Relapsed Multiple Myeloma
Conditions
Keywords
Multiple Myeloma
Brief summary
The primary objective was to compare progression-free survival in adults with relapsed multiple myeloma who are receiving CRd vs participants receiving Rd in a randomized multicenter setting.
Detailed description
This is a Phase 3, randomized, open-label, multicenter study comparing two treatment regimens for adults with relapsed multiple myeloma. Eligible subjects will be randomized in a 1:1 ratio to receive either the control Rd or CRd. Randomization will be stratified by β2 microglobulin levels (\< vs ≥ 2.5 mg/L), prior bortezomib (no vs yes), and prior lenalidomide (no vs yes). Participants will receive the treatment determined by randomization in 28-day cycles until disease progression or unacceptable toxicity (whichever occurs first).
Interventions
DRUGDexamethasone
40 mg orally or IV on days 1, 8, 15, 22
DRUGLenalidomide
25 mg orally on days 1-21
DRUGCarfilzomib
20 mg/m², 27 mg/m² intravenously
Sponsors
Amgen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Symptomatic multiple myeloma 2. Measurable disease, as defined by one or more of the following (assessed within 21 days prior to randomization): * Serum M-protein ≥ 0.5 g/dL * Urine Bence-Jones protein ≥ 200 mg/24 hours * For immunoglobulin A (IgA) patients whose disease can only be reliably measured by serum quantitative immunoglobulin (qIgA) ≥ 750 mg/dL (0.75 g/dL) 3. Prior treatment with at least one, but no more than three, regimens for multiple myeloma 4. Documented relapse or progressive disease on or after any regimen 5. Achieved a response to at least one prior regimen 6. Age ≥ 18 years 7. Life expectancy ≥ 3 months 8. Eastern Cooperative Oncology Group (ECOG) performance status 0-2 9. Adequate hepatic function, with serum alanine aminotransferase (ALT) ≤ 3.5 times the upper limit of normal and serum direct bilirubin ≤ 2 mg/dL (34 µmol/L) within 21 days prior to randomization 10. Absolute neutrophil count ≥ 1.0 × 10\^9/L within 21 days prior to randomization 11. Hemoglobin ≥ 8 g/dL (80 g/L) within 21 days prior to randomization 12. Platelet count ≥ 50 × 10\^9/L (≥ 30 × 10\^9/L if myeloma involvement in the bone marrow is \> 50%) within 21 days prior to randomization 13. Creatinine clearance (CrCl) ≥ 50 mL/minute within 21 days prior to randomization 14. Written informed consent in accordance with federal, local, and institutional guidelines 15. Females of childbearing potential must agree to ongoing pregnancy testing and to practice contraception 16. Male subjects must agree to practice contraception
Exclusion criteria
1. If previously treated with bortezomib (alone or in combination), progression during treatment 2. If previously treated with a lenalidomide and dexamethasone (len/dex) combination: * Progression during the first 3 months of initiating treatment * Any progression during treatment if the len/dex combination was the subject's most recent line of therapy 3. Discontinuation of previous lenalidomide or dexamethasone due to intolerance; subjects intolerant to bortezomib are not excluded 4. Prior carfilzomib treatment 5. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) 6. Waldenström's macroglobulinemia or IgM myeloma 7. Plasma cell leukemia (\> 2.0 × 10\^9/L circulating plasma cells by standard differential) 8. Chemotherapy or investigational agent within 3 weeks prior to randomization or antibody therapy within 6 weeks prior to randomization 9. Radiotherapy to multiple sites or immunotherapy/antibody therapy within 28 days prior to randomization; localized radiotherapy to a single site within 7 days prior to randomization 10. Corticosteroid therapy at a dose equivalent to dexamethasone \> 4 mg/day within 21 days prior to randomization 11. Pregnant or lactating females 12. Major surgery within 21 days prior to randomization 13. Acute active infection requiring treatment (systemic antibiotics, antivirals, or antifungals) within 14 days prior to randomization 14. Known human immunodeficiency virus infection 15. Active hepatitis B or C infection 16. Myocardial infarction within 4 months prior to randomization, New York Hear Association (NYHA) Class III or IV heart failure, uncontrolled angina, history of severe coronary artery disease, severe uncontrolled ventricular arrhythmias, sick sinus syndrome, or electrocardiographic evidence of acute ischemia or Grade 3 conduction system abnormalities unless subject has a pacemaker 17. Uncontrolled hypertension or uncontrolled diabetes within 14 days prior to randomization 18. Other malignancy, including myelodysplastic syndromes (MDS), within the past 3 years with the exception of a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) carcinoma in situ of the cervix or breast; c) prostate cancer of Gleason Grade 6 or less with stable prostate-specific antigen levels; or d) cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder or benign tumors of the adrenal or pancreas 19. Significant neuropathy (Grades 3-4, or Grade 2 with pain) within 14 days prior to randomization 20. Known history of allergy to Captisol® (a cyclodextrin derivative used to solubilize carfilzomib) 21. Contraindication to any of the required concomitant drugs or supportive treatments, including hypersensitivity to all anticoagulation and antiplatelet options, antiviral drugs, or intolerance to hydration due to preexisting pulmonary or cardiac impairment 22. Ongoing graft-vs-host disease 23. Subjects with pleural effusions requiring thoracentesis or ascites requiring paracentesis within 14 days prior to randomization 24. Any other clinically significant medical disease or condition that, in the Investigator's opinion, may interfere with protocol adherence or a subject's ability to give informed consent
