Multiple Myeloma
Conditions
Keywords
Lenalidomide, Bortezomib, Dexamethasone, Stem Cell Transplant, Myeloma, Multiple Myeloma
Brief summary
In this research study, we are looking to explore the drug combination, lenalidomide, bortezomib and dexamethasone alone or when combined with autologous stem cell transplantation to see what side effects it may have and how well it works for treatment of newly diagnosed multiple myeloma. Specifically, the objective of this trial is to determine if, in the era of novel drugs, high dose therapy (HDT) is still necessary in the initial management of multiple myeloma in younger patients. In this study, HDT as compared to conventional dose treatment would be considered superior if it significantly prolongs progression-free survival by at least 9 months or more, recognizing that particular subgroups may benefit more compared to others.
Detailed description
The drugs, lenalidomide, bortezomib, and dexamethasone, are approved by the FDA. They have not been approved in the combination for multiple myeloma or any other type of cancer. Bortezomib is currently approved by the FDA for the treatment of multiple myeloma. Lenalidomide is approved for use with dexamethasone for patients with multiple myeloma who have received at least one prior therapy and for the treatment of certain types of myelodysplastic syndrome (another type of cancer affecting the blood). Dexamethasone is commonly used, either alone, or in combination with other drugs, to treat multiple myeloma. Please note that Bortezomib and Lenalidomide are provided to patients participating in this trial at no charge. Melphalan and cyclophosphamide, the drugs used during stem cell collection and transplant, are also approved by the FDA. Melphalan is an FDA-approved chemotherapy for multiple myeloma and is used as a high-dose conditioning treatment prior to stem cell transplantation. Cyclophosphamide is used, either alone, or in combination with other drugs, to treat multiple myeloma. These drugs have been used in other multiple myeloma studies and information from those studies suggests that this combination of therapy may help to treat newly diagnosed multiple myeloma. After screening procedures determine if a patient is eligible for this research study, the patient will be randomized into one of the study groups: lenalidomide, bortezomib and dexamethasone without autologous stem cell transplantation, followed by lenalidomide maintenance (Arm A) or lenalidomide, bortezomib and dexamethasone with autologous stem cell transplantation, followed by lenalidomide maintenance (Arm B). There is an equal chance of being placed in either group. Randomization was stratified by International Staging System (ISS) disease stage (I, II, or III) and cytogenetics (high-risk \[presence of 17p deletion, t(4;14), or t(14;16) on fluorescence in-situ hybridization\], standard-risk \[absence of high-risk abnormalities\], or undetermined \[test failure\]) assessed locally in a screening bone marrow sample, with positivity cut-offs per institutional standards.
Interventions
DRUGLenalidomide
oral administration
DRUGBortezomib
intravenous or, following protocol amendment, subcutaneous administration
DRUGDexamethasone
oral administration Dose of 20 mg/day for first 3 cycles. Dose of 10 mg/day for remaining cycles.
PROCEDUREAutologous Stem Cell Transplant
Autologous refers to stem cells that are harvested from the participant to be a source of new blood cells after high-dose chemotherapy with melphalan.
Sponsors
Paul Richardson, MD
Celgene Corporation
Millennium Pharmaceuticals, Inc.
Massachusetts General Hospital
Cape Cod Hospital
Beth Israel Deaconess Medical Center
Emory University
University of Michigan
Fox Chase Cancer Center
Memorial Sloan Kettering Cancer Center
Fred Hutchinson Cancer Center
Barbara Ann Karmanos Cancer Institute
Duke University
University of California, San Francisco
University of Chicago
M.D. Anderson Cancer Center
UNC Lineberger Comprehensive Cancer Center
Roswell Park Cancer Institute
Stanford University
University of Mississippi Medical Center
Icahn School of Medicine at Mount Sinai
Wake Forest University Health Sciences
University of Arizona
OHSU Knight Cancer Institute
Eastern Maine Medical Center
University of California, San Diego
University of Alabama at Birmingham
University of Pittsburgh Medical Center
Ochsner Health System
University of Texas Southwestern Medical Center
State University of New York - Downstate Medical Center
Newton-Wellesley Hospital
Baylor College of Medicine
City of Hope Medical Center
University of Florida
Northwell Health
H. Lee Moffitt Cancer Center and Research Institute
Vanderbilt University Medical Center
Ohio State University
Huntsman Cancer Institute
Columbia University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of Multiple Myeloma, according to the International Myeloma Foundation 2003 Diagnostic Criteria * Documented symptomatic myeloma, with organ damage related to myeloma with laboratory assessments performed within 21 days of registration * Myeloma that is measurable by either serum or urine evaluation of the monoclonal component or by assay of serum free light chains. * ECOG performance status \</= 2 * Negative HIV blood test * Voluntary written informed consent
Exclusion criteria
