Multiple Myeloma
Conditions
Keywords
B-cell tumors, autologous stem cell transplantation, blood cancers
Brief summary
This is a phase 2, single arm, open-label, multicenter study to evaluate the feasibility and tolerance of the combination of elotuzumab, lenalidomide, and dexamethasone in the induction, consolidation, and maintenance treatment of transplant eligible, newly diagnosed multiple myeloma patients.
Detailed description
The primary purpose of this study is to evaluate the feasibility of using the combination of elotuzumab, lenalidomide, and dexamethasone (ERd) as induction therapy and the ability of the combination to facilitate the start of autologous stem cell transplantation (ASCT) in transplant-eligible patients newly diagnosed with multiple myeloma. In addition to induction, the efficacy, safety, and tolerability of ERd as consolidation and maintenance therapy in these patients will be observed. Eligible patients will undergo four 28-day cycles of an induction regimen of elotuzumab, lenalidomide, and dexamethasone. Following completion of 4 cycles of induction therapy, all patients will undergo standard mobilization, collection of stem cells, and then ASCT using a melphalan conditioning regimen as per institutional guidelines. Toxicity evaluation will be interrupted during the stem cell procedure and will resume with the onset of consolidation. Adverse events will be collected, however, from the end of induction up to mobilization. Consolidation therapy will begin 70 to 120 days following ASCT and will consist of four 28-day cycles of elotuzumab, lenalidomide, and dexamethasone. All patients that do not experience progressive disease will begin maintenance therapy of elotuzumab, lenalidomide, and dexamethasone. The duration of maintenance will be 24 months.
Interventions
DRUGelotuzumab
Given intravenously (IV)
DRUGLenalidomide
Given by IV
DRUGDexamethasone
Given orally (PO) or by IV
PROCEDUREautologous stem cell transplantation
Sponsors
Bristol-Myers Squibb
SCRI Development Innovations, LLC
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
* Newly diagnosed myeloma requiring systemic chemotherapy as per International Myeloma Working Group (IMWG) uniform criteria and Diagnostic Criteria and Staging for Multiple Myeloma * Ideally, no prior therapy, or * No more than 1 cycle of therapy for emergent control of disease prior to enrolling on study, including prior treatment of hypercalcemia, spinal cord compression, or active and/or aggressively progressing myeloma with corticosteroids or lenalidomide or bortezomib-based regimens (treatment dose should not exceed the equivalent of 160 mg of dexamethasone in a 4 week period, or not more than 1 cycle) * Bisphosphonates are permitted * Eligible and plan to undergo ASCT in first remission * Measurable disease, prior to initial treatment as indicated by one or more of the following: * Serum M-protein ≥1.0 g/dL * Urine M-protein ≥200 mg/24 hours * Serum free light chain assay: involved free light chain level ≥10 mg/dL (≥100 mg/L) provided the serum free light chain ratio is abnormal. * Ability to take aspirin or other venous thromboembolism (VTE) anticoagulant therapy * Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 thru 2 * Adequate hematologic, renal, and liver function. * All study participants must be registered into the mandatory Revlimid REMS® program and must be willing and able to comply with the requirements of that program. * Females of reproductive potential must adhere to the scheduled pregnancy testing as required in the Revlimid REMS® program. * Male patients with female partners of childbearing potential and female patients of childbearing potential are required to use two forms of acceptable contraception, including one barrier method, during their participation in the study and for 28 days following last dose of study drugs. Male patients must also refrain from donating semen or sperm during their participation in the study. * Willingness and ability to comply with study and follow-up procedures. * Ability to understand the nature of this study and give written informed consent.