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) | From randomization through the data cutoff date of 16 June 2014. Median follow-up time was approximately 31 months. | Kaplan-Meier estimate of median time from randomization to progressive disease (PD) or all-cause death. PD was assessed using International Myeloma Working Group-Uniform Response Criteria (IMWG-URC). One or more conditions were required to meet PD: 2 consecutive rising serum or urine M-protein from central lab; documented new bone lesion(s) or soft tissue plasmacytoma(s) or increased size of existing bone lesion(s) or plasmacytoma(s); or confirmed hypercalcemia due solely to plasma cell proliferative disorder (local lab greater than 11.5 mg/dL on 2 separate occasions). Censoring conditions (censoring dates) were: no post-baseline disease assessment (DA) (randomization date); started non-protocol systemic anticancer treatment before PD or death (last DA date before such treatment); died or had PD after more than 1 missed DA (last DA date without PD before the first missed visit); or were alive and without documentation of PD, including lost to follow-up without PD (last DA date). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate | From randomization through the data cutoff date of 16 June 2014. Median follow-up time was approximately 31 months. | Overall response rate is defined as the percentage of participants who achieved either a confirmed stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR) as their best response based on the Independent Review Committee (IRC) assessed response outcome. Response was determined using the International Myeloma Working Group - Uniform Response Criteria (IMWG-URC). |
| Disease Control Rate | From randomization through the data cutoff date of 16 June 2014. Median follow-up time was approximately 31 months. | Disease control rate was defined as the percentage of participants who achieved a best response of stringent complete response (sCR), complete response (CR), very good partial response (VGPR), partial response (PR), minimal response (MR), or stable disease (SD) lasting ≥ 8 weeks according to International Myeloma Working Group - Uniform Response Criteria (IMWG-URC) (MR was determined using European Group for Blood and Marrow Transplantation criteria). |
| Overall Survival | From randomization through the data cutoff date of 28 April 2017 for the final analysis of overall survival; median follow up time was 67.1 months in each treatment group. | Overall survival (OS) was defined as the duration from randomization to death due to any cause. Participants who were still alive were censored at the date when the participant was last known to be alive or the data cutoff date, whichever occurred earlier. |
| Duration of Disease Control | From randomization through the data cutoff date of 16 June 2014. Longest follow-up time was approximately 46 months. | Duration of disease control (DDC) was calculated for participants who achieved disease control. DDC was defined as the time in months from randomization to the earlier of documented progressive disease (PD) or death due to any cause. Participants who had not progressed or died were censored according to the censoring rules defined previously for PFS. |
| Quality of Life Core Module (QLQ-C30) Global Health Status/Quality of Life Scores | Cycle 1 Day 1 (Baseline), Day 1 of Cycles 3, 6, 12, 18 | Health-related quality of life was assessed with the use of the European Organization for Research and Treatment of Cancer Quality of Life Core Module (QLQ-C30) questionnaire, a validated instrument in multiple myeloma patients. Scores range from 0 to 100, with higher scores indicating better health related quality of life. |
| Duration of Response | From randomization through the data cutoff date of 16 June 2014. Longest follow-up time was approximately 42 months. | Duration of response (DOR) was calculated for participants who achieved a best response of stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR). Duration of response was defined as the time in months from the initial start of response (PR or better) to the earlier of documented progressive disease (PD) or death due to any cause. Participants who had not progressed or died were censored according to the censoring rules defined previously for PFS. |
Countries
Austria, Belgium, Bulgaria, Canada, Czechia, France, Germany, Greece, Hungary, Israel, Italy, Netherlands, Poland, Romania, Russia, Serbia, Spain, Sweden, United Kingdom, United States
Participant flow
Recruitment details
Participants were enrolled from 14 July 2010 to 15 March 2012. The primary analysis was conducted using a data cut-off date of 16 June 2014 and the final safety analysis after last subject last visit date (05 December 2017).