* Pregnant or lactating female * Prior systemic therapy for MM (localized radiotherapy allowed if at least 7 days before study entry, corticosteroids allowed if dose \</= equivalent of 160 mg dexamethasone over 2 weeks) * Primary amyloidosis (AL) or myeloma complicated by amylosis * Receiving any other investigational agents * Known brain metastases * Poor tolerability or allergy to any of the study drugs or compounds of similar composition * Platelet count \<50,000/mm3, within 21 days of registration * ANC \<1,000 cells/mm3, within 21 days of registration * Hemoglobin \<8 g/dL, within 21 days of registration * Hepatic impairment (\>/= 1.5 x institutional ULN or AST (SGOT), ALT (SGPT), or alkaline phosphatase \>2 x ULN). Patients with benign hyperbilirubinemia are eligible. * Renal insufficiency (serum creatinine \>2.0 mg/dl or creatinine clearance \<50 ml/min, within 21 days of registration) * Respiratory compromise (DLCO \< 50%) * Clinical signs of heart or coronary failure or LVEF \< 40%. Myocardial infarction within 6 months prior to enrollment, NYHA Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conductive system abnormalities * Intercurrent illness including, but not limited to ongoing or active severe infection, known infection with hepatitis B or C virus, poorly controlled diabetes, severe uncontrolled psychiatric disorder or psychiatric illness/social situations that would limit compliance with study requirements * Previous history of another malignant condition except for basal cell carcinoma and stage I cervical cancer. If malignancy was experienced more than 2 years ago and confirmed as cured, these participants may be considered for the study on case by case basis with PI discussion. * Inability to comply with an anti-thrombotic treatment regimen * Peripheral neuropathy \>/= Grade 2
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Median Progression-Free Survival (PFS) | On treatment, disease was assessed every cycle up to maintenance and every 3 cycles on maintenance. In long-term follow-up, disease was assessed every 2 months until PD or death. Median (maximum) PFS follow-up was 70 and 129 months. | PFS was estimated using the Kaplan-Meier (KM) method and defined as time from randomization to the earlier of disease progression (PD) as determined by central review or death from any cause (events). Patients who started non-protocol therapy (NPT) were censored at the date of NPT initiation if available or date treatment ended if date of NPT was missing. Deaths occurring beyond 1 year from the date last known progression-free are not counted as events and censored at date of last disease evaluation. Patients who had not started NPT, progressed, or died were censored at the date of last disease evaluation. PD was based upon the International Myeloma Working Group (IMWG) uniform response criteria. \[Kumar S, et al Lancet Oncol 2016;17(8):e328-e346\]. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Partial Response (PR) Rate | Disease was assessed every cycle up to maintenance and every 3 cycles on maintenance. Median treatment duration (months) from randomization 28.2 (RVD Alone) and 36.1 (RVD plus ASCT). Maximum treatment duration was 133.5 months in this study cohort. | The PR rate is the percentage of participants achieving PR or better on treatment and was evaluated based on the IMWG criteria. PR was defined as \> 50% reduction of serum M-protein and reduction in 24-h urinary M-protein by \> 90% or to \< 200mg per 24 hours. If the serum and urine M-protein are unmeasurable, a \> 50% decrease in the difference between involved and uninvolved free light chain levels is required in place of the M-protein criteria. If serum and urine M-protein are unmeasurable, and serum free light assay is also unmeasurable, \>50% reduction in plasma cells is required in place of M-protein, provided baseline bone marrow plasma cell percentage was \> 30%. In addition to the above listed criteria, if present at baseline, a \> 50% reduction in the size of soft tissue plasmacytomas was also required. Exact (Clopper-Pearson) confidence limits of 98.2857% represents Bonferroni adjustment for 7 tests (1-0.05/7) per statistical analysis plan for key secondary outcomes. |
| Very Good Partial Response (VGPR) Rate | Disease was assessed every cycle up to maintenance and every 3 cycles on maintenance. Median treatment duration (months) from randomization 28.2 (RVD Alone) and 36.1 (RVD plus ASCT). Maximum treatment duration was 134 months in this study cohort. | The VGPR rate is the percentage of participants achieving VGPR or better on treatment and was evaluated based on IMWG criteria. VGPR was defined as serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein plus urine M-protein level \<100mg per 24 hours. |
| Complete Response (CR) Rate | Disease was assessed every cycle up to maintenance and every 3 cycles on maintenance. Median treatment duration (months) from randomization 28.2 (RVD Alone) and 36.1 (RVD plus ASCT). Maximum treatment duration was 134 months in this study cohort. | The CR rate is the percentage of participants achieving CR or better on treatment and was evaluated based on IMWG criteria. CR was defined as the negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and \<5% plasma cells in bone marrow. Confirmation with repeat bone marrow biopsy was not needed. |
| Median Duration of Response: Partial Response (DOR PR) | On treatment, disease was assessed every cycle up to maintenance and every 3 cycles on maintenance. In long-term follow-up, disease was assessed every 2 months until PD or death. Median (maximum) DOR PR follow-up was 62.9 and 122.9 months. | DOR PR was estimated using the KM method and defined as the time from documented best response as CR to documented disease progression per IMWG criteria. Patients who have not progressed or died were censored at the date last known progression-free. |
