Multiple Myeloma
Conditions
Keywords
Multiple Myeloma, Elotuzumab, Carfilzomib (Kyprolis), Lenalidomide (Revlimid), Dexamethasone (E-KRd)
Brief summary
This study was a multi-center, open-label, single-arm, Phase 2 study where newly diagnosed Multiple Myeloma requiring systemic chemotherapy will be eligible for enrollment. A total of 46 subjects were enrolled. The primary end point was the rate of stringent complete response (sCR) and/or MRD-negativity (10-5) after C8 Elo-KRd. Secondary end points included safety, rate of response, MRD status, PFS, and overall survival (OS).
Detailed description
Primary Objective • The primary efficacy endpoint will be the rate of sCR and/or the rate of negative MRD by next generation gene sequencing (NGS) by clonoSIGHT (Adaptive Biotechnologies) at the end of 8 cycles among non-transplant candidates and transplant candidates who agreed to defer transplant Secondary Objectives * To evaluate the safety and tolerability of elotuzumab in combination with KRd, when administered to subjects with newly diagnosed multiple myeloma. * To determine the rate of MRD by next generation gene sequencing (NGS) by clonoSIGHT (Adaptive Biotechnologies) and by multi-color flow cytometry (MFC) at the end of Cycle 4, 8,and 12 for all subjects, and end of C18 (for subjects who are MRD+ at the end of C8 but MRD- at the end of C12 only), 24 months after C1D1, and yearly after that. * To estimate time to event, including duration of response (DOR), progression-free survival (PFS), time to progression (TTP), and overall survival (OS). Exploratory Objectives * GEP, proteomics, and gene sequencing to evaluate the correlation between treatment outcome and pre-treatment subject profile. * Immunologic correlative studies including FcγRIIIa V genotype.
Interventions
DRUGElotuzumab
Elotuzumab will be given on Cycles 1-2 on days 1, 8, 15, 22, Cycles 3 and Beyond on days 1 and 15
DRUGCarfilzomib
Carfilzomib will be given on Day 1 and 8 of Cycle 1, Days 1, 8, and 15 of Cycles 2-8, and Days 1 and 15 of Cycles 9 and beyond
DRUGLenalidomide
Lenalidomide will be given on days 1-21 for all cycles.
DRUGDexamethasone
Dexamethasone will be given as follows: Cycle 1 and 2: Days 1, 2, 8, 9, 15, 16, and 22 Cycles 3 and Beyond: Days 1, 8, 15, and 22
Sponsors
University of Chicago
Bristol-Myers Squibb
Amgen
Multiple Myeloma Research Foundation
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
All participants will receive E-KRd regimen (elotuzumab, carfilzomib, lenalidomide, and dexamethasone) for up to 12 Cycles. After Cycle 12, participants that are MRD negative will move to E-Rd (elotuzumab, carfilzomib, lenalidomide, and dexamethasone) maintenance regimen and continue until disease progression. Participants that are MRD positive will continue to receive E-KRd regimen for an additional 6 cycles followed by E-Rd maintenance regimen and continue until disease progression
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Subjects must meet all of the following inclusion criteria to be eligible to enroll in this study. No enrollment waivers will be granted. 1. Newly diagnosed, previously untreated myeloma requiring systemic chemotherapy a. Prior treatment of hypercalcemia or spinal cord compression or active and/or aggressively progressing myeloma with corticosteroids and/or lenalidomide and/or bortezomib/PI-based regimens does not disqualify the subject (the corticosteroid treatment dose should not exceed the equivalent of 160 mg of dexamethasone in a 4 week period or not more than 1 cycle of lenalidomide and/or PI-based therapy) 2. Both transplant and non-transplant candidates are eligible. 3. Diagnosis of symptomatic multiple myeloma as per current IMWG uniform criteria prior to initial treatment 4. Monoclonal plasma cells in the BM 10% or presence of a biopsy-proven plasmacytoma 5. Measurable disease, prior to initial treatment as indicated by one or more of the following: 1. Serum M-protein ≥ 1 g/dL 2. Urine M-protein ≥ 200 mg/24 hours 3. If serum protein electrophoresis is felt to be unreliable for routine M-protein measurement, then quantitative immunoglobulin levels are acceptable (≥ 1 g/dL) 4. Involved serum free light chains ≥ 10 mg/dL provided that free light chain ratio is abnormal 6. Screening laboratory values must meet the following criteria and should be obtained within 21 days prior to enrollment WBC ≥ 2000/µL Platelets ≥ 75 x103/µL ANC \>1000/µL Hemoglobin \> 8.0 g/dL Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥ 50 mL/min 1. Use the Cockcroft-Gault formula below): o Female CrCl = (140 - age in years) x weight in kg x 0.85 * 72 x serum creatinine in mg/dL o Male CrCl = (140 - age in years) x weight in kg x 1.00 * 72 x serum creatinine in mg/dL 2. Alternatively to Cockcroft-Gault formula of CrCl, 24hr urine CrCl can be used AST/ALT ≤ 3 x ULN Total Bilirubin ≤ 1.5 x ULN (except subjects with Gilbert Syndrome, who can have total bilirubin \< 3.0 mg/dL) or ≤ 2 x ULN if lenalidomide is being prescribed. 7. Males and females ≥ 18 years of age 8. ECOG performance status of 0-1 9. Females of childbearing potential (FCBP) must have 2 negative pregnancy tests (sensitivity of at least 50 mIU/mL) prior to initiating lenalidomide. The first pregnancy test must be performed within 10-14 days before and the second pregnancy test must be performed within 24 hours before lenalidomide is prescribed for Cycle 1 (prescriptions must be filled within 7 days). 