Pre-assignment details
Eligible participants were randomized in a 1:1 ratio to one of two treatment groups. Randomization was stratified by β2 microglobulin level (\< vs. ≥ 2.5 mg/L), prior bortezomib exposure (no vs. yes), and prior lenalidomide exposure (no vs. yes).
Participants by arm
| Arm | Count |
|---|---|
| Lenalidomide and Dexamethasone (Rd) Participants received their randomized study treatment in 28-day cycles until disease progression or unacceptable toxicity. Lenalidomide 25 mg was administered orally on days 1 to 21 and dexamethasone 40 mg was administered orally or intravenously on days 1, 8, 15, and 22. | 396 |
| Carfilzomib, Lenalidomide, and Dexamethasone (CRd) Participants received their randomized study treatment in 28-day cycles until disease progression or unacceptable toxicity. Carfilzomib 20 mg/m² was administered intravenously (IV) on days 1 and 2 of cycle 1, then escalated to 27 mg/m² on Days 8, 9, 15, and 16 of cycle 1 and continuing on days 1, 2, 8, 9, 15, and 16 of cycle 2 through cycle 12 and then from cycle 13 through cycle 18, 27 mg/m² on days 1, 2, 15, and 16. Lenalidomide 25 mg was administered orally on days 1 to 21 of every cycle. Dexamethasone 40 mg was administered orally or IV on days 1, 8, 15, and 22 of every cycle. | 396 |
| Total | 792 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Randomized but not treated | 7 | 4 |
Baseline characteristics
| Characteristic | Total | Lenalidomide and Dexamethasone (Rd) | Carfilzomib, Lenalidomide, and Dexamethasone (CRd) |
|---|---|---|---|
| Age, Continuous | 63.9 years STANDARD_DEVIATION 9.14 | 64.5 years STANDARD_DEVIATION 9.04 | 63.3 years STANDARD_DEVIATION 9.21 |
| Prior Bortezomib Exposure No | 270 Participants | 135 Participants | 135 Participants |
| Prior Bortezomib Exposure Yes | 522 Participants | 261 Participants | 261 Participants |
| Prior Lenalidomide Exposure No | 634 Participants | 318 Participants | 316 Participants |
| Prior Lenalidomide Exposure Yes | 158 Participants | 78 Participants | 80 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian/Native Hawaiian or Pacific Islander | 4 Participants | 3 Participants | 1 Participants |
| Race/Ethnicity, Customized Black or African American | 23 Participants | 11 Participants | 12 Participants |
| Race/Ethnicity, Customized Other | 10 Participants | 4 Participants | 6 Participants |
| Race/Ethnicity, Customized White | 754 Participants | 377 Participants | 377 Participants |
| Serum β2 Microglobulin < 2.5 mg/L | 154 Participants | 77 Participants | 77 Participants |
| Serum β2 Microglobulin ≥ 2.5 mg/L | 638 Participants | 319 Participants | 319 Participants |
| Sex: Female, Male Female | 345 Participants | 164 Participants | 181 Participants |
| Sex: Female, Male Male | 447 Participants | 232 Participants | 215 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 358 / 389 | 370 / 392 |
| serious Total, serious adverse events | 221 / 389 | 256 / 392 |
Outcome results
Primary
Progression-free Survival (PFS)
Kaplan-Meier estimate of median time from randomization to progressive disease (PD) or all-cause death. PD was assessed using International Myeloma Working Group-Uniform Response Criteria (IMWG-URC). One or more conditions were required to meet PD: 2 consecutive rising serum or urine M-protein from central lab; documented new bone lesion(s) or soft tissue plasmacytoma(s) or increased size of existing bone lesion(s) or plasmacytoma(s); or confirmed hypercalcemia due solely to plasma cell proliferative disorder (local lab greater than 11.5 mg/dL on 2 separate occasions). Censoring conditions (censoring dates) were: no post-baseline disease assessment (DA) (randomization date); started non-protocol systemic anticancer treatment before PD or death (last DA date before such treatment); died or had PD after more than 1 missed DA (last DA date without PD before the first missed visit); or were alive and without documentation of PD, including lost to follow-up without PD (last DA date).