| 5-Year Time to Progression (TTP) | On treatment, disease was assessed every cycle up to maintenance and every 3 cycles on maintenance. In long-term follow-up, disease was assessed every 2 months until PD or death. Median TTP follow-up was 70 months. The probability estimate is at 5 years. | TTP was estimated using the KM method and defined as time from randomization to time of documented IMWG disease progression or censoring time (time of last disease evaluation for those alive, time to death among those who died). Patients initiating non-protocol therapy prior to progression or death were censored at the date of non-protocol therapy in the TTP analysis. The 5-year TTP endpoint is a probability. |
| 5-Year Overall Survival (OS) | In long-term follow-up, survival follow-up every 2 months until death. Median (maximum) OS follow-up was 76 and 129 months.The probability estimate is at 5 years. | OS was estimated using the KM method and defined as time from randomization to death due to any cause. Patients alive were censored at date last known alive. The 5-year OS endpoint is a probability. |
| Grade 3 or Higher Treatment-Related Non-Hematologic Adverse Event (AE) Rate | AEs was assessed every cycle on treatment. Median treatment duration (months) from randomization 28.2 (RVD Alone) and 36.1 (RVD plus ASCT). Maximum treatment duration was 133.5 months in this study cohort. | Safety was evaluated throughout trial treatment, including ASCT, and through 30 days after receipt of the last dose of a trial drug. Treatment attribution and grade were based on the NCI CTCAE v4. The Grade 3 or Higher Treatment-Related Non-Hematologic AE Rate is percentage of participants who experienced any grade 3-5 treatment-related (possible, probable or definite attribution) non-hematologic adverse event based on CTCAEv4 as reported on case report forms. The difference in the rate of all grade 3 or higher toxicities was compared between the two groups using Fisher's exact test. |
| 5-year Cumulative Incidence of Second Primary Malignancy (SPM) | 5 years | Second primary malignancy (SPM) is defined as the development of another new, unrelated cancer, regardless of treatment for previous malignancy attribution. The cumulative incidence of SPMs was estimated with death as a competing risk. SPMs were collected using an SAE form or MEDWATCH 3500A form, with intensity determined by using the NCI CTCAE version 4 as a guideline. |
| Median Treatment Duration | Up to 134 months | Treatment duration estimated using the KM method is defined as the time from registration (C1) to the time off treatment (event) or censored at date of last treatment. |
| Median Maintenance Treatment Duration | Up to 128 months | Maintenance treatment duration estimated using the KM method is defined as the time from start of maintenance to the time off maintenance (event) or censored at date of last maintenance treatment. |
| Subsequent Therapy Rate | Up to 129 months | Subsequent therapy rate was the percentage of participants who discontinued treatment and initiated subsequent non-protocol therapy. |
| Change From Baseline on the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-NTX) | Cycle 1 (Baseline), Cycle 2, Pre-Mobilization, Cycle 5 Arm A / Post Auto-HSCT Arm B, Cycle 8 Arm A /Cycle 5 Arm B, Maintenance Day 1, 2 years from baseline, 3 years from baseline | The FACT/GOG-NTX assessment consists of 11 questions that are all used to construct 1 subscale to summarize symptoms of peripheral neuropathy, including sensory, motor, and auditory problems and cold sensitivity. (https://www.facit.org/measures/FACT-GOG-NTX) Each question has 4 possible responses from 0 (Not at all) to 4 (Very Much) which are reverse-scored and summed. This sum is then scaled by the number of questions answered by multiplying by 11 and then dividing by the number of questions that are non-blank, in order to keep all final scores proportional to one another even if some questions are left blank. The aggregate score ranges from 0 to 44, with higher scores indicating less neurotoxicity and lower scores indicating more neurotoxicity. Change from baseline is the difference |
| Change From Baseline on the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire Core 30 (EORTC QLQ-C30): Global Health Status/Quality of Life (QoL) Sub-scale | Cycle 1 (Baseline), Cycle 2, Pre-Mobilization, Cycle 5 Arm A / Post Auto-HSCT Arm B, Cycle 8 Arm A /Cycle 5 Arm B, Maintenance Day 1, 2 years from baseline, 3 years from baseline | The EORTC QLQ-C30 assessment consists of 30 questions that are used to construct 15 distinct sub-scales (five function scales, nine symptom scales, and a global health status/QoL scale). The global health status/QoL scale is comprised of two questions each with a range of 6 (1=Very Poor to 7=Excellent). Scores on all sub-scales range from 0 to 100 after linear transformation of the raw scores, with higher scores representing better global health status and quality of life. |
| Quality-Adjusted Life Years (QALYs) | Maximum observation of survival for this study cohort was 129.4 months. | QALYs were estimated with a model beginning at initiation of first-line therapy by arm. A lifetime horizon, as well as subsequent lines of therapy, was examined using open-source Amua 0.3.0 software. Base case analysis was performed using 10,000 first-order Monte Carlo simulations. Conditional probabilities were extracted from Kaplan-Meier curves from pivotal clinical trials using WebPlotDigitizer. Costs were estimated from RED BOOK and DFCI charge reporting in US Dollars ($) after inflation adjustment to 2022 and 3% discounting, and QALYs effects were measured using EQ-5D data from Hatswell et al. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORPaul G. Richardson, MD
Dana-Farber Cancer Institute
Participant flow
Recruitment details
Participants were enrolled at 56 clinical sites in the U.S. from Oct 1, 2010 to January 30, 2018.