Exclusion criteria
* Polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes (POEMS) syndrome * Plasma cell leukemia * Waldenström's macroglobulinemia or IgM myeloma * Presence of other active cancers, or history of treatment for invasive cancer ≤5 years. Patients with Stage I cancer who have received definitive local treatment and are considered unlikely to recur are eligible. All patients with previously treated in situ carcinoma (i.e., non-invasive) are eligible, as are patients with a history of non-melanoma skin cancer. * Radiotherapy to multiple sites or immunotherapy within 4 weeks before start of protocol treatment (localized radiotherapy to a single site at least 1 week before start is permissible) * Major surgical procedures ≤28 days of beginning study drug, or minor surgical procedures ≤7 days. No waiting required following port-a-cath placement. * Acute active infection requiring systemic antibiotics, antivirals, or antifungals within 2 weeks prior to first dose of study treatment * Presence of active gastrointestinal disease or other condition that will interfere significantly with the absorption, distribution, metabolism, or excretion of oral therapy (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea Grade ≥2, and malabsorption syndrome) * Any of the following cardiac diseases currently or within the last 6 months: * Left ventricular ejection fraction (LVEF) \<40% as determined by echocardiogram (ECHO) or multiple-gated acquisition (MUGA) scan * Unstable angina pectoris * Congestive heart failure (New York Heart Association ≥ Grade 2 * Acute myocardial infarction * Conduction abnormality not controlled with pacemaker or medication * Significant ventricular or supraventricular arrhythmias (patients with chronic rate-controlled atrial fibrillation in the absence of other cardiac abnormalities are eligible) * Valvular disease with significant compromise in cardiac function * Known seropositive for or active viral infection with human immunodeficiency virus or hepatitis A, B, or C virus. Patients who are seropositive because of hepatitis B virus vaccine are eligible. * Any clinically significant medical disease or condition that, in the treating Investigator's opinion, may interfere with protocol adherence or a patient's ability to give informed consent * Pregnant or lactating females * Contraindication to any of the required concomitant drugs, including dexamethasone, H1 and H2 blockers, and acetaminophen, or if patient has a history of prior thrombotic disease, warfarin or low molecular weight heparin * No health coverage, or if the copay for lenalidomide is not acceptable to the patient. * Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Induction Feasibility Rate (IFR) | approximately 22 weeks (16 weeks of treatment and 6 weeks allowance for planning and scheduling mobilization and ASCT). | Defined as the percentage of patients who successfully complete four 28-day cycles of induction therapy with elotuzumab, lenalidomide and dexamethasone (ERd) and start autologous stem cell transplantation (ASCT). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) for Complete Time on Study | every 4 weeks until end of treatment visit, and every 3 months thereafter up to 3 years | Defined as percentage of patients receiving at least 1 cycle with confirmed complete response, very good partial response, or partial response (CR, VGPR, or PR) to treatment at each stage of the study (induction, ASCT, consolidation, end of study) per IMWG and EBMT criteria. CR=bone marrow contains ≤5% plasma cells; negative fixation on serum and urine; the disappearance of soft tissue plasmacytomas. VGPR=serum and urine M-protein detectable by immunofixation but not by electrophoresis or ≥90% reduction from baseline serum and urine M-protein level \<100mg for 24h and In case of presence of soft tissue plasmacytoma(s) at baseline, the disappearance of any soft tissue plasmacytomas. PR=≥50% reduction from baseline in serum M-protein and ≥90% reduction from baseline in 24h urinary M-protein or urine M-protein \<200 mg/24 hours and In case of presence of soft tissue plasmacytoma(s) at baseline, a reduction in the sum of products of the two longest perpendicular diameters (SPD) by \>50%. |