Time frame: From randomization through the data cutoff date of 16 June 2014. Median follow-up time was approximately 31 months.
Population: ITT analysis set comprised of all randomized participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lenalidomide and Dexamethasone (Rd) | Progression-free Survival (PFS) | 17.6 months |
| Carfilzomib, Lenalidomide, and Dexamethasone (CRd) | Progression-free Survival (PFS) | 26.3 months |
p-value: <0.000195% CI: [0.57, 0.834]Log Rank
Secondary
Disease Control Rate
Disease control rate was defined as the percentage of participants who achieved a best response of stringent complete response (sCR), complete response (CR), very good partial response (VGPR), partial response (PR), minimal response (MR), or stable disease (SD) lasting ≥ 8 weeks according to International Myeloma Working Group - Uniform Response Criteria (IMWG-URC) (MR was determined using European Group for Blood and Marrow Transplantation criteria).
Time frame: From randomization through the data cutoff date of 16 June 2014. Median follow-up time was approximately 31 months.
Population: ITT analysis set comprised of all randomized participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lenalidomide and Dexamethasone (Rd) | Disease Control Rate | 87.1 percentage of participants |
| Carfilzomib, Lenalidomide, and Dexamethasone (CRd) | Disease Control Rate | 92.7 percentage of participants |
p-value: 0.004495% CI: [1.17, 3.08]Cochran-Mantel Haenszel chi-square test
Secondary
Duration of Disease Control
Duration of disease control (DDC) was calculated for participants who achieved disease control. DDC was defined as the time in months from randomization to the earlier of documented progressive disease (PD) or death due to any cause. Participants who had not progressed or died were censored according to the censoring rules defined previously for PFS.
Time frame: From randomization through the data cutoff date of 16 June 2014. Longest follow-up time was approximately 46 months.
Population: The Intent to treat (ITT) population with participantants who achieved disease control.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lenalidomide and Dexamethasone (Rd) | Duration of Disease Control | 18.9 months |
| Carfilzomib, Lenalidomide, and Dexamethasone (CRd) | Duration of Disease Control | 28.7 months |
Secondary
Duration of Response
Duration of response (DOR) was calculated for participants who achieved a best response of stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR). Duration of response was defined as the time in months from the initial start of response (PR or better) to the earlier of documented progressive disease (PD) or death due to any cause. Participants who had not progressed or died were censored according to the censoring rules defined previously for PFS.
Time frame: From randomization through the data cutoff date of 16 June 2014. Longest follow-up time was approximately 42 months.
Population: The Intent to treat (ITT) population with participantant who achieved a best overall response of PR or better.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lenalidomide and Dexamethasone (Rd) | Duration of Response | 21.2 months |
| Carfilzomib, Lenalidomide, and Dexamethasone (CRd) | Duration of Response | 28.6 months |
Secondary
Overall Response Rate
Overall response rate is defined as the percentage of participants who achieved either a confirmed stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR) as their best response based on the Independent Review Committee (IRC) assessed response outcome. Response was determined using the International Myeloma Working Group - Uniform Response Criteria (IMWG-URC).
Time frame: From randomization through the data cutoff date of 16 June 2014. Median follow-up time was approximately 31 months.