Participants by arm
| Arm | Count |
|---|---|
| RVD Alone All participants received one cycle of lenalidomide (R), bortezomib (V) and dexamethasone (D) and then were randomized. All participants then received two additional RVD cycles, followed by stem-cell collection. RVD Alone participants received five additional RVD cycles. Maintenance in both arms comprised daily lenalidomide 10 mg, escalated to 15 mg if tolerated, until disease progression, unacceptable toxicity, or withdrawal from treatment or study. After finishing protocol-specified treatment, off-study salvage transplantation was recommended but not mandated for RVD Alone participants at relapse.
RVD cycle duration=21 days R: 25 mg oral on days 1-14 V: 1.3 mg per square meter of body surface area IV or subcutaneous on days 1, 4, 8, and 11 D: 20 mg oral (cycles 1-3) or 10 mg (cycles 4-8) on days 1, 2, 4, 5, 8, 9, 11, and 12 | 357 |
| RVD Plus ASCT All participants received one cycle of lenalidomide (R), bortezomib (V) and dexamethasone (d) and then were randomized. All participants then received two additional RVD cycles, followed by stem-cell collection. RVD plus autologous stem cell transplant (ASCT) participants received high-dose melphalan (200 mg/m2, adjusted for ideal body weight) ASCT and, upon recovery (\
day 60), two additional RVD cycles. Maintenance in both arms comprised daily lenalidomide 10 mg, escalated to 15 mg if tolerated, until disease progression, unacceptable toxicity, or withdrawal from treatment or study.
After finishing protocol-specified treatment, RVD plus ASCT participants could undergo a second transplant.
RVD cycle duration=21 days R: 25 mg oral on days 1-14 V: 1.3 mg per square meter of body surface area IV or subcutaneous on days 1, 4, 8, and 11 D: 20 mg oral (cycles 1-3) or 10 mg (cycles 4-8) on days 1, 2, 4, 5, 8, 9, 11, and 12 | 365 |
| RVD Cycle 1 Only Some participants started cycle 1 lenalidomide (R), bortezomib (V) and dexamethasone (D) therapy but were not randomized.
RVD cycle duration=21 days R: 25 mg oral on days 1-14 V: 1.3 mg per square meter of body surface area IV or subcutaneous on days 1, 4, 8, and 11 D: 20 mg oral (cycles 1-3) or 10 mg (cycles 4-8) on days 1, 2, 4, 5, 8, 9, 11, and 12 | 7 |
| Total | 729 |
Baseline characteristics
| Characteristic | RVD Alone | Total | RVD Plus ASCT | RVD Cycle 1 Only |
|---|---|---|---|---|
| Age, Continuous | 57 years | 56 years | 55 years | 59 years |
| BMI <25 | 80 Participants | 162 Participants | 81 Participants | 1 Participants |
| BMI 25 to <30 | 141 Participants | 270 Participants | 127 Participants | 2 Participants |
| BMI >/= 30 | 136 Participants | 297 Participants | 157 Participants | 4 Participants |
| Cytogenetic Risk Category High risk | 66 Participants | 132 Participants | 66 Participants | — |
| Cytogenetic Risk Category Standard risk | 268 Participants | 542 Participants | 274 Participants | — |
| ECOG Performance Status 0 | 153 Participants | 321 Participants | 164 Participants | 4 Participants |
| ECOG Performance Status 1 | 177 Participants | 341 Participants | 161 Participants | 3 Participants |
| ECOG Performance Status 2 | 27 Participants | 66 Participants | 39 Participants | 0 Participants |
| ECOG Performance Status Unknown | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 19 Participants | 42 Participants | 23 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 336 Participants | 675 Participants | 332 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 12 Participants | 10 Participants | 0 Participants |
| ISS Multiple Myeloma Stage I | 178 Participants | 362 Participants | 184 Participants | — |
| ISS Multiple Myeloma Stage II | 130 Participants | 264 Participants | 134 Participants | — |
| ISS Multiple Myeloma Stage III | 49 Participants | 96 Participants | 47 Participants | — |
| Race/Ethnicity, Customized Asian | 8 Participants | 20 Participants | 12 Participants | 0 Participants |
| Race/Ethnicity, Customized Black | 66 Participants | 134 Participants | 66 Participants | 2 Participants |
| Race/Ethnicity, Customized Other | 9 Participants | 18 Participants | 9 Participants | 0 Participants |
| Race/Ethnicity, Customized Unknown | 6 Participants | 12 Participants | 6 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 268 Participants | 545 Participants | 272 Participants | 5 Participants |
| Region of Enrollment United States | 357 participants | 729 participants | 365 participants | 7 participants |
| Sex: Female, Male Female | 155 Participants | 308 Participants | 150 Participants | 3 Participants |
| Sex: Female, Male Male | 202 Participants | 421 Participants | 215 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 89 / 357 | 88 / 365 | 1 / 7 |
| other Total, other adverse events | 343 / 357 | 345 / 365 | 7 / 7 |
| serious Total, serious adverse events | 279 / 357 | 344 / 365 | 4 / 7 |
Outcome results
Primary
Median Progression-Free Survival (PFS)
PFS was estimated using the Kaplan-Meier (KM) method and defined as time from randomization to the earlier of disease progression (PD) as determined by central review or death from any cause (events). Patients who started non-protocol therapy (NPT) were censored at the date of NPT initiation if available or date treatment ended if date of NPT was missing. Deaths occurring beyond 1 year from the date last known progression-free are not counted as events and censored at date of last disease evaluation. Patients who had not started NPT, progressed, or died were censored at the date of last disease evaluation. PD was based upon the International Myeloma Working Group (IMWG) uniform response criteria. \[Kumar S, et al Lancet Oncol 2016;17(8):e328-e346\].