10. FCBP must agree to use 2 reliable forms of contraception simultaneously or to practice complete abstinence from heterosexual intercourse during the following time periods related to this study: 1) for at least 28 days before starting lenalidomide; 2) while participating in the study; and 3) for at least 28 days after discontinuation from the study. 11. Male subjects must agree to use a latex condom during sexual contact with females of childbearing potential while participating in the study and for at least 28 days following discontinuation from the study even if he has undergone a successful vasectomy. 12. All study participants in the US must be consented to and registered into the mandatory Revlimid REMS program and be willing and able to comply with the requirements of Revlimid REMS. 13. Voluntary written informed consent
Exclusion criteria
* Subjects meeting any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Stringent Complete Response (sCR) | Landmark evaluations were performed after cycles 4, 8, 12, 18 and 24 (that is, 4, 8, 12, 18 and 24 months) | Response will be determined according to the International Myeloma Working Group (IMWG) response criteria for multiple myeloma. sCR is defined as CR plus : * normal FLC ratio and * absence of clonal cells in bone marrow by immunohistochemistry or 2 - 4 color flow cytometry CR is defined as below : * Negative immunofixation on the serum and urine and * disappearance of any soft tissue plasmacytomas and * \< 5% plasma cells in bone marrow. * In subjects with only FLC disease, a normal FLC ratio of 0.26-1.65 is required. |
| Number of Participants With MRD-negativity (10^-5) After C8 Elo-KRd | Landmark evaluations were performed after cycle 8 | Subjects will be tested for Minimal Residual Disease (MRD) by Next Generation Sequencing (NGS) and flow cytometry after cycle 8. The flow cytometry analysis procedure used to determine MRD is performed on a NAVIOS FLOW CYTOMETER SYSTEM manufactured by BECKMAN COULTER, INC., using a laboratory developed assay. The Premarket Notification 510(k) (Number K130373) for the device can be found using the following link. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm?ID=K130373. |
| The Number of Participants With Stringent Complete Response (sCR) and/or MRD Negative (10^-5) by NGS | Landmark evaluations were performed after cycles 4, 8, 12, 18 and 24 (that is, 4, 8, 12, 18 and 24 months) | Response will be determined according to the International Myeloma Working Group (IMWG) response criteria for multiple myeloma. sCR is defined as CR plus : * normal FLC ratio and * absence of clonal cells in bone marrow by immunohistochemistry or 2 - 4 color flow cytometry CR is defined as below : * Negative immunofixation on the serum and urine and * disappearance of any soft tissue plasmacytomas and * \< 5% plasma cells in bone marrow. * In subjects with only FLC disease, a normal FLC ratio of 0.26-1.65 is required. Subjects will be tested for Minimal Residual Disease (MRD) by Next Generation Sequencing (NGS) and flow cytometry after cycles 4,8,12,18 and 24. The flow cytometry analysis procedure used to determine MRD is performed on a NAVIOS FLOW CYTOMETER SYSTEM manufactured by BECKMAN COULTER, INC., using a laboratory developed assay. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events of Elotuzumab in Combination With KRd | AEs were recorded from the day of signed consent through 30 days after the last does of Elo-KRd or initiation of new therapy, an average of 2 years. | AEs were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0) |
| Duration of Response | Up to two years | These events will be analyzed at differing points of time based on the individual subjects disease progression. It will be measured by the number of cycles of therapy. |
| Median Progression Free Survival | up to two years | Progression free survival (PFS) was assessed based on time to disease progression or death (whichever occurred first) from the start of treatment. |
| Median Overall Survival | up to two years | Overall survival (OS) was assessed based on time to disease progression or death (whichever occurred first) from the start of treatment. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORAndrzej Jakubowiak, MD
University of Chicago
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Elo-KRd Regimen Subjects will be tested for Minimal Residual Disease (MRD) by Next Generation Sequencing (NGS) and flow cytometry after cycles 8 and 12. A treatment decision was made after cycle 12 based on these results. There are three outcomes based on the IFM trial (Avet-Loiseau et al., 2015): 1) if the subject is MRD-negative by NGS after cycle 8 and 12, the subject went on E-Rd maintenance until disease progression. 2) If the subject is MRD-positive after cycle 8 but MRD-negative after cycle 12, 6 more cycles of E-KRd was given and at the end of 18 cycles, the subject went on E-Rd maintenance until disease progression. 3) Finally, if the subject is MRD-positive at both instances, 12 additional cycles of E-KRd was given and at the end of 24 cycles total, the subject went on E-Rd maintenance until disease progression.