| Progression-free Survival (PFS) | every 4 weeks until end of treatment visit, and every 3 months thereafter up to 3 years | The time from start of induction treatment to documented progressive disease (PD) or death from any cause up to 3 years post first study treatment. PD is defined as an increase of ≥ 25% from the nadir in at least one of the following criteria: serum M-protein (absolute increase must be ≥0.5 g/dL); urine M-protein (absolute increase must be ≥200 mg/24h) ; only in patients with non-measurable serum and urine M-protein levels: difference in involved and uninvolved FLC levels (absolute increase must be \>10 mg/dL); only in patients with non-measurable serum and urine M-protein levels and non-measurable disease by FLC levels, bone marrow plasma cell % (absolute % must be ≥10%) OR Definite development of new bone lesions or soft tissue plasmacytomas OR definite increase in the size of existing bone lesions or soft tissue plasmacytomas OR Development of hypercalcemia (corrected serum Ca \>11.5mg/dL) for patients without hypercalcemia at baseline. Must have completed 1 cycle to be included. |
| Overall Survival (OS) | every 4 weeks until end of treatment visit, and up to 3 years thereafter | Defined as the time from start of induction treatment to 3 years post first study treatment or death from any cause, whichever comes first. Patient must have completed at least 1 cycle to be included in analysis. |
| Complete Response Rate (CRR) for Complete Time on Study | every 4 weeks until end of treatment visit, and every 3 months thereafter up to 3 years | Defined as the percentage of patients who achieve a complete response (CR) or near complete response (nCR) to treatment at each stage of the study (induction, ASCT, consolidation, end of study) per International Myeloma Working Group (IMWG) and European Group for Blood and Marrow Transplantation (EBMT) criteria.CR=bone marrow contains ≤5% plasma cells; negative immunofixation on serum and urine; disappearance of soft tissue plasmacytomas. nCR = the absence of myeloma protein on electrophoresis, with positive immunofixation, stable bone disease, and a normal serum calcium concentration. Patient must have completed at least 1 cycle to be included in analysis. |
| Consolidation Feasibility Rate (CFR) | approximately 55 weeks (16 weeks of induction treatment, 6 weeks allowance for planning and scheduling mobilization and ASCT, 17 weeks pause in treatment after ASCT, 16 weeks of consolidation treatment). | defined as the percentage of patients starting induction treatment with ERd successfully completing treatment to end of consolidation |
| Maintenance Feasibility Rate (MFR) | approximately 159 weeks (16 weeks of induction treatment, 6 weeks allowance for planning and scheduling mobilization and ASCT, 17 weeks pause in treatment after ASCT, 16 weeks of consolidation treatment, 104 weeks/2 years of maintenance treatment) | defined as the percentage of patients starting induction treatment with ERd successfully completing treatment to end of maintenance |
| Number of Participants With Treatment-emergent Adverse Events as a Measure of Safety | weekly for 8 weeks, then every 2 weeks till the start of mobilization for Induction and 70-120 days post-ASCT, every 2 weeks during 16 weeks of Consolidation, and monthly for 24 months of Maintenance, up to 30 days after last dose of study drugs. | Safety data and abnormal lab values and abnormal vital signs were collected and assessed using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE V4.03). |
Countries
United States
Participant flow
Pre-assignment details
One participant withdrew consent before the study treatment assignment.
Participants by arm
| Arm | Count |
|---|---|
| ERd Therapy INDUCTION:
Cycles 1-2: elotuzumab 10mg/kg IV days 1, 8, 15, 22; lenalidomide (len) 25mg orally (PO), once daily (QD) on days 1-21; dexamethasone (dex) 28 mg PO (3-24 hrs before elotuzumab IV) and 8mg IV (45-90 minutes before elotuzumab) days 1, 8, 15, 22.
Cycles 3-4: elotuzumab 10mg/kg IV days 1 and 15; len 25mg PO QD days 1-21; dex 8mg PO (3-24 hrs before elotuzumab IV) and 8mg IV (45-90 minutes before elotuzumab) days 1 and 15; dex 40mg PO days 8 and 22.
CONSOLIDATION:
Four 28-day cycles: elotuzumab 10mg/kg IV days 1 and 15; len 15mg PO QD days 1-21; dex 28mg PO (3-24 hrs before elotuzumab) and 8mg IV (45-90 minutes before elotuzumab) days 1 and 15; dex 40mg PO days 8 and 22.