Time frame: On treatment, disease was assessed every cycle up to maintenance and every 3 cycles on maintenance. In long-term follow-up, disease was assessed every 2 months until PD or death. Median (maximum) PFS follow-up was 70 and 129 months.
Population: The analysis population is comprised of all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| RVD Alone | Median Progression-Free Survival (PFS) | 46.2 months |
| RVD Plus ASCT | Median Progression-Free Survival (PFS) | 67.5 months |
p-value: <0.00195% CI: [1.23, 1.91]Log Rank
Secondary
5-year Cumulative Incidence of Second Primary Malignancy (SPM)
Second primary malignancy (SPM) is defined as the development of another new, unrelated cancer, regardless of treatment for previous malignancy attribution. The cumulative incidence of SPMs was estimated with death as a competing risk. SPMs were collected using an SAE form or MEDWATCH 3500A form, with intensity determined by using the NCI CTCAE version 4 as a guideline.
Time frame: 5 years
Population: The analysis population is comprised of all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| RVD Alone | 5-year Cumulative Incidence of Second Primary Malignancy (SPM) | 4.9 percentage of patients |
| RVD Plus ASCT | 5-year Cumulative Incidence of Second Primary Malignancy (SPM) | 6.5 percentage of patients |
Comparison: Exact (Clopper-Pearson) confidence limits of 98.2857% represents Bonferroni adjustment for 7 tests (1-0.05/7) per statistical analysis plan for key secondary outcomes.p-value: 0.9999.29% CI: [0.73, 1.65]Log Rank
Secondary
5-Year Overall Survival (OS)
OS was estimated using the KM method and defined as time from randomization to death due to any cause. Patients alive were censored at date last known alive. The 5-year OS endpoint is a probability.
Time frame: In long-term follow-up, survival follow-up every 2 months until death. Median (maximum) OS follow-up was 76 and 129 months.The probability estimate is at 5 years.
Population: The analysis population is comprised of all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| RVD Alone | 5-Year Overall Survival (OS) | 79.2 percent probability |
| RVD Plus ASCT | 5-Year Overall Survival (OS) | 80.7 percent probability |
p-value: >0.9995% CI: [0.73, 1.65]Log Rank
Secondary
5-Year Time to Progression (TTP)
TTP was estimated using the KM method and defined as time from randomization to time of documented IMWG disease progression or censoring time (time of last disease evaluation for those alive, time to death among those who died). Patients initiating non-protocol therapy prior to progression or death were censored at the date of non-protocol therapy in the TTP analysis. The 5-year TTP endpoint is a probability.
Time frame: On treatment, disease was assessed every cycle up to maintenance and every 3 cycles on maintenance. In long-term follow-up, disease was assessed every 2 months until PD or death. Median TTP follow-up was 70 months. The probability estimate is at 5 years.
Population: The analysis population is comprised of all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| RVD Alone | 5-Year Time to Progression (TTP) | 41.6 percent probability |
| RVD Plus ASCT | 5-Year Time to Progression (TTP) | 58.4 percent probability |
Comparison: Exact (Clopper-Pearson) confidence limits of 98.2857% represents Bonferroni adjustment for 7 tests (1-0.05/7) per statistical analysis plan for key secondary outcomes.p-value: <0.00199.29% CI: [1.21, 2.27]Log Rank
Secondary
Change From Baseline on the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire Core 30 (EORTC QLQ-C30): Global Health Status/Quality of Life (QoL) Sub-scale
The EORTC QLQ-C30 assessment consists of 30 questions that are used to construct 15 distinct sub-scales (five function scales, nine symptom scales, and a global health status/QoL scale). The global health status/QoL scale is comprised of two questions each with a range of 6 (1=Very Poor to 7=Excellent). Scores on all sub-scales range from 0 to 100 after linear transformation of the raw scores, with higher scores representing better global health status and quality of life.