Elotuzumab: Elotuzumab will be given on Cycles 1-2 on days 1, 8, 15, 22, Cycles 3 and Beyond on days 1 and 15
Carfilzomib: Carfilzomib will be given on Day 1 and 8 of Cycle 1, Days 1, 8, and 15 of Cycles 2-8, and Days 1 and 15 of Cycles 9 and beyond
Lenalidomide: Lenalidomide will be given on days 1-21 for all cycles.
Dexamethasone: Dexamethasone will be given as follows:
Cycle 1 and 2: Days 1, 2, 8, 9, 15, 16, and 22 Cycles 3 and Beyond: Days 1, 8, 15, and 22 | 46 |
| Total | 46 |
Baseline characteristics
| Characteristic | Elo-KRd Regimen |
|---|---|
| Age, Continuous | 62 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants |
| Race (NIH/OMB) More than one race | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 5 Participants |
| Race (NIH/OMB) White | 32 Participants |
| Sex: Female, Male Female | 13 Participants |
| Sex: Female, Male Male | 33 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 8 / 46 |
| other Total, other adverse events | 42 / 46 |
| serious Total, serious adverse events | 18 / 46 |
Outcome results
Primary
Number of Participants With MRD-negativity (10^-5) After C8 Elo-KRd
Subjects will be tested for Minimal Residual Disease (MRD) by Next Generation Sequencing (NGS) and flow cytometry after cycle 8. The flow cytometry analysis procedure used to determine MRD is performed on a NAVIOS FLOW CYTOMETER SYSTEM manufactured by BECKMAN COULTER, INC., using a laboratory developed assay. The Premarket Notification 510(k) (Number K130373) for the device can be found using the following link. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm?ID=K130373.
Time frame: Landmark evaluations were performed after cycle 8
Population: One censored because of autologous stem cell transplant cycle 8 without progression
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Elo-KRd Regimen | Number of Participants With MRD-negativity (10^-5) After C8 Elo-KRd | 26 Participants |
Primary
Number of Participants With Stringent Complete Response (sCR)
Response will be determined according to the International Myeloma Working Group (IMWG) response criteria for multiple myeloma. sCR is defined as CR plus : * normal FLC ratio and * absence of clonal cells in bone marrow by immunohistochemistry or 2 - 4 color flow cytometry CR is defined as below : * Negative immunofixation on the serum and urine and * disappearance of any soft tissue plasmacytomas and * \< 5% plasma cells in bone marrow. * In subjects with only FLC disease, a normal FLC ratio of 0.26-1.65 is required.
Time frame: Landmark evaluations were performed after cycles 4, 8, 12, 18 and 24 (that is, 4, 8, 12, 18 and 24 months)
Population: One censored because of autologous stem cell transplant cycle 8 without progression
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Elo-KRd Regimen | Number of Participants With Stringent Complete Response (sCR) | 17 Participants |
Primary
The Number of Participants With Stringent Complete Response (sCR) and/or MRD Negative (10^-5) by NGS
Response will be determined according to the International Myeloma Working Group (IMWG) response criteria for multiple myeloma. sCR is defined as CR plus : * normal FLC ratio and * absence of clonal cells in bone marrow by immunohistochemistry or 2 - 4 color flow cytometry CR is defined as below : * Negative immunofixation on the serum and urine and * disappearance of any soft tissue plasmacytomas and * \< 5% plasma cells in bone marrow. * In subjects with only FLC disease, a normal FLC ratio of 0.26-1.65 is required. Subjects will be tested for Minimal Residual Disease (MRD) by Next Generation Sequencing (NGS) and flow cytometry after cycles 4,8,12,18 and 24. The flow cytometry analysis procedure used to determine MRD is performed on a NAVIOS FLOW CYTOMETER SYSTEM manufactured by BECKMAN COULTER, INC., using a laboratory developed assay.