MAINTENANCE:
After completing consolidation therapy patients without progressive disease will receive, for up to 24 months, 28-day cycles of elotuzumab 20mg/kg IV day 1; len 10mg +/- 5mg PO QD days 1-21; dex 28mg PO (3-24 hrs before elotuzumab) and 8mg IV (45-90 minutes prior to elotuzumab) day 1.
elotuzumab: Given intravenously (IV)
Lenalidomide: Given by IV
Dexamethasone: Given orally (PO) or by IV
autologous stem cell transplantation | 52 |
| Total | 52 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 9 |
| Overall Study | Lost to Follow-up | 1 |
| Overall Study | Physician Decision | 1 |
| Overall Study | Progressive disease | 1 |
| Overall Study | Withdrawal by Subject | 5 |
Baseline characteristics
| Characteristic | ERd Therapy |
|---|---|
| Age, Continuous | 60.7 years STANDARD_DEVIATION 9.11 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 11 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 41 Participants |
| Region of Enrollment United States | 52 participants |
| Sex: Female, Male Female | 29 Participants |
| Sex: Female, Male Male | 23 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 9 / 52 |
| other Total, other adverse events | 52 / 52 |
| serious Total, serious adverse events | 20 / 52 |
Outcome results
Primary
Induction Feasibility Rate (IFR)
Defined as the percentage of patients who successfully complete four 28-day cycles of induction therapy with elotuzumab, lenalidomide and dexamethasone (ERd) and start autologous stem cell transplantation (ASCT).
Time frame: approximately 22 weeks (16 weeks of treatment and 6 weeks allowance for planning and scheduling mobilization and ASCT).
Population: Four participants who completed four 28-day cycles of induction therapy refused transplantation (ASCT). These 4 participants were excluded from the IFR analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ERd Therapy | Induction Feasibility Rate (IFR) | 33 Participants |
Secondary
Complete Response Rate (CRR) for Complete Time on Study
Defined as the percentage of patients who achieve a complete response (CR) or near complete response (nCR) to treatment at each stage of the study (induction, ASCT, consolidation, end of study) per International Myeloma Working Group (IMWG) and European Group for Blood and Marrow Transplantation (EBMT) criteria.CR=bone marrow contains ≤5% plasma cells; negative immunofixation on serum and urine; disappearance of soft tissue plasmacytomas. nCR = the absence of myeloma protein on electrophoresis, with positive immunofixation, stable bone disease, and a normal serum calcium concentration. Patient must have completed at least 1 cycle to be included in analysis.
Time frame: every 4 weeks until end of treatment visit, and every 3 months thereafter up to 3 years
Population: Participants who completed at least one cycle of treatment were included in the analysis. One participant didn't complete cycle 1 due to adverse events; therefore, excluded from the analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ERd Therapy | Complete Response Rate (CRR) for Complete Time on Study | 25 Participants |
Secondary
Consolidation Feasibility Rate (CFR)
defined as the percentage of patients starting induction treatment with ERd successfully completing treatment to end of consolidation
Time frame: approximately 55 weeks (16 weeks of induction treatment, 6 weeks allowance for planning and scheduling mobilization and ASCT, 17 weeks pause in treatment after ASCT, 16 weeks of consolidation treatment).
Population: All patients starting induction treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ERd Therapy | Consolidation Feasibility Rate (CFR) | 34 Participants |
Secondary
Maintenance Feasibility Rate (MFR)
defined as the percentage of patients starting induction treatment with ERd successfully completing treatment to end of maintenance
Time frame: approximately 159 weeks (16 weeks of induction treatment, 6 weeks allowance for planning and scheduling mobilization and ASCT, 17 weeks pause in treatment after ASCT, 16 weeks of consolidation treatment, 104 weeks/2 years of maintenance treatment)
Population: All patients starting induction treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ERd Therapy | Maintenance Feasibility Rate (MFR) | 19 Participants |
Secondary
Number of Participants With Treatment-emergent Adverse Events as a Measure of Safety
Safety data and abnormal lab values and abnormal vital signs were collected and assessed using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE V4.03).