Time frame: Cycle 1 (Baseline), Cycle 2, Pre-Mobilization, Cycle 5 Arm A / Post Auto-HSCT Arm B, Cycle 8 Arm A /Cycle 5 Arm B, Maintenance Day 1, 2 years from baseline, 3 years from baseline
Population: The analysis population is comprised of all randomized participants who completed the assessment both at baseline and at the respective timepoint on treatment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| RVD Alone | Change From Baseline on the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire Core 30 (EORTC QLQ-C30): Global Health Status/Quality of Life (QoL) Sub-scale | Cycle 2 | 0.1 units on a scale | Standard Deviation 20.8 |
| RVD Alone | Change From Baseline on the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire Core 30 (EORTC QLQ-C30): Global Health Status/Quality of Life (QoL) Sub-scale | Maintenance Day 1 | 5.3 units on a scale | Standard Deviation 23 |
| RVD Alone | Change From Baseline on the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire Core 30 (EORTC QLQ-C30): Global Health Status/Quality of Life (QoL) Sub-scale | Pre-Mobilization | 0.4 units on a scale | Standard Deviation 21.7 |
| RVD Alone | Change From Baseline on the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire Core 30 (EORTC QLQ-C30): Global Health Status/Quality of Life (QoL) Sub-scale | Cycle 5 Arm A / Post Auto-HSCT Arm B | 3.0 units on a scale | Standard Deviation 24.8 |
| RVD Alone | Change From Baseline on the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire Core 30 (EORTC QLQ-C30): Global Health Status/Quality of Life (QoL) Sub-scale | Cycle 8 Arm A /Cycle 5 Arm B | 1.2 units on a scale | Standard Deviation 23.5 |
| RVD Alone | Change From Baseline on the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire Core 30 (EORTC QLQ-C30): Global Health Status/Quality of Life (QoL) Sub-scale | 2 years from baseline | 5.1 units on a scale | Standard Deviation 22.4 |
| RVD Alone | Change From Baseline on the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire Core 30 (EORTC QLQ-C30): Global Health Status/Quality of Life (QoL) Sub-scale | 3 years from baseline | 3.5 units on a scale | Standard Deviation 23.6 |
| RVD Plus ASCT | Change From Baseline on the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire Core 30 (EORTC QLQ-C30): Global Health Status/Quality of Life (QoL) Sub-scale | 2 years from baseline | 11.1 units on a scale | Standard Deviation 26 |
| RVD Plus ASCT | Change From Baseline on the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire Core 30 (EORTC QLQ-C30): Global Health Status/Quality of Life (QoL) Sub-scale | Cycle 8 Arm A /Cycle 5 Arm B | 8.3 units on a scale | Standard Deviation 25.2 |
| RVD Plus ASCT | Change From Baseline on the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire Core 30 (EORTC QLQ-C30): Global Health Status/Quality of Life (QoL) Sub-scale | Cycle 2 | 4.3 units on a scale | Standard Deviation 21.8 |
| RVD Plus ASCT | Change From Baseline on the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire Core 30 (EORTC QLQ-C30): Global Health Status/Quality of Life (QoL) Sub-scale | Maintenance Day 1 | 9.9 units on a scale | Standard Deviation 23.6 |
| RVD Plus ASCT | Change From Baseline on the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire Core 30 (EORTC QLQ-C30): Global Health Status/Quality of Life (QoL) Sub-scale | Pre-Mobilization | 4.4 units on a scale | Standard Deviation 23.8 |
| RVD Plus ASCT | Change From Baseline on the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire Core 30 (EORTC QLQ-C30): Global Health Status/Quality of Life (QoL) Sub-scale | 3 years from baseline | 12.7 units on a scale | Standard Deviation 27.4 |
| RVD Plus ASCT | Change From Baseline on the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire Core 30 (EORTC QLQ-C30): Global Health Status/Quality of Life (QoL) Sub-scale | Cycle 5 Arm A / Post Auto-HSCT Arm B | -11.1 units on a scale | Standard Deviation 28.9 |
Secondary
Change From Baseline on the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-NTX)
The FACT/GOG-NTX assessment consists of 11 questions that are all used to construct 1 subscale to summarize symptoms of peripheral neuropathy, including sensory, motor, and auditory problems and cold sensitivity. (https://www.facit.org/measures/FACT-GOG-NTX) Each question has 4 possible responses from 0 (Not at all) to 4 (Very Much) which are reverse-scored and summed. This sum is then scaled by the number of questions answered by multiplying by 11 and then dividing by the number of questions that are non-blank, in order to keep all final scores proportional to one another even if some questions are left blank. The aggregate score ranges from 0 to 44, with higher scores indicating less neurotoxicity and lower scores indicating more neurotoxicity. Change from baseline is the difference
Time frame: Cycle 1 (Baseline), Cycle 2, Pre-Mobilization, Cycle 5 Arm A / Post Auto-HSCT Arm B, Cycle 8 Arm A /Cycle 5 Arm B, Maintenance Day 1, 2 years from baseline, 3 years from baseline
Population: The analysis population is comprised of all randomized participants who completed the assessment both at baseline and at the respective timepoint on treatment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| RVD Alone | Change From Baseline on the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-NTX) | Pre-Mobilization | -3.9 units on a scale | Standard Deviation 6.9 |
| RVD Alone | Change From Baseline on the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-NTX) | Cycle 8 Arm A /Cycle 5 Arm B | -4.7 units on a scale | Standard Deviation 6.7 |
| RVD Alone | Change From Baseline on the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-NTX) | 2 years from baseline | -4.9 units on a scale | Standard Deviation 6.8 |
| RVD Alone | Change From Baseline on the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-NTX) | Maintenance Day 1 | -3.7 units on a scale | Standard Deviation 6.9 |
| RVD Alone | Change From Baseline on the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-NTX) | Cycle 5 Arm A / Post Auto-HSCT Arm B | -4.4 units on a scale | Standard Deviation 6.5 |
| RVD Alone | Change From Baseline on the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-NTX) | 3 years from baseline | -4.6 units on a scale | Standard Deviation 7.4 |
| RVD Alone | Change From Baseline on the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-NTX) | Cycle 2 | -1.8 units on a scale | Standard Deviation 4.8 |
| RVD Plus ASCT | Change From Baseline on the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-NTX) | 3 years from baseline | -3.2 units on a scale | Standard Deviation 7.2 |
| RVD Plus ASCT | Change From Baseline on the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-NTX) | Maintenance Day 1 | -2.3 units on a scale | Standard Deviation 6.4 |
| RVD Plus ASCT | Change From Baseline on the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-NTX) | Cycle 2 | -1.3 units on a scale | Standard Deviation 5 |
| RVD Plus ASCT | Change From Baseline on the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-NTX) | Pre-Mobilization | -3.5 units on a scale | Standard Deviation 7.4 |
| RVD Plus ASCT | Change From Baseline on the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-NTX) | Cycle 5 Arm A / Post Auto-HSCT Arm B | -4.4 units on a scale | Standard Deviation 7.5 |
| RVD Plus ASCT | Change From Baseline on the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-NTX) | Cycle 8 Arm A /Cycle 5 Arm B | -2.5 units on a scale | Standard Deviation 6.5 |
| RVD Plus ASCT | Change From Baseline on the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-NTX) | 2 years from baseline | -2.6 units on a scale | Standard Deviation 6.1 |
Secondary
Complete Response (CR) Rate
The CR rate is the percentage of participants achieving CR or better on treatment and was evaluated based on IMWG criteria. CR was defined as the negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and \<5% plasma cells in bone marrow. Confirmation with repeat bone marrow biopsy was not needed.
