up to 18 months after completion of maintenance therapy (Up to 5 years after starting the study)
Secondary
Rate of MRD-positive to MRD-negative Conversion Between the Two Maintenance Arms
Time frame: Cycle 13 Day 1 of maintenance treatment (Approximately Day 364 of maintenance treatment)
Population: This outcome measure is only for participants who went onto the maintenance arms. For the maintenance arms, the overall number of participants analyzed only includes those participants who were MRD positive at the start of maintenance.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Maintenance Arm 1: Ixazomib | Rate of MRD-positive to MRD-negative Conversion Between the Two Maintenance Arms | 5 Participants |
| Maintenance Arm 2: Lenalidomide | Rate of MRD-positive to MRD-negative Conversion Between the Two Maintenance Arms | 11 Participants |
Secondary
Response Rate of IRD Consolidation
For the purposes of this study, response rate is defined as the improvement in complete response rate. Response will be determined by the International Myeloma Working Group (IMWG) Uniform Response Criteria.
Time frame: After 4 cycles of IRD consolidation treatment (approximately Day 112 of consolidation treatment)
Population: Only participants in the consolidation portion of the trial are evaluable for this outcome measure.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Consolidation: Ixazomib, Lenalidomide, & Dexamethasone | Response Rate of IRD Consolidation | 49 Participants |
Secondary
Toxicity of IRD Consolidation
For the purposes of this study, toxicity will be defined as inability to receive 4 cycles of IRD consolidation due to toxicity.
Time frame: After 4 cycles of IRD consolidation treatment (approximately Day 112 of consolidation treatment)
Population: Only participants in the consolidation portion of the trial are evaluable for this outcome measure. 10 patients in consolidation were not evaluable for this outcome because they discontinued prior to 4 cycles of IRD for reasons other than toxicity.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Consolidation: Ixazomib, Lenalidomide, & Dexamethasone | Toxicity of IRD Consolidation | 7 Participants |