Time frame: Landmark evaluations were performed after cycles 4, 8, 12, 18 and 24 (that is, 4, 8, 12, 18 and 24 months)
Population: One censored because of autologous stem cell transplant cycle 8 without progression
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Elo-KRd Regimen | The Number of Participants With Stringent Complete Response (sCR) and/or MRD Negative (10^-5) by NGS | 26 Participants |
Secondary
Duration of Response
These events will be analyzed at differing points of time based on the individual subjects disease progression. It will be measured by the number of cycles of therapy.
Time frame: Up to two years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Elo-KRd Regimen | Duration of Response | 23 cycles of therapy |
Secondary
Median Overall Survival
Overall survival (OS) was assessed based on time to disease progression or death (whichever occurred first) from the start of treatment.
Time frame: up to two years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Elo-KRd Regimen | Median Overall Survival | NA months |
Secondary
Median Progression Free Survival
Progression free survival (PFS) was assessed based on time to disease progression or death (whichever occurred first) from the start of treatment.
Time frame: up to two years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Elo-KRd Regimen | Median Progression Free Survival | NA months |
Secondary
Number of Participants With Adverse Events of Elotuzumab in Combination With KRd
AEs were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.0)
Time frame: AEs were recorded from the day of signed consent through 30 days after the last does of Elo-KRd or initiation of new therapy, an average of 2 years.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Elo-KRd Regimen | Number of Participants With Adverse Events of Elotuzumab in Combination With KRd | Nausea | 16 Participants |
| Elo-KRd Regimen | Number of Participants With Adverse Events of Elotuzumab in Combination With KRd | Hyperglycemia | 14 Participants |
| Elo-KRd Regimen | Number of Participants With Adverse Events of Elotuzumab in Combination With KRd | Anemia | 11 Participants |
| Elo-KRd Regimen | Number of Participants With Adverse Events of Elotuzumab in Combination With KRd | Neutropenia | 9 Participants |
| Elo-KRd Regimen | Number of Participants With Adverse Events of Elotuzumab in Combination With KRd | Thrombocytopenia | 8 Participants |
| Elo-KRd Regimen | Number of Participants With Adverse Events of Elotuzumab in Combination With KRd | Lymphopenia | 4 Participants |
| Elo-KRd Regimen | Number of Participants With Adverse Events of Elotuzumab in Combination With KRd | Fatigue | 33 Participants |
| Elo-KRd Regimen | Number of Participants With Adverse Events of Elotuzumab in Combination With KRd | Infection-Upper respiratory | 19 Participants |
| Elo-KRd Regimen | Number of Participants With Adverse Events of Elotuzumab in Combination With KRd | Infection-Non-pulmonary | 22 Participants |
| Elo-KRd Regimen | Number of Participants With Adverse Events of Elotuzumab in Combination With KRd | Infection-Lung | 7 Participants |
| Elo-KRd Regimen | Number of Participants With Adverse Events of Elotuzumab in Combination With KRd | Infection-Bronchial | 2 Participants |
| Elo-KRd Regimen | Number of Participants With Adverse Events of Elotuzumab in Combination With KRd | Diarrhea | 29 Participants |
| Elo-KRd Regimen | Number of Participants With Adverse Events of Elotuzumab in Combination With KRd | Dyspnea | 20 Participants |
| Elo-KRd Regimen | Number of Participants With Adverse Events of Elotuzumab in Combination With KRd | Peripheral neuropathy | 19 Participants |
| Elo-KRd Regimen | Number of Participants With Adverse Events of Elotuzumab in Combination With KRd | Cardia events, any | 12 Participants |
| Elo-KRd Regimen | Number of Participants With Adverse Events of Elotuzumab in Combination With KRd | Electrolyte imbalances, any | 12 Participants |
| Elo-KRd Regimen | Number of Participants With Adverse Events of Elotuzumab in Combination With KRd | Hypertension | 11 Participants |
| Elo-KRd Regimen | Number of Participants With Adverse Events of Elotuzumab in Combination With KRd | Rash | 7 Participants |
| Elo-KRd Regimen | Number of Participants With Adverse Events of Elotuzumab in Combination With KRd | Thromboembolic events | 5 Participants |
| Elo-KRd Regimen | Number of Participants With Adverse Events of Elotuzumab in Combination With KRd | Infusion reactions | 5 Participants |
| Elo-KRd Regimen | Number of Participants With Adverse Events of Elotuzumab in Combination With KRd | Acute kidney injury | 5 Participants |