Time frame: Disease was assessed every cycle up to maintenance and every 3 cycles on maintenance. Median treatment duration (months) from randomization 28.2 (RVD Alone) and 36.1 (RVD plus ASCT). Maximum treatment duration was 134 months in this study cohort.
Population: The analysis population is comprised of all randomized patients.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| RVD Alone | Complete Response (CR) Rate | 42.0 percentage of patients |
| RVD Plus ASCT | Complete Response (CR) Rate | 46.8 percentage of patients |
Comparison: Exact (Clopper-Pearson) confidence limits of 98.2857% represents Bonferroni adjustment for 7 tests (1-0.05/7) per statistical analysis plan for key secondary outcomes.p-value: 0.99Fisher Exact
Secondary
Grade 3 or Higher Treatment-Related Non-Hematologic Adverse Event (AE) Rate
Safety was evaluated throughout trial treatment, including ASCT, and through 30 days after receipt of the last dose of a trial drug. Treatment attribution and grade were based on the NCI CTCAE v4. The Grade 3 or Higher Treatment-Related Non-Hematologic AE Rate is percentage of participants who experienced any grade 3-5 treatment-related (possible, probable or definite attribution) non-hematologic adverse event based on CTCAEv4 as reported on case report forms. The difference in the rate of all grade 3 or higher toxicities was compared between the two groups using Fisher's exact test.
Time frame: AEs was assessed every cycle on treatment. Median treatment duration (months) from randomization 28.2 (RVD Alone) and 36.1 (RVD plus ASCT). Maximum treatment duration was 133.5 months in this study cohort.
Population: The analysis population comprised of all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| RVD Alone | Grade 3 or Higher Treatment-Related Non-Hematologic Adverse Event (AE) Rate | 78.2 percentage of participants |
| RVD Plus ASCT | Grade 3 or Higher Treatment-Related Non-Hematologic Adverse Event (AE) Rate | 94.2 percentage of participants |
Secondary
Median Duration of Response: Partial Response (DOR PR)
DOR PR was estimated using the KM method and defined as the time from documented best response as CR to documented disease progression per IMWG criteria. Patients who have not progressed or died were censored at the date last known progression-free.
Time frame: On treatment, disease was assessed every cycle up to maintenance and every 3 cycles on maintenance. In long-term follow-up, disease was assessed every 2 months until PD or death. Median (maximum) DOR PR follow-up was 62.9 and 122.9 months.
Population: The analysis population is comprised of all randomized participants who achieved PR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| RVD Alone | Median Duration of Response: Partial Response (DOR PR) | 38.9 months |
| RVD Plus ASCT | Median Duration of Response: Partial Response (DOR PR) | 56.4 months |
Secondary
Median Maintenance Treatment Duration
Maintenance treatment duration estimated using the KM method is defined as the time from start of maintenance to the time off maintenance (event) or censored at date of last maintenance treatment.
Time frame: Up to 128 months
Population: The analysis population is comprised of all patients that started maintenance treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| RVD Alone | Median Maintenance Treatment Duration | 36.4 months |
| RVD Plus ASCT | Median Maintenance Treatment Duration | 41.5 months |
Secondary
Median Treatment Duration
Treatment duration estimated using the KM method is defined as the time from registration (C1) to the time off treatment (event) or censored at date of last treatment.