Time frame: weekly for 8 weeks, then every 2 weeks till the start of mobilization for Induction and 70-120 days post-ASCT, every 2 weeks during 16 weeks of Consolidation, and monthly for 24 months of Maintenance, up to 30 days after last dose of study drugs.
Population: All treated patients
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ERd Therapy | Number of Participants With Treatment-emergent Adverse Events as a Measure of Safety | 52 Participants |
Secondary
Overall Response Rate (ORR) for Complete Time on Study
Defined as percentage of patients receiving at least 1 cycle with confirmed complete response, very good partial response, or partial response (CR, VGPR, or PR) to treatment at each stage of the study (induction, ASCT, consolidation, end of study) per IMWG and EBMT criteria. CR=bone marrow contains ≤5% plasma cells; negative fixation on serum and urine; the disappearance of soft tissue plasmacytomas. VGPR=serum and urine M-protein detectable by immunofixation but not by electrophoresis or ≥90% reduction from baseline serum and urine M-protein level \<100mg for 24h and In case of presence of soft tissue plasmacytoma(s) at baseline, the disappearance of any soft tissue plasmacytomas. PR=≥50% reduction from baseline in serum M-protein and ≥90% reduction from baseline in 24h urinary M-protein or urine M-protein \<200 mg/24 hours and In case of presence of soft tissue plasmacytoma(s) at baseline, a reduction in the sum of products of the two longest perpendicular diameters (SPD) by \>50%.
Time frame: every 4 weeks until end of treatment visit, and every 3 months thereafter up to 3 years
Population: Participants who completed at least one cycle of treatment were included in the analysis. One participant didn't complete cycle 1 due to adverse events; therefore, excluded from the analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ERd Therapy | Overall Response Rate (ORR) for Complete Time on Study | 47 Participants |
Secondary
Overall Survival (OS)
Defined as the time from start of induction treatment to 3 years post first study treatment or death from any cause, whichever comes first. Patient must have completed at least 1 cycle to be included in analysis.
Time frame: every 4 weeks until end of treatment visit, and up to 3 years thereafter
Population: Participants who completed at least one cycle of treatment were included in the analysis. One participant didn't complete cycle 1 due to adverse events; therefore, excluded from the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| ERd Therapy | Overall Survival (OS) | NA months |
Secondary
Progression-free Survival (PFS)
The time from start of induction treatment to documented progressive disease (PD) or death from any cause up to 3 years post first study treatment. PD is defined as an increase of ≥ 25% from the nadir in at least one of the following criteria: serum M-protein (absolute increase must be ≥0.5 g/dL); urine M-protein (absolute increase must be ≥200 mg/24h) ; only in patients with non-measurable serum and urine M-protein levels: difference in involved and uninvolved FLC levels (absolute increase must be \>10 mg/dL); only in patients with non-measurable serum and urine M-protein levels and non-measurable disease by FLC levels, bone marrow plasma cell % (absolute % must be ≥10%) OR Definite development of new bone lesions or soft tissue plasmacytomas OR definite increase in the size of existing bone lesions or soft tissue plasmacytomas OR Development of hypercalcemia (corrected serum Ca \>11.5mg/dL) for patients without hypercalcemia at baseline. Must have completed 1 cycle to be included.
Time frame: every 4 weeks until end of treatment visit, and every 3 months thereafter up to 3 years
Population: Participants who completed at least one cycle of treatment were included in the analysis. One participant didn't complete cycle 1 due to adverse events; therefore, excluded from the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| ERd Therapy | Progression-free Survival (PFS) | 29.7002 months |