Population: ITT analysis set comprised of all randomized participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lenalidomide and Dexamethasone (Rd) | Overall Response Rate | 66.7 percentage of participants |
| Carfilzomib, Lenalidomide, and Dexamethasone (CRd) | Overall Response Rate | 87.1 percentage of participants |
p-value: <0.000195% CI: [2.411, 5.001]Cochran-Mantel Haenszel chi-square test
Secondary
Overall Survival
Overall survival (OS) was defined as the duration from randomization to death due to any cause. Participants who were still alive were censored at the date when the participant was last known to be alive or the data cutoff date, whichever occurred earlier.
Time frame: From randomization through the data cutoff date of 28 April 2017 for the final analysis of overall survival; median follow up time was 67.1 months in each treatment group.
Population: ITT analysis set comprised of all randomized participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lenalidomide and Dexamethasone (Rd) | Overall Survival | 40.4 months |
| Carfilzomib, Lenalidomide, and Dexamethasone (CRd) | Overall Survival | 48.3 months |
Comparison: The final analysis of OS was to be performed after 510 deaths occur. A total of 510 deaths would provide 85% power to detect, with a 1-sided significance level of 0.025, a hazard ratio of 0.765 corresponding to a 23.5% reduction in risk for death for CRd versus Rd (39.2 vs. 30.0 months, respectively).p-value: 0.004595% CI: [0.667, 0.945]Log Rank
Secondary
Quality of Life Core Module (QLQ-C30) Global Health Status/Quality of Life Scores
Health-related quality of life was assessed with the use of the European Organization for Research and Treatment of Cancer Quality of Life Core Module (QLQ-C30) questionnaire, a validated instrument in multiple myeloma patients. Scores range from 0 to 100, with higher scores indicating better health related quality of life.
Time frame: Cycle 1 Day 1 (Baseline), Day 1 of Cycles 3, 6, 12, 18
Population: ITT analysis set participants with a baseline value.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lenalidomide and Dexamethasone (Rd) | Quality of Life Core Module (QLQ-C30) Global Health Status/Quality of Life Scores | Cycle 3, Day 1 | 56.8 scores on a scale | Standard Deviation 19.4 |
| Lenalidomide and Dexamethasone (Rd) | Quality of Life Core Module (QLQ-C30) Global Health Status/Quality of Life Scores | Cycle 12, Day 1 | 57.3 scores on a scale | Standard Deviation 19.7 |
| Lenalidomide and Dexamethasone (Rd) | Quality of Life Core Module (QLQ-C30) Global Health Status/Quality of Life Scores | Cycle 6, Day 1 | 58.9 scores on a scale | Standard Deviation 19.7 |
| Lenalidomide and Dexamethasone (Rd) | Quality of Life Core Module (QLQ-C30) Global Health Status/Quality of Life Scores | Cycle 18, Day 1 | 59.9 scores on a scale | Standard Deviation 18.8 |
| Lenalidomide and Dexamethasone (Rd) | Quality of Life Core Module (QLQ-C30) Global Health Status/Quality of Life Scores | Cycle 1 Day 1 (Baseline) | 58.1 scores on a scale | Standard Deviation 21.7 |
| Carfilzomib, Lenalidomide, and Dexamethasone (CRd) | Quality of Life Core Module (QLQ-C30) Global Health Status/Quality of Life Scores | Cycle 18, Day 1 | 64.3 scores on a scale | Standard Deviation 19.2 |
| Carfilzomib, Lenalidomide, and Dexamethasone (CRd) | Quality of Life Core Module (QLQ-C30) Global Health Status/Quality of Life Scores | Cycle 1 Day 1 (Baseline) | 58.3 scores on a scale | Standard Deviation 21.7 |
| Carfilzomib, Lenalidomide, and Dexamethasone (CRd) | Quality of Life Core Module (QLQ-C30) Global Health Status/Quality of Life Scores | Cycle 3, Day 1 | 59.9 scores on a scale | Standard Deviation 20.4 |
| Carfilzomib, Lenalidomide, and Dexamethasone (CRd) | Quality of Life Core Module (QLQ-C30) Global Health Status/Quality of Life Scores | Cycle 6, Day 1 | 62.5 scores on a scale | Standard Deviation 20.1 |
| Carfilzomib, Lenalidomide, and Dexamethasone (CRd) | Quality of Life Core Module (QLQ-C30) Global Health Status/Quality of Life Scores | Cycle 12, Day 1 | 62.7 scores on a scale | Standard Deviation 19.6 |