Time frame: Up to 134 months
Population: The analysis population is comprised of all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| RVD Alone | Median Treatment Duration | 28.2 months |
| RVD Plus ASCT | Median Treatment Duration | 36.8 months |
Secondary
Partial Response (PR) Rate
The PR rate is the percentage of participants achieving PR or better on treatment and was evaluated based on the IMWG criteria. PR was defined as \> 50% reduction of serum M-protein and reduction in 24-h urinary M-protein by \> 90% or to \< 200mg per 24 hours. If the serum and urine M-protein are unmeasurable, a \> 50% decrease in the difference between involved and uninvolved free light chain levels is required in place of the M-protein criteria. If serum and urine M-protein are unmeasurable, and serum free light assay is also unmeasurable, \>50% reduction in plasma cells is required in place of M-protein, provided baseline bone marrow plasma cell percentage was \> 30%. In addition to the above listed criteria, if present at baseline, a \> 50% reduction in the size of soft tissue plasmacytomas was also required. Exact (Clopper-Pearson) confidence limits of 98.2857% represents Bonferroni adjustment for 7 tests (1-0.05/7) per statistical analysis plan for key secondary outcomes.
Time frame: Disease was assessed every cycle up to maintenance and every 3 cycles on maintenance. Median treatment duration (months) from randomization 28.2 (RVD Alone) and 36.1 (RVD plus ASCT). Maximum treatment duration was 133.5 months in this study cohort.
Population: The analysis population is comprised of all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| RVD Alone | Partial Response (PR) Rate | 95 percentage of participants |
| RVD Plus ASCT | Partial Response (PR) Rate | 97.5 percentage of participants |
Comparison: Exact (Clopper-Pearson) confidence limits of 98.2857% represents Bonferroni adjustment for 7 tests (1-0.05/7) per statistical analysis plan for key secondary outcomes.p-value: 0.55Fisher Exact
Secondary
Quality-Adjusted Life Years (QALYs)
QALYs were estimated with a model beginning at initiation of first-line therapy by arm. A lifetime horizon, as well as subsequent lines of therapy, was examined using open-source Amua 0.3.0 software. Base case analysis was performed using 10,000 first-order Monte Carlo simulations. Conditional probabilities were extracted from Kaplan-Meier curves from pivotal clinical trials using WebPlotDigitizer. Costs were estimated from RED BOOK and DFCI charge reporting in US Dollars ($) after inflation adjustment to 2022 and 3% discounting, and QALYs effects were measured using EQ-5D data from Hatswell et al.
Time frame: Maximum observation of survival for this study cohort was 129.4 months.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| RVD Alone | Quality-Adjusted Life Years (QALYs) | 5.67 years gained | Standard Deviation 3.52 |
| RVD Plus ASCT | Quality-Adjusted Life Years (QALYs) | 6.10 years gained | Standard Deviation 3.59 |
Secondary
Subsequent Therapy Rate
Subsequent therapy rate was the percentage of participants who discontinued treatment and initiated subsequent non-protocol therapy.
Time frame: Up to 129 months
Population: All participants off treatment per protocol.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| RVD Alone | Subsequent Therapy Rate | 222 Participants |
| RVD Plus ASCT | Subsequent Therapy Rate | 192 Participants |
Secondary
Very Good Partial Response (VGPR) Rate
The VGPR rate is the percentage of participants achieving VGPR or better on treatment and was evaluated based on IMWG criteria. VGPR was defined as serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein plus urine M-protein level \<100mg per 24 hours.
Time frame: Disease was assessed every cycle up to maintenance and every 3 cycles on maintenance. Median treatment duration (months) from randomization 28.2 (RVD Alone) and 36.1 (RVD plus ASCT). Maximum treatment duration was 134 months in this study cohort.
Population: The analysis population is comprised of all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| RVD Alone | Very Good Partial Response (VGPR) Rate | 79.6 percentage of patients |
| RVD Plus ASCT | Very Good Partial Response (VGPR) Rate | 82.7 percentage of patients |
Comparison: Exact (Clopper-Pearson) confidence limits of 98.2857% represents Bonferroni adjustment for 7 tests (1-0.05/7) per statistical analysis plan for key secondary outcomes.p-value: 0.99Fisher Exact
Post Hoc
Median Event Free Survival (EFS)
EFS was estimated using the KM method and defined as the time from randomization to the earliest of IMWG disease progression, death, or initiation of non-protocol therapy (events); patients were censored date of last disease evaluation.
Time frame: Assessed up to approximately 130 months.
Population: The analysis population is comprised of all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| RVD Alone | Median Event Free Survival (EFS) | 32.0 months |
| RVD Plus ASCT | Median Event Free Survival (EFS) | 47.3 months |
Post Hoc
Next Generation Sequencing (NGS) Minimal Residual Disease Negative (MRD-) Rate at Maintenance Start
Bone marrow aspirate samples were obtained from patients prior to the start of lenalidomide maintenance. NGS MRD- rate is the percentage of evaluable participants with MRD level of \<1 x 10-5 (indicating detection of 1 malignant plasma cell in 100,000 bone marrow cells) using the validated, US Food and Drug Administration approved clonoSEQ® NGS platform (Adaptive Biotechnologies) with a minimum sensitivity of 1 x 10-5.
Time frame: Maintenance treatment occurred after induction, up to 11.5 months.
Population: The analysis population is comprised of the participants with evaluable samples at baseline and start of maintenance.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| RVD Alone | Next Generation Sequencing (NGS) Minimal Residual Disease Negative (MRD-) Rate at Maintenance Start | 39.8 percentage of participants |
| RVD Plus ASCT | Next Generation Sequencing (NGS) Minimal Residual Disease Negative (MRD-) Rate at Maintenance Start | 54.4 percentage of participants |
95% CI: [0.3, 1.01]